Autoantibodies to selenoprotein P in chronic fatigue syndrome suggest selenium transport impairment and acquired resistance to thyroid hormone.

Chronic Fatigue Syndrome (CFS) presents with symptoms of hypothyroidism, including mental and physical fatigue, poor sleep, depression, and anxiety. However, thyroid hormone (TH) profiles of elevated thyrotropin and low thyroxine (T4) are not consistently observed. Recently, autoantibodies to the Se transporter SELENOP (SELENOP-aAb) have been identified in Hashimoto's thyroiditis and shown to impair selenoprotein expression. We hypothesized that SELENOP-aAb are prevalent in CFS, and associate with reduced selenoprotein expression and impaired TH deiodination. Se status and SELENOP-aAb prevalence was compared by combining European CFS patients (n = 167) and healthy controls (n = 545) from different sources. The biomarkers total Se, glutathione peroxidase (GPx3) and SELENOP showed linear correlations across the samples without reaching saturation, indicative of Se deficiency. SELENOP-aAb prevalence was 9.6-15.6% in CFS versus 0.9-2.0% in controls, depending on cut-off for positivity. The linear correlation between Se and GPx3 activity was absent in SELENOP-aAb positive patients, suggesting impaired Se supply of kidney. A subgroup of paired control (n = 119) and CSF (n = 111) patients had been characterized for TH and biochemical parameters before. Within this subgroup, SELENOP-aAb positive patients displayed particularly low deiodinase activity (SPINA-GD index), free T3 levels, total T3 to total T4 (TT3/TT4) and free T3 to free T4 (FT3/FT4) ratios. In 24 h urine, iodine concentrations were significantly lower in SELENOP-aAb positive than in SELENOP-aAb negative patients or controls (median (IQR); 43.2 (16.0) vs. 58.9 (45.2) vs. 89.0 (54.9) µg/L). The data indicate that SELENOP-aAb associate with low deiodination rate and reduced activation of TH to active T3. We conclude that a subset of CFS patients express SELENOP-aAb that disturb Se transport and reduce selenoprotein expression in target tissues. Hereby, TH activation decreases as an acquired condition not reflected by thyrotropin and T4 in blood. This hypothesis opens new diagnostic and therapeutic options for SELENOP-aAb positive CFS, but requires clinical evidence from intervention trials.

Thyroidal and Extrathyroidal Requirements for Iodine and Selenium: A Combined Evolutionary and (Patho)Physiological Approach.

Iodide is an antioxidant, oxidant and thyroid hormone constituent. Selenoproteins are needed for triiodothyronine synthesis, its deactivation and iodine release. They also protect thyroidal and extrathyroidal tissues from hydrogen peroxide used in the 'peroxidase partner system'. This system produces thyroid hormone and reactive iodine in exocrine glands to kill microbes. Exocrine glands recycle iodine and with high urinary clearance require constant dietary supply, unlike the thyroid. Disbalanced iodine-selenium explains relations between thyroid autoimmune disease (TAD) and cancer of thyroid and exocrine organs, notably stomach, breast, and prostate. Seafood is iodine unconstrained, but selenium constrained. Terrestrial food contains little iodine while selenium ranges from highly deficient to highly toxic. Iodine vs. TAD is U-shaped, but only low selenium relates to TAD. Oxidative stress from low selenium, and infection from disbalanced iodine-selenium, may generate cancer of thyroid and exocrine glands. Traditional Japanese diet resembles our ancient seashore-based diet and relates to aforementioned diseases. Adequate iodine might be in the milligram range but is toxic at low selenium. Optimal selenoprotein-P at 105 µg selenium/day agrees with Japanese intakes. Selenium upper limit may remain at 300-400 µg/day. Seafood combines iodine, selenium and other critical nutrients. It brings us back to the seashore diet that made us what we currently still are.

Pregnant Dutch Women Have Inadequate Iodine Status and Selenium Intake.

Iodine and selenium are essential for thyroid hormone synthesis. Iodine and selenium interact. Pregnancy increases the maternal iodine requirement. We previously reported inadequate iodine status in pregnant Dutch women. Since little is known about their selenium intake, we investigated the iodine status and selenium intake in relation to iodine and selenium supplement use during pregnancy. Iodine status was established in 201 apparently healthy pregnant women as 24 h iodine excretion (24H-UIE; sufficient if median ≥225 µg), iodine concentration (24H-UIC; ≥150 µg/L) and iodine/creatinine ratio (24H-UICR; ≥150 µg/g). Selenium intake was calculated from 24 h selenium excretion. Iodine status in pregnancy proved insufficient (medians: 24H-UIE 185 µg; 24H-UIC 95 µg/L; 24H-UICR 141 µg/g). Only women taking 150 µg iodine/day were sufficient (median 24H-UIE 244 µg). Selenium intake was below the Estimated Average Requirement (EAR; 49 µg/day) in 53.8%, below the Recommended Dietary Allowance (RDA; 60 µg/day) in 77.4% and below the Adequate Intake (AI; 70 µg/day) in 88.7%. Combined inadequate iodine status and selenium intake

Influence of daily 10-85 µg vitamin D supplements during pregnancy and lactation on maternal vitamin D status and mature milk antirachitic activity.

Pregnant and lactating women and breastfed infants are at risk of vitamin D deficiency. The supplemental vitamin D dose that optimises maternal vitamin D status and breast milk antirachitic activity (ARA) is unclear. Healthy pregnant women were randomised to 10 (n 10), 35 (n 11), 60 (n 11) and 85 (n 11) µg vitamin D3/d from 20 gestational weeks (GW) to 4 weeks postpartum (PP). The participants also received increasing dosages of fish oil supplements and a multivitamin. Treatment allocation was not blinded. Parent vitamin D and 25-hydroxyvitamin D (25(OH)D) were measured in maternal plasma at 20 GW, 36 GW and 4 weeks PP, and in milk at 4 weeks PP. Median 25(OH)D and parent vitamin D at 20 GW were 85 (range 25-131) nmol/l and 'not detectable (nd)' (range nd-40) nmol/l. Both increased, seemingly dose dependent, from 20 to 36 GW and decreased from 36 GW to 4 weeks PP. In all, 35 µg vitamin D/d was needed to increase 25(OH)D to adequacy (80-249 nmol/l) in >97·5 % of participants at 36 GW, while >85 µg/d was needed to reach this criterion at 4 weeks PP. The 25(OH)D increments from 20 to 36 GW and from 20 GW to 4 weeks PP diminished with supplemental dose and related inversely to 25(OH)D at 20 GW. Milk ARA related to vitamin D3 dose, but the infant adequate intake of 513 IU/l was not reached. Vitamin D3 dosages of 35 and >85 µg/d were needed to reach adequate maternal vitamin D status at 36 GW and 4 weeks PP, respectively.

Milk vitamin D in relation to the 'adequate intake' for 0-6-month-old infants: a study in lactating women with different cultural backgrounds, living at different latitudes.

Breast-fed infants are susceptible to vitamin D deficiency rickets. The current vitamin D 'adequate intake' (AI) for 0-6-month-old infants is 10 µg/d, corresponding with a human milk antirachitic activity (ARA) of 513 IU/l. We were particularly interested to see whether milk ARA of mothers with lifetime abundant sunlight exposure reaches the AI. We measured milk ARA of lactating mothers with different cultural backgrounds, living at different latitudes. Mature milk was derived from 181 lactating women in the Netherlands, Curaçao, Vietnam, Malaysia and Tanzania. Milk ARA and plasma 25-hydroxyvitamin D (25(OH)D) were analysed by liquid-chromatography-MS/MS; milk fatty acids were analysed by GC-flame ionisation detector (FID). None of the mothers reached the milk vitamin D AI. Milk ARA (n; median; range) were as follows: Netherlands (n 9; 46 IU/l; 3-51), Curaçao (n 10; 31 IU/l; 5-113), Vietnam: Halong Bay (n 20; 58 IU/l; 23-110), Phu Tho (n 22; 28 IU/l; 1-62), Tien Giang (n 20; 63 IU/l; 26-247), Ho-Chi-Minh-City (n 18; 49 IU/l; 24-116), Hanoi (n 21; 37 IU/l; 11-118), Malaysia-Kuala Lumpur (n 20; 14 IU/l; 1-46) and Tanzania-Ukerewe (n 21; 77 IU/l; 12-232) and Maasai (n 20; 88 IU/l; 43-189). We collected blood samples of these lactating women in Curaçao, Vietnam and from Tanzania-Ukerewe, and found that 33·3 % had plasma 25(OH)D levels between 80 and 249·9 nmol/l, 47·3 % between 50 and 79·9 nmol/l and 19·4 % between 25 and 49·9 nmol/l. Milk ARA correlated positively with maternal plasma 25(OH)D (range 27-132 nmol/l, r 0·40) and milk EPA+DHA (0·1-3·1 g%, r 0·20), and negatively with latitude (2°S-53°N, r -0·21). Milk ARA of mothers with lifetime abundant sunlight exposure is not even close to the vitamin D AI for 0-6-month-old infants. Our data may point at the importance of adequate fetal vitamin D stores.

DHA status is positively related to motor development in breastfed African and Dutch infants.

OBJECTIVES: Docosahexaenoic (DHA) and arachidonic (AA) acids are important for neurodevelopment. We investigated the relation between erythrocyte (RBC) DHA and AA contents and neurological development, by assessment of General Movements (GMs), in populations with substantial differences in fish intakes. METHODS: We included 3-month-old breastfed infants of three Tanzanian tribes: Maasai (low fish, n = 5), Pare (intermediate fish, n = 32), and Sengerema (high fish, n = 60); and a Dutch population (low-intermediate, fish, n = 15). GMs were assessed by motor optimality score (MOS) and the number of observed movement patterns (OMP; an MOS sub-score). RBC-DHA and AA contents were determined by capillary gas chromatography. RESULTS: We found no between-population differences in MOS. OMP of Sengerema infants (high fish) was higher than OMP of Dutch infants (low-intermediate fish). MOS related to age. OMP related positively to infant age (P < 0.001) and RBC-DHA (P = 0.015), and was unrelated to ethnicity and RBC-AA. DISCUSSION: The positive relation between RBC-DHA and the number of observed movement patterns of 3-month old infants might reflect the connection of DHA with motor development.

Fatty acid compositions of preterm and term colostrum, transitional and mature milks in a sub-Saharan population with high fish intakes.

BACKGROUND: There are no data on the fatty acid (FA) compositions of preterm and term milks for sub-Saharan African populations with advancing lactation. However, it is generally acknowledged that our ancestors evolved in sub-Saharan East-Africa, where they inhabited the land-water ecosystems. METHODS: We compared the FA-compositions of preterm (28-36 weeks) and term (37-42) colostrum (2-5 day), transitional (6-15) and mature (16-56) milks in rural African women with stable dietary habits and lifelong high freshwater fish intakes. RESULTS: From colostrum to mature milk: the median docosahexaenoic acid (DHA) content decreased from 1.11 to 0.75; and arachidonic acid (AA) from 0.93 to 0.69 g% in preterm milk. In term milk, DHA decreased from 0.81 to 0.53 and AA from 1.08 to 0.55 g%. Medium-chain saturated-FA (MCSAFA) increased from 16.9 to 33.7, and 7.92-29.0 g%, while mono-unsaturated FA (MUFA) decreased from 32.5 to 22.6, and 40.0-26.5 g%, in preterm and term milk, respectively. Consistent with the literature, preterm colostrum contained higher DHA and MCSAFA, and lower MUFA compared to term colostrum. These differences vanished rapidly with advancing lactation. MUFA and MCSAFA were inversely related. CONCLUSIONS: The presently found DHA in preterm colostrum and mature milks and AA in premature mature milk proved the highest reported in the literature so far, as derived from analysis with capillary GC-columns. We confirmed the much higher MCSAFA and lower MUFA contents in milk of rural African, compared to Westernized women. The milk FA composition of this traditional population might show us the FA composition on which our species evolved and consequently to which our genome has become adapted to optimally support (infant) health.

Differences in preterm and term milk fatty acid compositions may be caused by the different hormonal milieu of early parturition.

INTRODUCTION: The hormonal milieus of pregnancy and lactation are driving forces of nutrient fluxes supporting infant growth and development. The decrease of insulin sensitivity with compensatory hyperinsulinemia with advancing gestation, causes adipose tissue lipolysis and hepatic de novo lipogenesis (DNL). SUBJECTS AND METHODS: We compared fatty acid (FA) contents and FA-indices for enzyme activities between preterm (28-36 weeks) and term (37-42) milks, and between colostrum (2-5 days), transitional (6-15) and mature (16-56) milks. We interpreted FA differences between preterm and term milks, and their changes with lactation, in terms of the well known decrease of insulin sensitivity during gestation and its subsequent postpartum restoration, respectively. RESULTS: Compared with term colostrum, preterm colostrum contained higher indices of DNL in the breast (DNL-breast) and medium chain saturated-FA (MCSAFA), and lower DNL-liver and monounsaturated-FA (MUFA). Preterm milk also had higher docosahexaenoic acid (DHA) in colostrum and transitional milk and higher arachidonic acid (AA) in mature milk. Most preterm-term differences vanished with advancing lactation. In both preterm and term milks, DNL-breast and MCSAFA increased with advancing lactation, while DNL-liver, MUFA, long chain SAFA and AA decreased. DHA decreased in term milk. MUFA was inversely related to MCSAFA in all samples, correlated inversely with PUFA in colostrum and transitional milks, but positively in mature milk. MCSAFA correlated inversely with PUFA in mature milk. CONCLUSION: Higher maternal insulin sensitivity at preterm birth may be the cause of lower MUFA (a proxy for DNL-liver) and higher MCSAFA (a proxy for DNL-breast) in preterm colostrum, compared with term colostrum. Restoring insulin sensitivity after delivery may be an important driving force for milk FA-changes in early lactation.

Postdelivery changes in maternal and infant erythrocyte fatty acids in 3 populations differing in fresh water fish intakes.

INTRODUCTION: Long-chain polyunsaturated (LCP) fatty acids (FA) are important during infant development. Mother-to-infant FA-transport occurs at the expense of the maternal status. Maternal and infant FA-status change rapidly after delivery. METHODS: Comparison of maternal (mRBC) and infant erythrocyte (iRBC)-FA-profiles at delivery and after 3 months exclusive breastfeeding in relation to freshwater-fish intakes. Approximation of de-novo-lipogenesis (DNL), stearoyl-CoA-desaturase (SCD), elongation-of-very-long-chain-FA-family-member-6 (Elovl-6), delta-5-desaturase (D5D) and delta-6-desaturase (D6D)-enzymatic activities from their product/essential-FA and product/substrate-ratios. RESULTS AND DISCUSSION: Increasing iRBC-14:0 derived from mammary-gland DNL. Decreasing mRBC-ω9, but increasing iRBC-ω9, suggest high ω9-FA-transfer via breastmilk. Decreasing (m+i)RBC-16:0, DNL- and SCD-activities, but increasing (m+i)RBC-18:0 and Elovl-6-activity suggest more pronounced postpartum decreases in DNL- and SCD-activities, compared to Elovl-6-activity. Increasing (m+i)RBC-18:3ω3, 20:5ω3, 22:5ω3, 18:2ω6, mRBC-20:4ω6 and (m+i)D5D-activity, but decreasing mRBC-22:6ω3 and (m+i)D6D-activity and dose-dependent changes in iRBC-22:6ω3 confirm that D6D-activity is rate-limiting and 22:6ω3 is important during lactation. Fish-intake related magnitudes of postpartum FA-changes suggest that LCPω3 influence DNL-, SCD- and desaturase-activities.

The relation between the omega-3 index and arachidonic acid is bell shaped: synergistic at low EPA+DHA status and antagonistic at high EPA+DHA status.

INTRODUCTION: The relation between docosahexaenoic (DHA) and eicosapentaenoic (EPA) vs. arachidonic acid (AA) seems characterized by both synergism and antagonism. MATERIALS AND METHODS: Investigate the relation between EPA+DHA and AA in populations with a wide range of EPA+DHA status and across the life cycle. EPA+DHA and AA were determined in erythrocytes (RBC; n=1979), umbilical arteries (UA; n=789) and umbilical veins (UV; n=785). RESULTS: In all compartments, notably RBC, the relation between EPA+DHA and AA appeared bell-shaped. Populations with low RBC-EPA+DHA (<2g%) exhibited positive relationships; those with high RBC-EPA+DHA (>8g%) negative relationships. Antagonism in UA and UV could not be demonstrated. CONCLUSION: Both synergism and antagonism might aim at a balance between ω6 and ω3 long-chain polyunsaturated fatty acid (LCP) to maintain homeostasis. Synergism might be a feature of low LCPω3 status. AA becomes suppressed by antagonism from an RBC-EPA+DHA >8g%.

The influence of supplemental docosahexaenoic and arachidonic acids during pregnancy and lactation on neurodevelopment at eighteen months.

Docosahexaenoic acid (DHA) and arachidonic acid (AA) are important for neurodevelopment. The effects of DHA (220 mg/day, n=41), DHA+AA (220 mg/day, n=39) or placebo (n=34) during pregnancy and lactation on neurodevelopment at 18 months, and the relations between umbilical cord DHA, AA and Mead acid and neurodevelopment were studied. An age-specific, standardized neurological assessment for the evaluation of minor neurological dysfunction (MND), and the Bayley Scales of Infant Development (BSID) were used. The intervention did not influence any of the outcomes. Umbilical venous (UV) Mead acid was negatively and n-6 fatty acids were weakly positively associated to the BSID mental developmental index. Children with simple MND had lower UV DHA compared to normally classified children. We conclude that relatively short-term maternal DHA or DHA+AA supplementation does not influence neurodevelopment at toddler age, although some parameters of brain development are related to perinatal DHA and AA status.

Supplementation of DHA but not DHA with arachidonic acid during pregnancy and lactation influences general movement quality in 12-week-old term infants.

DHA and arachidonic acid (AA) are important for neurodevelopment. A traditional neonatal neurological examination and the evaluation of general movement quality are sensitive techniques for assessing neurodevelopment in young infants. Mildly abnormal general movements at 3 months have been associated with a non-optimal current brain condition. We investigated whether supplementation of DHA during pregnancy and lactation influences the infant's brain development and whether additional AA modulates this effect. Healthy women were randomly assigned to DHA (220 mg/d, n 42), DHA+AA (220 mg each/d, n 41) or control (n 36), from about week 17 (range 14-20 weeks) of pregnancy until 12 weeks postpartum. The control and the DHA+AA groups had approximately comparable dietary DHA/AA ratios. The standardised neonatal neurological examination was carried out at 2 weeks. General movement quality was assessed at 2 and 12 weeks. Neither DHA alone nor DHA+AA influenced outcomes in the traditional examination. General movement quality of infants in the DHA group was lower than that of infants in the other two groups, especially at 12 weeks: 61 % of the infants in the DHA group showed mildly abnormal general movements compared with 31 % in the control group (P = 0.008) and 34 % in the DHA+AA group (P = 0.015). We conclude that general movement quality at 12 weeks is sensitive to the maternal dietary DHA/AA balance.

Higher de novo synthesized fatty acids and lower omega3- and omega6-long-chain polyunsaturated fatty acids in umbilical vessels of women with preeclampsia and high fish intakes.

Umbilical veins (UV) and arteries (UA) of preeclamptic women in Curaçao harbor lower long-chain polyunsaturated fatty acids (LCP). The present aim was to test these findings in Mwanza (Tanzania), whose inhabitants have high LCPomega3 and LCPomega6 intakes from Lake Victoria fish. Women with preeclampsia (n=28) in Mwanza had lower PUFA and higher 20:0 in UV and UA, compared with normotensive/non-proteinuric controls (n=31). Their UV 22:6omega3, 22:4omega6, LCPomega6, omega6, and LCPomega3+omega6 were lower, while saturated FA, potentially de novo synthesized FA (Sigmade novo) and (Sigmade novo)/(LCPomega3+omega6) ratio were higher. Their UA had higher 16:1omega7, omega7, 18:0, and 16:1omega7/16:0. Umbilical vessels in Mwanza had higher 22:6omega3, LCPomega3, omega3, and 16:0, and lower 22:5omega6, 20:2omega6, 18:1omega9, and omega9, compared to those in Curaçao. Preeclampsia in both Mwanza and Curaçao is characterized by lower LCP and higher Sigmade novo. An explanation of this might be placental dysfunction, while the similarity of umbilical vessel FA-abnormalities in preeclamptic and diabetic pregnancies suggests insulin resistance as a common denominator.

Human milk arachidonic acid and docosahexaenoic acid contents increase following supplementation during pregnancy and lactation.

INTRODUCTION: Docosahexaenoic acid (DHA) and arachidonic acid (AA) are important for neurodevelopment. Maternal diet influences milk DHA, whereas milk AA seems rather constant. We investigated milk AA, DHA and DHA/AA after supplementation of AA plus DHA, or DHA alone during pregnancy and lactation. SUBJECTS AND METHODS: Women were supplemented with AA+DHA (220mg each/day), DHA (220mg/day) or placebo during pregnancy and lactation. Milk samples were collected at 2 (n=86) and 12 weeks (n=69) postpartum. RESULTS: Supplementation of AA+DHA elevated milk AA (week 2, 14%; week 12, 23%) and DHA (43% and 52%) as compared to placebo. DHA tended to decrease milk AA and vice versa. Milk AA, DHA and DHA/AA decreased from 2 to 12 weeks postpartum. CONCLUSIONS: Milk AA and in particular DHA are sensitive to maternal supplementation. It seems that maternal AA and notably DHA status decline with advancing lactation.

Prenatal and early postnatal fatty acid status and neurodevelopmental outcome.

The present review addresses the effect of pre- and postnatal supplementation of nutrition with long-chain polyunsaturated fatty acids (LCPUFA) on neurodevelopmental outcome. The few studies which addressed the effect of prenatal LCPUFA status or prenatal LCPUFA supplementation suggest that a better prenatal arachidonic acid (AA) and doxosahexaenoic acid (DHA) status might be related to a better neurodevelopmental outcome until at least 18 months of age. A review of the few randomized controlled trials on formula supplementation with LCPUFA in preterm infants did not provide evidence for a significant beneficial effect of LCPUFA on developmental outcome. A review of the trials on formula supplementation with LCPUFA in term infants revealed that supplementation with LCPUFA, in particularly supplementation with >or=0.30% DHA, has a beneficial effect on neurodevelopmental outcome until 4 months. The studies could not demonstrate a consistent positive effect beyond that age. It was concluded that the relatively subtle effects of LCPUFA supplementation on neurodevelopmental outcome do not only depend on dosage but also on the gestational period during which the nutritional components are supplied: supplementation prior to term seems to have more effect than that after term.

Long-chain polyunsaturated fatty acids in maternal and infant nutrition.

Homo sapiens has evolved on a diet rich in alpha-linolenic acid and long chain polyunsaturated fatty acids (LCP). We have, however, gradually changed our diet from about 10,000 years ago and accelerated this change from about 100 to 200 years ago. The many dietary changes, including lower intake of omega3-fatty acids, are related to 'typically Western' diseases. After a brief introduction in essential fatty acids (EFA), LCP and their functions, this contribution discusses our present low status of notably LCPomega3 in the context of our rapidly changing diet within an evolutionary short time frame. It then focuses on the consequences in pregnancy, lactation and neonatal nutrition, as illustrated by some recent data from our group. We discuss the concept of a 'relative' EFA/LCP deficiency in the fetus as the outcome of high transplacental glucose flux. This flux may in the fetus augment de novo synthesis of fatty acids, which not only dilutes transplacentally transported EFA/LCP, but also causes competition of de novo synthesized oleic acid with linoleic acid for delta-6 desaturation. Such conditions were encountered by us in mothers with high body mass indices, diabetes mellitus and preeclampsia. The unifying factor might be compromised glucose homeostasis. In search of the milk arachidonic acid (AA) and docosahexaenoic acid (DHA) contents of our African ancestors, we investigated women in Tanzania with high intakes of freshwater fish as only animal lipid source. These women had milk AA and DHA contents that were well above present recommendations for infant formulae. Both studies stimulate rethinking of 'optimal homeostasis'. Subtle signs of dysbalanced maternal glucose homeostasis may be important and observations from current Western societies may not provide us with an adequate basis for dietary recommendations.

Long-chain polyunsaturated fatty acids have a positive effect on the quality of general movements of healthy term infants.

BACKGROUND: Whether long-chain polyunsaturated fatty acids (LCPs) play a role in the development of the young nervous system in term infants is debated. OBJECTIVE: We investigated whether supplementation of formula with LCPs for 2 mo improves the quality of general movements (GMs) in healthy term infants at 3 mo of age. DESIGN: A prospective, double-blind, randomized controlled study was conducted with 2 groups of healthy term infants: a control-formula (CF) group (n = 131) and an LCP-supplemented-formula (LF) group (n = 119). A breastfed (BF) group (n = 147) served as a reference. Information on potential confounders was collected at enrollment. Videotapes were made of the infants' spontaneous motor behavior at 3 mo of age to assess the quality of their GMs. On the basis of quality, normal GMs were classified as normal-optimal or normal-suboptimal, and abnormal GMs were classified as mildly or definitely abnormal. Attrition at 3 mo of age was 15% and nonselective. Multivariate regression analyses with adjustment for confounders were carried out to evaluate the effect of the type of feeding. RESULTS: None of the infants had definitely abnormal GMs. Infants in the CF group had mildly abnormal GMs significantly more often than did infants in the LF and BF groups (31% compared with 19% and 20%, respectively). Infants in the BF group had normal-optimal GMs more frequently than did infants in the LF and CF groups (34% compared with 18% and 21%, respectively). Logistic regression analyses confirmed these findings. CONCLUSION: Supplementation of healthy term infants with LCPs during the first 2 mo of life reduces the occurrence of mildly abnormal GMs.

Optimization of folic acid, vitamin B(12), and vitamin B(6) supplements in pediatric patients with sickle cell disease.

Using homocysteine as a functional marker, we determined optimal folic acid, vitamin B(12), and vitamin B(6) dosages in 21 pediatric sickle cell disease (SCD) patients (11 HbSS, 10 HbSC; 7-16 years). Daily supplements of folic acid (400, 700, or 1,000 microg), vitamin B(12) (1, 3, or 5 U.S. 1989 RDA), and vitamin B(6) (1 or 3 U.S. 1989 RDA) were gradually increased in an 82-week dose-escalation study. Blood was taken at 9 occasions for measurements of erythrocyte (RBC) and serum folate, plasma vitamin B(12), whole-blood vitamin B(6), and plasma homocysteine. Augmentation of folic acid from 700 to 1,000 microg and vitamin B(12) from 3 to 5 RDA did not further decrease homocysteine. Percentages of patients exhibiting significant individual homocysteine decreases amounted to 43% (folic acid from 0 to 400 microg, vitamins B(12) and B(6) from 0 to 1 RDA), 14% (folic acid from 400 to 700 microg), 24% (vitamin B(12) from 1 to 3 RDA), and 18% (vitamin B(6) from 1 to 3 RDA ). The lowest plasma homocysteine at 82 weeks was 5.9 +/- 2.2 micromol/L. Patients with HbSS had higher RBC folate than HbSC. The entire group exhibited an inverse relation between RBC folate and hemoglobin. We conclude that RBC folate is less valuable for folate status assessment in SCD patients. Optimal dosages are as follows: 700 microg folic acid (3.5-7 U.S. 1989 RDA), 3 U.S. 1989 RDA vitamin B(12) (4.2-6.0 microg), and 3 U.S. 1989 RDA vitamin B(6) (4.2-6.0 mg). A practical daily combination is 1 mg folic acid (4.3-8.5 U.S. 1998 RDA when taken with meals), 6 microg vitamin B(12) (2.5-5 U.S. 1998 RDA), and 6 mg vitamin B(6) (4.6-10 U.S. 1998 RDA). This combination may by simple and relatively inexpensive means reduce these patients' inherently high risk of endothelial damage.