Developmental and reproductive toxicological evaluation of arachidonic acid (ARA)-Rich oil and docosahexaenoic acid (DHA)-Rich oil.

The purpose of this study was to investigate the reproductive and developmental toxicity of dietary exposure to DHA-rich oil from Schizochytrium sp. and ARA-rich oil from Mortierella alpina. In a developmental toxicity study, pregnant Wistar rats were untreated (control) or administered corn oil (vehicle control), 1000, 2500, or 5000 mg/kg bw/day of DHA-rich oil or ARA-rich oil via gavage from gestation days 6 through 20. In the reproductive toxicity study, male and female Wistar rats were administered vehicle control (corn oil), or 1000, 2500, or 5000 mg/kg bw/day of DHA- or ARA-rich oil via gavage throughout the mating period, pregnancy, and the nursing and lactation period. Differences in the number of fetuses, fetal skeletal malformations, and external and visceral anomalies in the developmental study and mortality, clinical signs, fertility indices, physical observations, gross necropsy findings, and gestation period length in the reproductive toxicity study were not dose-related or significantly different from control groups, and were not considered to be treatment related. The no observed adverse effect level (NOAEL) for maternal toxicity and embryo/fetal development and for paternal or maternal treatment-related reproductive toxicity for the DHA-rich oil and ARA-rich oil administered by gavage, was 5000 mg/kg bw/day.

Toxicological evaluation of arachidonic acid (ARA)-rich oil and docosahexaenoic acid (DHA)-rich oil.

The safety of DHA-rich oil from Schizochytrium sp. and ARA-rich oil from Mortierella alpina was separately evaluated by testing for gene mutations, clastogenicity, and aneugenicity, and by conducting 28-day and 90-day dietary studies in Wistar rats. The results of all genotoxicity tests were negative. The 28-day and 90-day studies involved dietary exposure to 1000, 2500, and 5000 mg per kg bw of the DHA-rich and ARA-rich oils and two control diets: water and corn oil (vehicle control). There were no treatment-related effects of either the DHA-rich or ARA-rich oils on clinical observations, body weight, food consumption, behavior, hematology, clinical chemistry, coagulation, urinalysis parameters, or necropsy findings. Increases in cholesterol and triglyceride levels were considered related to a high oil diet and non-adverse. The no observable adverse effect level (NOAEL) for both the DHA-rich and ARA-rich oils was 5000 mg per kg bw, the highest dose tested. The results confirm that these oils possess toxicity profiles similar to those of other currently marketed oils and support the safety of DHA-rich oil from Schizochytrium sp. and ARA-rich oil from Mortierella alpina for their proposed uses in food.

Effects of tree nuts on blood lipids, apolipoproteins, and blood pressure: systematic review, meta-analysis, and dose-response of 61 controlled intervention trials.

BACKGROUND: The effects of nuts on major cardiovascular disease (CVD) risk factors, including dose-responses and potential heterogeneity by nut type or phytosterol content, are not well established. OBJECTIVES: We examined the effects of tree nuts (walnuts, pistachios, macadamia nuts, pecans, cashews, almonds, hazelnuts, and Brazil nuts) on blood lipids [total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein, and triglycerides], lipoproteins [apolipoprotein A1, apolipoprotein B (ApoB), and apolipoprotein B100], blood pressure, and inflammation (C-reactive protein) in adults aged ≥18 y without prevalent CVD. DESIGN: We conducted a systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two investigators screened 1301 potentially eligible PubMed articles in duplicate. We calculated mean differences between nut intervention and control arms, dose-standardized to one 1-oz (28.4 g) serving/d, by using inverse-variance fixed-effects meta-analysis. Dose-response for nut intake was examined by using linear regression and fractional polynomial modeling. Heterogeneity by age, sex, background diet, baseline risk factors, nut type, disease condition, duration, and quality score was assessed with meta-regression. Publication bias was evaluated by using funnel plots and Egger's and Begg's tests. RESULTS: Sixty-one trials met eligibility criteria (n = 2582). Interventions ranged from 3 to 26 wk. Nut intake (per serving/d) lowered total cholesterol (-4.7 mg/dL; 95% CI: -5.3, -4.0 mg/dL), LDL cholesterol (-4.8 mg/dL; 95% CI: -5.5, -4.2 mg/dL), ApoB (-3.7 mg/dL; 95% CI: -5.2, -2.3 mg/dL), and triglycerides (-2.2 mg/dL; 95% CI: -3.8, -0.5 mg/dL) with no statistically significant effects on other outcomes. The dose-response between nut intake and total cholesterol and LDL cholesterol was nonlinear (P-nonlinearity < 0.001 each); stronger effects were observed for ≥60 g nuts/d. Significant heterogeneity was not observed by nut type or other factors. For ApoB, stronger effects were observed in populations with type 2 diabetes (-11.5 mg/dL; 95% CI: -16.2, -6.8 mg/dL) than in healthy populations (-2.5 mg/dL; 95% CI: -4.7, -0.3 mg/dL) (P-heterogeneity = 0.015). Little evidence of publication bias was found. CONCLUSIONS: Tree nut intake lowers total cholesterol, LDL cholesterol, ApoB, and triglycerides. The major determinant of cholesterol lowering appears to be nut dose rather than nut type. Our findings also highlight the need for investigation of possible stronger effects at high nut doses and among diabetic populations.

Do specific dietary constituents and supplements affect mental energy? Review of the evidence.

The numbers of marketing claims and food, beverage, and drug products claiming to increase mental energy have risen rapidly, thus increasing the need for scientific specificity in marketing and food label claims. Mental energy is a three-dimensional construct consisting of mood (transient feelings about the presence of fatigue or energy), motivation (determination and enthusiasm), and cognition (sustained attention and vigilance). The present review focuses on four dietary constituents/supplements (Ginkgo biloba, ginseng, glucose, and omega-3 polyunsaturated fatty acids) to illustrate the current state of the literature on dietary constituents and mental energy. The strongest evidence suggests effects of Ginkgo biloba on certain aspects of mood and on attention in healthy subjects, as well as associations between omega-3 polyunsaturated fatty acids and reduced risk of age-related cognitive decline. Limitations of the current data and challenges for future research are discussed.

Cholesterol: where science and public health policy intersect.

Current US guidelines for cholesterol recommend limiting intake of cholesterol to <300 mg/day for the general population and <200 mg/day for individuals with elevated low-density lipoprotein cholesterol. These recommendations, however, are at odds with international (e.g., Canada, United Kingdom, and Australia) guidelines that provide no specific numerical recommendation, but instead recommend reducing total fat intake and shifting fat consumption away from saturated and trans fats to unsaturated fats. A conference was held on December 3, 2008, to evaluate the data supporting current US nutrition policy recommendations to limit dietary cholesterol and analyze the consequences of this policy on the eating patterns and health of the US population. This review is a summary of the information and perspectives presented by conference speakers and discussed by conference participants.

Are renal volumes measured by magnetic resonance imaging and three-dimensional ultrasound in the term neonate comparable?

Renal volume, but not renal length, has been shown to be positively correlated with renal function. Three-dimensional (3D) ultrasound and magnetic resonance imaging (MRI) are two modalities used to assess renal volume. The aim of our study was to determine whether 3D ultrasound measurements of renal volume in the neonate are comparable to those of MRI measurements. Preterm and term neonates had an MRI and 3D ultrasound to determine renal volume at the same time as they had an MRI brain scan for other clinical conditions. The preterm neonates were all term corrected age, and the term neonates were 1-4 weeks of age. None of the kidneys examined were abnormal. There were no significant differences in the weight or length of the preterm and term infants at the time of their MRI scan. The left renal length was significantly longer according to MRI measurements than according to 3D ultrasound measurements (p=0.02). Renal volumes of both the left and right kidney were greater when measured by MRI than by 3D ultrasound (p<0.0001, respectively). Total volumes of the kidneys were greater when measured by MRI than by 3D ultrasound (p=0.008). Renal volume in neonates was significantly less when evaluated by 3D ultrasound than by MRI. These results demonstrate that MRI and 3D ultrasound renal volumes are not comparable in the neonatal population and, therefore, the same radiological modality should be used if repeat volume measurements are to be performed.

Applying the FDA definition of whole grains to the evidence for cardiovascular disease health claims.

The U.S. FDA defines whole grains as consisting of the intact, ground, cracked, or flaked fruit of the grains whose principal components, the starchy endosperm, germ, and bran, are present in the same relative proportions as they exist in the intact grain. We evaluated the effect of applying the FDA definition of whole grains to the strength of scientific evidence in support of claims for risk reduction of cardiovascular disease (CVD). We concluded that using the FDA definition for whole grains as a selection criterion is limiting, because the majority of existing studies often use a broader meaning to define whole grains. When considering only whole grain studies that met the FDA definition, we found insufficient scientific evidence to support a claim that whole grain intake reduces the risk of CVD. However, a whole grain and reduced risk of CVD health claim is supported when using a broader concept of whole grain to include studies that considered intake of fiber-rich bran and germ as well as whole grain. This type of analysis is complicated by diversity in nutrients and bioactive components among different types of whole grains.

Do maternal- or pregnancy-associated disease states affect blood pressure in the early neonatal period?

BACKGROUND: Placental vascular changes associated with maternal disease states may affect fetal vascular development. There is evidence suggesting that being born prematurely is associated with a higher blood pressure (BP) in later life. AIM: To determine whether maternal disease state affects BP in the early neonatal period. METHODS: Cohort study of neonates admitted to neonatal intensive care unit with exposure to maternal hypertension and diabetes. Inclusion criteria were neonates greater than 27 weeks gestation not ventilated or requiring inotropes for more than 24 h, materna l hypertension (pregnancy induced or essential) or diabetes of any kind requiring treatment, and spontaneous delivery. Exclusion criteria included chromosomal or congenital anomaly and illicit maternal drug use. Oscillometric BP measurements taken until discharge on days 1, 2, 3, 4, 7, 14, 21 and 28. Placental histopathology was performed. RESULTS: One hundred and ninety infants enrolled, 104 in the control and 86 in the study group. Sixty-five infants were born between 28-31 weeks and 125 infants between 32-41 weeks gestation. Those born between 28-31 weeks with a history of diabetes had a statistically higher systolic, mean and diastolic BP throughout the first 28 days of life (P = 0.001; P = 0.007; P = 0.02). Those born between 32-41 weeks gestation with placental pathology associated with altered uteroplacental perfusion had a higher systolic BP (P = 0.005). CONCLUSIONS: Maternal- or pregnancy-associated disease states appear to influence BP in the early neonatal period. Diabetes and altered placental perfusion were associated with higher BP readings. Clinical significance of these statistically elevated BPs in the early neonatal period is unknown.

Does extreme prematurity affect kidney volume at term corrected age?

OBJECTIVE: Extreme prematurity exposes the neonate to a number of potential renal insults that may result in a reduced number of glomeruli and/or renal size. This may predispose these individuals to cardiovascular disease later in life. The objective was to determine using magnetic resonance imaging (MRI) whether extreme prematurity results in decreased renal volume. METHODS: Neonates <29 weeks' gestation and term infants undergoing MRI of the brain were enrolled in the study. An MRI was performed at term corrected age in the premature neonate and within the first 4 weeks of life in the term neonate. RESULTS: Seventeen preterm infants and 13 term infants had MRIs performed. There was no significant difference in weight and length at the time of MRI (p = 0.76 and 0.11, respectively). There was no significant difference in total renal volume or total kidney volume to weight ratio between the preterm and term neonates (p = 0.83 and 0.6, respectively). CONCLUSIONS: At term corrected age, extremely premature neonates have the same renal volume as term infants. It is unclear whether renal volume is a good indicator of glomerular number.

Indomethacin, ibuprofen and gentamicin administered during late stages of glomerulogenesis do not reduce glomerular number at 14 days of age in the neonatal rat.

Premature neonates are frequently administered indomethacin, ibuprofen and gentamicin during the period of active glomerulogenesis. These drugs are known to have nephrotoxic effects, but the morphological effect of these drugs is unknown. The purpose of this study was to determine whether administration of these drugs during the late stages of glomerulogenesis in the rat has an effect on glomerular endowment. Rat pups were given, intraperitoneally, indomethacin, ibuprofen or indomethacin and gentamicin for the first 5 days of their postnatal life. The pups were killed at 14 days of age at completion of glomerulogenesis. The total number of glomeruli in the left kidney was determined by the physical disector/fractionator stereological technique. There was no difference between treatment groups in total number of glomeruli per kidney (P = 0.45). There were significantly fewer glomeruli per gram of kidney in those rat pups that had received indomethacin or ibuprofen (P < 0.0001). The reduction in the number of glomeruli per gram of kidney may indicate augmented growth of nephron tubules and/or collecting ducts, and/or be a consequence of oedema secondary to drug exposure. Further study is required to determine whether reduced glomerular number is seen in older animals or following exposure to these drugs at different time-points in kidney development.

Normative blood pressure data in non-ventilated premature neonates from 28-36 weeks gestation.

Blood pressure (BP) measurement in the premature neonate is an essential component of neonatal intensive care. Despite significant advances in neonatal care, the data available on BP in the premature neonate are limited. The aim of this study was to determine normative BP measurements for non-ventilated stable premature neonates of gestation age 28-36 weeks in the first month of life using an oscillometric method. Neonates born at 28-36 weeks gestation who did not require ventilation for >24 h or inotrope support for >24 h were enrolled into the study. Blood pressure measurements were taken on days 1, 2, 3, 4, 7, 14, 21 and 28 where possible prior to discharge. A total of 147 infants were included in the study, and 10th and 90th percentiles BPs were obtained for gestation as well as birthweight. Changes in BP over time for each gestational week were determined. A significant difference in BP from day 1 to day 7 and from day 7 to 14 was observed in those born at less than 31 weeks gestation, and from day 1 to 7 in those born at more than 31 weeks gestation, but not from day 14 to 21 and from day 21 to 28 for any gestation period. Data on BP for stable non-ventilated premature infants using an oscillometric method provide useful information for determining hypotension and hypertension in the premature neonate. Premature neonates stabilize their BP after 14 days of life, and at this time they have a BP similar to that of term infants.

The effect of mode of delivery and anaesthesia on neonatal blood pressure.

BACKGROUND: Many factors may effect blood pressure (BP) in the early neonatal period, including mode of delivery and anaesthesia, on which there is little reported. AIMS: To determine whether the mode of delivery, anaesthesia and maternal age have an effect on neonatal BP in the first three days of life. METHODS: Healthy, term neonates from August 2003-2005 were enrolled in the study. Infants of mothers with hypertension of any cause, diabetes of any cause, illicit substance use, congenital or chromosomal anomaly, and admission to the neonatal intensive care unit were excluded. Information on maternal age, duration of labour, mode of delivery, anaesthesia and postdelivery analgesic use was obtained. Blood pressure readings from day one to three of life were analysed. RESULTS: Four hundred and six infants were enrolled into the study. Both spinal anaesthesia and elective caesarean delivery were associated with a lower systolic BP reading on day one, but not on day two or three (P = 0.004 and P = 0.023, respectively). Multivariate analysis indicated that spinal anaesthesia was the most significant variable for a lower systolic BP on day one (P = 0.022). There was no correlation between maternal age and BP on day one to three. CONCLUSIONS: Spinal anaesthesia is associated with a statistically lower systolic BP on the first day of life; the clinical significance is as yet unclear.

Antenatal and postnatal risk factors for neonatal hypertension and infant follow-up.

Neonatal hypertension is an uncommon but important complication of intensive care management. The aims of this study were to identify in neonates with hypertension: antenatal and postnatal risk factors; aldosterone and renin levels; and report on outcome in early infancy. The study involved a retrospective review of neonates diagnosed with systemic hypertension from January 2001 to December 2005. Demographic data, risk factors, laboratory investigation, and follow-up data at 3-6 months of age were collected. Of the 2,572 newborn infants included, 34 (1.3%) had neonatal hypertension. Gestational age and birth weight and length were significantly lower in infants with hypertension. The median postnatal age at diagnosis of systemic hypertension was 5.0 days. Antenatal steroid administration, maternal hypertension, umbilical arterial catheter, postnatal acute renal failure, patent ductus arteriosus, indomethacin treatment and chronic lung disease were associated with the development of neonatal hypertension [odds ratios (OR) 8.7, 3.8, 10.0, 51.8, 5.9, 5.7 and 7.7, respectively]. Elevated aldosterone and renin levels occurred in 60% and 33% but had normalised in the majority by 6 months of age. The majority of infants do not require treatment for hypertension by 6 months of age.

Blood pressure in the first year of life in healthy infants born at term.

Neonatal hypertension occurs in up to 2% of neonatal intensive care survivors and in up to 3% of all neonates. Normal blood pressure (BP) measurements are required to diagnose and manage appropriately both hypotension and hypertension in the neonate and infant. The aim of this study was to provide normative BP measurements during the first year of life of healthy infants born at term, using an oscillometric method. Neonates were enrolled from August 2003 to August 2005. Exclusion criteria included: infants of mothers with hypertension or diabetes of any type, use of illicit substances, congenital or chromosomal anomaly, admission to the neonatal intensive care unit or possible sepsis. There were 406 infants enrolled, with 150 children followed at 6 months of age and 118 children at 12 months of age. There were no differences in BP measurements at 6 months or 12 months of age by gender, weight or height. A BP measurement above the 90th percentile on day 2 or at 6 months was not predictive of a BP above the 90th percentile at 12 months of age. Higher systolic and diastolic measurements at 6 months and 12 months were found, in comparison to those in previous studies using ultrasonic devices. The findings of this study provide normative BP values for infants during their first year of life, using the oscillometric method, the most frequently used method in paediatric, neonatal intensive care and emergency departments.

Renal glomeruli and tubular injury following indomethacin, ibuprofen, and gentamicin exposure in a neonatal rat model.

Indomethacin, ibuprofen, and gentamicin are commonly administered to neonates between 24 and 28 wk gestation when glomerulogenesis is still occurring. Indomethacin is known to cause renal failure in up to 25% of infants treated. Possible morphologic effects of these drugs are largely unknown. The purpose of this study was to determine the type of renal changes found on light (LM) and electron microscopy (EM) following administration of indomethacin, ibuprofen, and gentamicin in a neonatal rat model. Rat pups were exposed to indomethacin or ibuprofen and/or gentamicin antenatally for 5 d before birth or postnatally for 5 d from d 1 of life. Pups were killed at 14 d of age. LM examination in all indomethacin- and ibuprofen-treated pups both antenatally and postnatally showed vacuolization of the epithelial proximal tubules, interstitial edema, intratubular protein deposition but no significant glomerular changes. EM examination showed pleomorphic mitochondria and loss of microvilli in the tubules. The glomeruli showed extensive foot process effacement and irregularities of the glomerular basement membrane. EM changes were most marked in pups treated antenatally with ibuprofen, and indomethacin with gentamicin postnatally. Indomethacin, ibuprofen, and gentamicin cause significant change in glomerular and tubular structure in the neonatal rat model.

Normative blood pressure data in the early neonatal period.

There has been a temporal trend towards increased birth weight over the past three decades. This increase in birth weight may have resulted in an increase in neonatal blood pressure. Neonatal hypertension is becoming more common, especially in neonatal intensive care unit survivors. Current normative values are required to assist in diagnosis and appropriate management of neonatal hypotension and hypertension. The objective of this study was to determine normative blood pressure readings in healthy term neonates. Term neonates from the postnatal ward were enrolled from August 2003 to August 2005. Exclusion criteria included infants of mothers with preeclampsia, hypertension of any cause, gestational diabetes, type 1 diabetes mellitus and illicit substance use, infant congenital or chromosomal anomaly, admission to the neonatal intensive care unit or possible sepsis. Of the 406 infants enrolled, 218 were male. The median systolic, diastolic and mean blood pressures on day 1 of life were 65 mmHg, 45 mmHg, and 48 mmHg, respectively. On day 4, these values had increased to 70 mmHg, 46 mmHg and 54 mmHg. There was a significant elevation in blood pressure from day 1 to day 2 of life. There was no significant difference in blood pressure readings with respect to birth weight or length. The only significant difference between the sexes was a lower mean and diastolic pressure on day 2 in boys. This study has provided current normative blood pressure readings of healthy term neonates that can be used to assess both hypotension and hypertension in the term neonate. No increase in blood pressure was noted from previous studies.