Asymmetric Allylation Catalyzed by Chiral Phosphoric Acids: Stereoselective Synthesis of Tertiary Alcohols and a Reagent-Based Switch in Stereopreference.

The substrate scope of the asymmetric allylation with zinc organyls catalyzed by 3,3-bis(2,4,6-triisopropylphenyl)-1,1-binaphthyl-2,2-diyl hydrogenphosphate (TRIP) has been extended to non-cyclic ester organozinc reagents and ketones. Tertiary chiral alcohols are obtained with ee's up to 94% and two stereogenic centers can be created. Compared to the previous lactone reagent the stereopreference switches almost completely, proving the fact that the nature of the organometallic compound is of immense importance for the asymmetry of the product.

Human milk immunomodulatory proteins are related to development of infant body composition during the first year of lactation.

BACKGROUND: To investigate relationships between infant body composition (BC) and human milk (HM) immunomodulatory proteins (IMPs) during the first 12 months of lactation. METHODS: BC of breastfeeding dyads (n = 20) was measured with ultrasound skinfolds (infants) and bioimpedance spectroscopy (infants/mothers) at 2, 5, 9, and/or 12 months post partum. Breastfeeding frequency, 24-h milk intake, and IMP concentrations (lactoferrin, lysozyme, secretory immunoglobulin A (sIgA)) were measured, and calculated daily intakes (CDIs) were determined. We used linear regression/mixed-effects models and adjusted results for multiple comparisons. RESULTS: No associations were seen between maternal characteristics and IMP concentrations/CDIs or between IMP concentrations and infant BC. Lactoferrin CDI was negatively associated with infant fat-free mass index (P = 0.002); lysozyme CDI was positively associated with infant fat mass (P = 0.004) and fat mass index (P = 0.004) measured with ultrasound skinfolds. CONCLUSION: In this small cohort of infants breastfed on demand during first year of life, we report differential associations of HM IMPs with infant BC, showing that in addition to their critical role in shaping infant immunity, lactoferrin, and lysozyme also influence development of infant BC, highlighting the importance of breastfeeding for 12 months and beyond. IMPACT: HM IMPs (concentrations and, most importantly, daily intakes) time-dependently and differentially associate with development of infant lean mass and adiposity during first 12 months of lactation. There is no information on how intakes and concentrations of these components affect development of infant BC. HM contains IMPs-lactoferrin, lysozyme, and sIgA, which not only play a critical role in shaping infant's immunity, but also influence infant growth and development of BC, highlighting the importance of breastfeeding for 12 months and beyond and warranting careful consideration of the dose effects of supplemented formula.

Integrating approaches for quality guideline development in LactaMap, an online lactation care support system.

BACKGROUND: Health professionals caring for women and infants experiencing difficulty with breastfeeding have reported deficiencies in evidence-based lactation knowledge. LactaMap is an online lactation care support system with more than 100 clinical practice guidelines to support breastfeeding care. Clinical practice guidelines support medical decision-making by summarising scientific evidence into systematically developed statements for specific clinical circumstances. Both common-sense and theory-based approaches have been used for guideline development and debate continues regarding which is superior. LactaMap clinical practice guidelines were created over the course of 5 years using a common-sense approach that was refined inductively. The aim of this study was to incorporate a theory-based framework approach into the methodology for ongoing update and review of LactaMap clinical practice guidelines. METHODS: The Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument was chosen as the framework-based approach to appraise LactaMap guideline quality. The study was conducted in two phases. The first phase appraised all 103 original LactaMap guidelines. The second phase appraised a subset of 15 updated LactaMap guidelines using improved methodology guided by phase 1, as well as 15 corresponding original (un-updated) guidelines. RESULTS: Mean Domain scores for 103 LactaMap original guidelines were above 75% in 3 of the 6 AGREE II quality Domains and no mean Domain score rated poorly. Update of guideline methodology was guided by phase 1 appraisals. Improved documentation of methods relating to questions in the Rigour of Development Domain resulted in improvement in mean Domain score from 39 to 72%. CONCLUSIONS: This study showed that a theory-based approach to guideline development methodology can be readily integrated with a common-sense approach. Factors identified by AGREE II theory-based framework provided practical guidance for changes in methodology that were integrated prior to LactaMap website publication. Demonstration of high quality in LactaMap clinical practice guideline methodology ensures clinicians and the public can have trust that the content founded on them is robust, scientific and of highest possible quality.

High-dynamic-range areal profilometry using an imaging, dispersion-encoded low-coherence interferometer.

This work presents the design and characterization of an approach for areal surface profilometry with sub-nm axial resolution. The developed approach is based on a low-coherence interferometer enhanced by an dispersive element to control the axial resolution and measurement range. Optical path differences are detected by an imaging spectrometer where equalization wavelengths are determined as a basis for fitting spectra. This enables the acquisition of surface profiles with a length of up to 1.5 mm without mechanical scanning where a minimal resolution of 0.1 nm in an axial measurement range of nearly 80 µm was achieved. The resolution calculation was based on the standard deviation of measured feature heights. In addition to the system design, its capabilities are demonstrated on samples such as height standards.

Mechanistic Studies of the TRIP-Catalyzed Allylation with Organozinc Reagents.

3,3-Bis(2,4,6-triisopropylphenyl)-1,1-binaphthyl-2,2-diyl hydrogenphosphate (TRIP) catalyzes the asymmetric allylation of aldehydes with organozinc compounds, leading to highly valuable structural motifs, like precursors to lignan natural products. Our previously reported mechanistic proposal relies on two reaction intermediates and requires further investigation to really understand the mode of action and the origins of stereoselectivity. Detailed ab initio calculations, supported by experimental data, render a substantially different mode of action to the allyl boronate congener. Instead of a Brønsted acid-based catalytic activation, the chiral phosphate acts as a counterion for the Lewis acidic zinc ion, which provides the activation of the aldehyde.

Development of LactaPedia: A lactation glossary for science and medicine.

During the last decade, there have been several publications highlighting the need for consistent terminology in breastfeeding research. Standard terms and definitions are essential for the comparison and interpretation of scientific studies that, in turn, support evidence-based education, consistency of health care, and breastfeeding policy. Inconsistent advice is commonly reported by mothers to contribute to early weaning. A standard language is the fundamental starting point required for the provision of consistent advice. LactaPedia (www.lactapedia.com) is a comprehensive lactation glossary of over 500 terms and definitions created during the development of LactaMap (www.lactamap.com), an online lactation care support system. This paper describes the development of LactaPedia, a website that is accessible free of charge to anyone with access to the Internet. Multiple methodological frameworks were incorporated in LactaPedia's development in order to meet the needs of a glossary to support both consistent health care and scientific research. The resulting LactaPedia methodology is a six-stage process that was developed inductively and includes framework to guide vetting and extension of its content using public feedback via discussion forums. The discussion forums support ongoing usability and refinement of the glossary. The development of LactaPedia provides a fundamental first step towards improving breastfeeding outcomes that are currently well below World Health Organisation recommendations globally.

TRIP-Catalyzed Asymmetric Synthesis of (+)-Yatein, (-)-α-Conidendrin, (+)-Isostegane, and (+)-Neoisostegane.

The asymmetric allylation under the assistance of catalytic amounts of 3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (TRIP) allows the concise construction of the lignan scaffold from simple aldehydes and allylic bromides with full control of the two formed stereocenters. This young methodology has been employed to synthesize four naturally and pharmaceutically active lignans. Members of the dibenzylbutyrolactone, the tetraline, and the dibenzocyclooctadiene classes have been synthesized in 40-47% overall yield along four-step synthetic routes.

Spatially Resolved Cross-Linking Characterization by Imaging Low-Coherence Interferometry.

A method to characterize cross-linking differences in polymers such as waveguide polymers has been developed. The method is based on the scan-free information acquisition utilizing a low-coherence interferometer in conjunction with an imaging spectrometer. By the introduction of a novel analyzing algorithm, the recorded spectral-phase data was interpreted as wavelength-dependent optical thickness which is matchable with the refractive index and therefore with the degree of cross-linking. In the course of this work, the method was described in its hardware and algorithmic implementation as well as in its accuracy. Comparative measurements and error estimations showed an accuracy in the range of 10-6 in terms of the refractive index. Finally, photo-lithographically produced samples with laterally defined cross-linking differences have been characterized. It could be shown, that differences in the optical thickness of ±1.5 µm are distinguishable.

Chemoenzymatic Total Synthesis of Deoxy-, epi-, and Podophyllotoxin and a Biocatalytic Kinetic Resolution of Dibenzylbutyrolactones.

Podophyllotoxin is probably the most prominent representative of lignan natural products. Deoxy-, epi-, and podophyllotoxin, which are all precursors to frequently used chemotherapeutic agents, were prepared by a stereodivergent biotransformation and a biocatalytic kinetic resolution of the corresponding dibenzylbutyrolactones with the same 2-oxoglutarate-dependent dioxygenase. The reaction can be conducted on 2 g scale, and the enzyme allows tailoring of the initial, "natural" structure and thus transforms various non-natural derivatives. Depending on the substitution pattern, the enzyme performs an oxidative C-C bond formation by C-H activation or hydroxylation at the benzylic position prone to ring closure.

Gastric emptying of different meal volumes of identical composition in preterm infants: a time series analysis.

BackgroundPreterm infants' meals typically progress to higher volumes over time. Knowledge of gastric emptying (GE) responses to differing meal volumes may inform enteral feeding management. We examined the effect of meal volume and composition on preterm GE.MethodsForty infants were studied at 33.3±1.4 (29.7-35.6) weeks postmenstrual age when fully enteral fed (target 150 ml/kg/day). Intraindividual comparisons of GE were made for paired meals of 100% and 75% prescribed volume and identical composition of mother's own milk (n=21) and pasteurized donor human milk (n=19). Serial stomach ultrasound images were used to calculate gastric residual volumes (GRVs) and remaining meal proportions (% meal).ResultsGE was faster in the early postprandial period and slowed over time (P<0.001). Reduced volume meals had slower GE rates and lower GRV (P<0.001). Serial postprandial % meal was similar between reduced and full volume meals (P=0.41). Higher milk casein concentration was associated with slower GE (P=0.04). Complete gastric emptying (GRV=0 ml) was more common in infants fed at 3 h intervals compared with those fed every 2 h (P=0.002).ConclusionEarly postprandial GE is more rapid for larger meal volumes. Stable preterm infants may tolerate feeding of a 3 h meal volume at shorter intervals.

Determinants of body composition in breastfed infants using bioimpedance spectroscopy and ultrasound skinfolds-methods comparison.

BACKGROUND: Accurate, noninvasive, and inexpensive methods are required to measure infant body composition. Ultrasound (US) and bioimpedance spectroscopy (BIS) have been validated in adults and introduced in pediatric populations. The aim of this study was to evaluate the performance of both methods in determining percentage fat mass (%FM) in breastfed infants. METHODS: %FM of 2, 5, 9, and 12 mo-old healthy, breastfed term infants (n = 58) was calculated using BIS-derived total body water equations and skinfold equations then compared with reference models. Skinfolds were measured with US at two and four sites (biceps, suprailiac and/or triceps, and subscapular). RESULTS: %FM differed widely within and between methods, with the degree of variation affected by infant age/sex. Not a single method/equation was consistent with the distributions of appropriate reference values for all age/sex groups. Moderate number of matches with references values (13-24 out of 36) was seen for both types of equations. High number of matches (25-36) was seen for US skinfold-based equations. %FM values calculated from US and BIS were not significantly different (P = 0.35). CONCLUSION: Both BIS and US are practical for predicting %FM in infants. BIS calculations are highly dependent upon an appropriate set of validated age-matched equations.

The relationship of human milk leptin and macronutrients with gastric emptying in term breastfed infants.

BackgroundInfants breastfed on demand exhibit a variety of feeding patterns and self-regulate their nutrient intake, but factors influencing their gastric emptying (GE) are poorly understood. Despite research into appetite regulation properties of leptin, there is limited information about relationships between human milk leptin and infant GE.MethodsGastric volumes were calculated from ultrasound scans of infants' stomachs (n=20) taken before and after breastfeeding, and then every 12.5 min (median; range: 3-45 min) until the next feed. Skim milk leptin and macronutrient concentrations were measured and doses were calculated.ResultsThe leptin concentration was (mean±SD) 0.51±0.16 ng/ml; the leptin dose was 45.5±20.5 ng per feed. No relationships between both concentration and dose of leptin and time between the feeds (P=0.57; P=1, respectively) or residual stomach volumes before the subsequent feed (P=0.20; P=0.050) were found. Post-feed stomach volumes (GE rate) were not associated with leptin concentration (P=0.77) or dose (P=0.85).ConclusionGE in term breastfed infants was not associated with either skim milk leptin concentration or dose. Further investigation with inclusion of whole-milk leptin and other hormones that affect gastrointestinal activity is warranted.

Milk ejection patterns remain consistent during the first and second lactations.

OBJECTIVE: Milk ejection is a critical physiological process for successful lactation in humans and without it little milk can be removed. Individual milk ejection patterns have been shown to remain consistent between breasts at different lactation stages and using different vacuum patterns with an electric breast pump. Little is known about the milk ejection characteristics during the second lactation period in the same mother. The objective of this study was to examine milk ejection characteristics in the same woman over two lactations. METHODS: One mother took part in two pumping studies during consecutive lactations. One pumping study examined milk ejection characteristics during simultaneous breast expression during the first lactation. The second pumping study (second lactation) used two different pumping patterns. Three distinct milk ejections were measured during each pumping session. RESULTS: Measurements of milk flow were used to compare the duration and time taken to reach the peak of each milk ejection for two pumping sessions from each of the lactations. There were no significant differences in milk ejection characteristics between breasts, using different pumping patterns, or between lactations in this mother (P > .05). CONCLUSION: Milk ejection appears to be a physiological response that is consistent across consecutive lactations within the same mother. This suggests that milk ejection characteristics are established during or prior to the first lactation. The infant appears to have little influence on the milk ejection characteristics of the mother.

Changes in milk composition associated with pethidine-PCEA usage after Caesarean section.

The effect of pethidine as patient-controlled epidural analgesia (PCEA) on specific biochemical components in breast milk in relation to the timing of secretory activation is not well investigated. The aim of this study was to compare biochemical timing of secretory activation between women who had a vaginal (V) or Caesarean birth with pethidine-PCEA (CBP). Several milk samples were collected daily from 36 mothers (17 V, 19 CBP) for the first 265 h post-partum. Protein and lactose concentrations and Na+ and K+ ion levels were measured. Samples were assigned to three time periods: 0-72, >72-165 and >165-265 h post-partum for statistical analyses. Data were analyzed using linear mixed effect models. In the first 72 h post-partum, the mean difference in lactose concentration was 5 gL-1 higher in group V (P < 0.05). From >72-165 h post-partum, protein and Na+ concentrations were lower in group V (P = 0.05, P = 0.02), and K+ levels were higher in group V (P < 0.001). From >165-265 h post-partum, there were no significant differences between the groups. Biochemically, secretory activation had occurred by 72 h post-partum in both groups. There were greater variations in measured biochemical components observed within group CBP initially. However, by 165 h post-partum, there were no differences in the biochemical components between the groups. This suggests that effects of pethidine-PCEA are diminished by 72 h post-partum and undetected by 165 h.

Comparing different methods of human breast milk fortification using measured v. assumed macronutrient composition to target reference growth: a randomised controlled trial.

The variable content of human breast milk suggests that its routine fortification may result in sub-optimal nutritional intakes and growth. In a pragmatic trial, we randomised infants born below 30 weeks of gestation to either the intervention (Igp) of fortifying milk on measured composition according to birth weight criteria and postmenstrual age (PMA) or our routine practice (RPgp) of fortifying on assumed milk composition to target 3·8-4·4 g protein/kg per d and 545-629 kJ/kg per d. Milk composition was measured using the MIRIS® Human Milk Analyser. Percentage fat mass (%FM) was measured using PEA POD (COSMED). The effects of macronutrient intakes and clinical variables on growth were assessed using mixed model analysis. Mean measured protein content (1·6 g/100 ml) was higher than the assumed value (1·4 g/100 ml), often leading to lower amounts of fortifier added to the milk of intervention infants. At discharge (Igp v. RPgp), total protein (3·2 (SD 0·3) v. 3·4 (SD 0·4) g; P=0·067) and energy (456 (SD 39) v. 481 (SD 48) kJ; P=0·079) intakes from all nutrition sources, weight gain velocity (11·4 (SD 1·4) v. 12·1 (SD 1·6) g/kg per d; P=0·135) and %FM (13·7 (SD 3·6) v.13·6 (SD 3·5) %; P=0·984) did not significantly differ between groups. A protein intake >3·4 g/kg per d reduced %FM by 2%. Nutrition and growth was not improved by targeting milk fortification according to birth weight criteria and PMA using measured milk composition, compared with routine practice. Targeting fortification on measured composition is labour intensive, requiring frequent milk sampling and precision measuring equipment, perhaps reasons for its limited practice. Guidance around safe upper levels of milk fortification is needed.

Human Milk Cells Contain Numerous miRNAs that May Change with Milk Removal and Regulate Multiple Physiological Processes.

Human milk (HM) is a complex biofluid conferring nutritional, protective and developmental components for optimal infant growth. Amongst these are maternal cells, which change in response to feeding and were recently shown to be a rich source of miRNAs. We used next generation sequencing to characterize the cellular miRNA profile of HM collected before and after feeding. HM cells conserved higher miRNA content than the lipid and skim HM fractions or other body fluids, in accordance with previous studies. In total, 1467 known mature and 1996 novel miRNAs were identified, with 89 high-confidence novel miRNAs. HM cell content was higher post-feeding (p < 0.05), and was positively associated with total miRNA content (p = 0.014) and species number (p < 0.001). This coincided with upregulation of 29 known and 2 novel miRNAs, and downregulation of 4 known and 1 novel miRNAs post-feeding, but no statistically significant change in expression was found for the remaining miRNAs. These findings suggest that feeding may influence the miRNA content of HM cells. The most highly and differentially expressed miRNAs were key regulators of milk components, with potential diagnostic value in lactation performance. They are also involved in the control of body fluid balance, thirst, appetite, immune response, and development, implicating their functional significance for the infant.

Human Milk MicroRNA and Total RNA Differ Depending on Milk Fractionation.

MicroRNA have been recently discovered in human milk signifying potentially important functions for both the lactating breast and the infant. Whilst human milk microRNA have started to be explored, little data exist on the evaluation of sample processing, and analysis to ensure that a full spectrum of microRNA can be obtained. Human milk comprises three main fractions: cells, skim milk, and lipids. Typically, the skim milk fraction has been measured in isolation despite evidence that the lipid fraction may contain more microRNA. This study aimed to standardize isolation of microRNA and total RNA from all three fractions of human milk to determine the most appropriate sampling and analysis procedure for future studies. Three different methods from eight commercially available kits were tested for their efficacy in extracting total RNA and microRNA from the lipid, skim, and cell fractions of human milk. Each fraction yielded different concentrations of RNA and microRNA, with the highest quantities found in the cell and lipid fractions, and the lowest in skim milk. The column-based phenol-free method was the most efficient extraction method for all three milk fractions. Two microRNAs were expressed and validated in the three milk fractions by qPCR using the three recommended extraction kits for each fraction. High expression levels were identified in the skim and lipid milk factions for these microRNAs. These results suggest that careful consideration of both the human milk sample preparation and extraction protocols should be made prior to embarking upon research in this area.

Gastric Emptying and Curding of Pasteurized Donor Human Milk and Mother's Own Milk in Preterm Infants.

We evaluated the effects of fortification and composition on gastric emptying and curding in un/fortified pairs of mother's own milk (MOM, n = 17) and pasteurized donor human milk (PDHM, n = 15) in preterm infants. Retained meal proportions (%) and curding were determined from sonography. Immediate and subsequent postprandial % were higher for PDHM (23%, P = 0.026; 15%, P = 0.006) and fortified meals (31.5%; 8.8%, both P < 0.001), whereas higher casein, whey, and lactose concentrations were associated with lower immediate postprandial % (all P < 0.006). Curding did not affect emptying. Influences of fortification, pasteurization, and differing breast milk compositions are small and unlikely implicated in preterm feeding intolerance.

Milk ejection patterns: an intra- individual comparison of breastfeeding and pumping.

BACKGROUND: Milk ejection is a transient episode critical to milk removal and women typically have multiple milk ejections during breastfeeding and pumping. Recently it was found that milk ejection characteristics such as number of milk ejections and periodicity were consistent throughout 12 months of lactation in women who expressed their milk with an electric breast pump. It is not known whether the stimulation of an infant at the breast influences milk ejection patterns or whether this is a programmed event. The aim of this study was to compare milk ejection patterns during breastfeeding and expressing milk with an electric pump within mothers. METHODS: Twelve lactating mothers with normal milk production (502-1356 mL) had milk ejection recorded by measuring the diameter of a major milk duct with ultrasound imaging throughout an entire breastfeed and a 15-min pumping session. Scans were analysed for timing, duration of duct dilation and maximum duct diameter. RESULTS: The initial milk ejection defined as the first increase in duct diameter was observed earlier during breastfeeding than during two phase pumping sessions but was not statistically significant (p = .057). There were no significant differences between the duration of the first or second milk ejection for mothers when breastfeeding or pumping at their maximum comfortable vacuum (p = .18; p = .99). The times taken to reach the peak duct diameter, or the first half of the milk ejection were also not found to be significantly different between breastfeeding and pumping. CONCLUSION: This study suggests that milk ejection patterns remain consistent within individual mothers regardless of whether the mother is breastfeeding or expressing milk indicating a likelihood of the process either being programmed or innate to the individual.

Feasibility study: Assessing the influence of macronutrient intakes on preterm body composition, using air displacement plethysmography.

AIM: Preterm nutrition guidelines target nutrient accretion and growth at intrauterine rates, yet at term equivalent age, the phenotype of the preterm infant differs from that of term infants. Monitoring early changes in preterm body composition (BC) in response to macronutrient intakes may facilitate our understanding of how best to meet preterm nutrition and growth targets. METHOD: Macronutrient intakes based on milk analysis were calculated from birth for infants born <33 weeks gestation. BC was measured in the PEA POD when infants were thermodynamically stable, free of intravenous lines and independent of respiratory support. Subsequent BC measurements were taken at least fortnightly until term age. Regression analysis was used to assess macronutrient influences on changes in BC. RESULTS: Median (range) gestation and birthweight of preterm infants (n = 27) were 29 (25-32) weeks and 1395 (560-2148) g, respectively. The youngest corrected gestational and postnatal ages that infants qualified for a PEA POD measurement were 31.86 and 1.43 weeks, respectively. Fat and total energy intakes were positively associated with increasing fat mass. Protein (with carbohydrate) intake was positively associated with increasing fat-free mass. CONCLUSION: Preterm infants can be measured in the PEA POD as early as 31 weeks corrected gestational age and the method appears sufficiently sensitive to detect influences of macronutrient intake on changes in BC.