The SLC30A2 zinc transporter has been investigated due to its important role in zinc secretion into human milk. SLC30A2 is expressed in mammary epithelial cells, and the presence of genetic variations in this transporter could cause low zinc transport into the milk, leading to Transient Neonatal Zinc Deficiency (TNZD) in newborns. Through bioinformatics analysis 22 SNPs were identified. Therefore, we aim to identify the functional changes caused by 4 SNPs. By subcloning the SLC30A2 open reading frames into the Gateway expression plasmid tagged with red and green fluorescent proteins (mCherry, tGFP). Four SNPs were introduced by mutagenesis and tagged with mCherry. We transfected individual plasmids into mammary epithelial cells (HC11) and observed cellular targeting using epifluorescent imaging. The most common variants located to secreting endosomes and membrane in HC11 cells. Incorrect targeting of SLC30A2 causes mislocalization. It may be possible to identify mothers carrying risk genotypes for infant zinc deficiency.

The following study analyzes birthweight-specific neonatal health using a combination of a mixture model and logistic regression: the extended Parametric Mixture of Logistic Regression. The data are collected from the Obstetric database at Muhimbili National Hospital in Dar es Salaam, Tanzania and the years 2009 -2013 are used in the analysis. Due to rounding in the birthweight data a novel method to adjust for rounding when estimating a mixture model is applied. The influence of rounding on the estimates is then investigated. A three-component model is selected. The variables used in the analysis of neonatal health are early neonatal mortality, if the mother has HIV, anaemia, is a private patient and if the neonate is born after 36 completed weeks of gestation. It can be concluded that the mortality rates are high especially for low birthweights (2000 or less) in the estimated first and second components. However, due to wide confidence bounds it is hard to draw conclusions from the data.

The SLC30A2 zinc transporter has been investigated due to its important role in zinc secretion into human milk. SLC30A2 is expressed in mammary epithelial cells, and the presence of genetic variations in this transporter could cause low zinc transport into the milk, leading to Transient Neonatal Zinc Deficiency (TNZD) in newborns. Through bioinformatics analysis 22 SNPs were identified. Therefore, we aim to identify the functional changes caused by 4 SNPs. By subcloning the SLC30A2 open reading frames into the Gateway expression plasmid tagged with red and green fluorescent proteins (mCherry, tGFP). Four SNPs were introduced by mutagenesis and tagged with mCherry. We transfected individual plasmids into mammary epithelial cells (HC11) and observed cellular targeting using epifluorescent imaging. The most common variants located to secreting endosomes and membrane in HC11 cells. Incorrect targeting of SLC30A2 causes mislocalization. It may be possible to identify mothers carrying risk genotypes for infant zinc deficiency.

Background/Project Description: There is a growing interest in the contribution of late preterm (34 – 36 week gestational age (GA)) birth to neonatal morbidity and mortality. Late preterm infants have an increased incidence of both respiratory and non- respiratory complications over the first year of life. Rates of prematurity as well as morbidity/mortality in infancy are higher in lower socioeconomic status (SES) groups but how GA and SES interact is relatively unexplored. Methods/Participant Population: A retrospective cohort study was undertaken utilizing anonymized data housed at the Manitoba Centre for Health Policy (MCHP). A population-based cohort of infants born at 34 to 41 weeks of GA was assembled; individual and area-level income information was used to develop SES groups. Outcomes studied included diagnoses received during the birth hospitalisation, neonatal and post-neonatal admissions. Regression models were constructed to explore the effects of GA and SES as well as control for multiple perinatal variables. Appropriate approvals and safeguards for data privacy were maintained. Results: GA and SES exerted a gradient effect on morbidity, which persisted after controlling for multiple confounding variables. The effect of GA was strongest during the birth hospitalisation but persisted throughout the first year with increased morbidity evident with each week of decreasing GA. The detrimental association of low SES with morbidity increased in effect size throughout the first year surpassing that of GA for post-neonatal admissions. An interaction effect of maternal diabetes, respiratory morbidity and SES was suggested and merits further investigation. Neonatal stays of 3 days or longer negated the association of GA with readmission within the first 28 days; in addition shorter stay infants had the highest risks of readmission at 37 weeks as compared to the late preterm gestations. Conclusions: The consistent associations between poverty, prematurity and morbidity require both further study and attention. Attention to the neonatal health of both late preterm and term infants is important due to their large numbers and population impact. The added risk of poverty merits urgent and multifaceted interventions to lay the groundwork for healthy childhood and long-term success.

With asphyxia, newborns may suffer cardiogenic shock with myocardial dysfunction and dysregulation of vasomotor tone resulting in multiorgan dysfunction. Vasoactive medications are often administered with limited evidence directing clinicians regarding the use of high-dose monotherapy with dopamine relative to combination treatment with dopamine and a second different agent. We hypothesized that the treatment of hypoxia-reoxygenated newborn piglets with combinations of vasoactive medications would improve systemic and regional hemodynamics. Instrumented newborn piglets were subjected to hypoxia-reoxygenation with subsequent infusion of high-dose dopamine or moderate-dose dopamine and one of epinephrine, milrinone or levosimendan. Treatment with high-dose dopamine improved systemic and mesenteric perfusion. The addition of low-dose epinephrine showed some benefits regarding pulmonary hypertension and should a non-catecholamine agent be added to dopamine, milrinone is preferred to levosimendan given benefits to mesenteric perfusion. We conclude that the selection of appropriate vasoactive medical therapy should be directed by the clinical effects desired. / Experimental Surgery

The aims of this Thesis were to investigate early markers of neonatal sepsis and patient-factors affecting the pharmacokinetics and pharmacodynamics (PKPD) of aminoglycosides in the treatment of neonatal sepsis. A prospective cohort study of neonates commenced on gentamicin for suspected sepsis was performed between 1 July 2002 and 28 February 2007. Receiver operator characteristics (ROC) plots were used to assess potential markers of sepsis against culture positive sepsis. When sepsis was first suspected, the most promising tests were interleukin (IL) IL-12(p70) with an area under the curve (95% CI) for the ROC of 0.74 (0.63-0.86), and which (with a cut-off at 75 pg/mL) had a sensitivity (95% CI) of 28% (20-36%) and a specificity of 98% (96-100%). IL-10 had a sensitivity of 17% (10-23%) and a specificity of 99% (97-100%). Retrospective studies of neonates treated with gentamicin, amikacin and netilmicin for suspected sepsis were used to identify patient characteristics that affected aminoglycoside PKPD properties. Population PK modelling used NONMEM� v.5 to determine aminoglycoside clearance (CL) and volume of distribution (V). Logistic regression was used to examine the treatment outcome measures (serum peak and trough concentrations and ototoxicity). Simulations of new dosing regimens were undertaken for netilmicin and amikacin using MATLAB� The final gentamicin PK covariate model gave CL = 0.097 x (current weight/2)[1.3] x (postnatal age/7)[0.29] and V = 1.07 x (current weight/2)[0.8]+ (confirmed sepsis) x 0.13. A 10% increase in gentamicin V in neonates with sepsis was estimated. For amikacin, 17 (35%) of 49 episodes of confirmed sepsis met the treatment failure criteria from 12 (15%) individual patients. The final amikacin PK covariate model was CL = 0.23 x (current weight/2)[0.691] x (postmenstrual age/40)[3.23] and V = 0.957 x (current weight/2)[0.89]. PD analysis determined risk factors linked to hearing impairment in neonates treated with amikacin included: co-medication with vancomycin, high C-reactive protein concentration and low gestational age. Simulation of a new amikacin dosing regimen recommended: 15 mg/kg 36 hourly, 14 mg/kg 24 hourly, and 15 mg/kg 24 hourly, for neonates [less than or equal to] 28 weeks, 29 to 36 weeks, and [greater than or equal to] 37 postmenstrual age, respectively. For netilmicin, the final PK covariate model was CL = 0.192 x (current weight/2)[1.35] x (postmenstrual age/40)[1.03], V = 1.5 x (current weight/2)[0.3]. Simulation of a new optimal dosing regimen for netilmicin was: 5 mg/kg 36 hourly, 5 mg/kg 24 hourly, 6 mg/kg 24 hourly, and 7 mg/kg 24 hourly, for neonates [less than or equal to] 27, 28 to 30, 31 to 33, and [greater than or equal to] 34 weeks postmenstrual age, respectively. IV infusions representing gentamicin administration to neonates of 2.5 kg and 0.5 kg in the NICU setting (30 minutes gentamicin infusion then a 30 minute saline flush) showed the larger neonates received 80% of the drug within 60 minutes. This increased to 90-95% by 75 minutes. However, in extremely low birth weight neonates (0.5 kg), only 60% of the intended gentamicin dose was delivered by 60 minutes (70% by 75 minutes). In conclusion: IL-12(p70) and IL-10 were identified as promising diagnostic tests to confirm sepsis in neonates. Confirmed sepsis caused a 10% increase in V of gentamicin in neonates, suggesting larger initial dosages (mg/kg) are required for effective treatment of neonates with sepsis. Aminoglycoside clearance in neonates is predominantly affected by current weight, postmenstrual age or postnatal age. Adjusting netilmicin and amikacin doses based on current weight, and dosing interval based on both postmenstrual age and current weight improves drug efficacy. Identification of co-medication with vancomycin, low gestational age, and high C-reactive protein during treatment with amikacin increases risk of hearing impairment. The delivery of gentamicin administrated by IV infusion is substantially extended in extremely low birth weight neonates.

The psychometric properties of this Parental Stressor Scale: Neonatal Intensive Care Unit (PSS:NICU) were assessed, before using the scale to describe stress experienced by parents in a Neonatal Intensive Care Unit (NICU). The extent to which parental stress from the parent-infant relationship in the unit was linked to parenting they received as a child, and adjustment to their couple relationship, was also examined. The sample consisted of 182 mothers and 183 fathers, who were in a cohabitating relationship, of infants from the NICU at Christchurch Women's Hospital. The self-report questionnaires included the PSS:NICU, Parental Bonding Instrument, and the Dyadic Adjustment Scale, and were administered to parents within 2-3 weeks of their infant's birth. This study extends the finding of satisfactory psychometric properties of the PSS:NICU (Franck, Cox, Allen & Winter, 2005; Miles, Funk & Carlson, 1993; Reid & Bramwell, 2003) to this New Zealand sample. Mothers experienced significantly higher stress from the unit compared to fathers (p < .01). A previous finding, for mothers, of the parent-infant relationship being the most stressful aspect of the unit (Franck et al., 2005; Reid & Bramwell, 2003; Shields-Poe & Pinelli, 1997) extends to the New Zealand sample. The most stressful aspect of the unit for fathers was sights and sounds. Lack of evidence was found for associations between parental stress from the parent-infant relationship in the unit and parenting received as a child, or adjustment to their couple relationship. A weak but significant negative correlation was, however, found between stress from the mother-infant relationship and maternal care received in childhood. It is unnecessary to provide all parents with intervention further to what is already being practiced in the unit, as overall low levels of stress were reported. Some parents, however, did find the unit more stressful, and they may benefit from increased intervention.

Diss. (sammanfattning) Uppsala : Univ., 2003. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Canterbury, 2009. / Typescript (photocopy). "6 July 2009." Includes bibliographical references (p. [205]-224). Also available via the World Wide Web.

Thesis (Ph.D.) -- University of Rhode Island, 2009. / Typescript. Includes bibliographical references (leaves 150-165).