Plant size, latitude, and phylogeny explain within-population variability in herbivory.

Interactions between plants and herbivores are central in most ecosystems, but their strength is highly variable. The amount of variability within a system is thought to influence most aspects of plant-herbivore biology, from ecological stability to plant defense evolution. Our understanding of what influences variability, however, is limited by sparse data. We collected standardized surveys of herbivory for 503 plant species at 790 sites across 116° of latitude. With these data, we show that within-population variability in herbivory increases with latitude, decreases with plant size, and is phylogenetically structured. Differences in the magnitude of variability are thus central to how plant-herbivore biology varies across macroscale gradients. We argue that increased focus on interaction variability will advance understanding of patterns of life on Earth.

Storage time of platelet concentrates and all-cause bacteremia in hematologic patients.

BACKGROUND: Extension of storage time of platelet (PLT) concentrates may result in an increased risk of bacteremia, directly via transfusion of contaminated products or indirectly via transfusion-related immunomodulation. We aimed to quantify the association of storage time of PLT concentrates and all-cause bacteremia in hematologic patients. STUDY DESIGN AND METHODS: We established a cohort of hematologic patients who received a PLT transfusion between 2005 and 2015. Cases were defined as patients with a bacteremia the day after transfusion and matched to as many controls as possible. A conditional logistic regression was performed, stratified by storage medium. RESULTS: Among 3514 patients receiving 36,032 PLT concentrates stored in plasma, 613 cases of bacteremia were found. The relative risk of all-cause bacteremia the day after transfusion was 0.80 (95% confidence interval [CI], 0.58-1.12) for PLT concentrates stored 3 to 4 days and 0.67 (95% CI, 0.49-0.92) for at least 5 days, compared to no more than 2 days. Among 1527 patients receiving 11,822 PLT concentrates stored in PLT additive solution, 182 cases of bacteremia were found. The relative risk of all-cause bacteremia was 1.14 (95% CI, 0.70-1.84) for PLT concentrates stored for 3 to 4 days and 1.19 (95% CI, 0.70-2.01) for at least 5 days, compared to not more than 2 days. CONCLUSION: Storage time of PLT concentrates was not associated with increased occurrence of all-cause bacteremia the day after transfusion. If anything, fewer cases of bacteremia occurred with increasing storage time of PLT concentrates in plasma. These bacteremias are not directly caused by transfusion of a contaminated product and the underlying mechanism warrants further research.

Rare Genetic Variant in SORL1 May Increase Penetrance of Alzheimer's Disease in a Family with Several Generations of APOE-ɛ4 Homozygosity.

BACKGROUND: The major genetic risk factor for late onset Alzheimer's disease (AD) is the APOE-ɛ4 allele. However, APOE-ɛ4 homozygosity is not fully penetrant, suggesting co-occurrence of additional genetic variants. OBJECTIVE: To identify genetic factors that, next to APOE-ɛ4 homozygosity, contribute to the development of AD. METHODS: We identified a family with nine AD patients spanning four generations, with an inheritance pattern suggestive of autosomal dominant AD, with no variants in PSEN1, PSEN2, or APP. We collected DNA from four affected and seven unaffected family members and performed exome sequencing on DNA from three affected and one unaffected family members. RESULTS: All affected family members were homozygous for the APOE-ɛ4 allele. Statistical analysis revealed that AD onset in this family was significantly earlier than could be expected based on APOE genotype and gender. Next to APOE-ɛ4 homozygosity, we found that all four affected family members carried a rare variant in the VPS10 domain of the SORL1 gene, associated with AßPP processing and AD risk. Furthermore, three of four affected family members carried a rare variant in the TSHZ3 gene, also associated with AßPP processing. Affected family members presented between 61 and 74 years, with variable presence of microbleeds/cerebral amyloid angiopathy and electroencephalographic abnormalities. CONCLUSION: We hypothesize that next to APOE-ɛ4 homozygosity, impaired SORL1 protein function, and possibly impaired TSHZ3 function, further disturbed Aß processing. The convergence of these genetic factors over several generations might clarify the increased AD penetrance and the autosomal dominant-like inheritance pattern of AD as observed in this family.

A pharmacogenetic analysis of determinants of hypertension and blood pressure response to angiotensin-converting enzyme inhibitor therapy in patients with vascular disease and healthy individuals.

AIMS: To investigate whether genetic variation in the renin-angiotensin-aldosterone system (RAAS) and kallikrein-bradykinin pathways is related to hypertension and blood pressure (BP) response to angiotensin-converting enzyme (ACE) inhibitor therapy in stable coronary artery disease (CAD) patients. METHODS AND RESULTS: In 8907 stable CAD patients from the EUROPA trial, 52 haplotype-tagging single-nucleotide polymorphisms (SNPs) in 12 candidate genes within the RAAS and kallikrein-bradykinin pathways were investigated for association with hypertension (defined as BP ≥160/95 mmHg or use of antihypertensives) and BP response to ACE inhibitors, during a 4-week run-in period. All analyses were adjusted for age, sex, body mass index and creatinine clearance and corrected for multiple testing. RESULTS: Hypertension was present in 28.3% of the patients (n = 2526); median BP reduction after perindopril was 10/4 mmHg. Four polymorphisms, located in the ACE (rs4291), angiotensinogen (rs5049) and (pro)renin receptor (rs2968915; rs5981008) genes were significantly associated with hypertension in two vascular disease populations of CAD (EUROPA) and cerebrovascular disease (PROGRESS; n = 3571). A cumulative profile demonstrated a stepwise increase in the prevalence of hypertension, mounting to a 2-3-fold increase (P for trend <0.001). Similar associations on hypertension were observed for angiotensinogen in a healthy population (n = 2197). In addition, genetic polymorphisms were identified that significantly modified the BP reduction by ACE inhibitor therapy; however, the observed BP differences were small and did not remain significant after permutation analysis. CONCLUSION: This large genetic association study identified genetic determinants of hypertension in three cohorts of patients with vascular disease and healthy individuals.

The Generation R Study: design and cohort update 2010.

The Generation R Study is a population-based prospective cohort study from fetal life until young adulthood. The study is designed to identify early environmental and genetic causes of normal and abnormal growth, development and health during fetal life, childhood and adulthood. The study focuses on four primary areas of research: (1) growth and physical development; (2) behavioural and cognitive development; (3) diseases in childhood; and (4) health and healthcare for pregnant women and children. In total, 9,778 mothers with a delivery date from April 2002 until January 2006 were enrolled in the study. General follow-up rates until the age of 4 years exceed 75%. Data collection in mothers, fathers and preschool children included questionnaires, detailed physical and ultrasound examinations, behavioural observations, and biological samples. A genome wide association screen is available in the participating children. Regular detailed hands on assessment are performed from the age of 5 years onwards. Eventually, results forthcoming from the Generation R Study have to contribute to the development of strategies for optimizing health and healthcare for pregnant women and children.

Genetic determinants of treatment benefit of the angiotensin-converting enzyme-inhibitor perindopril in patients with stable coronary artery disease.

AIMS: The efficacy of angiotensin-converting enzyme (ACE)-inhibitors in stable coronary artery disease (CAD) may be increased by targeting the therapy to those patients most likely to benefit. However, these patients cannot be identified by clinical characteristics. We developed a genetic profile to predict the treatment benefit of ACE-inhibitors exist and to optimize therapy with ACE-inhibitors. METHODS AND RESULTS: In 8907 stable CAD patients participating in the randomized placebo-controlled EUROPA-trial, we analysed 12 candidate genes within the pharmacodynamic pathway of ACE-inhibitors, using 52 haplotype-tagging-single nucleotide polymorphisms (SNPs). The primary outcome was the reduction in cardiovascular mortality, non-fatal myocardial infarction, and resuscitated cardiac arrest during 4.2 years of follow-up. Multivariate Cox regression was performed with multiple testing corrections using permutation analysis. Three polymorphisms, located in the angiotensin-II type I receptor and bradykinin type I receptor genes, were significantly associated with the treatment benefit of perindopril after multivariate adjustment for confounders and correction for multiple testing. A pharmacogenetic score, combining these three SNPs, demonstrated a stepwise reduction of risk in the placebo group and a stepwise decrease in treatment benefit of perindopril with an increasing scores (interaction P < 0.0001). A pronounced treatment benefit was observed in a subgroup of 73.5% of the patients [hazard ratio (HR) 0.67; 95% confidence interval (CI) 0.56-0.79], whereas no benefit was apparent in the remaining 26.5% (HR 1.26; 95% CI 0.97-1.67) with a trend towards a harmful effect. In 1051 patients with cerebrovascular disease from the PROGRESS-trial, treated with perindopril or placebo, an interaction effect of similar direction and magnitude, although not statistically significant, was observed. CONCLUSION: The current study is the first to identify genetic determinants of treatment benefit of ACE-inhibitor therapy. We developed a genetic profile which predicts the treatment benefit of ACE-inhibitors and which could be used to optimize therapy.

Maternal medication use, carriership of the ABCB1 3435C > T polymorphism and the risk of a child with cleft lip with or without cleft palate.

Gene-environment interactions in the periconceptional period play an increasing role in the pathogenesis of birth defects, including cleft lip and/or cleft palate (CL/P). The P-glycoprotein, encoded by the ABCB1 gene, is suggested to protect the developing embryo from medication and other xenobiotic exposures. Furthermore, maternal medication use during early pregnancy is a significant risk factor for CL/P offspring. Therefore, the aim of this study is to investigate the association between the maternal and child's functional ABCB1 3435C > T polymorphism, periconceptional medication exposure, and the risk of a child with CL/P. A case-control study was performed among 175 mothers and 98 of their children with CL/P and 83 control mothers and their 65 children. Information on medication and folic acid use was collected. Mothers carrying the 3435TT genotype and using medication showed a 6.2-fold (95% CI = 1.6-24.2) increased risk of having a child with CL/P compared to mothers carrying the 3435CC genotype and not using medication. Periconceptional folic acid use reduced this risk by approximately 30% (OR = 3.9, 95% CI = 0.9-18.0). Mothers carrying the 3435TT genotype, using medication and not taking folic acid showed the highest risk estimate (OR = 19.2, 95% CI = 1.0-369.2). These data suggest that mothers who carry the ABCB1 3435C > T polymorphism are at significantly increased risk for having offspring with CL/P, especially mothers using medication in the periconceptional period.

The Generation R Study Biobank: a resource for epidemiological studies in children and their parents.

The Generation R Study is a population-based prospective cohort study from fetal life until young adulthood. The study is designed to identify early environmental and genetic causes of normal and abnormal growth, development and health from fetal life until young adulthood. In total, 9,778 mothers were enrolled in the study. Prenatal and postnatal data collection is conducted by physical examinations, questionnaires, interviews, ultrasound examinations and biological samples. Major efforts have been conducted for collecting biological specimens including DNA, blood for phenotypes and urine samples. In this paper, the collection, processing and storage of these biological specimens are described. Together with detailed phenotype measurements, these biological specimens form a unique resource for epidemiological studies focused on environmental exposures, genetic determinants and their interactions in relation to growth, health and development from fetal life onwards.

Chondrosarcoma of the larynx: a report of two cases and a review of the literature.

Chondrosarcoma of the larynx: a report of two cases and a review of the literature. This paper describes two cases of low-grade laryngeal chondrosarcoma. In both cases, the tumours were located on the cricoid, and could be visualized with a CT scan and magnetic resonance imaging. The diagnosis was made by a deep wedge biopsy with a CO2 laser, and after subtotal supracricoid laryngectomy. Most of the reported cases have been successfully managed by voice-sparing surgery, but the two cases reported here, needed more radical treatment.

Differential effects of prenatal exposure to dexamethasone or cortisol on circulatory control mechanisms mediated by angiotensin II in the central nervous system of adult sheep.

Prenatal exposure to elevated maternal glucocorticoids (dexamethasone (DEX) or cortisol (CORT)) for 2 days early in pregnancy can 'programme' alterations in adult offspring of sheep, including elevated arterial pressure. DEX treatment also results in greater angiotensin II type 1 (AT1) receptor expression in the medulla oblongata in late gestation fetuses than in saline (SAL)- or CORT-exposed animals. We hypothesized that this would result in functional changes in brainstem angiotensinergic control of cardiovascular function in DEX- but not CORT-exposed animals. To test this hypothesis, cardiovascular responses to intracerebroventricular (I.C.V.) angiotensin II were examined in adult male offspring exposed to DEX (0.48 mg h(-1); n = 7), CORT (5 mg h(-1), n = 6) or SAL (n = 9) from 26 to 28 days of gestation. Increases in mean arterial pressure during i.c.v. infusion of angiotensin II (1 or 10 microg h(-1)) were significantly greater in the DEX group (10 +/- 1 mmHg at 1 microg h(-1)) compared with SAL (6 +/- 1 mmHg) or CORT (6 +/- 1 mmHg) animals (P < 0.05). I.C.V. infusion of the AT1 antagonist losartan significantly decreased cardiac output and heart rate in DEX animals, but not in SAL or CORT animals. Thus, increased expression of brainstem AT1 receptor mRNA after prenatal DEX is associated with increased responsiveness of cardiovascular control to activation of brain AT receptors by exogenous and endogenous angiotensin II. The altered role of the brain RAS in sheep exposed prenatally to DEX was not observed in sheep exposed prenatally to cortisol, suggesting these two glucocorticoids have distinct programming actions.

Activation of NF-kappaB transcription factor in the preterm ovine brain and placenta after acute LPS exposure.

Intrauterine infection may be causally related to inflammation and injury of the fetal brain, however the mechanisms by which this occurs are unclear. We have investigated whether nuclear factor (NF)-kappaB, a transcription factor for proinflammatory cytokines, is activated in the fetal brain after acute LPS-exposure. At 95 days of gestation (term = approximately 147 days), 5 fetuses received a single intravenous bolus dose of LPS (1 microg/kg); 6 fetuses served as controls. Fetal blood samples were taken hourly for 6 hr post LPS-exposure to assess physiological status. Ewes and fetuses were then euthanased, placental and brain tissue examined histologically, and NF-kappaB activation assessed in several regions of the fetal brain using an electromobility shift assay (EMSA). Oxidative stress was measured using lipid peroxidation and 8-isoprostane biochemical assays and brain cytokine concentrations analysed by enzyme linked immunosorbent assay (ELISA). LPS-exposed fetuses (relative to controls) were hypoxemic and the haematocrit and lactate levels had increased. In the brains of LPS-exposed fetuses compared to controls, NF-kappaB binding activity was elevated in the hippocampus and the thalamus/basal ganglia; 8-isoprostane levels were elevated overall (P < 0.05) in the parietal/occipital/temporal lobes and thalamus/basal ganglia. TNF-alpha and IL-6 concentrations were not elevated, however, there was a tendency for an elevation of IFN-gamma concentrations in the thalamus/basal ganglia. IFN-gamma concentration was elevated (P < 0.05) in the plasma 4 hr after LPS-exposure. In the placenta, NF-kappaB binding activity was increased (P < 0.05). We conclude that acute systemic administration of LPS leads to increased binding activity of NF-kappaB subunits in specific regions of the fetal brain and in the placenta, but that there is no clear-cut relationship between this elevation and vulnerability to endotoxic damage.

[Neuropsychological Assessment of Children: a test battery for children between 5 and 16 years of age. A Colombian normative study]. / Evaluacion Neuropsicologica Infantil (ENI): bateria para la evaluacion de niños entre 5 y 16 años de edad. Estudio normativo colombiano.

INTRODUCTION: A neuropsychological test battery for 5 to 16 year old children has recently been developed. This battery is called Neuropsychological Assessment of Children (Evaluacion Neuropsicológica Infantil, ENI) and it includes the following sections: attention, constructional skills, memory encoding, perceptual skills, memory recall, language, metalinguistic skills, reading, writing, arithmetic, spatial skills, conceptual skills and executive functions. AIMS: Our aim was to obtain norms for the ENI in a Colombian population between 5 and 16 years of age. SUBJECTS AND METHODS: We selected 252 children (92 boys and 160 girls) in the city of Manizales (Colombia), and they were administered the ENI. In order to obtain an external validity, 21 of the participants were also given the Wechsler Intelligence Scale for Children Revised (WISC R). RESULTS: Statistically significant differences were found on most of the subtests across age groups. Differences between boys and girls appeared more specifically in tests of visuoperceptual, visual constructional, spatial and numerical skills. Some of the ENI subtests correlated with the WISC R subtests. CONCLUSIONS: It is suggested that the ENI could satisfy the existing need in the Spanish speaking world for neuropsychological tools with which to assess children and adolescents.

Evaluación Neuropsicológica Infantil (ENI): una batería para la evaluación de niños entre 5 y 16 años de edad. Estudio normativo colombiano / Neuropsychological assessment of children: a test battery for children between 5 and 16 years of age. A colombian normative study

Introducción. Recientemente se desarrolló una batería neuropsicológica para niños con edades entre los 5 y los 16 años. Esta batería se denominó Evaluación Neuropsicológica Infantil (ENI), y comprende las siguientes secciones: atención, habilidades constructivas, memoria de codificación, habilidades perceptuales, memoria de evocación, lenguaje, habilidades metalingüísticas, lectura, escritura, aritmética, habilidades espaciales, habilidades conceptuales y funciones ejecutivas. Objetivo. Obtener las normas de la ENI para una población de niños colombianos entre los 5 y los 16 años. Sujetos y métodos. Se seleccionaron 252 niños (92 niños y 160 niñas) en la ciudad de Manizales (Colombia), y se les administró la ENI. Para obtener un índice de validez externa, a 21 de los participantes también se les aplicó la escala de inteligencia Wechsler para niños-revisada (WISC-R). Resultados. Se encontraron diferencias significativas en la mayoría de las subpruebas al comparar los diferentes intervalos de edad. Las diferencias entre niños y niñas aparecieron más específicamente en pruebas de habilidades visuoperceptuales, visuoconstructivas, espaciales y numéricas. Algunas subpruebas de la ENI se correlacionaron con las subpruebas del WISC-R. Conclusión. Se sugiere que la batería ENI podría llenar la necesidad existente en el mundo hispanohablante de disponer de instrumentos neuropsicológicos para la evaluación de niños y adolescentes (AU)

Introduction. A neuropsychological test battery for 5 to 16-year-old children has recently been developed. This battery is called Neuropsychological Assessment of Children (Evaluacion Neuropsicológica Infantil, ENI) and it includes the following sections: attention, constructional skills, memory encoding, perceptual skills, memory recall, language, metalinguistic skills, reading, writing, arithmetic, spatial skills, conceptual skills and executive functions. Aims. Our aim was to obtain norms for the ENI in a Colombian population between 5 and 16 years of age. Subjects and methods. We selected 252 children (92 boys and 160 girls) in the city of Manizales (Colombia), and they were administered the ENI. In order to obtain an external validity, 21 of the participants were also given the Wechsler Intelligence Scale for Children-Revised (WISC-R). Results. Statistically significant differences were found on most of the subtests across age groups. Differences between boys and girls appeared more specifically in tests of visuoperceptual, visual constructional, spatial and numerical skills. Some of the ENI subtests correlated with the WISC-R subtests. Conclusions. It is suggested that the ENI could satisfy the existing need in the Spanish-speaking world for neuropsychological tools with which to assess children and adolescents (AU)

The effects of repeated endotoxin exposure on placental structure in sheep.

Intrauterine infection has been associated with fetal brain injury and preterm birth. We have recently shown that repeated exposure to bacterial endotoxin leads to hypoxia and brain injury in the preterm ovine fetus and we considered it possible that endotoxin could also damage the placenta. Our aim therefore was to assess placental structure following repeated exposure to endotoxin. Endotoxin was administered on 3-5 occasions (1 microg/kg, i.v.) over 5 days from 95-99 days of gestation (term approximately 147 days) to 6 fetal sheep and placental structure assessed at 105 days. In LPS-exposed animals there was a 17 per cent reduction (P<0.05) in placental weight and the average cross-sectional area of placentomes was reduced (P<0.05) by 20 per cent. In addition, all LPS-exposed placentae showed significant injury as evidenced by calcium deposits associated with areas of infarcted tissue. We conclude that repeated endotoxin exposure results in damage to the placenta which could lead to persistent alterations in placental exchange function.

Prolonged reductions in placental blood flow and cerebral oxygen delivery in preterm fetal sheep exposed to endotoxin: possible factors in white matter injury after acute infection.

OBJECTIVE: Endotoxin causes hypoxemia and white matter injury in the preterm ovine fetus. Because cerebral hypoxia could contribute to brain injury, our objective was to determine the effects of endotoxin on regional cerebral oxygen (O(2)) delivery. To investigate causes of fetal hypoxemia, we also measured placental blood flow. METHODS: We administered endotoxin (lipopolysaccharide, LPS) at 1 microgram/kg (intravenously) to 11 catheterized fetal sheep at approximately 0.7 of term; controls (n = 7) received saline. We measured fetal cerebral blood flow (CBF) and placental blood flow using microspheres, arterial blood gases, arterial pressure, and heart rate. RESULTS: Seven fetuses survived LPS administration (LPS-S) and four died. LPS-S fetuses were hypoxemic at 4-8 hours after LPS. Fetal hemoglobin concentration and hematocrit increased by about 14% at 4 hours after LPS exposure, and mean arterial pressure decreased significantly from 4-8 hours. After LPS, CBF did not change significantly, but total cerebral O(2) delivery decreased by 35.7% at 4 hours and by 28.3% at 8 hours. O(2) delivery to cerebral white matter decreased below pre-LPS values at 4 hours (-35.9%) and 8 hours (-28.6%) after LPS. Relative to pre-LPS values, placental blood flow decreased by 53.3% at 4 hours and 43.0% at 8 hours after LPS. CONCLUSIONS: Immature fetal sheep exposed to LPS had profound reductions in placental blood flow and cerebral O(2) delivery, which could contribute to fetal brain injury. Reduced O(2) delivery to white matter was similar to that in other brain regions. Mechanisms that enable fetal CBF to increase in hypoxemic conditions were apparently ineffective in the presence of LPS.

Changes in alveolar epithelial cell proportions during fetal and postnatal development in sheep.

Basal lung expansion is an important determinant of alveolar epithelial cell (AEC) phenotype in the fetus. Because basal lung expansion increases toward term and is reduced after birth, we hypothesized that these changes would be associated with altered proportions of AECs. AEC proportions were calculated with electron microscopy in fetal and postnatal sheep. Type I AECs increased from 4.8 +/- 1.3% at 91 days to 63.0 +/- 3.6% at 111 days of gestation, remained at this level until term, and decreased to 44.8 +/- 1.8% after birth. Type II AECs increased from 4.3 +/- 1.5% at 111 days to 29.6 +/- 4.1% at 128 days of gestation, remained at this level until term, and then increased to 52.9 +/- 1.5% after birth. Surfactant protein (SP)-A, -B and -C mRNA levels increased with increasing gestational age before birth, but the changes in SP expression after birth were inconsistent. Thus before birth type I AECs predominate, whereas after birth type II AECs predominate, possibly due to the reduction in basal lung expansion associated with the entry of air into the lungs.

Postnatal development of arterial pressure: influence of the intrauterine environment.

A substantial number of epidemiological studies have shown that small size at birth is associated with an increased risk of developing hypertension and metabolic dysfunction later in life; however these associations have not been found in all studies. In animals, several models have been used to investigate the effects of perturbations to the fetal environment on later arterial pressure, with differing effects on size at birth and arterial pressure. Ovine models include maternal dietary manipulations, antenatal glucocorticoid exposure, and restriction of placental size and function. In our laboratory, we have induced late gestational placental insufficiency and growth restriction in sheep by umbilico-placental embolisation; during the early postnatal period the growth restricted lambs remained small and were hypotensive relative to controls. More recent long-term studies indicate that these growth restricted animals were able to catch up in body weight within the first postnatal year; however, their arterial pressure remained lower than that of controls throughout the first 2 postnatal years (deltaMAP, -4.2 +/- 1.4 mmHg). This relative hypotension may be due to altered vascular or cardiac development resulting from increased vascular resistance or nutrient restriction during fetal life. As late gestational placental insufficiency led to a persistent reduction in arterial pressure from birth to adulthood, our findings do not support the hypothesis that restricted fetal growth per se leads to hypertension after birth. It is likely that the effects of a prenatal compromise on postnatal arterial pressure will vary depending on the nature of the associated developmental perturbations and their gestational timing.

Postnatal outcomes in term and preterm lambs following fetal growth restriction.

1. Epidemiological evidence indicates that low birthweight increases the risk of a number of adult-onset diseases. It is now apparent that many babies with a low birthweight may have been subjected to a combination of reduced growth rates in utero as well as preterm birth. However, the long-term effects of preterm birth following intra-uterine growth restriction (IUGR) are unknown. Thus, our objectives were: (i) to identify prenatal factors associated with preterm birth in IUGR fetuses; and (ii) to characterize postnatal effects of preterm birth following IUGR. 2. We studied pregnant sheep and their offspring, in which fetal growth was restricted by umbilico-placental embolization during late gestation. Some of these animals were born at term (146 +/- 1 days) and some were born prematurely (139 +/- 1 days). In both groups, we have conducted longitudinal studies of postnatal respiratory function, cardiovascular function and learning ability up to 6-8 weeks of age. 3. Before birth, IUGR fetuses born prematurely (P-IUGR) were more hypoxaemic and acidaemic and had higher haemoglobin concentrations than both control fetuses and IUGR fetuses born at term (T-IUGR). In P-IUGR fetuses, plasma cortisol concentrations increased earlier than in the two other groups. The P-IUGR lambs had lower birthweights than T-IUGR lambs and both groups of IUGR lambs remained lighter than controls for 8 weeks. 4. After birth, P-IUGR lambs were hypoxaemic compared with T-IUGR and control lambs. Pulmonary diffusing capacity (adjusted for lung volume) was significantly lower in both groups of IUGR lambs than in controls, with P-IUGR lambs having lower values than T-IUGR lambs. Lung compliance (adjusted for lung volume), was not different between P-IUGR and control lambs, but values were higher in T-IUGR lambs than in control and P-IUGR lambs. Chest wall compliance (adjusted for lung volume) was higher in both groups of IUGR lambs than in controls. 5. During the 8 week postnatal study period, both groups of IUGR lambs had lower mean arterial pressures than control lambs; this relative hypotension was greatest in P-IUGR lambs. 6. In tests of learning ability, P-IUGR lambs took longer to complete a simple maze task at all ages and, in the second postnatal week, made a greater number of errors compared with controls. In an obstacle course, P-IUGR lambs recorded longer trial durations; they also made more errors than control lambs. 7. We conclude that preterm birth in the presence of late- gestational placental insufficiency and IUGR can result in specific effects on respiratory and cardiovascular development after birth, in addition to the effects of IUGR alone.

Compromised respiratory function in postnatal lambs after placental insufficiency and intrauterine growth restriction.

Epidemiologic studies have shown persistent effects of low birth weight on respiratory function and lung health, but underlying mechanisms are not understood. Our aim was to determine the effects of intrauterine growth restriction (IUGR), a major cause of low birth weight, on postnatal respiratory function. IUGR was induced by umbilico-placental embolization during late gestation in chronically catheterized sheep. Umbilico-placental embolization was performed between 120 d of gestation and term ( approximately 146 d) during which fetuses were hypoxemic and hypoglycemic relative to controls. Umbilico-placental embolization led to a 48% reduction in birth weight compared with controls, and throughout the postnatal study period IUGR lambs (n = 8) remained lighter than controls (n = 8). Respiratory function was repeatedly studied in lambs for 8 wk after birth; during this period, IUGR lambs were mildly hypoxemic and tended to be hypercapnic compared with controls. In IUGR lambs, relative to controls, O(2) consumption (mL/min/kg) and minute ventilation (mL/kg) were increased and pulmonary diffusing capacity (adjusted for functional residual capacity) was decreased. Functional residual capacity, measured by helium dilution, and total lung capacity (measured at 30 cm H(2)O) were smaller in IUGR lambs than in controls. When adjusted for functional residual capacity, static lung compliance was reduced and chest wall compliance was increased in IUGR lambs. At 8 wk, pulmonary DNA and protein concentrations were decreased in IUGR lambs relative to controls. We conclude that restriction of fetal growth by placental insufficiency induces alterations in the lungs and chest wall that result in persistent impairments in respiratory function during early postnatal life.

Stimulation of lung growth in fetuses with lung hypoplasia leads to altered postnatal lung structure in sheep.

Increased lung expansion in the fetus stimulates lung growth and is being trialed clinically to reverse severe fetal lung hypoplasia. Our aim was to examine the effects of increased fetal lung expansion in the presence of lung hypoplasia on lung structure in sheep at term and 8 weeks after birth. Lung hypoplasia was induced in 15 fetal sheep by continuous drainage of tracheal fluid, commencing at approximately 113 days of gestation (term, approximately 148 days). In 10 of these fetuses, tracheal obstruction (TO) was performed from 137-147 days of gestation (treated lung hypoplasia, TLH), while lung liquid drainage continued until term in the remaining 5 fetuses (untreated lung hypoplasia, ULH). Lung tissues were obtained from 5 TLH, 5 ULH, and 5 control lambs at birth, and from 5 TLH and 5 control lambs at 8 weeks after birth. At birth, alveolar number, surface area, and interalveolar wall thickness were not different between TLH and control lambs, whereas airspace diameter was greater in TLH lambs (72.7 +/- 3.0 microm) than in controls (58.4 +/- 4.3 microm). Diameters of airspaces were not different between ULH and control lambs; however, alveolar numbers and surface area were reduced, while interalveolar wall thickness was increased in ULH lambs compared to controls. At 8 weeks after birth, alveolar number (928.0 +/- 66.1 x 10(6)) and surface area (30.3 +/- 2.2 m(2)) in TLH lambs were lower, whereas interalveolar wall thickness (83.0 +/- 3.1 microm) was greater than in control lambs (2,263.6 +/- 261.6 x 10(6), 46.7 +/- 4.8 m(2), and 68.6 +/- 2.1 microm, respectively). Our data show that TO restores most aspects of lung structure to normal in fetuses with lung hypoplasia but leads to altered alveolar development. The presence of fewer, larger alveoli in postnatal TLH animals may predispose these animals to respiratory complications during later life.