Patent Application: US-23138308-A

Abstract:
a method for determining the effect of critical glyconutrient dietary supplements in premature and term infants on growth , health , and brain function during early childhood development is described . the method comprises determining a critical target nutrient profile in typical samples of preterm and mother &# 39 ; s milk , developing a supplement of the missing critical target nutrients to simulate mother &# 39 ; s milk , performing an evaluation of early child development by correlating physiologic brain function with cognitive / behavioral brain function in low birth weight premature and term infants , assessing family influence and home environment on developmental outcome on infants under treatment , and comparing term siblings of low birth weight premature vs . term babies . a composition having the critical nutrients , an algorithm for screening and treatment , and a useful kit for employing the above are also described .

Description:
analyses of the monosaccharide content of term and preterm breast milk and infant formulas samples of hydrolyzed term and preterm breast milk and infant formulas were evaluated for total levels of the following monosaccharides : glucose , galactose , fucose , glucosamine , mannose , sialic acid and galactosamine using standardized techniques for anion - exchange liquid chromatography with integrated pulsed amperometric detection ( eberendu , 2005 ). the resulting values in term and preterm breast milk and infant formula are listed below in table 1 . the following monosaccharides are higher in term than in preterm breast milk by the following percentages : glucose 13 %, galactose 7 %, fucose 37 %, and mannose 79 %. on the other hand , the following monosaccharides are lower in term than in preterm breast milk by the following percentages : glucosamine 60 %, sialic acid 11 - 20 %. fucose was not detected in term and preterm formulas , nor was glucosamine which serves as a precursor for sialic acid . mannose content of infant formulas was less than that found in term breast milk . sialic acid content , obtained from the limited available literature ( wang et al ., 2001 ; brand - miller et al ., 1994 ; sanchez - diaz et al ., 1997 ), was significantly less in formula compared to term breast milk . the estimated daily intake in infants of the monosaccharides ( mg / kg ) of interest are listed in table 2 ( based on an estimated oral intake of 120 ml / kg / day of breast milk ). the maximum safe total dose of sugars used as dietary supplements can be estimated based on adme ( absorption , distribution , metabolism , excretion ) and safety data , and use of a margin - of - safety ( gardiner , 2004 ). these values , based on daily dose ( mg / kg / d ) and daily dose for a 68 kg human , are listed in table 3 . based on available data , it is estimated that all of the glyconutritional sugars daily dose would have to be divided into two to three doses per day to maintain blood levels . although excessive doses of some of these sugars can be potentially toxic ( e . g ., single mannose doses of & gt ; 200 mg / kg body wt induces osmotic diarrhea and limits the maximal serum concentrations that can be reached by oral uptake ), this has no relevance for oral mannose therapy and other monosaccharides , since the uptake capacity of the gut provides natural protection ( alton et al ., 1997 ). early nutrition is critical for normal fetal and infant growth and development . with regard to fetal nutrition , glucose metabolism , placental transport and fetal utilization have been described , but there is little known regarding other important nutritional components for the fetus . there is increased transplacental transport of many nutrients as pregnancy progresses ; however , this may result in relative deficiencies if the infant is delivered prematurely . although several important sugars are metabolized from glucose , there is little information on additional monosaccharides that may be important for fetal growth and development . the neonate receives additional exposure to important oligosaccharides postnatally through mother &# 39 ; s breast milk . there is little information on the monosaccharides that comprise important dietary oligosaccharides found in human breast milk . inventor &# 39 ; s studies have shown that in addition to glucose and galactose , human milk contains fucose , glucosamine , mannose , sialic acid , and galactosamine . concentrations of these sugars in human milk vary based on gestational as well as postnatal age . inventor &# 39 ; s studies have shown that premature , term and soy formulas only contain glucose and galactose . therefore , postnatal diets are likely unable to adequately compensate for intrauterine deficiencies . there is evidence from animal and human studies that the monosaccharides fucose , glucosamine , mannose , and sialic acid are important in brain development ( brunngraber et al ., 1975 , 1976 ; webster and klingman , 1980 ; druse et al ., 1982 ; mcveagh and brand - miller , 1997 ). a lack of critical monosaccharides for incorporation into brain gangliosides during critical intrauterine and postnatal periods may account for some of the cognitive and behavioral deficits in preterm infants . although many monosaccharides can be derived from glucose , individual studies of these sugars show that there may be separate transport systems , and certain sugars may be utilized preferentially over glucose . infants born prematurely may be disadvantaged in terms of these additional monosaccharides because of 1 ) less intrauterine exposure ( duration , amounts and / or array of nutrients , 2 ) inadequate postnatal nutrition to compensate for deficiencies , and 3 ) lack of enzymes to metabolize other monosaccharides from glucose , resulting in limited de novo synthesis . inventor designed this study to evaluate maternal - fetal levels of several monosaccharides that are incorporated into brain gangliosides and routinely comprise human milk oligosaccharides , but are lacking in infant formulas . this study provides preliminary information regarding early fetal exposure and requirements of these additional monosaccharides . subjects and design : inventor studied 19 healthy mother - infant pairs : 11 preterm ( 30 - 37 wks gestation ) and 8 term ( 38 - 42 wks gestation ). mothers ranged in age from 17 to 33 years . mothers were excluded for significant alcohol , tobacco or drug use ; significant medical complications ( infection , diabetes , chronic hypertension , pre - eclampsia ) or chronic medication use ( anti - depressants , etc .). infants were appropriate weight for gestational age and were excluded for major illness , congenital or surgical anomalies . for all mothers enrolled into the study , maternal blood was collected within 24 h prior to delivery . intrauterine fetal exposure to monosaccharides was determined from cord umbilical venous blood obtained from a clamped cord sample immediately after the baby was delivered and before placental separation . blood samples were collected and centrifuged , and serum was separated and stored at − 20 ° c . serum monosaccharide concentrations ( glucose , galactose , fucose , glucosamine , mannose , and galactosamine ) were determined by hpaec - pad . the temperature and acid concentration used for hydrolysis of neutral and amino saccharide - containing complex carbohydrates were detrimental to sialic acids , which were processed and analyzed separately . maternal serum fucose , galactosamine ( galnh 2 ), glucosamine ( glcnh 2 ), galactose , glucose , mannose , and sialic acid were not significantly different between mothers delivering preterm or term infants . inventor &# 39 ; s results suggest that maternal serum concentrations of these monosaccharides remain relatively constant between 30 and 42 wks gestation . maternal vs . cord glucose levels were not significantly different for preterm pregnancies . preterm umbilical venous cord levels were significantly less than maternal levels for all other monosaccharides studied : fucose , galactosamine ( galnh 2 ), glucosamine ( glcnh 2 ), galactose , mannose , and sialic acid . maternal vs . cord glucose levels were not significantly different for term pregnancies . term umbilical venous cord levels were significantly less than maternal levels for all other monosaccharides studied : fucose , galactosamine ( galnh 2 ), glucosamine ( glcnh 2 ), galactose , mannose , and sialic acid . inventor evaluated the percentage of monosaccharide content of umbilical cord vs . maternal serum . the percentage of sialic acid was significantly higher in the preterm fetus , while levels of the other monosaccharides were not significantly different . placental transport of various substances is complex and influenced by the following : placental transport capacity increases with advancing gestation , probably due to an increased number of transporter proteins as surface area increases ( hay , 1995 ). glucose and galactose are transported by carrier - mediated and diffusional processes ( quraishi and illsley , 1999 ). fucose has a specific facilitative transporter ( wiese et al ., 1994 ). concentrations of fucose - containing glycopeptides increase markedly during the latter stages of pregnancy and during lactation ( lemonnier et al ., 1978 ). mannose is capable of crossing the placenta when available at normal physiological concentrations , allowing incorporation of maternal sugar into the fetus . mannose concentrations in human amniotic fluid are comparable to maternal blood concentrations ( alton et al ., 1998 ). sialic acid is found in red blood cell membranes ( viverge et al ., 1985 ; 1990 ), as well as amniotic fluid , milk , serum , and urine ( hayakawa et al ., 1993 ; martin et al ., 1998 ). in humans , urinary excretion of sialyl - oligosaccharides significantly increases during lactation ( lemonnier et al ., 1978 ), which coincides with markedly increased serum sialic acid levels during late - stage pregnancy ( lemonnier and bourrillon , 1976 ). hereinabove results describe maternal and fetal concentrations at preterm and term gestation , and indicate monosaccharide concentrations to which the fetus is exposed . inventor &# 39 ; s studies were not designed to determine uterine and fetal uptake and metabolism , and results likely indicate the sum of uteroplacental - fetal transfer , synthesis and degradation . maternal serum levels of fucose , galactosamine , glucosamine , galactose , glucose , mannose and sialic acid did not change significantly as pregnancy progressed towards term . glucose levels between mother and fetus were not significantly different in preterm or term pregnancies . this indicates effective glucose transport to the fetus throughout gestation . other monosaccharides found in fetal serum included fucose , galactosamine , glucosamine , galactose , mannose , and sialic acid , although in amounts significantly less than maternal levels in both preterm and term pregnancies . cord serum levels of galactosamine , glucose , and sialic acid were significantly higher in preterm fetuses . this suggests that preterm infants were exposed to higher concentrations of these monosaccharides in utero , implying a greater need for these substrates during critical periods of early development . higher monosaccharide content of cord vs . maternal serum (%) sialic acid in the preterm fetus , while concentrations of other monosaccharides were not different , suggests a significantly greater need for sialic acid during critical periods of intrauterine development . these findings suggest that for the premature infant there is potentially a greater nutritional need for these monosaccharides : if they are not obtained in utero , if they cannot be metabolized from glucose , if exogenous dietary sugars are unavailable in the newborn infant &# 39 ; s diet . human milk oligosaccharides ( hmos ), unique to breast milk , vary in content in term ( t ) vs . preterm ( p ) milks . previous studies have shown that hmo content is related to mother &# 39 ; s abo and lewis blood - group phenotypes . inventor has found , in a related study , that p delivery is significantly increased among mothers with lewis recessive phenotype . human milk oligosaccharides ( hmos ) are unique to breast milk , and their content varies between mothers and between term and preterm milk . the oligosaccharide spectrum and content of mother &# 39 ; s milk is genetically determined and related to her abo and lewis secretor status ( viverge et al ., 1985 , 1990 ; thurl et al ., 1997 ; nakhla et al ., 1999 ; erney et al ., 2001 ). the lewis secretor is expressed by oligosaccharides rich in fucose , n - acetylglucosamine and sialic acid ( viverge et al ., 1990 ; d &# 39 ; adamo and kelly , 2001 ). several oligosaccharides are missing in the milk of non - secretor or lewis - negative individuals ( kobata , 2004 ), which suggests that breastfeeding by a secretor or nonsecretor mother might offer different degrees of immunologic protection to the infant ( lependu , 2004 ). the present example examined the hypothesis that maternal lewis blood - group phenotype is associated with monosaccharide composition of human breast milk in preterm and term infants . inventor enrolled 35 breast - feeding mother - infant pairs : 23 preterm ( 30 - 37 wks gestation ) and 12 term (≧ 38 wks gestation ). mothers were excluded if there were significant alcohol , tobacco or drug use ; significant medical complications ( infection , diabetes , chronic hypertension , pre - eclampsia ); or chronic medication use ( anti - depressants , etc .). infants were excluded if there were major illness , congenital or surgical anomalies . mothers were classified according to the following lewis blood - group phenotypes : secretor ( a − b +), non - secretor ( a + b −), or recessive ( a − b −). mothers expressed and collected their initial breast milk samples at 1 to 6 days following delivery , immediately before feeding the infant . individual samples were frozen as soon after collection as possible , and stored until monosaccharide analyses were performed using standardized techniques for anion exchange chromatography ( mannatech , coppell , tex .). samples of hydrolyzed term and preterm breast milk were evaluated for levels of the following monosaccharides : glucose , galactose , fucose , glucosamine , mannose , and sialic acid . inventor compared breast milk monosaccharides at days 1 - 6 for preterm and term infants based on lewis blood - group phenotypes as listed in tables 9 - 11 . all results are m ± sd . in order to determine if breast milk monosaccharide content for preterm infants at term adjusted age was similar to term infants , inventor analyzed breast milk monosaccharide content based on secretor types in tables 12 - 14 . glucose and galactose levels were significantly higher in preterm breast milk ; and glucosamine , sialic acid , and galactosamine were significantly lower . in lewis secretor mothers , glucosamine and galactosamine were significantly lower in preterm breast milk . preterm human milk ( d . 1 - 6 ) from lewis non - secretor type vs . secretor mothers had significantly less fucose . breast milk obtained at term adjusted age had significantly less fucose from non - secretor type mothers for all infants in the study ( p = 0 . 002 , data not shown ), and specifically preterm infants . preterm human milk monosaccharide content is significantly different from breast milk at term or term - adjusted age . maternal lewis phenotype is significantly associated with preterm human milk monosaccharide content , indicating a genetic / dietary link . inventor &# 39 ; s related study shows that maternal lewis blood - group recessive phenotype is associated with preterm delivery ( szabo , 2008 ); while these data show that preterm milk monosaccharide content is significantly different from breast milk at term or term adjusted age . this could account for some of the differences in immune function and brain development observed between preterm and term infants . one major difference between mother &# 39 ; s milk and infant formula is human milk oligosaccharides ( hmos ), which contain monosaccharides important in cell interaction and communication . hmos are metabolized in the infant to provide important monosaccharide substrates ; however , this may be limited in premature infants because of immature hepatic and renal function . inventor &# 39 ; s is the first study to evaluate the monosaccharide composition of breast milk from preterm ( p ) and term ( t ) infants of different gestational and postnatal ages , and compare it to preterm and term infant formulas . inventor studied 35 breast - feeding mothers to determine monosaccharide content of expressed breast milk for 23 preterm ( 30 - 37 wks ) and 12 term infants (≧ 38 wks ). mothers expressed and collected d 1 - 6 , d 7 - 10 , and 1 mo . samples of breast milk , which were frozen and stored until hplc monosaccharide analysis . inventor determined between group breast milk comparisons , and the following table shows trends as gestation progressed towards term ( 30 to ≧ 38 wks ). at 1 - 6 d , breast milk glc and neu5ac levels were higher in p infants ( p & lt ; 0 . 05 ) while fuc , glcnh 2 , man and galnh 2 levels were lower ( p & lt ; 0 . 05 ). by one month , breast milk glc , gal , and fuc levels were not significantly different in p and t milks while glcnh 2 , man , and galnh 2 levels remained lower ( p & lt ; 0 . 05 ) and neu5ac levels remained equal or higher in preterm breast milk . when inventor analyzed milk monosaccharide levels at term - adjusted age , inventor found that glc and gal were higher in preterm milk ( p = 0 . 003 , 0 . 029 , respectively ) and glcnh 2 , neu5ac and galnh 2 were less ( p ≦ 0 . 007 ) in preterm milk . infant formulas ( preterm and post - discharge , term , and soy ) contained only glc and gal . this study suggests that monosaccharide supplementation of infant formulas to levels more closely resembling sugar concentrations found in breast milk might prove beneficial to infant growth , cns and immune function development in preterm and term infants . monosaccharide composition of human breast milk and infant formulas in preterm and term infants relative to commercial infant formulas , mother &# 39 ; s milk has been shown to offer unique advantages to term and preterm infants with regard to immunologic processes ( hanson , 1998 ; hylander , 1998 ) and cognitive development ( morley et al ., 1988 ; lucas et al ., 1992 , 1994 , 1996 ). one major difference between mother &# 39 ; s milk and infant formula is human milk oligosaccharides ( hmos ), which contain monosaccharides important in cell interaction and communication . with the exception of glucose , there is little information regarding the role of dietary sugars in mothers and infants or their availability in expressed breast milk . fucose , glucosamine , mannose , and sialic acid have all been shown to be essential to various biological activities , including immunologic and neurologic function . hmos are metabolized in the infant to provide these additional monosaccharide substrates ; however , this may be limited in premature infants because of immature hepatic and renal function . inventor &# 39 ; s is the first study to evaluate the monosaccharide composition of breast milk from preterm and term infants of different gestational and postnatal ages , and compare it to preterm and term infant formulas . inventor enrolled 35 breast - feeding mother - infant pairs : 23 preterm ( 30 - 31 , 32 - 33 , 34 - 35 , 36 - 37 wks gestation ) and 12 term ( 38 - 39 , 40 - 41 wks gestation ). mothers were excluded for significant alcohol , tobacco or drug use ; significant medical complications ( infection , diabetes , chronic hypertension , pre - eclampsia ); or chronic medication use ( anti - depressants , etc .). infants were excluded for major illness , congenital or surgical anomalies . mothers expressed and collected their initial breast milk samples at day 1 - 6 following delivery , immediately before feeding the infant . additional samples were collected at day 7 - 10 and 1 month following delivery . individual samples were frozen as soon after collection as possible , and stored until monosaccharide analyses were performed using standardized techniques for anion exchange chromatography ( mannatech , coppell , tex .). infant formula samples included preterm and preterm post - discharge , term and soy . individual samples of hydrolyzed preterm and term breast milk and infant formulas were evaluated for levels of the following monosaccharides : glucose , galactose , fucose , glucosamine , mannose , sialic acid , and galactosamine . fig2 - 9 show breast milk values on day 1 - 6 , day 7 - 10 and 1 month for glucose , galactose , fucose , glucosamine , mannose , sialic acid , and galactosamine . in fig2 and subsequent figures / tables , all values are expressed as m ± sd and n =( ) for between group measures , * p & lt ; 0 . 05 , + p & lt ; 0 . 01 . table 17 summarizes trends of each breast milk monosaccharide as gestation progresses from preterm ( 30 - 37 wks ) towards term gestation ( 38 - 41 wks ). at day i - 6 , breast milk glucose and sialic acid levels were higher in preterm infants ( p & lt ; 0 . 05 ) while fucose , glucosamine , mannose and galactosamine levels were lower ( p & lt ; 0 . 05 ). at one month , breast milk glucose , galactose , and fucose levels were not significantly different in preterm and term milk while glucosamine , mannose , and galactosamine levels remained lower ( p & lt ; 0 . 05 ) and sialic acid levels remained equal or higher in preterm breast milk . inventor &# 39 ; s analyses showed that glucose and galactose levels were higher in preterm milk at term adjusted age ; fucose and mannose levels were not different ; and glucosamine , sialic acid and galactosamine levels were lower . only glucose and galactose were found in all infant formulas tested . glucose levels in premature and premature post discharge formulas were significantly less than values in term and soy formulas . galactose values in premature formula were significantly less than in term formula , and values in term formula were significantly higher than in premature and soy formulas . human milk oligosaccharides are comprised of several monosaccharides that may contribute to the many beneficial effects of breast milk . breast milk monosaccharides vary between preterm and term milk , and remain different in preterm milk at term adjusted age . with the exception of glucose and galactose , these monosaccharides are absent in infant formulas . this study suggests that monosaccharide supplementation of infant formulas to levels more closely resembling sugar concentrations found in breast milk might prove beneficial to infant growth , cns and immune function development in preterm and term infants . at day 1 - 6 , breast milk glucose and sialic acid levels were higher in preterm milk ( p & lt ; 0 . 05 ) while fucose , glucosamine , mannose and galactosamine levels were lower ( p & lt ; 0 . 05 ). at 7 - 10 days of life , glucose , galactose , fucose , and glucosamine levels were lower in preterm breast milk ( p & lt ; 0 . 05 ); and sialic acid and galactosamine levels were not significantly different between preterm and term breast milk . at one month , breast milk glucose , galactose , and fucose levels were not significantly different in preterm and term milk while glucosamine , mannose , and galactosamine levels remained lower ( p & lt ; 0 . 05 ) and sialic acid levels remained equal or higher in preterm breast milk . human breast milk oligosaccharides provide an array of monosaccharide substrates that vary between preterm and term milk during early lactation ( d 1 - 6 through 1 month ). of particular interest are dynamic variations in fucose , glucosamine , mannose and sialic acid — monosaccharides known to play a role in cns and immune function development . at term adjusted age , preterm breast milk continues to have higher levels of glucose and galactose ( substrates also found in infant formula ), with significantly lower levels of glucosamine and sialic acid ( substrates lacking in infant formulas that may be important in infant neurologic development ). human milk oligosaccharides are composed of several monosaccharides that may contribute to the many beneficial effects of breast milk . with the exception of glucose and galactose , these monosaccharides are absent in infant formulas . this study suggests that monosaccharide supplementation of infant formulas to levels more closely resembling sugar concentrations found in breast milk would be beneficial to infant growth , cns and immune function development in preterm and term infants . a custom blend of these monosaccharides to supplement term and preterm formulas has been developed to simulate their composition in mother &# 39 ; s milk . based upon preliminary data , an example of the possible compositions of the term and preterm formula monosaccharide supplements added to term and preterm infant formula is shown in table 19 . a separate group of infants ( 5 lbw premature , 5 term ) is used to pilot formula supplementation with this combination of monosaccharides during their initial hospitalization and through the first 2 weeks of life . the monosaccharide supplement is added to the appropriate preterm or term formula when infants are tolerating 100 ml / kg / day of oral formula . if babies fall within normal limits for growth , formula tolerance , and stool output according to well accepted medical standards , inventor consides this acceptable outcome to proceed with enrollment of monosaccharide - supplemented formula fed infants . longitudinal evaluation ( 0 - 3 yrs ) of growth , body composition , general health and morbidity in term control and lbw premature infants a longitudinal evaluation is performed ( 0 - 3 yrs ) of growth , body composition , general health and morbidity in term control and lbw premature infants assigned to each of the following feeding groups : a ) mother &# 39 ; s milk [ mm ], b ) appropriate non - supplemented term or premature infant formula [ f ], or c ) infant formula supplemented with additional critical monosaccharides that are contained in mother &# 39 ; s milk [ ms + f ]. the following data , listed in table 20 , are collected on study infants assigned to the three feeding groups : dietary assessment . human milk and formula intakes is extracted from medical record flow sheets ( volumes and energy density ) during initial hospitalization and from three - day dietary records ( number of times fed , volume if available , energy density ) collected prior to the term , 6 , 12 , 24 , and 36 months . once the child is taking food ( 6 - 36 months visits ), the parent is instructed on the use of the food record guide , a booklet that assists the parent in the completion of the food record . the parent is given the food record to complete at home and a postage - paid envelope with instructions to return the record to the study coordinator . nutrient analysis utilizes the minnesota nutrition data system for research ( food nutrient and data base version 4 . 04 — 32 ). anthropometry and body composition . anthropometric measures , e . g ., weight , length or height , and head circumference are obtained using standardized techniques at 37 - 42 weeks , 6 , 12 , 24 , and 36 months . growth measures are obtained at each visit and growth velocity is calculated . growth parameters in lbw infants are generally corrected for various periods following birth , e . g ., head circumference until 18 months post - term , weight until 24 months post - term , and length until 3 . 5 years post - term . lbw infants have all growth parameters age corrected for prematurity through the 36 month evaluation to provide more consistency . body composition is determined using standardized techniques for measuring mid - arm circumference , triceps skin - fold , and calculate body mass index as appropriate . infants and children also have bia and dexa studies performed . blood analyses . all infants enrolled in the study have blood drawn in the hospital to determine baseline laboratory values ( electrolytes , liver function , chemistries , and complete blood count as listed in appendix v ) and monosaccharide levels . separate manovas and anovas are computed for each variable described above . to assess general health and morbidity in term and lbw premature infants assigned to each of the three feeding groups , typical in hospital and postdischarge clinical problems / morbidity data are collected and groups are compared using maximum likelihood methods for estimating the exact p - value ( e . g ., likelihood ratio test ). results are confirmed using the fisher - freeman - halton test . cognitive / behavioral brain function is correlated with physiologic brain function ( 0 - 3 yrs ) in lbw premature and term infants assigned to each of the three feeding groups . rationale : the neuropathology ( fuller et al ., 1983 ) and subsequent deficits associated with premature infants have been examined by several investigators ( ross et al ., 1996 ; dehaene - lambertz , 1997 ; fuller et al ., 1983 ). the neuropathology in preterm infants often results in deficits affecting “ higher order ” cognitive and executive functions , language , visual attention , visual - motor control , memory and memory consolidation , fine and gross motor control , and internal inhibitory control . the complex cognitive and attention deficits which can occur in as many as 25 % to 50 % of small premature infants may have no accompanying motor deficits , and may not be easily attributed entirely to white matter disease . higher cortical function deficits may be disturbed secondary to cerebral cortical disturbances , such as aberrations of cortical connectivity and synapse formation ( ross et al ., 1996 ; volpe , 1996 ). language development is one of the most reliable predictors of intelligence and can be used to help identify children with cognitive impairment ( capute et al ., 1986 ). socioeconomic status has been reported to predict language ability and recovery of attention to a novel stimulus independent of other predictors , but systematic , prospective studies in this area remain to be done . medical complications besides intraventricular hemorrhage may also make an important independent contribution to the variance in language outcome ( lewis and bendersky , 1989 ). developmental and neuropsychologic evaluations are done in order to assess the role of nutrition in predicting cognitive and behavioral outcome in term and lbw premature infants . the following data on study infants assigned to the three feeding groups are collected . the studies , listed in table 21 , are among the cognitive / behavioral assessments to be performed in the brain function laboratory : the following data are collected on study infants assigned to the three feeding groups . the studies , listed in table 22 , are among the psychophysiologic assessments to be performed in the brain function laboratory : psychophysiologic assessments are done initially at term corrected age and subsequently at 6 , 12 , 24 , and 36 months corrected age for lbw premature infants and chronologic age for term infants . heart rate , skin conductance , respiration , chin muscle activity ( emg ), eye movements ( eog ) and brain waves ( eeg ) during testing conditions are continually recorded . the analyses planned here are more complicated than those described above because of the multiplicity of responses ( e . g ., variations in behavioral state , eeg frequencies and erp waves ). groups can be compared as described above with the standard repeated measures manovas and anovas after the data are grouped into relevant categories . every effort is made to reduce the multiplicity of statistical tests by constructing composite variables using pca / promax analyses . the influence of family and home environment on developmental outcome of lbw premature and term infants assigned to each of the three feeding groups to determine the role of environment vs . nutrition on each of the study variables is assessed . the following data on study infants assigned to the three feeding groups are collected . the studies , listed in table 23 , are among the standardized home and family assessments performed in the brain function laboratory . the personality measures are included in the study to identify parents who have a serious pathology , making it possible to look at their children in relation to the others when the study is over , using nonparametric statistics . since all the data to be obtained under this aim are at least ordinal , it is possible to do the manovas and anovas on each as described above for other measures . the correlations of all measures in table 23 are computed and factor analyzed if there are many correlations 0 . 50 or above . the objective is to compare term siblings of the lbw premature vs . term babies at age 3 yrs . to provide preliminary complementary information about the calculated estimate of heritability influencing the nutrition - development relationship . siblings of the same parentage (˜ 20 each for lbw and control groups ) that will reach 3 years of age during the study period are assessed once , at about the age of three years (± 1 month ). siblings enrolled in this study are healthy , with weight within normal range for age . physiological data gathered in this study are written to digital disks for archiving . performance data from paradigms ( e . g ., reaction times and accuracy of responses ), nutritional and psychological survey data , and general demographic data , are entered into a database with an access front end and an sql back end . analysis is accomplished with tools like excel , sas , spss , bmdp , and systat . grasp force data ( averages / hand of isometric force values ) is used to compare left - right hand strength differences . finger - length data ( ratios of second to fourth finger lengths ) is related to other lateralization measures . resting state recordings are evaluated using standardized scoring criteria for state determination ( anders et al ., 1971 ) based on eeg , emg and eog data coupled with quantitative analyses of eeg , autonomic activity and video recordings . heart rate analyses during resting periods and in association with stimuli is measured in terms of beat - to - beat intervals ( r - r ). respiratory rate is analyzed in the time domain and is measured by the fraction of a cycle occurring in comparable periods of time before and after a stimulus . groups are contrasted in terms of their mean responses in various periods of time . skin conductance is measured as the conductance change from stimulus onset to peak . general statistical considerations . the distributions of all variables are inspected separately and all variables with skewed distributions are transformed ( log , square root , etc .). statistical analyses of quantitative eeg procedures , heart period , respiratory rate , and skin conductance include correlational analyses , factor analyses , manovas and anovas as described above . the abovementioned examples define new methods and compositions to aid proper development of growth , cognitive and immunologic systems in lbw preterm versus term infants . furthermore , relative dosage amounts and delivery times are indicated . while the present invention has now been described in terms of certain preferred embodiments , and exemplified with respect thereto , one skilled in the art will readily appreciate that various modifications , changes , omissions and substitutions may be made without departing from the spirit thereof . it is intended , therefore , that the present invention be limited solely by the scope of the following claims . alton g , hasilik m , niehues r , panneerselvan k , etchison j r , fana f , freeze h h . direct utilization of mannose for mammalian glycoprotein biosynthesis . glycobiology . 1998 ; 8 : 285 - 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