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Articles by Donna K. Collins-McMillen in JoVE

 JoVE Immunology and Infection

A Quantitative Evaluation of Cell Migration by the Phagokinetic Track Motility Assay

1Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, 2Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center, 3Department of Microbiology and Immunology, SUNY Upstate Medical University, 4Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center


JoVE 4165

The phagokinetic motility track assay is a method used to assess the movement of cells. Specifically, the assay measures chemokinesis (random cell motility) over time in a quantitative manner. The assay takes advantage of the ability of cells to create a measurable track of their movement on colloidal gold-coated coverslips.

Other articles by Donna K. Collins-McMillen on PubMed

Edge Enhancement and Edge-enhanced Correlation with Photorefractive Polymers

We demonstrate a simple all-optical realization of programmable edge enhancement and edge-enhanced correlation using novel photorefractive polymers. We show that the higher non-Bragg order in a two-beam coupling scheme contains the edge enhancement of the object when placed in the path of one of the incident beams. Also, this arrangement provides a scheme for writing joint transform correlation dynamic holograms, which can be read by a third beam. The correlation is edge enhanced, and the correlation peak increases with the applied bias voltage. Numerical results without and with beam fanning are presented. Theoretical predictions are reconciled with experimental results.

Differences Between Sexually Abused and Non-sexually Abused Adolescent Girls in Foster Care

This descriptive study examines the differences between sexually abused and non-sexually abused adolescent females in the foster care system who were participating in an independent living program. Fifty-four percent of the 190 girls met the criteria for being categorized as sexually abused. Those who experienced sexual abuse had also experienced significantly more of other types of child maltreatment. In addition, those who had been sexually abused were much more likely to be living in a congregate living setting, such as a group home or residential center, than those who were not sexually abused. The girls who had been sexually abused exhibited significantly more behavioral difficulties, including internalizing and externalizing problems, with 51% of them having clinically significant scores on the Youth Self-Report version of the Child Behavior Checklist. When co-occurrence of substance use and mental health problems were examined, sexually abused girls were significantly more likely than the non-sexually abused girls to meet the established criteria.

Use of Mental Health Services Among Older Youths in Foster Care

This study examined lifetime, 12-month, and current mental health service use among older youths in the foster care system and examined variations in mental health care by race, gender, maltreatment history, living situation, and geographic region.

Differential Actions of Metyrapone on the Fetal Pituitary-adrenal Axis in the Sheep Fetus in Late Gestation

It is not clear if an increase in intra-adrenal cortisol is required to mediate the actions of adrenocorticotropic hormone (ACTH) on adrenal growth and steroidogenesis during the prepartum stimulation of the fetal pituitary-adrenal axis. We infused metyrapone, a competitive inhibitor of cortisol biosynthesis, into fetal sheep between 125 and 140 days of gestation (term = 147 +/- 3 days) and measured fetal plasma cortisol, 11-desoxycortisol, and ACTH; pituitary pro-opiomelanocortin mRNA and adrenal expression of ACTH receptor (melanocortin type 2 receptor), steroidogenic acute regulatory protein (StAR), 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2), cytochrome P450 cholesterol side-chain cleavage (CYP11A1), cytochrome P450 17-hydroxylase (CYP17), 3beta-hydroxysteroid dehydrogenase, and cytochrome P450 21-hydroxylase mRNA; and StAR protein in the fetal adrenal gland. Plasma ACTH and 11-desoxycortisol concentrations were higher (P < 0.05), whereas plasma cortisol concentrations were not significantly different in metyrapone- compared with vehicle-infused fetuses. The ratio of plasma cortisol to ACTH concentrations was higher (P < 0.0001) between 136 and 140 days than between 120 and 135 days of gestation in both metyrapone- and vehicle-infused fetuses. The combined adrenal weight and adrenocortical thickness were greater (P < 0.001), and cell density was lower (P < 0.01), in the zona fasciculata of adrenals from the metyrapone-infused group. Adrenal StAR mRNA expression was lower (P < 0.05), whereas the levels of mature StAR protein (30 kDa) were higher (P < 0.05), in the metyrapone-infused fetuses. In addition, adrenal mRNA expression of 11betaHSD2, CYP11A1, and CYP17 were higher (P < 0.05) in the metyrapone-infused fetuses. Thus, metyrapone administration may represent a unique model that allows the investigation of dissociation of the relative actions of ACTH and cortisol on fetal adrenal steroidogenesis and growth during late gestation.

Effects of Nutritional Status and Gonadal Steroids on Expression of Appetite-regulatory Genes in the Hypothalamic Arcuate Nucleus of Sheep

Sheep exhibit photoperiod-driven seasonal changes in appetite and body weight so that nutritional status increases in long days (LD) and decreases in short days (SD); additionally, they are reproductively active in SD and inactive in LD. We addressed the hypothesis that appetite-regulatory genes in the hypothalamus respond differently to changes in nutritional feedback induced by photoperiod as opposed to food restriction, and that responses would be influenced by gonadal steroid status. Castrated oestradiol-implanted male sheep were kept in SD (8 h light/day) or LD (16 h light/day) for 11 weeks, with ad libitum or restricted food (experiment 1; n=8/group). Rams were kept in SD or LD for 12 weeks with ad libitum or restricted food (experiment 2; n=6/group). Gene expression (by in situ hybridisation) in the hypothalamic arcuate nucleus for leptin receptor (OB-Rb), neuropeptide Y (NPY), pro-opiomelanocortin (POMC) and agouti-related peptide (AGRP) was unaffected by photoperiod treatment, but food restriction increased NPY and AGRP mRNAs, in experiment 1. In experiment 2, mRNAs for POMC and cocaine- and amphetamine-regulated transcript (CART) were up-regulated and AGRP down-regulated in SD, while food restriction increased OB-Rb mRNA, increased NPY and AGRP mRNAs only in LD and decreased POMC mRNA only in SD. Thus, gene expression responded differently to photoperiod and food restriction, and the melanocortin pathway was up-regulated in SD in reproductively activated rams but not in oestradiol-implanted castrates. These data support the hypothesis that hypothalamic appetite-regulatory pathways respond differently to changes in nutritional feedback induced by photoperiod as opposed to food restriction, with gonadal steroid feedback additionally influencing the responses.

Prenatal Programming of Postnatal Obesity: Fetal Nutrition and the Regulation of Leptin Synthesis and Secretion Before Birth

Exposure to either an increased or decreased level of intrauterine nutrition can result in an increase in adiposity and in circulating leptin concentrations in later life. In animals such as the sheep and pig in which fat is deposited before birth, leptin is synthesised in fetal adipose tissue and is present in the fetal circulation throughout late gestation. In the sheep a moderate increase or decrease in the level of maternal nutrition does not alter fetal plasma leptin concentrations, but there is evidence that chronic fetal hyperglycaemia and hyperinsulinaemia increase fetal fat mass and leptin synthesis within fetal fat depots. Importantly, there is a positive relationship between the relative mass of the 'unilocular' component of fetal perirenal and interscapular adipose tissue and circulating fetal leptin concentrations in the sheep. Thus, as in the neonate and adult, circulating leptin concentrations may be a signal of fat mass in fetal life. There is also evidence that leptin can act to regulate the lipid storage, leptin synthetic capacity and potential thermogenic functions of fat before birth. Thus, leptin may act as a signal of energy supply and have a 'lipostatic' role before birth. Future studies are clearly required to determine whether the intrauterine and early postnatal nutrient environment programme the endocrine feedback loop between adipose tissue and the central and peripheral neuroendocrine systems that regulate energy balance, resulting in an enhanced risk of obesity in adult life.

The Practice of Critical Care Surgery While on Long-term Hemodialysis

Effects of NMDA Glutamate Receptor Antagonist Drugs on the Volitional Consumption of Ethanol by a Genetic Drinking Rat

The ability of drugs that reduce NMDA receptor activity on the volitional consumption of ethanol in the genetic drinking rat, mHEP line, was investigated. After the consumption of ethanol solutions and water by each male or female mHEP rat had stabilized on its preferred concentration, different doses of LY 274614, a competitive NMDA antagonist, MK 801, a non-competitive NMDA antagonist, (+)-HA-966 or ACPC (1-aminocyclopropane-1-carboxylic acid), antagonists of the glycine site were administered daily for three days. The dose of 3.0 mg/kg i.p. LY 274614 reduced the consumption of ethanol by 64% compared to the pre-treatment baseline, while 0.3 mg/kg of MK 801 reduced consumption by 44%, 20 mg/kg (+)-HA-966 reduced consumption by 47% and 300 mg/kg of ACPC reduced consumption by 30%. These doses of LY 274614 and MK 801 reduced the ability of Sprague-Dawley rats to walk on a rotorod. Effects of these drugs on food intake were small except for the 20 mg/kg dose of (+)-HA-966. Therefore, the drugs did not have an anti-caloric effect and manipulations of the glutamatergic system through NMDA receptors may modify the consumption of ethanol. This interaction should be explored further for its therapeutic potential and to better understand the control by central neuronal systems of the consumption of ethanol.

The Scale Product Technique As a Means of Enhancing the Measurement of Patient Satisfaction

Measurement of patient satisfaction has long been hampered by two resolvable problems: a lack of content validity in commonly used instruments, and a lack of variability in satisfaction scores when these same instruments are used. Most patient satisfaction instruments have been developed from the perspective of the provider or institution rather than that of the patient, creating a situation of questionable content validity for these measures. Additionally, most patient satisfaction measures yield data that are invariant and consistently positively biased. Both of these problems can be addressed methodologically--through tool development using a qualitative method designed to obtain the patient's perspective, and through the use of the scale product technique to decrease the effect of acquiescence, thereby increasing variability in item responses.

Effect of Neuropeptide Y Microinjected into the Hypothalamus on Ethanol Consumption

Guide cannula were implanted in rats aimed at the paraventricular nucleus (PVN) of the hypothalamus for microinjection of neuropeptide Y (NPY), D-NPY27-36, or vehicle. In the Wistar rat, there was no significant effect on the consumption of ethanol. In Myers' high ethanol preferring (mHEP) rats, D-NPY27-36 caused a significant 54% decrease in ethanol consumption from baseline, but the response was not different from vehicle. NPY-induced feeding in satiated Wistar rats, was blocked by a Y1 receptor antagonist, D-NPY27-3). D-NPY27-36 decreased 78% feeding in food-deprived rats. Thus, neither the Wistar nor the mHEP rat perceives ethanol as a source of calories comparable to food.

Metyrapone Infusion Stimulates Adrenal Growth Without Activating the Cell Cycle or the IGF System in the Late Gestation Fetal Sheep

Recently, we have demonstrated that administration of metyrapone, to suppress cortisol synthesis and decrease negative feedback at the pituitary, results in an increase in circulating ACTH and adrenal growth in the late gestation sheep fetus. In these studies, we demonstrated a 2-fold increase in adrenocortical growth using morphometric techniques. To elucidate the potential molecular mechanisms leading to the increase in adrenal growth, we examined adrenal expression of the cell cycle regulatory proteins (cyclin D1) and cyclin-kinase inhibitory proteins (p16ink, p21Cip), and insulin-like growth factor-II (IGF-II), IGF-binding protein 2 (IGFBP-2) and IGF-I type 1 Receptor (IGF1R) from fetuses infused with metyrapone or vehicle for 15 days. There was a significant decrease in adrenal expression of cyclin D1 in metyrapone-(472.0 +/- 29.7) compared with vehicle-infused (662.7 +/- 29.2) fetuses. There was no significant difference, however, in the adrenal expression of the cyclin-kinase inhibitory proteins (p16ink or p21Cip) or in the IGF system (IGF-II, IGFBP-2 or IGF1R) mRNA between metyrapone- and vehicle-infused. In summary, in this model of metyrapone-activated adrenal cortical hypertrophy, growth occurs with a suppression of the rate-limiting cell cycle protein and without activation of the IGF system.

Early Embryonic Environment, the Fetal Pituitary-adrenal Axis and the Timing of Parturition

It is well established in the sheep, that the normal timing of parturition is dependent on a prepartum activation of the fetal pituitary-adrenal axis. We have recently demonstrated for the first time that embryo number, embryo sex, and alterations in the environment of the early embryo, including exposure to maternal undernutrition during the periconceptional period, alter the timing and level of activation of the pituitary-adrenal axis in the sheep fetus during late gestation. There is a delay in activation of the fetal HPA axis in twin fetuses and we speculate that the diminished adrenocortical responsiveness in the twin fetus may be an adaptive response, which counters the impact of the potential enhanced intrauterine stress experienced by a twin fetus, thereby reducing the possibility of preterm delivery. We have also reported that a moderate restriction of maternal nutrition to during the periconceptional period (from 60 days before and for one week after conception) resulted in an earlier activation of the pituitary-adrenal axis of twin, but not singleton, fetuses during late gestation. A series of studies using assisted reproductive technologies have also found that perturbation of the early embryonic environment results in a dysregulation of placental and fetal growth and development and in the timing of normal parturition. In summary, after several decades of work focussed on events in late gestation associated with the prepartum activation and stress responsiveness of the fetal HPA axis, our recent studies indicate that the environment of the early embryo may have a significant role to play in determining the timing and level of the prepartum activation of this axis and potentially on the functional capacity of the axis to respond to acute or chronic stress in later life.

Impact of Periconceptional Nutrition on Maternal and Fetal Leptin and Fetal Adiposity in Singleton and Twin Pregnancies

It has been proposed that maternal nutrient restriction may alter the functional development of the adipocyte and the synthesis and secretion of the adipocyte-derived hormone, leptin, before birth. We have investigated the effects of restricted periconceptional undernutrition and/or restricted gestational nutrition on fetal plasma leptin concentrations and fetal adiposity in late gestation. There was no effect of either restricted periconceptional or gestational nutrition on maternal or fetal plasma leptin concentrations in singleton or twin pregnancies during late gestation. In ewes carrying twins, but not singletons, maternal plasma leptin concentrations in late gestation were directly related to the change in ewe weight that occurred during the 60 days before mating [maternal leptin = 0.9 (change in ewe weight) + 7.8; r = 0.6, P < 0.05]. In twin, but not singleton, pregnancies, there was also a significant relationship between maternal and fetal leptin concentrations (maternal leptin = 0.5 fetal leptin + 4.2, r = 0.63, P < 0.005). The relative mass of perirenal fat was also significantly increased in twin fetal sheep in the control-restricted group (6.0 +/- 0.5) compared with the other nutritional groups (control-control: 4.1 +/- 0.4; restricted-restricted: 4.4 +/- 0.4; restricted-control: 4.3 +/- 0.3). In conclusion, the impact of maternal undernutrition on maternal plasma leptin concentrations during late gestation is dependent on fetal number. Furthermore, we have found that there is an increased fetal adiposity in the twins of ewes that experienced restricted nutrition throughout gestation, and this may be important in the programming of postnatal adiposity.

Differential Effects of Maternal Hypoxia or Nutrient Restriction on Carotid and Femoral Vascular Function in Neonatal Rats

In response to reduced oxygen or nutrient supply, the fetus may redistribute cardiac output to conserve brain and heart growth, at the expense of the peripheral tissues; however, it is not known whether alterations in vascular function are maintained after birth or whether reduced fetal oxygen versus nutrient supply produces distinct effects. Using a pressure myograph, we examined isolated carotid and femoral artery responses to phenylephrine and endothelin-1 in neonatal rats, after either reduced maternal oxygen or global nutrient restriction during late gestation. Timed-pregnant Sprague-Dawley rats were randomly assigned to control (n = 10), hypoxia (12% O2, n = 9), or nutrient restriction (NR, 40% of control diet, n = 7) protocol and treated from day 15-21 of pregnancy. Pups were collected 3-12 h after birth. Neonatal weights (P < 0.001) and relative liver weights (P < 0.001) were lower in hypoxia and nutrient restriction treatments compared with control, while relative heart weights were greater in the hypoxia than in the control or nutrient restriction groups (P < 0.01). Constriction to phenylephrine was reduced in carotid arteries from the hypoxia and nutrient restriction groups compared with control (P < 0.001), while the femoral artery response was greater in hypoxia-treated neonates compared with control or nutrient-restricted neonates (P < 0.01). Only the hypoxia reduced carotid responses to endothelin-1, while no differences were observed in the endothelin-1 responses in femoral arteries. Maternal hypoxia and maternal nutrient restriction produced distinct effects on heart growth and neonatal vascular function, suggesting that regional changes in cardiovascular function after poor fetal growth are dependent on the nature of the insult in utero.

Prevalence of Psychiatric Disorders Among Older Youths in the Foster Care System

To estimate the lifetime and past year prevalence rates of major psychiatric disorders in a sample of older youths in the foster care system, to examine the timing of disorder onset and system entry, and to explore variations in past year prevalence rates.

Restriction of Placental Growth Results in Greater Hypotensive Response to Alpha-adrenergic Blockade in Fetal Sheep During Late Gestation

Placental insufficiency resulting in restriction of fetal substrate supply and fetal hypoxaemia is a major cause of restricted fetal growth and increased neonatal morbidity. Fetal adaptations to placental restriction (PR) include increases in circulating catecholamines and cortisol and decreased fetal body growth, with relative sparing of brain growth. The mechanisms underlying the redistribution of fetal cardiac output in PR fetuses are not known and the aim of this study was to determine whether maintenance of fetal blood pressure (BP) in the PR fetus is dependent on alpha-adrenergic stimulation. PR was induced by removing the majority of uterine caruncles in the ewe before conception. Sterile vascular surgery was performed on seven PR and six control fetuses at 113-120 days' gestation (term = 150 +/- 3 days). Fetuses with a mean arterial PO2 < 17 mmHg between 123 and 127 days' gestation were defined as hypoxic. There was a greater fall (P < 0.05) in fetal BP during phentolamine infusion (i.v: 5 mg bolus, 0.2 mg kg(-1) min(-1) for 2 h) in the hypoxic PR group (-15 +/- 2 mmHg) compared with normoxic controls (-5 +/- 1 mmHg). The fall in fetal BP during phentolamine infusion was directly related to the level of fetal PO2. Fetal BP and HR responses to phenylephrine (i.v.: 40 microg kg(-1)) were not different between PR and control fetuses. The maintenance of BP in the chronically hypoxic fetus is therefore dependent on alpha-adrenergic activation, and this fetal adaptation to a suboptimal intrauterine environment pre-dates the development of significant growth restriction. While this adaptation may play a critical role in the redistribution of fetal cardiac output to ensure the sparing of brain growth, it may have adverse consequences for peripheral vascular function in the neonatal period and in adult life.

Impact of Glucose Infusion on the Structural and Functional Characteristics of Adipose Tissue and on Hypothalamic Gene Expression for Appetite Regulatory Neuropeptides in the Sheep Fetus During Late Gestation

In the present study, our aim was to determine whether intrafetal glucose infusion increases fetal adiposity, synthesis and secretion of leptin and regulates gene expression of the 'appetite regulatory' neuropeptides neuropepetide Y (NPY), agouti-related peptide (AGRP), pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) and receptors (leptin receptor (OB-Rb) and melancortin 3 receptor (MC3R)) within the fetal hypothalamus. Glucose (50% dextrose in saline) or saline was infused (7.5 ml h(-1)) into fetal sheep between 130 and 140 days gestation (term = 150 +/- 3 days gestation). Glucose infusion increased circulating glucose and insulin concentrations, mean lipid locule size (532.8 +/- 3.3 microm2 versus 456.7 +/- 14.8 microm2) and total unilocular fat mass (11.7 +/- 0.6 g versus 8.9 +/- 0.6 g) of the perirenal fat depot. The expression of OB-Rb mRNA was higher in the ventromedial nucleus compared to the arcuate nucleus of the hypothalamus in both glucose and saline infused fetuses (F= 8.04; P < 0.01) and there was a positive correlation between expression of OB-Rb and MC3R mRNA in the arcuate nucleus (r= 0.81; P < 0.005). Glucose infusion increased mRNA expression for POMC, but not for the anorectic neuropeptide CART, or the orexigenic neuropeptides NPY and AGRP, in the arcuate nucleus of the fetal hypothalamus. These findings demonstrate that increased circulating glucose and insulin regulate gene expression of the neuropeptides within the fetal hypothalamus that are part of the neural network regulating energy balance in adult life.

Early Origins of Obesity: Programming the Appetite Regulatory System

There is evidence that changes in perinatal nutrition programme the development of relative fat mass and the regulation of appetite in adult life. These studies have been primarily in the rodent utilizing maternal overnutrition or undernutrition imposed at different stages of pregnancy and beyond, mapping of neuropeptide localization and activity and appropriate null mutant models. Whilst the rodent offers significant advantages in terms of a short gestation and the availability of useful transgenic and null mutant models, there are also advantages to using an animal model more akin to the human, in which all components of the 'fat-brain axis' are present before birth, such as the sheep. This review summarizes recent work on the expression and localization of the 'appetite regulatory' peptides in the fetal rodent and sheep hypothalamus and their potential role in the early programming of postnatal appetite and obesity.

Kinetic Characterization of Novel Pyrazole TGF-beta Receptor I Kinase Inhibitors and Their Blockade of the Epithelial-mesenchymal Transition

Transforming growth factor beta (TGF-beta) signaling pathways regulate a wide variety of cellular processes including cell proliferation, differentiation, extracellular matrix deposition, development, and apoptosis. TGF-beta type-I receptor (TbetaRI) is the major receptor that triggers several signaling events by activating downstream targets such as the Smad proteins. The intracellular kinase domain of TbetaRI is essential for its function. In this study, we have identified a short phospho-Smad peptide, pSmad3(-3), KVLTQMGSPSIRCSS(PO4)VS as a substrate of TbetaRI kinase for in vitro kinase assays. This peptide is uniquely phosphorylated by TbetaRI kinase at the C-terminal serine residue, the phosphorylation site of its parent Smad protein in vivo. Specificity analysis demonstrated that the peptide is phosphorylated by only TbetaRI and not TGF-beta type-II receptor kinase, indicating that the peptide is a physiologically relevant substrate suitable for kinetic analysis and screening of TbetaRI kinase inhibitors. Utilizing pSmad3(-3) as a substrate, we have shown that novel pyrazole compounds are potent inhibitors of TbetaRI kinase with K(i) value as low as 15 nM. Kinetic analysis revealed that these pyrazoles act through the ATP-binding site and are typical ATP competitive inhibitors with tight binding kinetics. More importantly, these compounds were shown to inhibit TGF-beta-induced Smad2 phosphorylation in vivo in NMuMg mammary epithelial cells with potency equivalent to the inhibitory activity in the in vitro kinase assay. Cellular selectivity analysis demonstrated that these pyrazoles are capable of inhibiting activin signaling but not bone morphogenic protein or platelet-derived growth factor signal transduction pathways. Further functional analysis revealed that pyrazoles are capable of blocking the TGF-beta-induced epithelial-mesenchymal transition in NMuMg cells, a process involved in the progression of cancer, fibrosis, and other human diseases. These pyrazoles provide a foundation for future development of potent and selective TbetaRI kinase inhibitors to treat human disease.

Periadolescent Nicotine Exposure Causes Heterologous Sensitization to Cocaine Reinforcement

There is increasing concern that abuse of tobacco during periadolescence increases the potential for later abuse of other drugs. To test this hypothesis, Sprague-Dawley rats received once-daily injections of either water or 0.4 mg/kg nicotine from postnatal day 35 through 44. Beginning on postnatal day 80, animals were tested in a 12-day cocaine-induced conditioned place preference (CPP) paradigm. Prior nicotine treatment enhanced the dose-response to cocaine. CPP training with 3.0 mg/kg i.p. cocaine increased time in drug-paired chambers by 50% in control rats and 94% in nicotine-exposed animals. Thus, periadolescent nicotine exposure produced long-term sensitization to an indirect-acting dopamine agonist.

Periconceptional Nutrition and the Relationship Between Maternal Body Weight Changes in the Periconceptional Period and Feto-placental Growth in the Sheep

Recent studies in the sheep have shown that maternal undernutrition during the periconceptional period, when the nutrient demands of the embryo are minimal, can alter the subsequent development of the metabolic, endocrine and cardiovascular systems and that these effects may, in part, depend on embryo number. We have tested the hypotheses that there are relationships between maternal weight or body condition at the time of conception and feto-placental growth during the first 55 days of pregnancy, and that periconceptional undernutrition has a differential effect on these relationships in singleton and twin pregnancies. We have investigated the effect of periconceptional undernutrition in the ewe (control n= 24, restricted at 70% of control feed allowance, PCUN n= 21) from 45 days prior to mating until 7 days after mating on placental and fetal weight and on placental histology in singleton and twin pregnancies at 53-56 days' gestation, i.e. during the period of maximal placental growth. In control, but not PCUN ewes carrying singleton pregnancies, there were direct relationships between maternal weight gain during the periconceptional period and uteroplacental weights at 53-56 days' gestation. There were direct relationships, however, between placental and fetal weights in both control and PCUN singleton pregnancies. In contrast to the singletons, in control twin pregnancies, there was no effect of maternal weight gain in the periconceptional period on any measure of uteroplacental growth, and there was also no relationship between placental and fetal weight. This lack of a relationship may be related to the increased uteroplacental weight and mean placentome weight in the twin pregnancies (control singletons: 2.45 +/- 0.18 g; control twins: 4.10 +/- 0.62 g). In the PCUN group, however, a greater weight loss between the start of the feeding regime and post mortem at approximately day 55, was associated with a larger placenta and fetus, and the direct relationship between placental and fetal mass was restored. In summary, the present study has demonstrated that there are important relationships between maternal weight gain during the periconceptional period and feto-placental growth during the first 56 days of pregnancy, and that periconceptional undernutrition has a differential effect on these relationships in singleton and twin pregnancies. In singleton pregnancies, periconceptional undernutrition disrupts the relationship between maternal weight gain during the periconceptional period and uteroplacental growth, and in twin pregnancies periconceptional undernutrition results in the emergence of an inverse relationship between maternal weight gain during early pregnancy and uteroplacental growth and a dependence of fetal growth on placental growth. These changes highlight the importance of the periconceptional environment in setting the placental and fetal growth trajectories, and have implications for the programmed development of the metabolic, cardiovascular and endocrine systems of the fetus and adult.

Effects of Maternal Hypoxia or Nutrient Restriction During Pregnancy on Endothelial Function in Adult Male Rat Offspring

Compromised fetal growth impairs vascular function; however, it is unclear whether chronic hypoxia in utero affects adult endothelial function. We hypothesized that maternal hypoxia (H, 12% O2, n= 9) or nutrient restriction (NR, 40% of control, n= 7) imposed from day 15-21 pregnancy in rats would impair endothelial function in adult male offspring (relative to control, C, n= 10). Using a wire myograph, endothelium-dependent relaxation in response to methacholine was assessed in small mesenteric arteries from 4- and 7-month-old (mo) male offspring. Nitric oxide (NO) mediation of endothelium-dependent relaxation was evaluated using N(omega)-nitro-L-arginine methyl ester (L-NAME; NO synthase inhibitor). Observed differences in the NO pathway at 7 months were investigated using exogenous superoxide dismutase (SOD) to reduce NO scavenging, and sodium nitroprusside (SNP; NO donor) to assess smooth muscle sensitivity to NO. Sensitivity to methacholine-induced endothelium-dependent relaxation was reduced in H offspring at 4 months (P < 0.05), but was not different among groups at 7 months. L-NAME reduced methacholine sensitivity in C (P < 0.01), H (P < 0.01) and NR (P < 0.05) offspring at 4 months, but at 7 months L-NAME reduced sensitivity in C (P < 0.05), tended to in NR (P= 0.055) but had no effect in H offspring. SOD did not alter sensitivity to methacholine in C, but increased sensitivity in H offspring (P < 0.01). SNP responses did not differ among groups. In summary, prenatal hypoxia, but not nutrient restriction impaired endothelium-dependent relaxation at 4 months, and reduced NO mediation of endothelial function at 7 months, in part through reduced NO bio-availability. Distinct effects following reduced maternal oxygen versus nutrition suggest that decreased oxygen supply during fetal life may specifically impact adult vascular function.

Developmental Origins of the Metabolic Syndrome: Prediction, Plasticity, and Programming

The "fetal" or "early" origins of adult disease hypothesis was originally put forward by David Barker and colleagues and stated that environmental factors, particularly nutrition, act in early life to program the risks for adverse health outcomes in adult life. This hypothesis has been supported by a worldwide series of epidemiological studies that have provided evidence for the association between the perturbation of the early nutritional environment and the major risk factors (hypertension, insulin resistance, and obesity) for cardiovascular disease, diabetes, and the metabolic syndrome in adult life. It is also clear from experimental studies that a range of molecular, cellular, metabolic, neuroendocrine, and physiological adaptations to changes in the early nutritional environment result in a permanent alteration of the developmental pattern of cellular proliferation and differentiation in key tissue and organ systems that result in pathological consequences in adult life. This review focuses on those experimental studies that have investigated the critical windows during which perturbations of the intrauterine environment have major effects, the nature of the epigenetic, structural, and functional adaptive responses which result in a permanent programming of cardiovascular and metabolic function, and the role of the interaction between the pre- and postnatal environment in determining final health outcomes.

Child Health Care Clinicians' Use of Medications to Help Parents Quit Smoking: a National Parent Survey

Smokers who use cessation medications when they attempt to quit double their likelihood of success. No prior survey has assessed the acceptability to parents of receiving smoking cessation medication prescriptions in the context of their child's primary care visits.

Expression of Human Myeloperoxidase by Macrophages Promotes Atherosclerosis in Mice

Myeloperoxidase (MPO) colocalizes with macrophages in the human artery wall, and its characteristic oxidation products have been detected in atherosclerotic lesions. Thus, oxidants produced by the enzyme might promote atherosclerosis. However, macrophages in mouse atherosclerotic tissue do not express MPO. Therefore, mice are an inappropriate model for testing the role of MPO in vascular disease. To overcome this problem, we generated and studied transgenic (Tg) mice that contained the human MPO gene.

Maternal Fluoxetine Infusion Does Not Alter Fetal Endocrine and Biophysical Circadian Rhythms in Pregnant Sheep

Depression during pregnancy is frequently treated with the selective serotonin reuptake inhibitor (SSRI), fluoxetine (FX), commonly known as Prozac (Eli Lilly & Co, Indianapolis, IN). FX potentiates serotoninergic neurotransmission and serotonin has been implicated in the regulation of circadian rhythms. We have therefore investigated the effect of chronic administration of FX on maternal and fetal circadian rhythms in sheep.

Colouterine Fistula Mimicking Pyometrium--diagnosis Established with Multi-detector Computed Tomography

Admission to Neonatal Intensive Care with Respiratory Morbidity Following 'term' Elective Caesarean Section

Delaying the timing of elective caesarean section (ELCS) from 37/38 weeks to 39/40 weeks reduces the risk of respiratory morbidity in otherwise healthy neonates. The aims of this study were to clarify the number and clinical details of term infants delivered by ELCS who were admitted to neonatal intensive care (NIC) from 1st April 2001 to 31st March 2002 in Northern Ireland, to record the level of care required by these infants and to identify infants who were diagnosed with transient tachypnoea of the newborn (TTN) and/or Respiratory Distress Syndrome (RDS). Two hundred and ten (8%) of babies born by ELCS were admitted to NIC. Term infants delivered by ELCS used 343 days of level 1 & 2 care with 230 (68%) of these days being used by infants with RDS/TTN (n=105) the majority of whom were delivered at 37/38 weeks. Definitions of 'term' and clinical indications for ELCS urgently need to be debated to avoid unnecessary morbidity following ELCS in so called 'term' infants.

Effects of a Metabotropic, Mglu5, Glutamate Receptor Antagonist on Ethanol Consumption by Genetic Drinking Rats

To compare the effect of an antagonist of the mGlu5 glutamate receptor, 2-methyl-6-(phenylethynyl)pyridine (MPEP) on a test for anxiety and on the volitional consumption of ethanol.

Profiles of Pain in Mississippi: Results from the Southern Pain Prevalence Study

To estimate the prevalence, intensity, frequency, and origins of pain in Mississippi residents and explore the social and cultural aspects of pain and pain management by measuring the impacts of pain on everyday life as well as respondents' beliefs and attitudes toward pain.

The Co-occurrence of Maternal Depressive Symptoms and Smoking in a National Survey of Mothers

Both maternal smoking and depression are common and can adversely impact child health and functioning, yet few studies have explored their co-occurrence among mothers.

Differential Regulation of Suppressor of Cytokine Signaling-3 in the Liver and Adipose Tissue of the Sheep Fetus in Late Gestation

It is unknown whether the JAK/STAT/suppressor of cytokine signaling-3 (SOCS-3) intracellular signaling pathway plays a role in tissue growth and metabolism during fetal life. We investigated whether there is a differential profile of SOCS-3 expression in the liver and perirenal adipose tissue during the period of increased fetal growth in late gestation and the impact of fetal growth restriction on SOCS-3 expression in the fetal liver. We also determined whether basal SOCS-3 expression in the fetal liver and perirenal adipose tissue is regulated by endogenous fetal prolactin (PRL). SOCS-3 mRNA abundance was higher in the liver than in the pancreas, spleen, and kidney of the sheep fetus during late gestation. In the liver, SOCS-3 mRNA expression was increased (P < 0.05) between 125 (n = 4) and 145 days (n = 7) gestation and lower (P < 0.05) in growth-restricted compared with normally grown fetal sheep in late gestation. The relative expression of SOCS-3 mRNA in the fetal liver was directly related to the mean plasma PRL concentrations during a 48-h infusion of either a dopaminergic agonist, bromocriptine (n = 7), or saline (n = 5), such that SOCS-3 mRNA expression was lower when plasma PRL concentrations decreased below approximately 20 ng/ml [y = 0.99 - (2.47/x) + (4.96/x(2)); r(2) = 0.91, P < 0.0001, n = 12]. No relationship was shown between the abundance of phospho-STAT5 in the fetal liver and circulating PRL. SOCS-3 expression in perirenal adipose tissue decreased (P < 0001) between 90-91 (n = 6) and 140-145 days (n = 9) gestation and was not related to endogenous PRL concentrations. Thus SOCS-3 is differentially expressed and regulated in key fetal tissues and may play an important and tissue-specific role in the regulation of cellular proliferation and differentiation before birth.

A Bottom-up Approach to Gene Regulation

The ability to construct synthetic gene networks enables experimental investigations of deliberately simplified systems that can be compared to qualitative and quantitative models. If simple, well-characterized modules can be coupled together into more complex networks with behaviour that can be predicted from that of the individual components, we may begin to build an understanding of cellular regulatory processes from the 'bottom up'. Here we have engineered a promoter to allow simultaneous repression and activation of gene expression in Escherichia coli. We studied its behaviour in synthetic gene networks under increasingly complex conditions: unregulated, repressed, activated, and simultaneously repressed and activated. We develop a stochastic model that quantitatively captures the means and distributions of the expression from the engineered promoter of this modular system, and show that the model can be extended and used to accurately predict the in vivo behaviour of the network when it is expanded to include positive feedback. The model also reveals the counterintuitive prediction that noise in protein expression levels can increase upon arrest of cell growth and division, which we confirm experimentally. This work shows that the properties of regulatory subsystems can be used to predict the behaviour of larger, more complex regulatory networks, and that this bottom-up approach can provide insights into gene regulation.

Regulation of Leptin Synthesis and Secretion Before Birth: Implications for the Early Programming of Adult Obesity

A series of epidemiological, clinical and experimental studies have shown that there are associations between the fetal and neonatal nutritional environment and the amount and distribution of adipose tissue in adult life. This review considers the evidence for these relationships and discusses the potential impact of the prenatal nutritional experience on the development of the endocrine and neuroendocrine systems that regulate energy balance, with a particular emphasis on the role of the adipocyte-derived hormone, leptin. In the rodent, leptin derived from the mother may exert an important influence on the development of the appetite regulatory neural network and on the subsequent regulation of leptin synthesis and the risk for obesity in the offspring. In species such as the human and sheep, there is also recent evidence that the synthesis and secretion of adipocyte-derived hormones, such as leptin, are regulated in fetal life. Furthermore, the hypothalamic neuropeptides that regulate energy intake and expenditure in adult life are also present within the fetal brain and may be regulated by the prevailing level of maternal and hence fetal nutrient and hormonal signals, including leptin. This work is important in determining those initiating mechanisms within the 'fat-brain' axis in early life that precede the development of adult obesity.

Comparison of Culture and a Novel 5' Taq Nuclease Assay for Direct Detection of Campylobacter Fetus Subsp. Venerealis in Clinical Specimens from Cattle

A Campylobacter fetus subsp. venerealis-specific 5' Taq nuclease PCR assay using a 3' minor groove binder-DNA probe (TaqMan MGB) was developed based on a subspecies-specific fragment of unknown identity (S. Hum, K. Quinn, J. Brunner, and S. L. On, Aust. Vet. J. 75:827-831, 1997). The assay specifically detected four C. fetus subsp. venerealis strains with no observed cross-reaction with C. fetus subsp. fetus-related Campylobacter species or other bovine venereal microflora. The 5' Taq nuclease assay detected approximately one single cell compared to 100 and 10 cells in the conventional PCR assay and 2,500 and 25,000 cells from selective culture from inoculated smegma and mucus, respectively. The respective detection limits following the enrichments from smegma and mucus were 5,000 and 50 cells/inoculum for the conventional PCR compared to 500 and 50 cells/inoculum for the 5' Taq nuclease assay. Field sampling confirmed the sensitivity and the specificity of the 5' Taq nuclease assay by detecting an additional 40 bulls that were not detected by culture. Urine-inoculated samples demonstrated comparable detection of C. fetus subsp. venerealis by both culture and the 5' Taq nuclease assay; however, urine was found to be less effective than smegma for bull sampling. Three infected bulls were tested repetitively to compare sampling tools, and the bull rasper proved to be the most suitable, as evidenced by the improved ease of specimen collection and the consistent detection of higher levels of C. fetus subsp. venerealis. The 5' Taq nuclease assay demonstrates a statistically significant association with culture (chi2 = 29.8; P < 0.001) and significant improvements for the detection of C. fetus subsp. venerealis-infected animals from crude clinical extracts following prolonged transport.

Dihydropyrrolopyrazole Transforming Growth Factor-beta Type I Receptor Kinase Domain Inhibitors: a Novel Benzimidazole Series with Selectivity Versus Transforming Growth Factor-beta Type II Receptor Kinase and Mixed Lineage Kinase-7

Novel dihydropyrrolopyrazole-substituted benzimidazoles were synthesized and evaluated in vitro as inhibitors of transforming growth factor-beta type I receptor (TGF-beta RI), TGF-beta RII, and mixed lineage kinase-7 (MLK-7). These compounds were found to be potent TGF-beta RI inhibitors and selective versus TGF-beta RII and MLK-7 kinases. Benzimidazole derivative 8b was active in an in vivo target (TGF-beta RI) inhibition assay.

A National Survey of the Acceptability of Quitlines to Help Parents Quit Smoking

Provision of telephone smoking cessation counseling can increase the rate of quitting smoking. The US Public Health Service recently helped to establish a free national quitline enrollment service. No previous surveys have assessed the acceptability to parents of enrollment in quitline counseling in the context of their child's health care visits. Therefore, the objective of this study was to assess acceptability to parents of enrollment in quitline counseling and to compare that with the reported rate of actually being enrolled in any smoking cessation counseling outside the office in the context of the child's health care visit.

Experiences of and Attitudes Toward Mental Health Services Among Older Youths in Foster Care

This study explored the experiences of youths in the Missouri foster care system who were receiving mental health services in order to identify characteristics that they valued in relationships with mental health professionals and in the services they received and to examine whether their attitudes toward services were associated with their experiences with services.

Increased Maternal Nutrition Alters Development of the Appetite-regulating Network in the Brain

Individuals exposed to an increased nutrient supply before birth have a high risk of becoming obese children and adults. It has been proposed that exposure of the fetus to high maternal nutrient intake results in permanent changes within the central appetite regulatory network. No studies, however, have investigated the impact of increased maternal nutrition on the appetite regulatory network in species in which this network develops before birth, as in the human. In the present study, pregnant ewes were fed a diet which provided 100% (control, n = 8) or approximately 160% (well-fed, n = 8) of metabolizable energy requirements. Ewes were allowed to lamb spontaneously, and lambs were sacrificed at 30 days of postnatal age. All fat depots were dissected and weighed, and expression of the appetite-regulating neuropeptides and the leptin receptor (OBRb) were determined by in situ hybridization. Lambs of well-fed ewes had higher glucose (Glc) concentrations during early postnatal life (F = 5.93, P<0.01) and a higher relative subcutaneous (s.c.) fat mass at 30 days of age (34.9+/-4.7 g/kg vs. 22.8+/-3.3 g/kg; P<0.05). The hypothalamic expression of pro-opiomelanocortin was higher in lambs of well-fed ewes (0.48+/-0.09 vs. 0.28+/-0.04, P<0.05). In lambs of overnourished mothers, but not in controls, the expression of OBRb was inversely related to total relative fat mass (r2 = 0.50, P = 0.05, n = 8), and the direct relationship between the expression of the central appetite inhibitor CART and fat mass was lost. The expression of neuropeptide Y and AGRP was inversely related to total relative fat mass (NPY, r2 = 0.28, P<0.05; agouti-related peptide, r2 = 0.39, P<0.01). These findings suggest that exposure to increased nutrition before birth alters the responses of the central appetite regulatory system to signals of increased adiposity after birth.

Hydrogen Transfer in the Formation and Destruction of Retrograde Products in Coal Conversion

The conversion of coals to volatiles or liquids during pyrolysis and liquefaction is notoriously limited by the formation of retrograde products. Analysis of literature data for coals with grafted structures and for polymeric coal models demonstrates that the formation of volatile products from these materials does not correlate primarily with the weakness of the original bonding but correlates with the facility for retrogressive reaction. This analysis suggests further that simple recombination of resonance-stabilized radicals does not tend to yield true retrograde products, except in the case of aryloxy radicals. For pure hydrocarbon structural elements, radical addition to aromatic systems appears to be a key class of retrograde reactions, where the key factor is the kinetics of radical or H-atom loss from a cyclohexadienyl intermediate. We have used a mechanistic numerical model with a detailed set of radical reactions and thermochemically based kinetic parameters operating on a limited set of hydrocarbon structures to delineate important factors in mitigating retrograde processes. The modeling results show (1) how the "better" radical scavengers may reduce retrograde reaction at short reaction times but actually tend to increase it at longer times; (2) that the beneficial effects of H2 pressure at short reaction times are not primarily due to lowering of harmful radical concentrations by scavenging, nor to the maintenance of donor content; (3) that the benefit is due to the small population of free H-atoms thus produced, which are very active in causing increased scission of strong bonds; and (4) that under some conditions retrograde products are actually generated faster with added H2, but at longer reaction times and higher temperatures this temporary disadvantage of H2 is overcome by increased hydrogenolysis of those earlier-produced retrograde products. Thus, not only the cleavage of critical bonds in the original coal structures but also the net prevention of retrogression may be due to the H-transfer-induced cleavage of strong bonds.

Limited Role for SREBP-1c in Defective Glucose-induced Insulin Secretion from Zucker Diabetic Fatty Rat Islets: a Functional and Gene Profiling Analysis

Accumulation of intracellular lipid may contribute to defective insulin secretion in type 2 diabetes. Although Zucker diabetic fatty (ZDF; fa/fa) rat islets are fat-laden and overexpress the lipogenic master gene, sterol regulatory element binding protein 1c (SREBP-1c), the contribution of SREBP-1c to the secretory defects observed in this model remains unclear. Here we compare the gene expression profile of lean control (fa/+) and ZDF rat islets in the absence or presence of dominant-negative SREBP-1c (SREBP-1c DN). ZDF islets displayed elevated basal insulin secretion at 3 mmol/l glucose but a severely depressed response to 17 mmol/l glucose. While SREBP-1c DN reduced basal insulin secretion from ZDF islets, glucose-stimulated insulin secretion was not improved. Of 57 genes differentially regulated in ZDF islets and implicated in glucose metabolism, vesicle trafficking, ion fluxes, and/or exocytosis, 21 were upregulated and 5 were suppressed by SREBP-1c DN. Genes underrepresented in ZDF islets were either unaffected (Glut-2, Kir6.2, Rab3), stimulated (voltage-dependent Ca(2+) channel subunit alpha1D, CPT2, SUR2, rab9, syt13), or inhibited (syntaxin 7, secretogranin-2) by SREBP-1c inhibition. Correspondingly, SREBP-1c DN largely corrected decreases in the expression of the transcription factors Pdx-1 and MafA but did not affect the abnormalities in Pax6, Arx, hepatic nuclear factor-1alpha (HNF1alpha), HNF3beta/Forkhead box-a2 (Foxa2), inducible cyclic AMP early repressor (ICER), or transcription factor 7-like 2 (TCF7L2) expression observed in ZDF islets. We conclude that upregulation of SREBP-1c and mild increases in triglyceride content do not explain defective glucose-stimulated insulin secretion from ZDF rats. However, overexpression of SREBP-1c may contribute to enhanced basal insulin secretion in this model.

Prolactin and the Expression of Suppressor of Cytokine Signaling-3 in the Sheep Adrenal Gland Before Birth

The fetal pituitary-adrenal axis plays a key role in the fetal response to intrauterine stress and in the timing of parturition. The fetal sheep adrenal gland is relatively refractory to stimulation in midgestation (90-120 days) before the prepartum activation, which occurs around 135 days gestation (term=147+/-3 days). The mechanisms underlying the switch from adrenal quiescence to activation are unclear. Therefore, we have investigated the expression of suppressor of cytokine signaling-3 (SOCS-3), a putative inhibitor of tissue growth in the fetal sheep adrenal between 50 and 145 days gestation and in the adrenal of the growth-restricted fetal sheep in late gestation. SOCS-3 is activated by a range of cytokines, including prolactin (PRL), and we have, therefore, determined whether PRL administered in vivo or in vitro stimulates SOCS-3 mRNA expression in the fetal adrenal in late gestation. There was a decrease (P<0.005) in SOCS-3 expression in the fetal adrenal between 54 and 133 days and between 141 and 144 days gestation. Infusion of the dopaminergic agonist, bromocriptine, which suppressed fetal PRL concentrations but did not decrease adrenal SOCS-3 mRNA expression. PRL administration, however, significantly increased adrenal SOCS-3 mRNA expression (P<0.05). Similarly, there was an increase (P<0.05) in SOCS-3 mRNA expression in adrenocortical cells in vitro after exposure to PRL (50 ng/ml). Placental and fetal growth restriction had no effect on SOCS-3 expression in the adrenal during late gestation. In summary, the decrease in the expression of the inhibitor SOCS-3 after 133 days gestation may be permissive for a subsequent increase in fetal adrenal growth before birth. We conclude that factors other than PRL act to maintain adrenal SOCS-3 mRNA expression before 133 days gestation but that acute elevations of PRL can act to upregulate adrenal SOCS-3 expression in the sheep fetus during late gestation.

Subpopulations of Corticotrophs in the Sheep Pituitary During Late Gestation: Effects of Development and Placental Restriction

The prepartum surge in fetal plasma cortisol is essential for the normal timing of parturition in sheep and may result from an increase in the ratio of ACTH to proopiomelanocortin (POMC) in the fetal circulation. In fetuses subjected to experimental induction of placental restriction, the prepartum surge in fetal cortisol is exaggerated, whereas pituitary POMC mRNA levels are decreased, and in vitro, unstimulated ACTH secretion is elevated in corticotrophs nonresponsive to CRH. We therefore investigated the changes in the relative proportions of cells expressing POMC, ACTH, and the CRH type 1 receptor (CRHR(1)) shortly before birth and during chronic placental insufficiency. Placental restriction (PR) was induced by removal of the majority of placental attachment sites in five ewes before mating. Pituitaries were collected from control and PR fetal sheep at 140 d (control, n = 4; PR, n = 4) and 144 d (control, n = 6; PR, n = 4). Pituitary sections were labeled with specific antisera raised against POMC, ACTH, and CRHR(1). Three major subpopulations of corticotrophs were identified that expressed POMC + ACTH + CRHR(1), ACTH + CRHR(1), or POMC only. The proportion of pituitary corticotrophs expressing POMC + ACTH + CRHR(1) decreased (P < 0.05) between 140 (control, 60 +/- 1%; PR, 66 +/- 4%) and 144 (control, 45 +/- 2%; PR, 56 +/- 6%) d. A significantly higher (P < 0.05) proportion of corticotrophs expressed POMC + ACTH + CRHR(1) in the pituitary of the PR group compared with controls. This study is the first to demonstrate subpopulations of corticotrophs in the fetal sheep pituitary that differentially express POMC, ACTH, and CRHR(1) and the separate effects of gestational age and placental restriction on these subpopulations of corticotrophs.

Sensitivity Enhancement of Fiber Bragg Gratings to Transverse Stress by Using Microstructural Fibers

We present simulation and experimental results of fiber Bragg grating responses to transverse stress in microstructure fibers. The grating wavelength shifts and peak splits are studied as a function of external load and fiber orientation. Both simulation and measurement results indicate that the sensitivity of grating sensors to the transverse stress can be enhanced by a factor of eight in a two-hole fiber over that in a standard fiber.

Improved Detection of Tritrichomonas Foetus in Bovine Diagnostic Specimens Using a Novel Probe-based Real Time PCR Assay

A Tritrichomonas foetus-specific 5' Taq nuclease assay using a 3' minor groove binder-DNA probe (TaqMan MGB) targeting conserved regions of the internal transcribed spacer-1 (ITS-1) was developed and compared to established diagnostic procedures. Specificity of the assay was evaluated using bovine venereal microflora and a range of related trichomonad species. Assay sensitivity was evaluated with log(10) dilutions of known numbers of cells, and compared to that for microscopy following culture (InPouch TF test kit) and the conventional TFR3-TFR4 PCR assay. The 5' Taq nuclease assay detected a single cell per assay from smegma or mucus which was 2500-fold or 250-fold more sensitive than microscopy following selective culture from smegma or mucus respectively, and 500-fold more sensitive than culture followed by conventional PCR assay. The sensitivity of the conventional PCR assay was comparable to the 5' Taq nuclease assay when testing purified DNA extracted from clinical specimens, whereas the 5' Taq nuclease assay sensitivity improved using crude cell lysates, which were not suitable as template for the conventional PCR assay. Urine was evaluated as a diagnostic specimen providing improved and equivalent levels of T. foetus detection in spiked urine by both microscopy following culture and direct 5' Taq nuclease detection, respectively, compared with smegma and mucus, however inconclusive results were obtained with urine samples from the field study. Diagnostic specimens (n=159) were collected from herds with culture positive animals and of the 14 animals positive by 5' Taq nuclease assay, 3 were confirmed by selective culture/microscopy detection (Fisher's exact test P<0.001). The 5' Taq nuclease assay described here demonstrated superior sensitivity to traditional culture/microscopy and offers advantages over the application of conventional PCR for the detection of T. foetus in clinical samples.

An Elastic Rod Model for Anguilliform Swimming

We develop a model for anguilliform (eel-like) swimming as an elastic rod actuated via time-dependent intrinsic curvature and subject to hydrodynamic drag forces, the latter as proposed by Taylor (in Proc Roy Proc Lond A 214:158-183, 1952). We employ a eometrically exact theory and discretize the resulting nonlinear partial differential evolution both to perform numerical simulations, and to compare with previous models consisting of chains of rigid links or masses connected by springs, dampers, and prescribed force generators representing muscles. We show that muscle activations driven by motoneuronal spike trains via calcium dynamics produce intrinsic curvatures corresponding to near-sinusoidal body shapes in longitudinally-uniform rods, but that passive elasticity causes Taylor's assumption of prescribed shape to fail, leading to time-periodic motions and lower speeds than those predicted Taylor (in Proc Roy Proc Lond A 214:158-183, 1952). We investigate the effects of bending stiffness, body geometry, and activation patterns on swimming speed, turning behavior, and acceleration to steady swimming. We show that laterally-uniform activation yields stable straight swimming and laterally differential activation levels lead to stable turns, and we argue that tapered bodies with reduced caudal (tail-end) activation (to produce uniform intrinsic curvature) swim faster than ones with uniform activation.

Religious Involvement and Its Association to Risk Behaviors Among Older Youth in Foster Care

This study examined religious involvement and its association to risk behaviors (sexual behavior, marijuana use, alcohol use, and cigarette use) among older youth in foster care (N=383). Three dimensions of religious involvement were assessed-church or religious service attendance, religious practices, and religious beliefs. Findings showed that gender, ethnic group membership, sexual abuse history, and placement type were significantly associated with older foster care youth's religious involvement. Hierarchical logistic regression analyses showed that religious service attendance was associated with reduced odds of youth's engagement in sexual behavior in the past 2 months and current use of cigarettes. In addition, greater religious beliefs were associated with a reduction in odds of youth's use of alcohol in the past 6 months and current use of cigarettes. The consideration of religious involvement as a positive influence and resource that may reduce unhealthy risk behaviors among older youth in foster care is discussed.

Restricted Fetal Growth and Lung Development: a Morphometric Analysis of Pulmonary Structure

Intrauterine growth restriction (IUGR) in humans increases the risk of lung disease and impaired function suggesting that adverse intra-uterine conditions can alter lung development. We hypothesized that placental restriction (PR) of fetal growth would alter lung structure in late gestation. PR involved removal of implantation sites in pre-pregnant ewes. Normal (n = 7) and PR (n = 11) fetuses were delivered at day 140 gestation. Lungs were fixed by tracheal infusion, processed and analyzed by morphometry. PR reduced ponderal index (PI) of lambs by 13%, increased lung volume:body weight (BW) (19%), and decreased the proportion of lung volume that comprised parenchyma from 86.5(2.6)% to 76.7(2.1)% with no change in absolute volume of non-parenchyma. Within the parenchyma, PR increased the proportion comprising airspace from 42.0(2.2)% to 55.5(1.7)% with smaller (-13%) more dense (18%) airsacs/alveoli present. The overall effect was a reduction in total gas-exchange surface density (-10%). Lung wet-weight and volume, parenchymal volume, gas-exchange tissue, and airspace volumes and gas-exchange surface area correlated positively with BW and crown-rump length (CRL) for all animals. The relative lung weight and volume correlated negatively with BW, CRL, and lung weight:BW with PI. Lung weight, lung volume, parenchymal volume, airspace perimeter, percent of parenchymal gas-exchange tissue, gas-exchange surface density, and area correlated positively with PI. The results indicate increased sparing of lung growth but with increasing structural changes, predominantly within lung parenchyma, with increasing growth restriction. Structural alterations associated with PR and poor fetal growth may be important in the pathogenesis of impaired lung function associated with IUGR.

Extracting Biochemical Parameters for Cellular Modeling: A Mean-field Approach

Recent developments in molecular biology have made it feasible to carry out experimental verification of mathematical models for biochemical processes, offering the eventual prospect of creating a detailed, validated picture of gene expression. A persistent difficulty with this long-term goal is the incompleteness of the kinetic information available in the literature: Many rate constants cannot or have not yet been measured. Here, we present a method of filling in missing parameters using an approach conceptually analogous to mean-field approaches in statistical mechanics: When studying a particular gene, we extract key parameters by considering the averaged effect of all other genes in the system, analogously to considering the averaged magnetic field in a physical spin model. This methodology has been applied to account for the effect of the presence of the Escherichia coli genome on the availability of key enzymes involved in gene expression (RNA polymerases and ribosomes), yielding the number of free enzymes as a function of cellular growth rate. These conclusions have been obtained by deriving genome-wide averages and matching them to bulk literature values of E. coli K-12 and B/r. Average rate constants have been found for RNA polymerases and ribosomes binding to promoter and ribosome-binding sites, respectively; these results suggest that cells vary not only their production rates of RNA polymerase and ribosomes under different growth-rate conditions but also change their global level of transcriptional/translational activation and repression, thus altering the average binding rate constants for these enzymes. To test the mean-field method, the results from the genome-wide averages have been applied to the induced lac operon, where our derived on-rate for binding of RNA polymerase to the promoter is in good agreement with previous experimental results.

The Effect of Oral Consumption of Perchlorate, Alone and in Combination with Ethanol, on Plasma Thyroid Hormone and Brain Catecholamine Concentrations in the Rat

Literature has reported a controversy concerning the effects of the environmental pollutant perchlorate on pertinent physiological systems. However, no research to date has evaluated the effect of concomitant consumption of perchlorate and an additional environmental contaminant on physiological systems. The present preliminary investigation served to assess the effects of oral consumption of perchlorate, alone and in combination with ethanol, on thyroid hormone and brain catecholamine concentrations in female rats of gestational age. Forty, female Myers' high ethanol-preferring rats were randomly assigned to 1 of 7 groups that received: (1) deionized water, both bottles (2) deionized water and 10% ethanol (v/v), two separate bottles (3) 300 microg/l perchlorate solution in deionized water, both bottles (4) 300 microg/l perchlorate in deionized water and in 10% ethanol (v/v), two separate bottles (5) 3000 microg/l perchlorate solution in deionized water, both bottles (6) 3000 microg/l perchlorate in deionized water and in 10% ethanol (v/v), two separate bottles (7) 0.01% propylthiouracil solution in deionized water, both bottles. At cessation of the treatment period, plasma triiodothyronine (T3) and thyroxine (T4) levels were measured by radioimmunoassay and brain area concentrations of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and norepinephrine were measured by high performance liquid chromatography. Perchlorate consumption, alone and/or in combination with ethanol consumption, failed to produce significant alterations from control values for triiodothyronine, thyroxine, dopamine, DOPAC, or norepinephrine. The data suggest that the no-observed effect level of perchlorate consumption on thyroid hormone and brain catecholamine concentrations is above the 3000 microg/l concentration in the adult female rat.

Oviposition Activity Patterns and West Nile Virus Infection Rates for Members of the Culex Pipiens Complex at Different Habitat Types Within the Hybrid Zone, Shelby County, TN, 2002 (Diptera: Culicidae)

Oviposition activity and West Nile virus (family Flaviviridae, genus Flavivirus, WNV) infection rates were assessed for members of the Culex pipiens complex from July through December 2002 by using gravid traps placed at four ecologically different sites in the southern portion of the hybrid zone in Shelby County, TN. Molecular assays identified three members of the Cx. pipiens complex: Cx. pipiens pipiens L., Cx. p. quinquefasciatus Say, and Cx. p. pipiens-Cx. p. quinquefasciatus hybrids (hybrids). The Cx. pipiens complex accounted for 90% of mosquitoes collected in gravid traps. All 285 WNV-positive mosquitoes were Culex mosquitoes, and 277 (97%) were Cx. pipiens complex mosquitoes. Infection rates among members of the Cx. pipiens complex were not significantly different. Infection rates were significantly higher at two urban sites than at a rural site, and WNV was not detected at a forested site. At urban sites, abundances of members of the Cx. pipiens complex corresponded to a simple latitude model of the hybrid zone. Cx. p. quinquefasciatus was most abundant (46.4%), followed by hybrids (34.1%) and Cx. p. pipiens (19.5%). The relative abundances at a rural site were reversed with Cx. p. pipiens (48.4%) being most abundant. This demonstrates that spatial habitat variation may profoundly influence the distribution of members of the Cx. pipiens complex within the hybrid zone. Members of the Cx. pipiens complex did not display different oviposition patterns. However, oviposition patterns assessed hourly at urban and rural sites were significantly different. At urban sites, oviposition activity of Cx. pipiens complex mosquitoes was bimodal with an evening peak associated with sunset and a morning peak associated with sunrise. At the rural site, the evening peak was pronounced and the morning peak weak and similar to nighttime activity.

Systematic Reduction of a Stochastic Signalling Cascade Model

Biochemical systems involve chemical reactions occurring in low-number regimes, wherein fluctuations are not negligible and thus stochastic models are required to capture the system behaviour. The resulting models are often quite large and complex, involving many reactions and species. For clarity and computational tractability, it is important to be able to simplify these systems to equivalent ones involving fewer elements. While many model simplification approaches have been developed for deterministic systems, there has been limited work on applying these approaches to stochastic modelling. Here, we propose a method that reduces the complexity of stochastic biochemical network models, and apply this method to the reduction of a mammalian signalling cascade. Our results indicate that the simplified model gives an accurate representation for not only the average number of all species, but also for the associated fluctuations and statistical parameters.

A Crisis of Credibility: Professionals' Concerns About the Psychiatric Care Provided to Clients of the Child Welfare System

This study examined child welfare and mental health professionals' views of the quality of psychiatric services received by consumers of the child welfare system and explored root causes of perceived quality problems.

Increased Maternal Nutrition Stimulates Peroxisome Proliferator Activated Receptor-gamma, Adiponectin, and Leptin Messenger Ribonucleic Acid Expression in Adipose Tissue Before Birth

During fetal life, adipose tissue is predominantly comprised of brown or thermogenic adipocytes and there is a transition to white, lipid-storing adipocytes after birth concomitant with the onset of suckling. In pregnancies complicated by gestational diabetes, the fetus is hyperglycemic, has an increased fat mass, and is at increased risk of obesity in later life. In the present study, we have investigated the hypothesis that exposure to increased maternal nutrition during late gestation results in increased expression of genes that regulate adipogenesis and lipogenesis in perirenal fat in fetal sheep. Pregnant ewes were fed either at or approximately 55% above maintenance energy requirements during late pregnancy and quantitative RT-PCR was used to measure peroxisome proliferator-activated receptor gamma, lipoprotein lipase, glycerol-3-phosphate dehydrogenase, adiponectin, and leptin mRNA expression. We report that exposure to metabolic and hormonal signals of increased nutrition before birth results in an increase in the expression of the adipogenic factor, peroxisome proliferator-activated receptor gamma, and in lipoprotein lipase, adiponectin, and leptin mRNA expression in fetal perirenal fat. We propose that an increase in maternal, and hence fetal, nutrition results in a precocial increase in adipogenic, lipogenic, and adipokine gene expression in adipose tissue and that these changes may be important in the development of obesity in later life.

Periadolescent Nicotine Exposure Produces Sensitization to Reinforcement by Diazepam in the Rat

Epidemiologic studies establish a relationship between nicotine use by adolescents and a subsequent involvement with drugs of abuse in adulthood. Recent research implicates the periadolescent period as a crucial time in development, during which nicotine use produces persistent adaptations that serve to predispose an individual to substance use. The present investigation evaluated the effects of periadolescent nicotine priming on young adult sensitization to reinforcement by a drug of abuse. Nicotine (0.4 mg/kg, intraperitoneal), mecamylamine (2 mg/kg, subcutaneous), mecamylamine and nicotine, or saline was administered as a once-daily injection to periadolescent (postnatal days 35-44) Sprague-Dawley male rats. The effects of periadolescent nicotine priming on reinforcement parameters in the young adult animal (postnatal day 80) were measured by conditioning a place preference with diazepam (1 mg/kg, subcutaneous). Rats were tested for place conditioning in a drug-free state. In contrast to other periadolescent treatment groups, rats treated with only nicotine during periadolescence showed a heterologous sensitization to the subthreshold dose of diazepam utilized during conditioning. Pretreatment with mecamylamine before periadolescent nicotine priming prevented the enhanced response to diazepam observed in the young adult animal. Priming with nicotine during late adolescence (postnatal days 60-69) failed to sensitize the adult rats to diazepam. This study supports a relationship between periadolescent nicotine priming and the production of persistent, behavioral adaptations in the young adult animal.

Placental Restriction of Fetal Growth Increases Insulin Action, Growth, and Adiposity in the Young Lamb

Most children who are short or light at birth due to intrauterine growth restriction (IUGR) exhibit accelerated growth in infancy, termed "catch-up" growth, which together with IUGR, predicts increased risk of type 2 diabetes and obesity later in life. Placental restriction (PR) in sheep reduces size at birth, and also causes catch-up growth and increased adiposity at 6 wk of age. The physiological mechanisms responsible for catch-up growth after IUGR and its links to these adverse sequelae are unknown. Because insulin is a major anabolic hormone of infancy and its actions are commonly perturbed in these related disorders, we hypothesized that restriction of fetal growth would alter insulin secretion and sensitivity in the juvenile sheep at 1 month, which would be related to their altered growth and adiposity. We show that PR impairs glucose-stimulated insulin production, but not fasting insulin abundance or production in the young sheep. However, PR increases insulin sensitivity of circulating free fatty acids (FFAs), and insulin disposition indices for glucose and FFAs. Catch-up growth is predicted by the insulin disposition indices for amino acids and FFAs, and adiposity by that for FFAs. This suggests that catch-up growth and early-onset visceral obesity after IUGR may have a common underlying cause, that of increased insulin action due primarily to enhanced insulin sensitivity, which could account in part for their links to adverse metabolic and related outcomes in later life.

Impact of Periconceptional Undernutrition on Adrenal Growth and Adrenal Insulin-like Growth Factor and Steroidogenic Enzyme Expression in the Sheep Fetus During Early Pregnancy

Periconceptional undernutrition (PCUN) results in an earlier prepartum activation of the pituitary-adrenal axis in twin compared with singleton fetuses. We have tested the hypotheses that the functional development of the fetal sheep adrenal is delayed in twins compared with singletons in early gestation and that PCUN accelerates adrenal growth and increases the expression of intraadrenal IGF-I and -II and cytochrome P450 17-hydroxylase (CYP17) as early as 55 d gestation. We have investigated the effect of PCUN in the ewe (restricted at 70% of control allowance, n=21; control, n=24) from at least 45 d before mating until d 7 after mating on maternal cortisol and progesterone concentrations, fetal adrenal weight, adrenal IGF-I, IGF-I receptor (IGF-IR), IGF-II, IGF-IIR, and CYP17 mRNA expression and placental 11beta-hydroxysteroid dehydrogenase-1 and -2 mRNA and protein expression at d 53-56 pregnancy. The relative weight of the fetal adrenal and adrenal IGF-I, IGF-IR, IGF-II, IGF-IIR, and CYP17 mRNA expression were lower in twin compared with singleton fetuses. In singleton fetuses of PCUN ewes, there was a loss of the relationship between adrenal IGF-II/IGF-IIR expression and either adrenal weight or CYP17 mRNA, which was present in controls. Similarly in twin fetuses, PCUN resulted in the loss of the relationships between adrenal weight and IGF-I expression and between adrenal CYP17 and IGF-II expression, which were present in controls. Our findings suggest that differences in the timing of the prepartum activation of the fetal adrenal in twins and singletons have their origins in early gestation and highlight the importance of the interaction between the periconceptional environment and embryo number in setting the growth trajectory of the fetal adrenal.

Maternal Nutrient Restriction in Early Pregnancy Programs Hepatic MRNA Expression of Growth-related Genes and Liver Size in Adult Male Sheep

The liver is a major metabolic and endocrine organ of critical importance in the regulation of growth and metabolism. Its function is determined by a complex interaction of nutritionally regulated counter-regulatory hormones. The extent to which hepatic endocrine sensitivity can be programed in utero and whether the resultant adaptations persist into adulthood is unknown and was therefore the subject of this study. Young adult male sheep born to mothers that were fed either a control diet (i.e.100% of total live weight-maintenance requirements) throughout gestation or 50% of that intake (i.e. nutrient restricted (NR)) from 0 to 95 days gestation and thereafter 100% of requirements (taking into account increasing fetal mass) were entered into the study. All mothers gave birth normally at term, the singleton offspring were weaned at 16 weeks, and then reared at pasture until 3 years of age when their livers were sampled. NR offspring were of similar birth and body weights at 3 years of age when they had disproportionately smaller livers than controls. The abundance of mRNA for GH, prolactin, and IGF-II receptors, plus hepatocyte growth factor and suppressor of cytokine signaling-3 were all lower in livers of NR offspring. In contrast, the abundance of the mitochondrial protein voltage-dependent anion channel and the pro-apoptotic factor Bax were up regulated relative to controls. In conclusion, maternal nutrient restriction in early gestation results in adult offspring with smaller livers. This may be mediated by alterations in both hepatic mitogenic and apoptotic factors.

Tesaglitazar, a Dual Peroxisome Proliferator-activated Receptor Alpha/gamma Agonist, Reduces Atherosclerosis in Female Low Density Lipoprotein Receptor Deficient Mice

The transcription factors, peroxisome proliferator-activated receptors (PPAR) alpha (alpha) and gamma (gamma), which are involved in lipid and glucose homeostasis, also exert modulatory actions on vascular cells where they exhibit anti-inflammatory and anti-proliferative properties. Hence, PPAR agonists potentially can affect atherogenesis both via metabolic effects and direct effects on the vessel wall. We tested whether the dual PPAR-alpha/gamma agonist, tesaglitazar (TZ), would reduce atherosclerosis in a non-diabetic, atherosclerosis-prone mouse model, independent of effects on plasma lipids.

Substance Use and Abuse Among Older Youth in Foster Care

The purpose of this study was to explore prevalence and predictors of current and lifetime substance use, substance abuse disorder, and polysubstance use among older youth in foster care. Interviews were conducted with 406 17-year old youth (90% of those eligible) in one state's foster care system between December 2001 and June 2003. Forty-five percent of foster care youth reported using alcohol or illicit drugs within the last six months; 49% had tried drugs sometime during their lifetime and 35% met criteria for a substance use disorder. Having a diagnosis of Conduct Disorder and/or living in an independent living situation significantly increased the likelihood of current and lifetime substance use and disorder. A diagnosis of Post Traumatic Stress Disorder also predicted increased likelihood of polysubstance use and substance abuse disorder. In conclusion, older youth in the foster care system report similar levels of lifetime alcohol and illicit substance use when compared to the general adolescent population. However, rates of substance use disorder are high. Particularly at risk for both high rates of use and disorder are youth in independent living situations and youth with a diagnosis of Conduct Disorder or Post Traumatic Stress Disorder.

Somatic Cell Nuclear Transfer in the Sheep Induces Placental Defects That Likely Precede Fetal Demise

The efficiency of cloning by somatic cell nuclear transfer (SCNT) is poor in livestock with approximately 5% of transferred cloned embryos developing to term. SCNT is associated with gross placental structural abnormalities. We aimed to identify defects in placental histology and gene expression in failing ovine cloned pregnancies to better understand why so many clones generated by SCNT die in utero. Placentomes from SCNT pregnancies (n = 9) and age matched, naturally mated controls (n = 20) were collected at two gestational age ranges (105-134 days and 135-154 days; term = 147 days). There was no effect of cloning on total placental weight. However, cloning reduced the number of placentomes at both gestational ages (105-134 days: control 55.0 +/- 4.2, clone 44.7 +/- 8.0 and 135-154 days: control 72.2 +/- 5.1, clone 36.6 +/- 5.1; P < 0.001) and increased the mean individual placentome weight (105-134 days: control 10.6 +/- 1.3 g, clone 18.6 +/- 2.8 g and 135-154 days: control 6.6 +/- 0.6 g, clone 7.0 +/- 2.0 g; P < 0.02). Placentomes from cloned pregnancies had a significant volume of shed trophoblast and fetal villous hemorrhage, absent in controls, at both gestational age ranges (P < 0.001) that was shown to be apoptotic by activated caspase-3 immunoreactivity. Consequently, the volume of intact trophoblast was reduced and the arithmetic mean barrier thickness of trophoblast through which exchange occurs was altered (P < 0.001) at both gestational age ranges in clones. In addition, cloning reduced placental expression of key genes in placental differentiation and function. Thus, cloning by SCNT results in both gross and microscopic placental abnormalities. We speculate that trophoblast apoptosis, shedding, and hemorrhage may be causal in fetal death in ovine clones.

Hair Bundles Are Specialized for ATP Delivery Via Creatine Kinase

When stimulated strongly, a hair cell's mechanically sensitive hair bundle may consume ATP too rapidly for replenishment by diffusion. To provide a broad view of the bundle's protein complement, including those proteins participating in energy metabolism, we used shotgun mass spectrometry methods to identify proteins of purified chicken vestibular bundles. In addition to cytoskeletal proteins, proteins involved in Ca(2+) regulation, and stress-response proteins, many of the most abundant bundle proteins that were identified by mass spectrometry were involved in ATP synthesis. After beta-actin, the cytosolic brain isoform of creatine kinase was the next most abundant bundle protein; at approximately 0.5 mM, creatine kinase is capable of maintaining high ATP levels despite 1 mM/s ATP consumption by the plasma-membrane Ca(2+)-ATPase. Consistent with this critical role in hair bundle function, the creatine kinase circuit is essential for high-sensitivity hearing as demonstrated by hearing loss in creatine kinase knockout mice.

Measurement of Exhaled Nitric Oxide in Beef Cattle Using Tunable Diode Laser Absorption Spectroscopy

Measurement of nitric oxide (NO) in the expired breath of crossbred calves received at a research facility was performed using tunable diode laser absorption spectroscopy. Exhaled NO (eNO) concentrations were measured using NO absorption lines at 1912.07 cm(-1) and employing background subtraction. The lower detection limit and measurement precision were determined to be approximately 330 parts in 10(12) per unit volume. A custom breath collection system was designed to collect lower airway breath of spontaneously breathing calves while in a restraint chute. Breath was collected and analyzed from calves upon arrival and periodically during a 42 day receiving period. There was a statistically significant relationship between eNO, severity of bovine respiratory disease (BRD) in terms of number of times treated, and average daily weight gain over the first 15 days postarrival. In addition, breathing patterns and exhaled CO2 showed a statistically significant relationship with BRD morbidity.

Sex-specific Effects of Placental Restriction on Components of the Metabolic Syndrome in Young Adult Sheep

Prenatal and early postnatal life experiences, reflected by size at birth and postnatal catch-up growth, contribute to the risk of developing the metabolic syndrome in adulthood, but their relative importance is unclear. Therefore, we determined the effects of restricted placental and fetal growth on components of the metabolic syndrome in young adult sheep and the relationships of the latter to size at birth and early postnatal growth. Fasting plasma metabolites, glucose tolerance (by intravenous glucose tolerance test, IVGTT), insulin secretion and sensitivity, and resting blood pressure were measured in 22 control and 20 placentally restricted (PR) 1-yr-old sheep. In male sheep, PR increased the initial rise in glucose during an IVGTT and reduced diastolic blood pressure, and small size at birth independently predicted reduced adult size, glucose tolerance, and fasting plasma insulin and insulin disposition of glucose metabolism but increased insulin disposition of circulating FFAs. Also in males, high fractional growth rates in early postnatal life independently predicted impaired early glucose clearance during an IVGTT. In female animals, PR increased insulin sensitivity of glucose metabolism and reduced fasting plasma FFAs, and thinness at birth predicted increased adult size, fasting blood glucose, and pulse pressure. In conclusion, PR and small size at birth are associated with more components of the metabolic syndrome in adult male than in adult female sheep, with few independent effects of early postnatal growth. These sex differences in the onset and extent of adverse metabolic consequences after prenatal restraint in the sheep are consistent with observations in humans.

Nicotine Increases FosB Expression Within a Subset of Reward- and Memory-related Brain Regions During Both Peri- and Post-adolescence

Periadolescent nicotine exposure is associated with increased consumption and rewarding properties of abused drugs. In the case of peri- but not post-adolescent animals, these effects are persistent and last to adulthood, suggesting that early nicotine treatment may alter postnatal CNS development in ways that contribute to long-term problems with drug abuse.

Comorbidity of Obesity and Pain in a General Population: Results from the Southern Pain Prevalence Study

This cross-sectional study examines the relation between obesity and self-reported pain (moderate or severe pain occurring at least monthly) in a general population sample of adults in the southeastern United States (N = 3637). Results of the study suggest that obese adults (body mass index [BMI] >30) are more likely to experience pain than their normal-weight and underweight counterparts. Respondents classified as class I obese (BMI of 30 to 34.9) were 1.762 times as likely as the underweight and normal weight participants to report severe pain. Class II obese respondents (BMI of 35 to 39.9) were 1.888 times as likely to experience severe pain. Those respondents categorized as class III obese were most likely to report severe pain--2.297 times as likely as the underweight and normal-weight respondents. Analyses demonstrated a similar trend for respondents reporting moderate to severe pain. Adults who are obese are also more likely to report experiencing pain in multiple locations. This study complements clinical research that links pain and obesity and extends it into a general population. Because this is a cross-sectional study, further research is needed to discern causal explanations for the relation between self-reported pain and obesity. PERSPECTIVE: This article provides a population-level depiction of the positive relation between obesity and self-reported pain, which complements clinical research on the topic. It may prompt future research to shape interventions and treatment for both pain and obesity.

Toward Self-assembled Ferroelectric Random Access Memories: Hard-wired Switching Capacitor Arrays with Almost Tb/in.(2) Densities

We report on the successful fabrication of arrays of switchable nanocapacitors made by harnessing the self-assembly of materials. The structures are composed of arrays of 20-40 nm diameter Pt nanowires, spaced 50-100 nm apart, electrodeposited through nanoporous alumina onto a thin film lower electrode on a silicon wafer. A thin film ferroelectric (both barium titanate (BTO) and lead zirconium titanate (PZT)) has been deposited on top of the nanowire array, followed by the deposition of thin film upper electrodes. The PZT nanocapacitors exhibit hysteresis loops with substantial remnant polarizations, while although the switching performance was inferior, the low-field characteristics of the BTO nanocapacitors show dielectric behavior comparable to conventional thin film heterostructures. While registration is not sufficient for commercial RAM production, this is nevertheless an embryonic form of the highest density hard-wired FRAM capacitor array reported to date and compares favorably with atomic force microscopy read-write densities.

Restriction of Placental Function Alters Heart Development in the Sheep Fetus

Placental insufficiency, resulting in restriction of fetal substrate supply, is a major cause of intrauterine growth restriction (IUGR) and increased neonatal morbidity. Fetal adaptations to placental restriction maintain the growth of key organs, including the heart, but the impact of these adaptations on individual cardiomyocytes is unknown. Placental and hence fetal growth restriction was induced in fetal sheep by removing the majority of caruncles in the ewe before mating (placental restriction, PR). Vascular surgery was performed on 13 control and 11 PR fetuses at 110-125 days of gestation (term: 150 +/- 3 days). PR fetuses with a mean gestational Po(2) < 17 mmHg were defined as hypoxic. At postmortem (<135 or >135 days), fetal hearts were collected, and cardiomyocytes were isolated and fixed. Proliferating cardiomyocytes were counted by immunohistochemistry of Ki67 protein. Cardiomyocytes were stained with methylene blue to visualize the nuclei, and the proportion of mononucleated cells and length and width of cardiomyocytes were measured. PR resulted in chronic fetal hypoxia, IUGR, and elevated plasma cortisol concentrations. Although there was no difference in relative heart weights between control and PR fetuses, there was an increase in the proportion of mononucleated cardiomyocytes in PR fetuses. Whereas mononucleated and binucleated cardiomyocytes were smaller, the relative size of cardiomyocytes when expressed relative to heart weight was larger in PR compared with control fetuses. The increase in the relative proportion of mononucleated cardiomyocytes and the relative sparing of the growth of individual cardiomyocytes in the growth-restricted fetus are adaptations that may have long-term consequences for heart development in postnatal life.

Penetrating Craniocerebral Injuries from Nail-gun Use

Three patients with penetrating craniocerebral nail-gun injuries are described. In the first patient the nail was impinging on the internal carotid artery (ICA) in the carotid canal. On removal of the nail, the patient developed a false aneurysm at the site. To our knowledge, this is the first reported case of nail-gun injury affecting the ICA and also the first case of penetrating head injury affecting the ICA in the carotid canal. The second patient had seven intracranial nails in the frontal area. Three nails penetrated the left orbit, one of which perforated the globe. One nail damaged the optic nerve resulting in optic neuropathy. In the third patient the nail extended through the squamous temporal bone into the temporal lobe. All three were managed successfully via closed gentle traction without craniotomy and/or endovascular intervention. The literature is reviewed and management options for penetrating head injuries are discussed.

Understanding and Measuring Patients' Assessment of the Quality of Nursing Care

Traditionally, patients have been considered incapable of evaluating the quality of care they receive, leading to their minimal involvement.

Quality of Care: Expanding the Social Work Dialogue

For social work practitioners to engage fully in efforts designed to improve the quality of social services, they need to understand what is meant by quality of care, grapple with its complexity, and know how to identify and leverage the key factors most likely to influence it. This article introduces a conceptual model that articulates numerous influences on the quality of social services. It details the macrosystem, consumer, advocacy, organizational, and practitioner influences on technically proficient and sensitively delivered social services that affect consumer outcomes in desired ways. The model can be used to assess targets for quality improvement intervention in social services practice settings.

Impact of Periconceptional Undernutrition on the Development of the Hypothalamo-pituitary-adrenal Axis: Does the Timing of Parturition Start at Conception?

There are a number of critical windows during prenatal and postnatal life and a range of potential agents including exposure to maternal and fetal stressors, nutrition, and antenatal administration of synthetic glucocorticoids and postnatal maternal care and behaviour that are important in programming the subsequent reactivity of the HPA axis. Recently, it has become clear that the periconceptional period is also an important critical period during which changes in the level of maternal nutrition result in altered development of the fetal HPA axis. These findings have potential implications for the ability of the fetus to respond to acute and chronic stressors, for the timing of parturition and have potential implications for adult cardiovascular and metabolic health outcomes. In this review we focus on the different models which have been used to investigate the impact of maternal undernutrition during the periconceptional period on the prepartum activation of the fetal HPA axis. We propose that the term "periconceptional" should be used to refer to the developmental stages which include some or all of the following early events: oocyte maturation, follicular development, conception, and embryo/blastocyst growth up until implantation. When maternal undernutrition extends beyond implantation, up until early placentation, then it is appropriate to describe maternal undernutrition as occurring during 'early gestation'. Further work is required to define the relative contributions of nutritional factors operating in the periconceptional and early gestational periods on the programming of the subsequent development of the HPA axis and is of importance for fetal, postnatal and subsequent adult cardiovascular and metabolic health.

Synthesis and Antibacterial Activity of C11, C12-cyclic Urea Analogues of Ketolides

C11, C12-cyclic urea analogues of ketolides were designed and synthesized by use of a novel ketene acetal intermediate. This intermediate enabled introduction of an amino group at C12 stereospecifically and in high yield. The resulting cyclic urea ketolides appear to have in vitro activity similar to that of telithromycin which contains a C11, C12 cyclic carbamate moiety. Some of the C2 fluorinated compounds have improved potency against erm-containing Streptococcus pyogenes.

Intrafetal Insulin-like Growth Factor-I Infusion Stimulates Adrenal Growth but Not Steroidogenesis in the Sheep Fetus During Late Gestation

We investigated the effects of an intrafetal infusion of IGF-I on adrenal growth and expression of the adrenal steroidogenic and catecholamine-synthetic enzyme mRNAs in the sheep fetus during late gestation. Fetal sheep were infused for 10 d with either IGF-I (26 microg/kg.h; n = 14) or saline (n = 10) between 120 and 130 d gestation, and adrenal glands were collected for morphological analysis and determination of the mRNA expression of steroidogenic and catecholamine-synthetic enzymes. Fetal body weight was not altered by IGF-I infusion; however, adrenal weight was significantly increased by 145% after IGF-I infusion. The density of cell nuclei within the fetal adrenal cortex (the zona glomerulosa and zona fasciculata), and within the adrenaline synthesizing zone of the adrenal medulla, was significantly less in the IGF-I-infused fetuses compared with the saline-infused group. Thus, based on cell-density measurements, there was a significant increase in cell size in the zona glomerulosa and zona fasciculata of the adrenal cortex and in the adrenaline-synthesizing zone of the adrenal medulla. There was no effect of IGF-I infusion on the adrenal mRNA expression of the steroidogenic or catecholamine-synthetic enzymes or on fetal plasma cortisol concentrations. In summary, infusion of IGF-I in late gestation resulted in a marked hypertrophy of the steroidogenic and adrenaline-containing cells of the fetal adrenal in the absence of changes in the mRNA levels of adrenal steroidogenic or catecholamine-synthetic enzymes or in fetal plasma cortisol concentrations. Thus, IGF-I infusion results in a dissociation of adrenal growth and function during late gestation.

Predisposition to Seek Mental Health Care Among Black Males Transitioning from Foster Care

This study examined the predisposition to seek mental health care in the future for personal and mental health problems among Black males transitioning from the foster care system (n=74). Results of simultaneous multiple regression analysis showed that custody status, diagnosis of a DSM-IV psychiatric disorder, and emotional control contributed significantly to the prediction of Black male's predisposition to seek mental health care. Specifically, Black males who were still in foster care were more predisposed to seek mental health care, whereas those diagnosed with a DSM-IV psychiatric disorder and who adhered more to the norm of emotional control were less predisposed to seek mental health care. Implications for mental health service delivery are discussed.

Restriction of Placental Growth in Sheep Impairs Insulin Secretion but Not Sensitivity Before Birth

Restricted growth before birth is associated with impaired insulin secretion but with initially enhanced insulin sensitivity in early postnatal life, which then progresses to insulin resistance and impaired glucose homeostasis by adulthood. This suggests that prenatal restraint impairs insulin secretion, but increases insulin sensitivity, before birth. Poor placental growth and function are major causes of restricted fetal growth in humans. We have therefore investigated the effects of restricted placental growth and function on plasma glucose, alpha-amino nitrogen and insulin concentrations and glucose- and arginine-stimulated insulin secretion in the fetal sheep at 120 and 140 days gestational age, and on insulin sensitivity, measured by hyperinsulinaemic euglycaemic clamp, at 130 days gestational age. Placental restriction decreased fetal blood pH and oxygen content, and weight in late gestation by approximately 20%. Reduced fetal and placental weights and indices of poor placental function, in particular fetal hypoxia and hypoglycaemia, were associated with impaired glucose- and arginine-stimulated insulin secretion, but not with changes in insulin sensitivity in the fetal sheep. We conclude that the impaired insulin secretion capacity reported in children and adults after intrauterine growth restriction, and in the neonatal and young adult sheep which is small at birth, is present in utero and persists. Whether this reflects the actions of the adverse intrauterine environment or changes to intrinsic capacity is unclear, but in utero interventions may be necessary to improve postnatal insulin secretion in the infant who is growth-restricted before birth.

Host Choice and West Nile Virus Infection Rates in Blood-fed Mosquitoes, Including Members of the Culex Pipiens Complex, from Memphis and Shelby County, Tennessee, 2002-2003

The source of bloodmeals in 2,082 blood-fed mosquitoes collected from February 2002 through December 2003 in Memphis and surrounding areas of Shelby County, Tennessee were determined. Members of the genus Culex and Anopheles quadrimaculatus predominated in the collections. Members of the Cx. pipiens complex and Cx. restuans were found to feed predominately upon avian hosts, though mammalian hosts made up a substantial proportion of the bloodmeals in these species. No significant difference was seen in the host class of bloodmeals in mosquitoes identified as Cx. pipiens pipiens, Cx. p. quinquefasciatus, or hybrids between these two taxa. Anopheles quadrimaculatus and Cx. erraticus fed primarily upon mammalian hosts. Three avian species (the American Robin, the Common Grackle, and the Northern Cardinal) made up the majority of avian-derived bloodmeals, with the American Robin representing the most frequently fed upon avian host. An analysis of these host feeding data using a modification of a transmission model for Eastern Equine encephalitis virus suggested that the American Robin and Common Grackle represented the most important reservoir hosts for West Nile virus. A temporal analysis of the feeding patterns of the dominant Culex species did not support a shift in feeding behavior away from robins to mammals late in the summer. However, a significant degree of temporal variation was noted in the proportion of robin-derived bloodmeals when the data were analyzed by semi-monthly periods throughout the summers of 2002 and 2003. This pattern was consistent with the hypothesis that the mosquitoes were preferentially feeding upon nesting birds.

Including the Provider in the Assessment of Quality Care: Development and Testing of the Nurses' Assessment of Quality Scale - Acute Care Version

This study was designed to develop a psychometrically sound measure of nurses' evaluation of patient care delivered. The Nurses' Assessment of Quality Scale-Acute Care Version (NAQS-ACV), derived from the qualitative interviews of acute care nurses, was initially 138 items formatted as a Likert-type scale and administered to 1272 nurses from 7 acute care hospitals. After analysis, the scale was reduced to 77 items contained in 8 factors. Reliability estimates for the factors ranged from 74 to 94.

Increased Maternal Nutrition Increases Leptin Expression in Perirenal and Subcutaneous Adipose Tissue in the Postnatal Lamb

The present study tested the hypothesis that exposure to an increased level of maternal nutrition before birth results in altered expression of adipogenic, lipogenic, and adipokine genes in adipose tissue in early postnatal life. Pregnant ewes were fed either at or approximately 50% above maintenance energy requirements during late pregnancy, and quantitative RT-PCR was used to measure peroxisome proliferator-activated receptor (PPAR)-gamma, lipoprotein lipase (LPL), glycerol-3-phosphate-dehydrogenase (G3PDH), adiponectin, and leptin mRNA expression in perirenal (PAT) and sc adipose tissue (SCAT) in the offspring on postnatal d 30. Relative SCAT mass was higher in lambs of well-fed ewes (40.0 +/- 4.0 vs. 22.8 +/- 3.3 g/kg, P < 0.05) and was directly related to plasma insulin in the first 24 h after birth and to G3PDH and LPL expression. The expression of leptin mRNA in both the SCAT and PAT depots was higher (P < 0.05) in lambs of well-fed ewes. PPARgamma adiponectin, LPL, and G3PDH mRNA expression were not, however, different between well-fed and control groups in either depot. Relative PPARgamma expression in SCAT was directly related to plasma insulin concentrations in the first 24 h after birth (r(2) = 0.23; P < 0.05), and G3PDH and LPL expressions were also positively correlated with PPARgamma expression (r(2) = 0.27; P < 0.05). We have demonstrated that exposure to increased prenatal nutrition increases leptin expression at 1 month of age in both PAT and SCAT. The results of this study provide evidence that the nutritional environment before and immediately after birth can influence the development of adipose tissue in early postnatal life.

TandTRAQ: an Open-source Tool for Integrated Protein Identification and Quantitation

Integrating qualitative protein identification with quantitative protein analysis is non-trivial, given incompatibility in output formats. We present TandTRAQ, a standalone utility that integrates results from i-Tracker, an open-source iTRAQ quantitation program with the search results from X?Tandem, an open-source proteome search engine. The utility runs from the command-line and can be easily integrated into a pipeline for automation. Availability: The TandTRAQ Perl scripts are freely available for download at http://www.ohsucancer.com/isrdev/tandtraq/

Effect of DOV 102,677 on the Volitional Consumption of Ethanol by Myers' High Ethanol-preferring Rat

Inhibitors of monoamine neurotransmitter transporters are well established as antidepressants. However, the evidence that single (serotonin) or dual (serotonin-norepinephrine) neurotransmitter uptake inhibitors can treat ethanol abuse, either as a comorbidity with depression or as a separate entity, is inconsistent. Drugs that have, in addition, the ability to inhibit dopamine uptake may have an advantage in the treatment of alcohol abuse. Therefore, the inhibitor of norepinephrine, serotonin and dopamine uptake, DOV 102,677, was tested for its effects on the volitional consumption of ethanol by an ethanol-preferring rat strain.

The Leading Health Indicators of Mississippi: a Report from the 2004 Mississippi Health Assessment

Ruminococcus Bromii, Identification and Isolation As a Dominant Community Member in the Rumen of Cattle Fed a Barley Diet

To identify dominant bacteria in grain (barley)-fed cattle for isolation and future use to increase the efficiency of starch utilization in these cattle.

Merging Two Universities: the Medical University of Ohio and the University of Toledo

On July 1, 2006, the Medical University of Ohio officially merged with the University of Toledo and became the third largest public institution of higher education in the state of Ohio. The combination of the two neighboring institutions occurred through the efforts of a number of individuals who recognized the potential advantages of a merger and worked quickly through challenges by early engagement of stakeholders in the merger process. The advantages of a larger, more diverse institution with increased budget and research funding outweighed the challenges of bringing two different cultures together. Changing the culture and leadership was necessary to allow the process to move forward. In addition, statewide political support was mobilized to carry forward the legislative actions that permitted the formation of the new institution. The transformation of a free standing medical campus to a part of a larger university required a fusion of the existing boards of trustees, a new organizational structure and a unified strategic plan, all of which occurred in the first 12 months after the merger. The college of medicine of the former Medical University of Ohio has been strengthened by the merger process, and the new University of Toledo has emerged as a much more diverse and complete institution.

Simplification of Stochastic Chemical Reaction Models with Fast and Slow Dynamics

Biological systems often involve chemical reactions occurring in low-molecule-number regimes, where fluctuations are not negligible and thus stochastic models are required to capture the system behaviour. The resulting models are generally quite large and complex, involving many reactions and species. For clarity and computational tractability, it is important to be able to simplify these systems to equivalent ones involving fewer elements. While many model simplification approaches have been developed for deterministic systems, there has been limited work on applying these approaches to stochastic modelling. Here, we describe a method that reduces the complexity of stochastic biochemical network models, and apply this method to the reduction of a mammalian signalling cascade and a detailed model of the process of bacterial gene expression. Our results indicate that the simplified model gives an accurate representation for not only the average numbers of all species, but also for the associated fluctuations and statistical parameters.

Non-kin Natural Mentors in the Lives of Older Youths in Foster Care

This study explored the non-kin natural mentoring relationships among older youths in foster care. Three hundred thirty-nine youths nearing their exit from one state's alternative care system were interviewed. Those that reported the presence of a natural mentor, 62% (n=211), were subsequently asked about how they met their mentor, how long they have known their mentor, how frequently they have contact with their mentor, and the quality of the relationship. Seventy percent of the youth with mentors reported having known their mentors for over 1 year. Youth reported high levels of contact and relationship quality. Ethnic group membership, gender, where youth were living, and clinical characteristics were associated with individual mentoring characteristics. Child and adult service delivery systems might benefit from considering ways to support the continuation of these relationships during the transition period.

Hypothalamic Input is Required for Development of Normal Numbers of Thyrotrophs and Gonadotrophs, but Not Other Anterior Pituitary Cells in Late Gestation Sheep

To evaluate the hypothalamic contribution to the development of anterior pituitary (AP) cells we surgically disconnected the hypothalamus from the pituitary (hypothalamo-pituitary disconnection, HPD) in fetal sheep and collected pituitaries 31 days later. Pituitaries (n = 6 per group) were obtained from fetal sheep (term = 147 +/- 3 days) at 110 days (unoperated group) of gestation and at 141 days from animals that had undergone HPD or sham surgery at 110 days. Cells were identified by labelling pituitary sections with antisera against the six AP hormones. Additionally, we investigated the colocalization of glycoprotein hormones. The proportions of somatotrophs and corticotrophs were unchanged by age or HPD. Lactotrophs increased 80% over time, but the proportion was unaffected by HPD. Thyrotrophs, which were unaffected by age, increased 70% following HPD. Gonadotrophs increased with gestational age (LH+ cells 55%; FSH+ cells 19-fold), but this was severely attenuated by HPD. We investigated the possible existence of a reciprocal effect of HPD on multipotential glycoprotein-expressing cells. Co-expression of LH and TSH was extremely rare (< 1%) and unchanged over the last month of gestation or HPD. The increase of gonadotrophs expressing FSH only or LH and FSH was attenuated by HPD. Therefore, the proportions of somatotrophs, lactotrophs and corticotrophs are regulated independently of hypothalamic input in the late gestation fetal pituitary. In marked contrast, the determination of the thyrotroph and gonadotroph lineages over the same time period is subject to complex mechanisms involving hypothalamic factors, which inhibit differentiation and/or proliferation of thyrotrophs, but stimulate gonadotrophs down the FSH lineage. Development of a distinct population of gonadotrophs, expressing only LH, appears to be subject to alternative mechanisms.

Dietary Alpha-lipoic Acid Supplementation Inhibits Atherosclerotic Lesion Development in Apolipoprotein E-deficient and Apolipoprotein E/low-density Lipoprotein Receptor-deficient Mice

Vascular inflammation and lipid deposition are prominent features of atherosclerotic lesion formation. We have shown previously that the dithiol compound alpha-lipoic acid (LA) exerts antiinflammatory effects by inhibiting tumor necrosis factor-alpha- and lipopolysaccharide-induced endothelial and monocyte activation in vitro and lipopolysaccharide-induced acute inflammatory responses in vivo. Here, we investigated whether LA inhibits atherosclerosis in apolipoprotein E-deficient (apoE-/-) and apoE/low-density lipoprotein receptor-deficient mice, 2 well-established animal models of human atherosclerosis.

End of Life Decisions: Nurses Perceptions, Feelings and Experiences

Decisions to withdraw treatment are made on a regular basis in intensive care units. While nurses play a central role in patient care, previous studies have found that they are not always involved in withdrawal decisions.

Outcomes for Youth Residential Treatment Programs Using Administrative Data from the Child Welfare System: a Risk-adjustment Application

This study assessed whether administrative data from the public child welfare system could be used to develop risk-adjusted performance reports for residential mental health programs for adolescents. Regression methods were used with 3,759 residential treatment spells for 2,784 children and youth to determine which outcomes could be adequately risk adjusted for case mix. Expected outcomes were created for each residential program given its case mix; then, expected and achieved outcomes were compared. For most programs, achieved results did not differ significantly from expected results for individual outcomes. Overall, outcomes achieved were not impressive. Only one quarter of spells resulted in a youth being maintained in a single less restrictive setting in the year following discharge. Methodological implications of this study suggest further refinements are needed for child welfare administrative data in order to develop risk-adjusted report cards of program performance.

The Faroes Statement: Human Health Effects of Developmental Exposure to Chemicals in Our Environment

Developmental Origins of Adult Health and Disease: the Role of Periconceptional and Foetal Nutrition

The 'developmental origins of adult health and disease' hypothesis stated that environmental factors, particularly maternal undernutrition, act in early life to programme the risks for adverse health outcomes, such as cardiovascular disease, obesity and the metabolic syndrome in adult life. Early physiological tradeoffs, including activation of the foetal hypothalamo-pituitary-adrenal (HPA) axis, confer an early fitness advantage such as foetal survival, while incurring delayed health costs. We review the evidence that such tradeoffs are anticipated from conception and that the periconceptional nutritional environment can programme the developmental trajectory of the stress axis and the systems that maintain and regulate arterial blood pressure. There is also evidence that restriction of placental growth and function, results in an increased dependence of the maintenance of arterial blood pressure on the sequential recruitment of the sympathetic nervous system and HPA axis. While the 'early origins of adult disease' hypothesis has focussed on the impact of maternal undernutrition, an increase in maternal nutritional intake and in maternal body mass intake has become more prevalent in developed countries. Exposure to overnutrition in foetal life results in a series of central and peripheral neuroendocrine responses that in turn programme development of the fat cell and of the central appetite regulatory system. While the physiological responses to foetal undernutrition result in the physiological trade off between foetal survival and poor health outcomes that emerge after reproductive senescence, exposure to early overnutrition results in poor health outcomes that emerge in childhood and adolescence. Thus, the effects of early overnutrition can directly impact on reproductive fitness and on the health of the next generation. In this context, the physiological responses to relative overnutrition in early life may directly contribute to an intergenerational cycle of obesity.

Dietary Cholesterol Worsens Adipose Tissue Macrophage Accumulation and Atherosclerosis in Obese LDL Receptor-deficient Mice

Chronic systemic inflammation accompanies obesity and predicts development of cardiovascular disease. Dietary cholesterol has been shown to increase inflammation and atherosclerosis in LDL receptor-deficient (LDLR(-/-)) mice. This study was undertaken to determine whether dietary cholesterol and obesity have additive effects on inflammation and atherosclerosis.

Joint Observations with Lessons for Rheumatologists and Gastroenterologists

Placental Restriction of Fetal Growth Decreases IGF1 and Leptin MRNA Expression in the Perirenal Adipose Tissue of Late Gestation Fetal Sheep

Placental restriction (PR) of fetal growth results in a low birth weight and an increased visceral fat mass in postnatal life. We investigated whether PR alters expression of genes that regulate adipogenesis [IGF1, IGF1 receptor (IGF1R), IGF2, IGF2R, proliferator-activated receptor-gamma, retinoid-X-receptor-alpha], adipocyte metabolism (lipoprotein lipase, G3PDH, GAPDH) and adipokine signaling (leptin, adiponectin) in visceral adipose tissue before birth. PR was induced by removal of the majority of endometrial caruncles in nonpregnant ewes before mating. Fetal blood samples were collected from 116 days gestation, and perirenal visceral adipose tissue (PAT) was collected from PR and control fetuses at 145 days. PAT gene expression was measured by quantitative RT-PCR. PR fetuses had a lower weight (PR 2.90 +/- 0.32 kg; control, 5.12 +/- 0.24 kg; P < 0.0001), mean gestational arterial Po(2) (P < 0.0001), plasma glucose (P < 0.01), and insulin concentrations (P < 0.02), than controls. The expression of IGF1 mRNA in PAT was lower in the PR fetuses (PR, 0.332 +/- 0.063; control, 0.741 +/- 0.083; P < 0.01). Leptin mRNA expression in PAT was also lower in PR fetuses (PR, 0.077 +/- 0.009; control, 0.115 +/- 0.013; P < 0.05), although there was no difference in the expression of other adipokine or adipogenic genes in PAT between PR and control fetuses. Thus, restriction of placental and hence, fetal substrate supply results in decreased IGF1 and leptin expression in fetal visceral adipose tissue, which may alter the functional development of the perirenal fat depot and contribute to altered leptin signaling in the growth-restricted newborn and the subsequent emergence of an increased visceral adiposity.

Birth Weight and Gender Determine Expression of Adipogenic, Lipogenic and Adipokine Genes in Perirenal Adipose Tissue in the Young Adult Sheep

Epidemiological studies have demonstrated that low birth weight is associated with an increased incidence of visceral obesity and metabolic disorders in later life. In the present study, we have determined the impact of birth weight and gender on gene expression in visceral adipose tissue (VAT) in the young adult sheep. Lambs (n=19, birth weight range 2.6-7.55 kg) were born at term and growth monitored for 22.4+/-0.2 weeks, when body composition was determined by Dual X-ray Absorptiometry (DXA) and samples of VAT and subcutaneous (SCAT) adipose tissue collected. Plasma samples were collected at post-mortem for the determination of free fatty acids (FFA), glucose and insulin concentrations. Peroxisome-Proliferator Activated Receptor-gamma (PPARgamma), glycerol-3-phosphate dehydrogenase (G3PDH), lipoprotein lipase (LPL), adiponectin and leptin mRNA expression was determined by qRT-PCR. Fractional growth rate in postnatal weeks 1-3 was inversely related to birth weight in both males and females (R2=0.22, P<0.05, n=19). PPARgamma mRNA expression in VAT, but not SCAT, was inversely related to birth weight (R2=0.60, P<0.01, n=18). In males, but not females, PPARgamma mRNA in VAT was directly related to G3PDH mRNA expression (R2=0.69, P<0.01, n=9). Plasma FFA concentrations were inversely related to birth weight in both males and females (R2=0.22, P<0.05, n=19). These findings demonstrate that low birth weight is associated with an increased expression of a key adipogenic factor in visceral adipose tissue in young adulthood. In males, this is associated with an increased expression of lipogenic genes, and this may contribute to the increased propensity for visceral obesity in low birth weight males compared to females.

Optimization of a Dihydropyrrolopyrazole Series of Transforming Growth Factor-beta Type I Receptor Kinase Domain Inhibitors: Discovery of an Orally Bioavailable Transforming Growth Factor-beta Receptor Type I Inhibitor As Antitumor Agent

In our continuing effort to expand the SAR of the quinoline domain of dihydropyrrolopyrazole series, we have discovered compound 15d, which demonstrated the antitumor efficacy with oral bioavailability. This effort also demonstrated that the PK/PD in vivo target inhibition paradigm is an effective approach to assess potential for antitumor efficacy. The dihydropyrrolopyrazole inhibitor 15d (LY2109761) is representative of a novel series of antitumor agents.

Dark Proteins: Effect of Inclusion Body Formation on Quantification of Protein Expression

Plasmid-borne gene expression systems have found wide application in the emerging fields of systems biology and synthetic biology, where plasmids are used to implement simple network architectures, either to test systems biology hypotheses about issues such as gene expression noise or as a means of exerting artificial control over a cell's dynamics. In both these cases, fluorescent proteins are commonly applied as a means of monitoring the expression of genes in the living cell, and efforts have been made to quantify protein expression levels through fluorescence intensity calibration and by monitoring the partitioning of proteins among the two daughter cells after division; such quantification is important in formulating the predictive models desired in systems and synthetic biology research. A potential pitfall of using plasmid-based gene expression systems is that the high protein levels associated with expression from plasmids can lead to the formation of inclusion bodies, insoluble aggregates of misfolded, nonfunctional proteins that will not generate fluorescence output; proteins caught in these inclusion bodies are thus "dark" to fluorescence-based detection methods. If significant numbers of proteins are incorporated into inclusion bodies rather than becoming biologically active, quantitative results obtained by fluorescent measurements will be skewed; we investigate this phenomenon here. We have created two plasmid constructs with differing average copy numbers, both incorporating an unregulated promoter (P(LtetO-1) in the absence of TetR) expressing the GFP derivative enhanced green fluorescent protein (EGFP), and inserted them into Escherichia coli bacterial cells (a common model organism for work on the dynamics of prokaryotic gene expression). We extracted the inclusion bodies, denatured them, and refolded them to render them active, obtaining a measurement of the average number of EGFP per cell locked into these aggregates; at the same time, we used calibrated fluorescent intensity measurements to determine the average number of active EGFP present per cell. Both measurements were carried out as a function of cellular doubling time, over a range of 45-75 min. We found that the ratio of inclusion body EGFP to active EGFP varied strongly as a function of the cellular growth rate, and that the number of "dark" proteins in the aggregates could in fact be substantial, reaching ratios as high as approximately five proteins locked into inclusion bodies for every active protein (at the fastest growth rate), and dropping to ratios well below 1 (for the slowest growth rate). Our results suggest that efforts to compare computational models to protein numbers derived from fluorescence measurements should take inclusion body loss into account, especially when working with rapidly growing cells.

Effects of Protein Maturation on the Noise in Gene Expression

Fluorescent proteins are frequently used as reporters for gene expression in living cells, either by being expressed in tandem with a protein of interest or through the creation of fusion proteins. The data yielded by the fluorescence output are of considerable interest in efforts to formulate quantitative models of cellular behavior underway in fields such as systems biology and synthetic biology. An often neglected aspect of these proteins, however, is their maturation: Before a fluorescent protein can generate a fluorescent signal, it must mature through a series of steps (folding, cyclization, and oxidation) that may take from many minutes to over a day. The presence of these maturation steps creates a distinction between the observed gene expression profile and the actual profile. We examine this effect through a simplified gene expression model and conclude that fluorescent protein maturation can have significant effects on estimates of both the mean protein levels and the variability in gene expression. The model shows that in many regimes, the observed variability will be increased by the maturation process, but indicates the existence of regimes in which the observed variability will actually be less than the true variability of the target protein. The latter effect arises from a low-pass filtering effect introduced by the chain of maturation reactions. The results suggest that the maturation of fluorescent proteins should be taken into account when using such proteins as quantitative indicators of gene expression levels.

Plasmid-borne Prokaryotic Gene Expression: Sources of Variability and Quantitative System Characterization

One aim of synthetic biology is to exert systematic control over cellular behavior, either for medical purposes or to "program" microorganisms. An engineering approach to the design of biological controllers demands a quantitative understanding of the dynamics of both the system to be controlled and the controllers themselves. Here we focus on a widely used method of exerting control in bacterial cells: plasmid vectors bearing gene-promoter pairs. We study two variants of the simplest such element, an unregulated promoter constitutively expressing its gene, against the varying genomic background of four Escherichia coli cell strains. Absolute protein numbers and rates of expression vary with both cell strain and plasmid type, as does the variability of expression across the population. Total variability is most strongly coupled to the cell division process, and after cell size is scaled away, plasmid copy number regulation emerges as a significant effect. We present simple models that capture the main features of the system behavior. Our results confirm that complex interactions between plasmids and their hosts can have significant effects on both expression and variability, even in deliberately simplified systems.

Assessing College Students' Autonomy over Smoking with the Hooked On Nicotine Checklist

OBJECTIVE, PARTICIPANTS, AND METHODS: In this study, the authors explored the psychometric properties of the Hooked on Nicotine Checklist (HONC) among 300 college students who were current smokers. The HONC is a 10-item survey instrument designed to measure diminished autonomy over smoking, a key aspect of dependence. Autonomy is diminished when symptoms present a barrier to cessation. RESULTS: Internal consistency was high (alpha = .89), as was concurrent validity. Students who began smoking earlier and heavier smokers reported more symptoms than did those who started later and smoked less. After controlling for smoking frequency, the HONC was predictive of the likelihood of a failed cessation attempt, with each additional symptom doubling that likelihood. CONCLUSIONS: College health professionals could use the HONC to help new smokers recognize their symptoms of diminished autonomy. The HONC may serve as a recruiting tool for cessation programs, which could benefit such early-phase smokers.

Host-seeking Heights, Host-seeking Activity Patterns, and West Nile Virus Infection Rates for Members of the Culex Pipiens Complex at Different Habitat Types Within the Hybrid Zone, Shelby County, TN, 2002 (Diptera: Culicidae)

Host-seeking heights, host-seeking activity patterns, and West Nile virus (family Flaviviridae, genus Flavivirus, WNV) infection rates were assessed for members of the Culex pipiens complex from July to December 2002, by using chicken-baited can traps (CT) at four ecologically different sites in Shelby County, TN. Host-seeking height was assessed by CT placed at elevations of 3.1, 4.6, and 7.6 m during one 24-h period per month. Host-seeking activity was assessed by paired CT placed at an elevation of 4.6 m. Can traps were sampled at one 10-h daytime interval and at seven 2-h intervals during the evening, night, and morning. Cx. pipiens complex mosquitoes accounted for 87.1% of collected mosquitoes. Culex (Melanoconion) erraticus (Dyar & Knab) accounted for 11.9% of specimens. The average number of Cx. pipiens complex mosquitoes collected per 24-h CT period from July to September was lowest at a rural middle income site (1.7), intermediate at an urban middle income site (11.3), and highest at an urban low income site (47.4). Can traps at the forested site failed to collect Cx. pipiens complex mosquitoes. From July to September at urban sites, Culex pipiens pipiens L. was the rarest of the three complex members accounting for 11.1-25.6% of specimens. At the rural site, Culex pipiens quinquefasciatus Say was the rarest member of the complex. Cx. p. pipiens was not collected after September. Mean abundance of Cx. pipiens complex mosquitoes was higher in traps at 7.6 m than in traps at 4.6 m. Abundances at 3.1 m were intermediate and not significantly different from abundances at the other heights. Initiation of host-seeking activity was associated with the end of civil twilight and activity occurred over an extended nighttime period lasting 8-10 h. All 11 WNV-positive mosquitoes were Cx. pipiens complex mosquitoes collected from urban sites in traps placed at elevations of 4.6 and 7.6 m. Infection rates were marginally nonsignificant by height. Infection rates, host-seeking heights, and activity patterns were not significantly different among members of the Cx. pipiens complex.

The Practice of Critical Care Surgery After Renal Transplant

How to See Your Practice Through Your Patients' Eyes

The Sociocultural Dimensions of Pain in the Mid-South

Quality Assurance and Improvement Practice in Mental Health Agencies: Roles, Activities, Targets and Contributions

Accompanying the rise in the number of mental health agency personnel tasked with quality assurance and improvement (QA/I) responsibilities is an increased need to understand the nature of the work these professionals undertake. Four aspects of the work of quality assurance and improvement (QA/I) professionals in mental health were explored in this qualitative study: their perceived roles, their major activities, their QA/I targets, and their contributions. In-person interviews were conducted with QA/I professionals at 16 mental health agencies. Respondents perceived their roles at varying levels of complexity, focused on different targets, and used different methods to conduct their work. Few targets of QA/I work served as indicators of high quality care. Most QA/I professionals provided concrete descriptions of how they had improved agency services, while others could describe none. Accreditation framed much of agency QA/I work, perhaps to its detriment.

ReCAPTCHA: Human-based Character Recognition Via Web Security Measures

CAPTCHAs (Completely Automated Public Turing test to tell Computers and Humans Apart) are widespread security measures on the World Wide Web that prevent automated programs from abusing online services. They do so by asking humans to perform a task that computers cannot yet perform, such as deciphering distorted characters. Our research explored whether such human effort can be channeled into a useful purpose: helping to digitize old printed material by asking users to decipher scanned words from books that computerized optical character recognition failed to recognize. We showed that this method can transcribe text with a word accuracy exceeding 99%, matching the guarantee of professional human transcribers. Our apparatus is deployed in more than 40,000 Web sites and has transcribed over 440 million words.

Use of Multiple Psychotropic Medications Among Adolescents Aging out of Foster Care

This study described the prevalence of and risk factors for using multiple concurrent psychotropics among adolescents leaving foster care.

Nonlinear Muscles, Passive Viscoelasticity and Body Taper Conspire to Create Neuromechanical Phase Lags in Anguilliform Swimmers

Locomotion provides superb examples of cooperation among neuromuscular systems, environmental reaction forces, and sensory feedback. As part of a program to understand the neuromechanics of locomotion, here we construct a model of anguilliform (eel-like) swimming in slender fishes. Building on a continuum mechanical representation of the body as an viscoelastic rod, actuated by a traveling wave of preferred curvature and subject to hydrodynamic reaction forces, we incorporate a new version of a calcium release and muscle force model, fitted to data from the lamprey Ichthyomyzon unicuspis, that interactively generates the curvature wave. We use the model to investigate the source of the difference in speeds observed between electromyographic waves of muscle activation and mechanical waves of body curvature, concluding that it is due to a combination of passive viscoelastic and geometric properties of the body and active muscle properties. Moreover, we find that nonlinear force dependence on muscle length and shortening velocity may reduce the work done by the swimming muscles in steady swimming.

Maternal Overnutrition Suppresses the Phosphorylation of 5'-AMP-activated Protein Kinase in Liver, but Not Skeletal Muscle, in the Fetal and Neonatal Sheep

Epidemiological studies have shown that infants exposed to an increased supply of nutrients before birth are at increased risk of type 2 diabetes in later life. We have investigated the hypothesis that fetal overnutrition results in reduced expression and phosphorylation of the cellular fuel sensor, AMP-activated kinase (AMPK) in liver and skeletal muscle before and after birth. From 115 days gestation, ewes were fed either at or approximately 55% above maintenance energy requirements. Postmortem was performed on lamb fetuses at 139-141 days gestation (n = 14) and lambs at 30 days of postnatal age (n = 21), and liver and quadriceps muscle were collected at each time point. The expression of AMPKalpha1 and AMPKalpha2 mRNA was determined by quantitative RT-PCR (qRT-PCR). The abundance of AMPKalpha and phospho-AMPKalpha (P-AMPKalpha) was determined by Western blot analysis, and the proportion of the total AMPKalpha pool that was phosphorylated in each sample (%P-AMPKalpha) was determined. The ratio of AMPKalpha2 to AMPKalpha1 mRNA expression was lower in fetuses compared with lambs in both liver and muscle, independent of maternal nutrition. Hepatic %P-AMPKalpha was lower in both fetuses and lambs in the Overfed group and %P-AMPKalpha in the lamb liver was inversely related to plasma glucose concentrations in the first 24 h after birth (r = 0.73, P < 0.025). There was no effect of maternal overnutrition on total AMPKalpha or P-AMPKalpha abundance in liver or skeletal muscle. We have, therefore, demonstrated that AMPKalpha responds to signals of increased nutrient availability in the fetal liver. Suppression of hepatic AMPK phosphorylation may contribute to increased glucose production, and basal hyperglycemia, present in lambs of overfed ewes in early postnatal life.

Increasing the Efficiency of Bacterial Transcription Simulations: when to Exclude the Genome Without Loss of Accuracy

Simulating the major molecular events inside an Escherichia coli cell can lead to a very large number of reactions that compose its overall behaviour. Not only should the model be accurate, but it is imperative for the experimenter to create an efficient model to obtain the results in a timely fashion. Here, we show that for many parameter regimes, the effect of the host cell genome on the transcription of a gene from a plasmid-borne promoter is negligible, allowing one to simulate the system more efficiently by removing the computational load associated with representing the presence of the rest of the genome. The key parameter is the on-rate of RNAP binding to the promoter (k_on), and we compare the total number of transcripts produced from a plasmid vector generated as a function of this rate constant, for two versions of our gene expression model, one incorporating the host cell genome and one excluding it. By sweeping parameters, we identify the k_on range for which the difference between the genome and no-genome models drops below 5%, over a wide range of doubling times, mRNA degradation rates, plasmid copy numbers, and gene lengths.

"The Red Man and the White Plague": Rethinking Race, Tuberculosis, and American Indians, Ca. 1890-1950

From the time it emerged as an epidemic in the last decades of the nineteenth century until it had become their number-one health problem in the 1950s, multiple explanations for the etiology of tuberculosis (TB) among American Indians competed for prominence. None was more debated than racial susceptibility-and none held on with such tenacity. Various race-based explanations -Indians' inherent racial susceptibility, virgin soil theory, and degree of Indian blood-had great explanatory power. These explanations faded from view by the 1950s as a result of epidemiological research begun in the 1930s-research that for the first time filled in many of the pieces of the Indian TB puzzle and allowed TB specialists to know the unknown: who and where the disease struck and why. Combining case finding, X rays, sputum tests-all the modern methods of tracking a TB epidemic-the Bureau of Indian Affairs (BIA) was finally able to understand the Indian TB epidemic. But they also wanted to control it. To this end, the BIA and the Phipps Institute, under the direction of Esmond Long and Joseph Aronson, joined together to begin the first controlled trial of the BCG vaccine.

Older Youth Leaving the Foster Care System: Who, What, When, Where, and Why?

Maternal Nutrition and the Programming of Obesity: The Brain

The increasing incidence of obesity in the developed and developing world in the last decade has led to a need to define our understanding of the physiological mechanisms which can predispose individuals to weight gain in infancy, childhood and adulthood. There is now a considerable body of evidence which has shown that the pathway to obesity may begin very early in life, and that exposure to an inappropriate level of nutrition during prenatal and/or early postnatal development can predispose individuals to obesity in later life The brain is at the heart of the regulation of appetite and food preferences, and it is increasingly being recognized that the development of central appetitive structures is acutely sensitive to the nutritional environment both before and immediately after birth. This review will summarize the body of work which has highlighted the critical role of the brain in the early origins of obesity and presents some perspectives as to the potential application of these research findings in the clinical setting.

Silicon Optical Fiber

Described herein are initial experimental details and properties of a silicon core, silica glass-clad optical fiber fabricated using conventional optical fiber draw methods. Such semiconductor core fibers have potential to greatly influence the fields of nonlinear fiber optics, infrared and THz power delivery. More specifically, x-ray diffraction and Raman spectroscopy showed the core to be highly crystalline silicon. The measured propagation losses were 4.3 dB/m at 2.936 microm, which likely are caused by either microcracks in the core arising from the large thermal expansion mismatch with the cladding or to SiO(2) precipitates formed from oxygen dissolved in the silicon melt. Suggestions for enhancing the performance of these semiconductor core fibers are provided. Here we show that lengths of an optical fiber containing a highly crystalline semiconducting core can be produced using scalable fiber fabrication techniques.

Funneling Child Welfare Consumers into and Through the Mental Health System: Assessment, Referral, and Quality Issues

This qualitative study explores how consumers of child welfare services reach nonpsychiatric mental health providers and the perceived quality of these services. It relies on iterative interviews with individuals and groups, as well as on court observations from one metropolitan area. Results suggest that, consistent with theories of street-level bureaucracy, efficiency issues drive mental health service use, as clients are routinely subjected to psychological evaluations and funneled into mental health services as a matter of course. Referral practices are shaped by child welfare professionals' routines, discretion, and desire to meet such system objectives as providing short turnaround times for reports. The results suggest that, despite stakeholders' best intentions, maltreated children are not benefiting from thoughtful processes geared to screen for, assess, and provide targeted treatment for unmet mental health needs.

Pediatric to Adult Mental Health Service Use of Young People Leaving the Foster Care System

To assess and predict changes in mental health service use as older youth leave the foster care system.

Health Insurance Discontinuities Among Adolescents Leaving Foster Care

To determine whether adolescents who lose Medicaid entitlements when they leave foster care are subsequently able to secure employer-sponsored or student health insurance coverage.

Beliefs About the Health Effects of "thirdhand" Smoke and Home Smoking Bans

There is no safe level of exposure to tobacco smoke. Thirdhand smoke is residual tobacco smoke contamination that remains after the cigarette is extinguished. Children are uniquely susceptible to thirdhand smoke exposure. The objective of this study was to assess health beliefs of adults regarding thirdhand smoke exposure of children and whether smokers and nonsmokers differ in those beliefs. We hypothesized that beliefs about thirdhand smoke would be associated with household smoking bans.

Intrauterine Growth Restriction and Differential Patterns of Hepatic Growth and Expression of IGF1, PCK2, and HSDL1 MRNA in the Sheep Fetus in Late Gestation

Fetal adaptations to periods of substrate deprivation can result in the programming of glucose intolerance, insulin resistance, and metabolic dysfunction in later life. Placental insufficiency can be associated with either sparing or sacrifice of fetal liver growth, and these different responses may have different metabolic consequences. It is unclear what intrahepatic mechanisms determine the differential responses of the fetal liver to substrate restriction. We investigated the effects of placental restriction (PR) on liver growth and the hepatic expression of SLC2A1, IGF1, IGF2, IGF1R, IGF2R, PPARGC1A, PPARA, PRKAA1, PRKAA2, PCK2, and HSDL1 mRNA in fetal sheep at 140-145 days of gestation. A mean gestational arterial partial pressure of oxygen less than 17 mmHg was defined as hypoxic, and a relative liver of weight more than 2 SD below the mean liver weight of controls was defined as reduced liver growth. Fetuses therefore were defined as control-normoxic (C-N; n = 9), PR-normoxic (PR-N; n = 7), PR-hypoxic (PR-H; n = 8), or PR-hypoxic reduced liver growth (PR-H RLG; n = 4). Hepatic SLC2A1 mRNA expression was highest (P < 0.05) in the PR-H fetuses, in which liver growth was maintained. Expression of IGF1 mRNA was decreased (P < 0.05) only in the PR-H RLG group. Hepatic expression of HSDL1, PPARGC1A, and PCK2 mRNA also were increased (P < 0.05) in the PR-H RLG fetuses. The present study highlights that intrahepatic responses to fetal substrate restriction may exist that protect the liver from decreased growth and, potentially, from a decreased responsiveness to the actions of insulin in postnatal life.

Overexpression of Apolipoprotein A5 in Mice is Not Protective Against Body Weight Gain and Aberrant Glucose Homeostasis

Apolipoprotein A5 (APOA5) is expressed primarily in the liver and modulates plasma triglyceride levels in mice and humans. Mice overexpressing APOA5 exhibit reduced plasma triglyceride levels. Because there is a tight association between plasma triglyceride concentration and traits of the metabolic syndrome, we used transgenic mice overexpressing human APOA5 to test the concept that these mice would be protected from diet-induced obesity and insulin resistance. Male and female transgenic and wild-type mice on the FVB/N genetic background were fed standard rodent chow or a diet rich in fat and sucrose for 18 weeks, during which time clinical phenotypes associated with obesity and glucose homeostasis were measured. We found that APOA5 transgenic (A5tg) mice were resistant to diet-induced changes in plasma triglyceride but not total cholesterol levels. Body weights were similar between the genotypes for females and males, although male A5tg mice showed a modest but significant increase in the relative size of inguinal fat pads. Although male A5tg mice showed a significantly increased ratio of plasma glucose to insulin, profiles of glucose clearance as evaluated after injections of glucose or insulin failed to reveal any differences between genotypes. Overall, our data showed that there was no advantage to responses to diet-induced obesity with chronic reduction of plasma triglyceride levels as mediated by overexpression of APOA5.

A Case of Noonan Syndrome and Whipple's Disease in the Same Patient

We report the first known case of both Noonan syndrome and Whipple's disease occurring in the same patient. A 36-year-old female with history of Noonan syndrome developed fatigue, anorexia, arthritis of the knees and hands with a diffuse hyperpigmented rash, night sweats, and an unintentional fifteen pound weight loss over 4 mo. Small bowel enteroscopy demonstrated mild edematous yellowish mucosa without friability. Random small bowel biopsies revealed extensive periodic acid-Schiff positive material within the foamy macrophages. She was treated with a 12 mo course of trimethoprim-sulfamethoxazole DS with clinical improvement to baseline status.

Intrauterine Growth Restriction and the Sex Specific Programming of Leptin and Peroxisome Proliferator-activated Receptor Gamma (PPARgamma) MRNA Expression in Visceral Fat in the Lamb

Being born small is associated with an increased risk of visceral obesity and insulin resistance in adult life. We have investigated the effect of IUGR on adipogenic and lipogenic gene expression in visceral fat in the lamb at 3 wk of age. Perirenal fat mass, but not adipocyte size was greater in females than males, independent of birth weight. Plasma insulin concentrations during the first 24 h after birth predicted the size of the adipocytes and expression of adiponectin in visceral adipose tissue in both males and females. In females, plasma nonesterified fatty acids (NEFA) concentrations during the first 24 h after birth were directly related to peroxisome proliferator-activated receptor gamma (PPARgamma) mRNA expression in the perirenal fat depot at 3 wk of age. In the males, in contrast to the females, PPARgamma and leptin expression in perirenal visceral fat were significantly lower in IUGR compared with control lambs. Thus, the early nutritional environment programs adipocyte growth and gene expression in visceral adipose tissue. The differential effect of sex and IUGR on PPARgamma and leptin expression in visceral fat may be important in the subsequent development of visceral obesity and the insulin resistant phenotype in later life.

Glass-clad Single-crystal Germanium Optical Fiber

Long lengths (250 meters) of a flexible 150 microm diameter glass-clad optical fiber containing a 15 microm diameter crystalline and phase-pure germanium core was fabricated using conventional optical fiber draw techniques. X-ray diffraction and spontaneous Raman scattering measurements showed the core to be very highly crystalline germanium with no observed secondary phases. Elemental analysis confirmed a very well-defined core-clad interface with a step-profile in composition and nominally 4 weight-percent oxygen having diffused into the germanium core from the glass cladding. For this proof-of-concept fiber, polycrystalline n-type germanium of unknown dopant concentration was used. The measured infrared transparency of the starting material was poor and, as a likely outcome, the attenuation of the resultant fiber was too high to be measured. However, the larger Raman cross-section, infrared and terahertz transparency of germanium over silicon should make these fibers of significant value for fiber-based mid- to long-wave infrared and terahertz waveguides and Raman-shifted infrared light sources once high-purity, high-resistivity germanium is employed.

Receptors for Tumor Necrosis Factor-alpha Play a Protective Role Against Obesity and Alter Adipose Tissue Macrophage Status

TNF-alpha signals through two receptors, TNFR1 and TNFR2. Our goals were: 1) determine the role of TNFRs in obesity and metabolic disease and 2) investigate whether TNFRs contribute to the link between obesity and adipose tissue macrophage infiltration and polarization. R1(-/-)R2(-/-) (RKO) and wild-type (WT) mice were fed standard chow or a high-fat/high-sucrose diet (HFHS) over 14 wk. Body composition, food intake, and energy expenditure were measured. Oral glucose tolerance and insulin sensitivity tests assessed glucose homeostasis. Adipose tissue and systemic inflammatory status were evaluated by quantifying plasma adipokine levels and macrophage-specific gene expression in fat. RKO mice were heavier (10%) and fatter (18%) than WT controls at 4 wk of age and were 26% heavier and 50% fatter than WT after 14 wk of HFHS diet feeding. Age- and diet-adjusted 24-h oxygen consumption, activity, and respiratory exchange ratio were significantly reduced in RKO mice. Obese RKO mice were markedly insulin resistant, suggesting that intact TNFR signaling is not required for the effect of obesity to impair glucose metabolism. Adipose tissue from HFHS-fed RKO mice exhibited increased macrophage infiltration, but compared with WT mice, macrophage phenotypic markers featured a predominance of antiinflammatory M2 over proinflammatory M1 cells. TNFRs play a physiological role to limit body weight and adiposity by modestly increasing metabolic rate and fatty acid oxidation, and they are required for obesity-induced activation of adipose tissue macrophages. Despite these effects, TNFRs are not required for obesity-induced insulin resistance.

Predicting Change in Children's Aggression and Victimization Using Classroom-level Descriptive Norms of Aggression and Pro-social Behavior

This study examined aggressive and pro-social classroom descriptive norms as predictors of change in aggression and victimization during middle childhood. Participants included 948 children in third through fifth grade. Measures of teacher-reported aggressive and peer-reported pro-social descriptive norms were completed at the onset of the study. Children completed self-report measures of aggression and victimization on three occasions during one academic year. Multilevel growth models were analyzed to determine the amount of student-reported change in aggression and victimization attributable to the classroom norm variables. Results indicated that students in classrooms with higher initial mean levels of aggression reported larger increases in aggression and victimization over the school year. In contrast, boys with higher initial levels of aggression reported smaller increases in aggression than boys with lower initial levels of aggression, and both boys and girls with higher initial aggression reported declining victimization over the school year. Pro-social classroom norms were unrelated to change in aggression and victimization. The implications of the findings for future studies on the influence of classroom social norms as well as interventions for aggression and victimization are discussed.

High Repetition Rate UV Ultrafast Laser Inscription of Buried Channel Waveguides in Sapphire: Fabrication and Fluorescence Imaging Via Ruby R Lines

We report on the fabrication of buried cannel waveguides in Sapphire crystals by 250-kHz high repetition rate ultrafast laser inscription with 385 nm pulses. The propagation properties of the waveguides were studied as a function of the writing conditions. The micro-fluorescence analysis of the R lines generated by trace Cr(3+) dopant in Sapphire is used to elucidate the micro-structural modifications induced in the crystal network. It is revealed that waveguide has been formed due to local dilatation of the Sapphire network generated in the surroundings of the focal volume. The refractive index increment due to the dilatation induced electronic polarizability enhancement has been estimated to be of the order of Deltan approximately 10(-4).

College Students' Responses to a 5/4 Drinking Question and Maximum Blood Alcohol Concentration Calculated from a Timeline Followback Questionnaire

Many surveys employed to study college drinking ask whether students have had a five-drink (for men) or four-drink (for women) episode in one sitting at least once during the previous 2 weeks to indicate risky or heavy episodic drinking. However, some researchers have questioned the predictive validity of the 5/4 measure. This study tested whether such students attained extremely high blood alcohol concentrations (BACs) during the previous 30 days.

No Evidence for an Enhanced Role of Endothelial Nitric Oxide in the Maintenance of Arterial Blood Pressure in the IUGR Sheep Fetus

The fetus makes a number of physiological adaptations to a restriction of placental substrate supply, including a decrease in body growth and an increase in peripheral vasoconstriction which maintains mean arterial pressure (MAP) and supports a redistribution of cardiac output to key fetal organs. It is not known, however, whether chronic restriction of placental substrate supply results in an enhanced or diminished role for vasodilators such as endothelial nitric oxide in the regulation of MAP. We hypothesised that there is an increased contribution of NO to blood pressure regulation in growth restricted fetuses and that a 2h infusion of a nitric oxide synthase inhibitor, N(omega)-nitro-l-arginine methyl ester (l-NAME) would result in an augmented rise in MAP in chronically hypoxemic, placentally restricted (PR, n=8) fetuses compared to controls (n=6) in late gestation. There was no difference in the increase in fetal MAP and decrease in HR during l-NAME infusion between Control and PR fetuses. In the PR group, fetuses with lower mean gestational PaO(2) had a lower increase in MAP during l-NAME infusion. Thus we have found no evidence for an enhanced role of NO in the maintenance of MAP in the chronically hypoxemic IUGR fetus.

Rosiglitazone Increases the Expression of Peroxisome Proliferator-activated Receptor-gamma Target Genes in Adipose Tissue, Liver, and Skeletal Muscle in the Sheep Fetus in Late Gestation

Exposure to maternal overnutrition increases the expression of peroxisome proliferator-activated receptor-gamma (PPARgamma) in adipose tissue before birth, and it has been proposed that the precocial activation of PPARgamma target genes may lead to increased fat deposition in postnatal life. In this study, we determined the effect of intrafetal administration of a PPARgamma agonist, rosiglitazone, on PPARgamma target gene expression in fetal adipose tissue as well indirect actions of rosiglitazone on fetal liver and skeletal muscle. Osmotic pumps containing rosiglitazone (n = 7) or vehicle (15% ethanol, n = 7) were implanted into fetuses at 123-126 d gestation (term = 150 +/- 3 d gestation). At 137-141 d gestation, tissues were collected and mRNA expression of PPARgamma, lipoprotein lipase (LPL), adiponectin, and glycerol-3-phosphate dehydrogenase (G3PDH) in adipose tissue, PPARalpha and PPARgamma-coactivator 1alpha (PGC1alpha) in liver and muscle and phosphoenolpyruvate carboxykinase (PEPCK) in liver determined by quantitative real-time RT-PCR. Plasma insulin concentrations were lower in rosiglitazone-treated fetuses (P < 0.02). Rosiglitazone treatment resulted in increased expression of LPL and adiponectin mRNA (P < 0.01) in fetal adipose tissue. The expression of PPARalpha mRNA in liver (P < 0.05) and PGC1alpha mRNA (P < 0.02) in skeletal muscle were also increased by rosiglitazone treatment. Rosiglitazone treatment increased expression of PPARgamma target genes within fetal adipose tissue and also had direct or indirect actions on the fetal liver and muscle. The effects of activating PPARgamma in fetal adipose tissue mimic those induced by prenatal overnutrition, and it is therefore possible that activation of PPARgamma may be the initiating mechanism in the pathway from prenatal overnutrition to postnatal obesity.

The Early Origins of Later Obesity: Pathways and Mechanisms

Excess bodyweight is the sixth most important risk factor contributing to the overall burden of disease worldwide. In excess of a billion adults and 10% of all children are now classified as overweight or obese. The main adverse consequences of obesity are the metabolic syndrome, cardiovascular disease and type 2 diabetes and a diminished average life expectancy. It has been argued that the complex pathological processes underlying obesity reflect environmental and genetic interactions, and individuals from disadvantaged communities seem to have greater risks than more affluent individuals partly because of fetal and postnatal programming interactions. Abundant evidence indicates that the obesity epidemic reflects progressive secular and age-related decreases in physical activity, together with passive over-consumption of energy dense foods despite neurobiological processes designed to regulate energy balance. The difficulty in treating obesity, however, highlights the deficits in our current understanding of the pathophysiology which underlies the initiation and chronic nature of this disorder. Large population based studies in Europe and North America in healthy women and in women with gestational diabetes have demonstrated that there are clear relationships between maternal and fetal nutrient supply, fetal growth patterns and the subsequent risk of obesity and glucose intolerance in childhood and adult life. In this review we discuss the impact of fetal nutrition on the biology of the developing adipocyte and brain and the growing evidence base supporting an intergenerational cycle of obesity.

Trigonal Structures of ABe2BO3F2 (A = Rb, Cs, Tl) Crystals

Several interesting fluoroberyllium borates were synthesized hydrothermally and characterized by single-crystal X-ray diffraction. The crystal structures of RbBe(2)BO(3)F(2) (RBBF; rubidium fluoroberyllium borate) and CsBe(2)BO(3)F(2) (CBBF; caesium fluoroberyllium borate), previously determined in the space group C2, were reinvestigated for higher symmetry and found to have more suitable solutions in the space group R32. TlBe(2)BO(3)F(2) (TBBF; thallium fluoroberyllium borate) was synthesized as a novel compound also having this trigonal structure type. Details of the space-group determination and unique structural features are discussed. These crystal structures were compared with that of KBe(2)BO(3)F(2), revealing interesting structural trends within this family of compounds that are also discussed. A crystallographic explanation of the physical morphology is postulated.

The Patient-centered Medical Home: 12 Tips to Help You Lead the Way

The Transition from Fetal Growth Restriction to Accelerated Postnatal Growth: a Potential Role for Insulin Signalling in Skeletal Muscle

A world-wide series of epidemiological and experimental studies have demonstrated that there is an association between being small at birth, accelerated growth in early postnatal life and the emergence of insulin resistance in adult life. The aim of this study was to investigate why accelerated growth occurs in postnatal life after in utero growth restriction. Samples of quadriceps muscle were collected at approximately 140 days gestation (term approximately 150 days gestation) from normally grown fetal lambs (Control, n = 7) and from growth restricted fetal lambs (placentally restricted: PR, n = 8) and from Control (n = 14) and PR (n = 9) lambs at 21 days after birth. The abundance of the insulin and IGF1 receptor protein was higher in the quadriceps muscle of the PR fetus, but there was a lower abundance of the insulin signalling molecule PKC, and GLUT4 protein in the PR group. At 21 days of postnatal age, insulin receptor abundance remained higher in the muscle of the PR lamb, and there was also an up-regulation of the insulin signalling molecules, PI3Kinase p85, Akt1 and Akt2 and of the GLUT4 protein in the PR group. Fetal growth restriction therefore results in an increased abundance of the insulin receptor in skeletal muscle, which persists after birth when it is associated with an upregulation of insulin signalling molecules and the glucose transporter, GLUT4. These data provide evidence that the origins of the accelerated growth experienced by the small baby after birth lie in the adaptive response of the growth restricted fetus to its low placental substrate supply.

The Ohio State University Richard M Ross Heart Hospital--proof of Concept--five Years of Growth and Development

Evaluation of Breath Biomarkers and Serum Haptoglobin Concentration for Diagnosis of Bovine Respiratory Disease in Heifers Newly Arrived at a Feedlot

To evaluate exhaled N(2)O (eN(2)O), exhaled CO (eCO), and serum haptoglobin concentrations as diagnostic criteria for bovine respiratory disease (BRD) and determine whether a combination of biomarkers would be useful for predicting health outcomes of heifer calves.

The Effect of Scutellaria Baicalensis on the Signaling Network in Hepatocellular Carcinoma Cells

Scutellaria baicalensis is an anti-inflammatory and antineoplastic Chinese herbal therapy. We have previously shown that S. baicalensis can inhibit hepatocellular carcinoma (HCC) cell growth in vitro. In this study, we sought to determine the effect of S. baicalensis on the cell signaling network using our newly developed Pathway Array technology, which screens cell signaling pathways involved in cell cycle regulation. The HCC cell line (HepG2) was treated with S. baicalensis extract in vitro. The effect on the cell cycle was analyzed by flow cytometry, and the expression of various signaling proteins was assayed with Pathway Array. Our results indicate that S. baicalensis exerts a strong growth inhibition of the HepG2 cells via G(2)/M phase arrest. The Pathway Array analysis of 56 proteins revealed a total of 14 differentially expressed proteins or phosphorylations after treatment. Of these, 9 showed a dose-dependent decrease (p53, ETS1, Cdc25B, p63, EGFR, ERK1/2, XIAP, HIF-2alpha, and Cdc25C) whereas one demonstrated a dose-dependent increase (Cyclin E) after treatment with 200 microg/ml of S. baicalensis. Using computer simulation software, we identified additional hubs in the signaling network activated by S. baicalensis. These results indicate that S. baicalensis exerts a broad effect on cell signaling networks leading to a collective inhibition of cell proliferation.

Natural Mentoring and Psychosocial Outcomes Among Older Youth Transitioning From Foster Care

Roles for Cathepsins S, L, and B in Insulitis and Diabetes in the NOD Mouse

We developed a panel of non-obese diabetic (NOD) mice deficient in major lysosomal cysteine proteases (cathepsins S, L and B) to identify protease enzymes essential for autoimmune diabetes. Null alleles for cathepsins (Cts) S, L or B were introgressed onto the NOD genetic background with 19 Idd markers at homozygosity. Diabetes onset was determined among females aged up to 6 months. We evaluated insulitis and sialadenitis in tissues using histology and computer assisted morphology. NOD mice deficient in Ctss or Ctsb were partially protected from diabetes with incidence at 33% and 28%, respectively, versus wild-type NOD (69%; p < 0.00001). NODs lacking cathepsin L (Ctsl-/-) are completely protected from IDDM, as originally shown by others. Ctsl, Ctss, or Ctsb heterozygous mice were able to develop IDDM, although incidence levels were significantly lower for Ctsb+/- (50%) and Ctsl+/- (55%) as compared to NODs (69%; p < 0.03). Ctsl-/- mice contain functional, diabetogenic T cells and an enriched Foxp3+ regulatory T cell population, and diabetes resistance was due to the presence of an expanded population of regulatory T cells. These data provide additional information about the potency of the diabetogenic T cell population in Ctsl-/- mice which were comparable in potency to wild-type NOD mice. These data illustrate the critical contribution of each of these proteases in determining IDDM in the NOD mouse and provide a useful set of models for further studies.

On the Effects of Signal Acuity in a Multi-alternative Model of Decision Making

We consider the effects of signal sharpness or acuity on the performance of neural models of decision making. In these models, a vector of signals is presented, and the subject must decide which of the elements of the vector is the largest. McMillen and Holmes ( 2006 ) derived asymptotically optimal tests under the assumption that the elements of the signal vector were all equal except one. In this letter, we consider the case of signals spread around a peak. The acuity is a measure of how strongly peaked the signal is. We find that the optimal test is one in which the detectors are passed through an output layer that encodes knowledge of the possible shapes of the incoming signals. The incorporation of such an output layer can lead to significant improvements in decision-making tasks.

Fetal Growth Restriction, Catch-up Growth and the Early Origins of Insulin Resistance and Visceral Obesity

There is an association between growing slowly before birth, accelerated growth in early postnatal life and the emergence of insulin resistance, visceral obesity and glucose intolerance in adult life. In this review we consider the pathway through which intrauterine growth restriction (IUGR) leads to the initial increase in insulin sensitivity and to catch-up growth. We also discuss the importance of the early insulin environment in determining later visceral adiposity and the intrahepatic mechanisms that may result in the emergence of glucose intolerance in a subset of IUGR infants. We present evidence that a key fetal adaptation to poor fetal nutrition is an upregulation of the abundance of the insulin receptor in the absence of an upregulation of insulin signalling in fetal skeletal muscle. After birth, however, there is an upregulation in the abundance of the insulin receptor and the insulin signalling pathway in the IUGR offspring. Thus, the origins of the accelerated postnatal growth rate experienced by IUGR infants lie in the fetal adaptations to a poor nutrient supply. We also discuss how the intracellular availability of free fatty acids and glucose within the visceral adipocyte and hepatocyte in fetal and neonatal life are critical in determining the subsequent metabolic phenotype of the IUGR offspring. It is clear that a better understanding of the relative contributions of the fetal and neonatal nutrient environment to the regulation of key insulin signalling pathways in muscle, visceral adipose tissue and the liver is required to support the development of evidence-based intervention strategies and better outcomes for the IUGR infant.

Periconceptional Undernutrition and Being a Twin Each Alter Kidney Development in the Sheep Fetus During Early Gestation

Adaptive growth responses of the embryo and fetus to nutritional restraint are important in ensuring early survival, but they are implicated in the programming of hypertension. It has been demonstrated that kidney growth and nephrogenesis are each regulated by intrarenal factors, including the insulin-like growth factors, glucocorticoids, and the renin-angiotensin system. Therefore, we have investigated the impact of periconceptional undernutrition (PCUN; from approximately 6 wk before to 7 days after conception) in singleton (control, n = 18; PCUN, n = 16) and twin pregnancies (control, n = 6; PCUN, n = 5) on the renal mRNA expression of 11beta- hydroxysteroid dehydrogensase type 1 and type 2 (11beta-HSD-1 and -2), the glucocorticoid (GR), and mineralocorticoid receptors, angiotensinogen, angiotensin receptor type 1 (AT1R) and 2 (AT2R), IGF-1 and IGF-2, and IGF1R and IGF2R at approximately 55 days gestation. There was no effect of PCUN or fetal number on fetal weight on relative kidney weight at approximately day 55 of gestation. There was an inverse relationship between the relative weight of the fetal kidney at approximately day 55 and maternal weight loss during the periconceptional period in fetuses exposed to PCUN. Exposure to PCUN resulted in a higher expression of IGF1 in the fetal kidney in singleton and twin pregnancies. Being a twin resulted in higher intrarenal expression of IGF-1 and IGF-2, GR, angiotensinogen, AT1R, and AT2R mRNA at 55 days gestation. Renal 11beta-HSD-2 mRNA expression was higher in PCUN singletons, but not PCUN twins, compared with controls. Thus, there may be an adaptive response in the kidney to the early environment of a twin pregnancy, which precedes the fetal growth restriction that occurs later in pregnancy. The kidney of the twin fetus exposed to periconceptional undernutrition may also be less protected from the consequences of glucocorticoid exposure.

Pinless Frameless Electromagnetic Image-guided Neuroendoscopy in Children

Frameless imaged-guided neuronavigation is a useful adjunct to neuroendoscopy in paediatric patients, especially those with abnormal or complex ventricular or cyst anatomy. The development of electromagnetic neuronavigation has allowed the use of image-guided navigation in the very young patient in whom rigid fixation in cranial pins is contraindicated. The technique and the authors' experience of its use in a series of paediatric patients are described.

Intrauterine Growth Restriction Delays Surfactant Protein Maturation in the Sheep Fetus

Pulmonary surfactant is synthesized by type II alveolar epithelial cells to regulate the surface tension at the air-liquid interface of the air-breathing lung. Developmental maturation of the surfactant system is controlled by many factors including oxygen, glucose, catecholamines, and cortisol. The intrauterine growth-restricted (IUGR) fetus is hypoxemic and hypoglycemic, with elevated plasma catecholamine and cortisol concentrations. The impact of IUGR on surfactant maturation is unclear. Here we investigate the expression of surfactant protein (SP) A, B, and C in lung tissue of fetal sheep at 133 and 141 days of gestation (term 150 +/- 3 days) from control and carunclectomized Merino ewes. Placentally restricted (PR) fetuses had a body weight <2 SD from the mean of control fetuses and a mean gestational Pa(O(2)) <17 mmHg. PR fetuses had reduced absolute, but not relative, lung weight, decreased plasma glucose concentration, and increased plasma cortisol concentration. Lung SP-A, -B, and -C protein and mRNA expression was reduced in PR compared with control fetuses at both ages. SP-B and -C but not SP-A mRNA expression and SP-A but not SP-B or -C protein expression increased with gestational age. Mean gestational Pa(O(2)) was positively correlated with SP-A, -B, and -C protein and SP-B and -C mRNA expression in the younger cohort. SP-A and -B gene expression was inversely related to plasma cortisol concentration. Placental restriction, leading to chronic hypoxemia and hypercortisolemia in the carunclectomy model, results in significant inhibition of surfactant maturation. These data suggest that IUGR fetuses are at significant risk of lung complications, especially if born prematurely.

Postoperative Infection Rates in Foot and Ankle Surgery: a Comparison of Patients with and Without Diabetes Mellitus

Patients with diabetes mellitus may be at increased risk for infection following foot and ankle surgery. This study aimed to determine whether patients with a diagnosis of diabetes mellitus have an increased rate of infection following foot and ankle surgery compared with a cohort of patients without diabetes. Furthermore, our study sought to demonstrate whether patients with complicated diabetes are at greater risk of postoperative wound infection than are patients with uncomplicated diabetes or patients without diabetes.

Substance Use and Substance Use Disorders As Foster Youth Transition to Adulthood

Effects of the Non-competitive NMDA Receptor Antagonist Memantine on the Volitional Consumption of Ethanol by Alcohol-preferring Rats

Potent N-methyl-d-aspartate (NMDA) receptor antagonists decrease volitional consumption of ethanol by rats. This study examined the effects of memantine, a low-affinity, open channel NMDA antagonist, on volitional consumption of ethanol by alcohol-preferring rats and potential locomotor, sedative and hypothermic effects. Volitional consumption of ethanol in a 24-hr two-choice paradigm was determined for male Myers' high-ethanol-preferring (mHEP) rats. Effects of memantine (0.3, 1.0, 3.0 and 10.0 mg/kg, i.p., b.i.d. [twice daily] for 3 days) or vehicle on volitional consumption of ethanol, proportion of ethanol to total fluids consumed, total fluid intake and consumption of food were observed. Potential sedating and locomotor effects of memantine (10.0 mg/kg, i.p., b.i.d.) were determined using an elevated plus maze and an Auto-Track Opto-Varimex activity monitoring system. Rectal temperature was measured to determine if memantine (10.0 mg/kg, i.p.) produces a hypothermic effect. The results indicate that memantine dose-dependently decreased the amount of ethanol and proportion of ethanol to total fluids consumed daily, reaching 48% and 24%, respectively, at the highest dose. These effects did not appear to be anti-caloric. Memantine (10.0 mg/kg) partially reversed both the sedation and the reductions in locomotor activity induced by ethanol. This dose did, however, produce a small, partially reversible hypothermic effect. In conclusion, memantine may decrease ethanol consumption with fewer side effects than other NMDA receptor antagonists, such as phencyclidine (PCP), MK 801 and ketamine.

Periconceptional Undernutrition in Normal and Overweight Ewes Leads to Increased Adrenal Growth and Epigenetic Changes in Adrenal IGF2/H19 Gene in Offspring

Adverse conditions in early life result in increased activation of the hypothalamo-pituitary-adrenal axis and in stress responsiveness in offspring. We have developed a model in which "donor" ewes are either normally nourished or overnourished prior to a period of dietary restriction, before transfer of the embryo at 6-7 d after conception to a ewe of normal weight and nutritional history. A moderate restriction of energy intake during the periconceptional period in both normal weight and overweight ewes resulted in increased adrenal mass in male and female lambs and an increased cortisol response to stress in female lambs. The increase in adrenal weight in lambs exposed to periconceptional undernutrition was associated with a decrease in the adrenal mRNA expression of IGF2 and decreased methylation in the proximal CTCF-binding site in the differentially methylated region of the IGF2/H19 gene. Thus, weight loss in both normal and overweight mothers during the periconceptional period results in epigenetic modification of IGF2 in the adrenal gland, adrenal overgrowth, and increased vulnerability to stress in offspring. Determining the appropriate approach to weight loss in the periconceptional period may therefore be important in overweight or obese women seeking to become pregnant.

Binary III-V Semiconductor Core Optical Fiber

For the first time to the best of our knowledge a glass-clad optical fiber comprising a crystalline binary III-V semiconductor core has been fabricated. More specifically, a phosphate glass-clad fiber containing an indium antimonide (InSb) core was drawn using a molten core approach. The core was found to be highly crystalline with some oxygen and phosphorus diffusing in from the cladding glass. While optical transmission measurements were unable to be made, most likely due to free carrier absorption associated with the conductivity of the core, this work constitutes a proof-of-concept that optical fibers comprising semiconductor cores of higher crystallographic complexity than previously realized can be drawn using conventional fiber fabrication techniques. Such binary semiconductors may open the door to future fiber-based nonlinear devices.

Considerations for Using Integral Feedback Control to Construct a Perfectly Adapting Synthetic Gene Network

It has long been known to control theorists and engineers that integral feedback control leads to, and is necessary for, "perfect" adaptation to step input perturbations in most systems. Consequently, implementation of this robust control strategy in a synthetic gene network is an attractive prospect. However, the nature of genetic regulatory networks (density-dependent kinetics and molecular signals that easily reach saturation) implies that the design and construction of such a device is not straightforward. In this study, we propose a generic two-promoter genetic regulatory network for the purpose of exhibiting perfect adaptation; our treatment highlights the challenges inherent in the implementation of a genetic integral controller. We also present a numerical case study for a specific realization of this two-promoter network, "constructed" using commonly available parts from the bacterium Escherichia coli. We illustrate the possibility of optimizing this network's transient response via analogy to a linear, free-damped harmonic oscillator. Finally, we discuss extensions of this two-promoter network to a proportional-integral controller and to a three-promoter network capable of perfect adaptation under conditions where first-order protein removal effects would otherwise disrupt the adaptation.

Epigenetics of Programmed Obesity: Alteration in IUGR Rat Hepatic IGF1 MRNA Expression and Histone Structure in Rapid Vs. Delayed Postnatal Catch-up Growth

Maternal food restriction (FR) during pregnancy results in intrauterine growth-restricted (IUGR) offspring that show rapid catch-up growth and develop metabolic syndrome and adult obesity. However, continued nutrient restriction during nursing delays catch-up growth and prevents development of obesity. Epigenetic regulation of IGF1, which modulates growth and is synthesized and secreted by the liver, may play a role in the development of these morbidities. Control (AdLib) pregnant rats received ad libitum food through gestation and lactation, and FR dams were exposed to 50% food restriction from days 10 to 21. FR pups were nursed by either ad libitum-fed control dams (FR/AdLib) or FR dams (FR/FR). All pups were weaned to ad libitum feed. Maternal FR resulted in IUGR newborns with significantly lower liver weight and, with the use of chromatin immunoprecipitation, decreased dimethylation at H3K4 in the IGF1 region was observed. Obese adult FR/AdLib males had decreased dimethylation and increased trimethylation of H3K4 in the IGF1 region. This corresponded to an increase in mRNA expression of IGF1-A (134 ± 5%), IGF1-B (165 ± 6%), IGF1 exon 1 (149 ± 6%), and IGF1 exon 2 (146 ± 7%) in the FR/AdLib compared with the AdLib/AdLib control group. In contrast, nonobese FR/FR had significantly higher IGF1-B mRNA levels (147 ± 19%) than controls with no difference in IGF1-A, exon 1 or exon 2. Modulation of the rate of IUGR newborn catch-up growth may thus protect against IGF1 epigenetic modifications and, consequently, obesity and associated metabolic abnormalities.

Impact of Maternal Periconceptional Overnutrition on Fat Mass and Expression of Adipogenic and Lipogenic Genes in Visceral and Subcutaneous Fat Depots in the Postnatal Lamb

Women entering pregnancy with a high body weight and fat mass have babies who are at increased risk of becoming overweight or obese in later life. We investigated whether maternal overnutrition in the periconceptional period results in an increased fat mass and expression of adipogenic and lipogenic genes in offspring and whether dietary restriction can reverse these changes. Nonpregnant donor ewes (n = 23) were assigned to one of four groups: control-control fed at 100% maintenance energy requirements (MER) for at least 5 months, control-restricted fed 100% MER for 4 months and 70% MER for 1 month, high-high (HH) fed ad libitum (170-190% MER) for 5 months, or high-restricted (HR) fed ad libitum for 4 months and 70% MER for 1 month. Single embryos were transferred to nonobese recipient ewes, and lamb fat depots were weighed at 4 months. Peroxisome proliferator-activated receptor-γ, glyceraldehyde-3-phosphate dehydrogenase, lipoprotein lipase, leptin, and adiponectin mRNA expression was measured in the lamb fat depots. Total fat mass was higher in female lambs in the HH but not HR group than controls. There was a relationship between donor ewe weight and total fat mass and G3PDH mRNA expression in perirenal fat in female lambs. There was no effect of periconceptional nutritional treatment on peroxisome proliferator-activated receptor-γ, glyceraldehyde-3-phosphate dehydrogenase, lipoprotein lipase, leptin, and adiponectin mRNA expression in any fat depot. Thus, exposure to maternal overnutrition in the periconceptional period alone results in an increased body fat mass in the offspring and that a short period of dietary restriction can reverse this effect.

Minimal Genetic Device with Multiple Tunable Functions

The ability to design artificial genetic devices with predictable functions is critical to the development of synthetic biology. Given the highly variable requirements of biological designs, the ability to tune the behavior of a genetic device is also of key importance; such tuning will allow devices to be matched with other components into larger systems, and to be shifted into the correct parameter regimes to elicit desired behaviors. Here, we have developed a minimal synthetic genetic system that acts as a multifunction, tunable biodevice in the bacterium Escherichia coli. First, it acts as a biochemical AND gate, sensing the extracellular small molecules isopropyl β-D -1-thiogalactopyranoside and anhydrotetracycline as two input signals and expressing enhanced green fluorescent protein as an output signal. Next, the output signal of the AND gate can be amplified by the application of another extracellular chemical, arabinose. Further, the system can generate a wide range of chemically tunable single input-output response curves, without any genetic alteration of the circuit, by varying the concentrations of a set of extracellular small molecules. We have developed and parameterized a simple transfer function model for the system, and shown that the model successfully explains and predicts the quantitative relationships between input and output signals in the system.

Epidermal Growth Factor Receptor (EGFR) Mutation and P-EGFR Expression in Resected Non-small Cell Lung Cancer

Lung cancer, specifically non-small cell lung cancer (NSCLC), is a leading cause of mortality worldwide. In China, a dramatic increase in the incidence of NSCLC is expected in the next 20 years (Molina et al. Mayo Clin Proc. 2008;83:584–594). Mutated epidermal growth factor receptor (EGFR) status is a known predictor of response to tyrosine kinase inhibitors (TKIs), and immunohistochemistry may be a less costly way of predicting presence of mutation. In this study, mutation analysis of EGFR in 218 cases of NSCLC was performed. One hundred thirty tissue samples were examined via immunohistochemistry of p-EGFR (Y1045 and Y1068) and correlated with mutation status. Mutations were seen in 29% of patients, and were correlated with female sex, nonsmoking history, and adenocarcinoma histology. Phosphorylation at Y1045 was noted in 52% of cases, but in 71% of cases with EGFR mutation (P = .003). Phosphorylation of Y1068 was seen in 55% of cases but in 73% of cases with EGFR mutation (P = .006). This study correlating EGFR mutation with p-EGFR expression in resected NSCLC is one of the largest to date, although TKI response could not be assessed. The data show that, among Chinese patients, detection of p-1045 and p-1068 expression with immunohistochemistry predicts EGFR mutations. Immunohistochemical analysis of p-EGFR may be useful to predict responses to TKI therapy, although future studies are necessary.

Before You Sign That Office Lease

An Active Intracellular Device to Prevent Lethal Disease Outcomes in Virus-infected Bacterial Cells

Synthetic biology includes an effort to logically control cellular behavior. One long-term goal is to implement medical interventions inside living cells, creating intracellular "disease fighters"; one may imagine a system that detects viral infection and responds to halt the spread of the virus. Here, we explore a system designed to display some of the qualitative features that such disease prevention systems should have, while not claiming that the system itself has any medical application. An intracellular disease prevention mechanism should: lie dormant in the absence of the disease state; detect the onset of a lethal disease pathway; respond to halt or mitigate the disease's effects; and be subject to external deactivation when required. We have created a device that displays these properties, in the highly simplified case of a bacterial viral disease. Our system detects the onset of the lytic phase of bacteriophage lambda in Escherichia coli, responds by preventing this lethal pathway from being followed, and is deactivated by a temperature shift. We have formulated a mathematical model of the engineered system, using parameters obtained from the literature and by local experimental measurement, and shown that the model captures the essential experimental behavior of the system in most parameter regimes.

The Efficacy of a Social Skills Group Intervention for Improving Social Behaviors in Children with High Functioning Autism Spectrum Disorders

This study tested the efficacy of a new social skills intervention, S ocial S kills GR oup IN tervention-High Functioning Autism (S.S.GRIN-HFA), designed to improve social behaviors in children with high functioning autism spectrum disorders. Fifty-five children were randomly assigned to S.S.GRIN-HFA treatment (n = 27) or control (i.e., traditional S.S.GRIN intervention; n = 28). Examination of the direction and magnitude of change in functioning revealed that children who participated in S.S.GRIN-HFA exhibited significantly greater mastery of social skill concepts compared to children in the control group. Parents of S.S.GRIN-HFA group participants reported an improved sense of social self-efficacy, whereas parents of control participants reported a decline. The advantages of a specialized intervention such as S.S.GRIN-HFA, designed specifically for children with high functioning autism spectrum disorders, are discussed.

Protein Intake During Gestation Affects Postnatal Bovine Skeletal Muscle Growth and Relative Expression of IGF1, IGF1R, IGF2 and IGF2R

Expression of insulin-like growth factor (IGF)1 and IGF2 and their receptor (IGF1R and IGF2R) mRNA in fetal skeletal muscle are changed by variations in maternal nutrient intake. The persistence of these effects into postnatal life and their association with phenotype in beef cattle is unknown. Here we report that the cross-sectional areas of longissimus dorsi and semitendinosus (ST) muscles were greater for mature male progeny born to heifers fed low protein diets (70% vs. 240% of recommended) during the first trimester. In ST, this was accompanied by greater IGF1, IGF2 and IGF2R mRNA at 680 d. Females exposed to low protein diets during the first trimester had decreased IGF2 mRNA in ST at 680 d, however this did not result in an effect to phenotype. Exposure to low protein diets during the second trimester increased IGF1R mRNA in ST of all progeny at 680 d. Changes to expression of IGF genes in progeny skeletal muscle resulting from variations to maternal protein intake during gestation may have permanent and sex-specific effect on postnatal skeletal muscle growth.

Periconceptional Nutrition and the Early Programming of a Life of Obesity or Adversity

Women entering pregnancy with a high body weight and fat mass have babies at increased risk of becoming overweight or obese in childhood and later life. It is not known, whether exposure to a high level of maternal nutrition before pregnancy and exposure to a high transplacental nutrient supply in later pregnancy act through similar mechanisms to program later obesity. Using the pregnant sheep we have shown that maternal overnutrition in late pregnancy results in an upregulation of PPARγ activated genes in fetal visceral fat and a subsequent increase in the mass of subcutaneous fat in the postnatal lamb. Exposure to maternal overnutrition during the periconceptional period alone, however, results in an increase in total body fat mass in female lambs only with a dominant effect on visceral fat depots. Thus the early programming of later obesity may result from 'two hits', the first occurring as a result of maternal overnutrition during the periconceptional period and the second occurring as a result of increased fetal nutrition in late pregnancy. Whilst a short period of dietary restriction during the periconceptional period reverses the impact of periconceptional overnutrition on the programming of obesity, it also results in an increased lamb adrenal weight and cortisol stress response, together with changes in the epigenetic state of the insulin like growth factor 2 (IGF2) gene in the adrenal. Thus, not all of the effects of dietary restriction in overweight or obese mother in the periconceptional period may be beneficial in the longer term.

Probing the Input-output Behavior of Biochemical and Genetic Systems System Identification Methods from Control Theory

A key aspect of the behavior of any system is the timescale on which it operates: when inputs change, do responses take milliseconds, seconds, minutes, hours, days, months? Does the system respond preferentially to inputs at certain timescales? These questions are well addressed by the methods of frequency response analysis. In this review, we introduce these methods and outline a procedure for applying this analysis directly to experimental data. This procedure, known as system identification, is a well-established tool in engineering systems and control theory and allows the construction of a predictive dynamic model of a biological system in the absence of any mechanistic details. When studying biochemical and genetic systems, the required experiments are not standard laboratory practice, but with advances in both our ability to measure system outputs (e.g., using fluorescent reporters) and our ability to generate precise inputs (with microfluidic chambers capable of changing cells' environments rapidly and under fine control), these frequency response methods are now experimentally practical for a wide range of biological systems, as evidenced by a number of successful recent applications of these techniques. We use a yeast G-protein signaling cascade as a running example, illustrating both theoretical concepts and practical considerations while keeping mathematical details to a minimum. The review aims to provide the reader with the tools required to design frequency response experiments for their own biological system and the background required to analyze and interpret the resulting data.

Incapacitated Sexual Violence Involving Alcohol Among College Women: the Impact of a Brief Drinking Intervention

This study assessed the impact of a motivational interviewing (MI) brief alcohol intervention and prior victimization on alcohol-involved sexual victimization experiences. First-year female college students (N = 229) were randomly assigned to an intervention condition: MI, MI with feedback (MIFB), feedback (FB), and assessment only (AO). Findings indicate reduced alcohol use for all conditions and violence for MIFB, with interactions for prior victimization. The mechanism of change for reduced victimization was not reductions in alcohol use and mechanisms for this effectiveness remain somewhat convoluted. Tailoring of brief interventions addressing alcohol use and sexual violence, particularly for women with prior victimization, is critical.

The Phylogeny of Sodalis-like Symbionts As Reconstructed Using Surface-encoding Loci

Phylogenetic analyses of 16S rRNA support close relationships between the Gammaproteobacteria Sodalis glossinidius, a tsetse (Diptera: Glossinidae) symbiont, and bacteria infecting diverse insect orders. To further examine the evolutionary relationships of these Sodalis-like symbionts, phylogenetic trees were constructed for a subset of putative surface-encoding genes (i.e. ompA, spr, slyB, rcsF, ycfM, and ompC). The ompA and ompC loci were used toward examining the intra- and interspecific diversity of Sodalis within tsetse, respectively. Intraspecific analyses of ompA support elevated nonsynonymous (dN) polymorphism with an excess of singletons, indicating diversifying selection, specifically within the tsetse Glossina morsitans. Additionally, interspecific ompC comparisons between Sodalis and Escherichia coli demonstrate deviation from neutrality, with higher fixed dN observed at sites associated with extracellular loops. Surface-encoding genes varied in their phylogenetic resolution of Sodalis and related bacteria, suggesting conserved vs. host-specific roles. Moreover, Sodalis and its close relatives exhibit genetic divergence at the rcsF, ompA, and ompC loci, indicative of initial molecular divergence. The application of outer membrane genes as markers for further delineating the systematics of recently diverged bacteria is discussed. These results increase our understanding of insect symbiont evolution, while also identifying early genome alterations occurring upon integration of microorganisms with eukaryotic hosts.

Heifer Nutrient Intake During Early- and Mid-gestation Programs Adult Offspring Adiposity and MRNA Expression of Growth-related Genes in Adipose Depots

Changes in maternal nutrient intake during gestation alter IGF receptor abundance and leptin (LEP) mRNA expression in fetal adipose tissue. It is not known whether such changes persist into adult life and whether they are associated with an effect on phenotype. We investigated the effect of high (240%) and low (70%) levels of recommended daily crude protein intake for beef heifers during the first and second trimesters of gestation on singleton progeny (n=68): subcutaneous (SC) adipose tissue depth at rump (P8) and rib (RF) sites from 65 until 657 days of age; plasma leptin concentrations from birth until 657 days and expression of IGF1 and IGF2, their receptors (IGF1R and IGF2R) and LEP mRNA in perirenal (PR), omental (OM) and SC adipose tissue at 680 days of age. High-protein diets during the first trimester increased LEP and IGF1 mRNA in PR of males and females, respectively, compared with low-protein diets, and decreased IGF1R mRNA in SC of all progeny but increased RF depth of males between 552 and 657 days. High-protein diets compared with low-protein diets during the second trimester increased IGF1R mRNA in PR and OM of all progeny; LEP mRNA in PR of males; and IGF2 and IGF2R mRNA in OM of all progeny. Conversely, LEP mRNA in OM and IGF2 mRNA in PR of all progeny were decreased following exposure to high- compared with low-protein diets during the second trimester. Heifer diet during gestation has permanent sex- and depot-specific effects on the expression of adipogenic and adipocytokine genes and offspring adiposity.

Simple HPLC Method for Determination of Rosiglitazone in Sheep Plasma and Amniotic Fluid and Its Application in a Pregnant Sheep Model

This paper describes the development of a sensitive high performance liquid chromatography (HPLC) method for quantification of rosiglitazone in sheep plasma and amniotic fluid. Samples were prepared by liquid-liquid extraction using tert-butyl methyl ether, and rosiglitazone was quantitated by HPLC using a C18 column and fluorescence detector with an excitation wavelength of 247 nm and emission wavelength of 367 nm. The mobile phase consisted of ammonium acetate (10 mM, pH 5.2) and acetonitrile (56.5:43.5, v/v) with a flow rate of 1 ml/min. Ketoconazole was used as the internal standard (IS). The plasma calibration curve was linear over the range of 2.5-250 ng/ml (mean r2=0.9940±0.0024; n=6) with accuracy of 99.4-102.8% over the calibration range. The intra-day and inter-day coefficient of variation (%CV, percent coefficient of variation) were in the range of 0.01-8.68% in sheep plasma. Similar performance was achieved for amniotic fluid. The described method was successfully applied to quantitate rosiglitazone concentrations in the pregnant ewe and her fetus.

Hebbian Learning in Linear-nonlinear Networks with Tuning Curves Leads to Near-optimal, Multi-alternative Decision Making

Optimal performance and physically plausible mechanisms for achieving it have been completely characterized for a general class of two-alternative, free response decision making tasks, and data suggest that humans can implement the optimal procedure. The situation is more complicated when the number of alternatives is greater than two and subjects are free to respond at any time, partly due to the fact that there is no generally applicable statistical test for deciding optimally in such cases. However, here, too, analytical approximations to optimality that are physically and psychologically plausible have been analyzed. These analyses leave open questions that have begun to be addressed: (1) How are near-optimal model parameterizations learned from experience? (2) What if a continuum of decision alternatives exists? (3) How can neurons' broad tuning curves be incorporated into an optimal-performance theory? We present a possible answer to all of these questions in the form of an extremely simple, reward-modulated Hebbian learning rule by which a neural network learns to approximate the multi-hypothesis sequential probability ratio test.

Acceptability of Testing Children for Tobacco-smoke Exposure: a National Parent Survey

Tests are available to measure children's exposure to tobacco smoke. One potential barrier to testing children for tobacco-smoke exposure is the belief that parents who smoke would not want their child tested. No previous surveys have assessed whether testing children for exposure to tobacco smoke in the context of their child's primary care visit is acceptable to parents.

Serum Amyloid A Facilitates the Binding of High-density Lipoprotein from Mice Injected with Lipopolysaccharide to Vascular Proteoglycans

Levels of serum amyloid A (SAA), an acute-phase protein carried on high-density lipoprotein (HDL), increase in inflammatory states and are associated with increased risk of cardiovascular disease. HDL colocalizes with vascular proteoglycans in atherosclerotic lesions. However, its major apolipoprotein, apolipoprotein A-I, has no proteoglycan-binding domains. Therefore, we investigated whether SAA, which has proteoglycan-binding domains, plays a role in HDL retention by proteoglycans.

Use of Inhaled Epoprostenol in Patients with H1N1 Influenza-associated Acute Respiratory Distress Syndrome: a Case Series

To report a series of patients with confirmed novel influenza A (H1N1) and refractory hypoxemia secondary to acute respiratory distress syndrome (ARDS) treated with inhaled epoprostenol.

US Attitudes About Banning Menthol in Cigarettes: Results from a Nationally Representative Survey

Menthol is a cigarette flavoring that makes smoking more appealing to smokers. The US Food and Drug Administration (FDA) has regulatory authority to ban mentholated cigarettes to reduce youth uptake and encourage adult cessation. Survey findings indicate that more than half of all Americans (56.1%) and of Blacks alone (68.0% in one sample and 75.8% in another) support banning menthol. Endorsement of a ban-especially by Blacks, who have the highest rates of menthol cigarette use-would support FDA action to ban menthol to protect the public's health.

Hydrothermal Synthesis and Crystal Structures of Two Novel Acentric Mixed Alkaline Earth Metal Berylloborates Sr3Be2B5O12(OH) and Ba3Be2B5O12(OH)

The synthesis and structure of the isostructural acentric compounds Sr(3)Be(2)B(5)O(12)(OH) (1) and Ba(3)Be(2)B(5)O(12)(OH) (2) are reported for the first time. These compounds crystallize in the space group R3m, and the unit cell parameters are a = 10.277(15) Ã… and c = 8.484(17) Ã… for 1 and a = 10.5615(15) Ã… and c = 8.8574(18) Ã… for 2. The structures consist of a network of [Be(2)B(4)O(12)(OH)] units interwoven with a network consisting of MO(9) polyhedra (M = Sr, Ba) and BO(3) triangles and exemplify how acentric building blocks such as [BO(3)](3-), [BO(4)](5-), and [BeO(4)](6-) can be especially suitable to build noncentrosymmetric long-range structures. Both networks are centered on the 3-fold rotation axis and present themselves in alternating fashion along [001]. Acentricity is imparted by the alignment of the polarities of BO(3) and BeO(4) environments. Infrared spectroscopy has been used to confirm the local geometries of B and Be, as well as the presence of hydroxide in the crystal structure. Another interesting feature of these compounds is the presence of disorder involving Be and B at the tetrahedral Be site. The degree of the disorder has been confirmed by observing a noticeable shortening of average Be-O bond distances.

Fetal Growth Restriction and the Programming of Heart Growth and Cardiac Insulin-like Growth Factor 2 Expression in the Lamb

Reduced growth in fetal life together with accelerated growth in childhood, results in a ~50% greater risk of coronary heart disease in adult life. It is unclear why changes in patterns of body and heart growth in early life can lead to an increased risk of cardiovascular disease in adulthood. We aimed to investigate the role of the insulin-like growth factors in heart growth in the growth-restricted fetus and lamb. Hearts were collected from control and placentally restricted (PR) fetuses at 137-144 days gestation and from average (ABW) and low (LBW) birth weight lambs at 21 days of age. We quantified cardiac mRNA expression of IGF-1, IGF-2 and their receptors, IGF-1R and IGF-2R, using real-time RT-PCR and protein expression of IGF-1R and IGF-2R using Western blotting. Combined bisulphite restriction analysis was used to assess DNA methylation in the differentially methylated region (DMR) of the IGF-2/H19 locus and of the IGF-2R gene. In PR fetal sheep, IGF-2, IGF-1R and IGF-2R mRNA expression was increased in the heart compared to controls. LBW lambs had a greater left ventricle weight relative to body weight as well as increased IGF-2 and IGF-2R mRNA expression in the heart, when compared to ABW lambs. No changes in the percentage of methylation of the DMRs of IGF-2/H19 or IGF-2R were found between PR and LBW when compared to their respective controls. In conclusion, a programmed increased in cardiac gene expression of IGF-2 and IGF-2R may represent an adaptive response to reduced substrate supply (e.g. glucose and/or oxygen) in order to maintain heart growth and may be the underlying cause for increased ventricular hypertrophy and the associated susceptibility of cardiomyocytes to ischaemic damage later in life.

Surgical Site Infections After Foot and Ankle Surgery: a Comparison of Patients with and Without Diabetes

This prospective study was designed to evaluate the rate of surgical site infection (SSI) after foot and ankle surgery in patients with and without diabetes.

Advancements in Percutaneous Fixation for Foot and Ankle Trauma

Operative fixation of foot and ankle trauma can be challenging. Often times, the soft tissue envelope can have extensive damage as a result of the fracture. In these cases, percutaneous fixation may be used. Percutaneous fixation can benefit both soft tissue and osseous healing when used correctly. Many techniques have been described in the literature that may help to preserve blood supply, minimize soft tissue dissection, and restore a functional limb. This article reviews general guidelines for fracture and soft tissue management, osseous healing of fractures, and how certain techniques influence fracture healing. It also illustrates certain techniques for specific fracture reduction.

Hydrothermal Descriptive Chemistry and Single Crystal Structure Determination of Cesium and Rubidium Thorium Fluorides

Two new cesium thorium fluorides and three new rubidium thorium fluorides have been synthesized hydrothermally and structurally characterized. The structures of two polymorphs of CsTh(3)F(13) are described in space group P6/mmm with a = 8.2608(14) and c = 8.6519(17) and space group Pmc2(1) with a = 8.1830(16), b = 7.5780(15), and c = 8.6244(17). The analogous orthorhombic compound RbTh(3)F(13), with a = 8.1805(16), b = 7.4378(15), and c = 8.6594(17) in space group Pmc2(1), is also reported. Two other rubidium thorium fluorides are also described: RbTh(2)F(9) crystallizes in the space group Pnma where a = 8.9101(18), b = 11.829(2), and c = 7.4048(15), and Rb(7)Th(6)F(31) crystallizes in the space group R3 where a = 15.609(2) and c = 10.823(2). Comparison of these materials was made on the basis of their structures and synthesis conditions. The formation of these species in hydrothermal fluids appears to be dependent upon the concentration of the alkali fluoride mineralizer solution and, thus, the ratio of alkali ions to thorium in the system.

Challenges to Quality Assurance and Improvement Efforts in Behavioral Health Organizations: A Qualitative Assessment

Behavioral health organizations have been increasingly required to implement plans to monitor and improve service quality. This qualitative study explores challenges that quality assurance and improvement (QA/I) personnel experience in performing their job in those practice settings. Sixteen QA/I personnel from different agencies in St. Louis, Missouri, U.S.A., were interviewed face-to-face using a semi-structured instrument to capture challenges and a questionnaire to capture participant and agency characteristics. Data analysis followed a grounded theory approach. Challenges involved agency resources, agency buy-in, personnel training, competing demands, shifting standards, authority, and research capacity. Further research is needed to assess these challenges given expected outcomes.

Maternal Obesity and the Early Origins of Childhood Obesity: Weighing Up the Benefits and Costs of Maternal Weight Loss in the Periconceptional Period for the Offspring

There is a need to understand the separate or interdependent contributions of maternal prepregnancy BMI, gestational weight gain, glycaemic control, and macronutrient intake on the metabolic outcomes for the offspring. Experimental studies highlight that there may be separate influences of maternal obesity during the periconceptional period and late gestation on the adiposity of the offspring. While a period of dietary restriction in obese mothers may ablate the programming of obesity, it is associated with an activation of the stress axis in the offspring. Thus, maternal obesity may result in epigenetic changes which predict the need for efficient fat storage in postnatal life, while maternal weight loss may lead to epigenetic changes which predict later adversity. Thus, development of dietary interventions for obese mothers during the periconceptional period requires a greater evidence base which allows the effective weighing up of the metabolic benefits and costs for the offspring.

Diagnosis and Medication Overload? A Nurse Review of the Psychiatric Histories of Older Youth in Treatment Foster Care

Prior research has raised concern about the appropriateness of psychotropic medication use and the validity of psychiatric diagnosing for youth in child welfare but has lacked in-depth case information. This study reports results from a psychiatric nurse review conducted with eight youth entering a foster care intervention using case records and multiple key informant interviews. Results revealed extensive histories of unique (nonoverlapping) psychiatric diagnoses (M = 8, range 7-9) and past psychotropic medications (M = 13, range 9-21). The findings highlight the need to improve assessment practices and to create mechanisms that promote greater continuity of psychiatric care.

WT1 Expression As a Marker of Minimal Residual Disease Predicts Outcome in Acute Myeloid Leukemia when Measured Post-consolidation

WT1 levels may be a useful predictor of leukemia free survival (LFS) following treatment of acute myeloid leukemia (AML). We report a retrospective study in which levels of WT1 expression from patients with de novo AML were measured from bone marrow and peripheral blood at diagnosis, post-induction, post-consolidation and relapse. We demonstrate that higher levels of WT1 in peripheral blood at diagnosis are associated with poorer LFS independent of age and cytogenetic risk-group (n=85, p=0.028). When measured at post-consolidation, the presence of detectable WT1 is associated with poorer LFS in univariate analysis of both peripheral blood (p=0.024) and bone marrow (p=0.019). In a multivariate analysis including age and cytogenetic risk, the association remained significant for bone marrow (p=0.016) with a trend observed for peripheral blood (p=0.06). These findings have formed the basis for ongoing research.

In Memoriam: Robert D. Myers Founding Editor, Alcohol: an International Biomedical Journal

Assessing Gender Equity in a Large Academic Department of Pediatrics

To determine the extent of gender inequity in a large academic pediatrics department and to demonstrate an assessment methodology other departments can use.

Early Origins of Heart Disease: Low Birth Weight and Determinants of Cardiomyocyte Endowment

1. World-wide epidemiological and experimental animal studies demonstrate that adversity in fetal life, resulting in intrauterine growth restriction, programmes the offspring for a greater susceptibility to ischaemic heart disease and heart failure in adult life. 2. After cardiogenesis, cardiomyocyte endowment is determined by a range of hormones and signalling pathways that regulate cardiomyocyte proliferation, apoptosis and the timing of multinucleation/terminal differentiation. 3. The small fetus may have reduced cardiomyocyte endowment owing to the impact of a suboptimal intrauterine environment on the signalling pathways that regulate cardiomyocyte proliferation, apoptosis and the timing of terminal differentiation.

Domain Wall Propagation in Meso- and Nanoscale Ferroelectrics

As part of an ongoing programme to evaluate the extent to which external morphology alters domain wall mobility in ferroelectrics, the electrical switching characteristics of single-crystal BaTiO(3) nanorods and thin film plates have been measured and compared. It was found that ferroelectric nanorods were more readily switched than thin plates; increasing the shape constraint therefore appears to enhance switchability. This observation is broadly consistent with previous work, in which local notches patterned along the length of nanorods enhanced switching (McMillen et al 2010 Appl. Phys. Lett. 96 042904), while antinotches had the opposite effect (McQuaid et al 2010 Nano Lett. 10 3566). In this prior work, local enhancement and denudation of the electric field was expected at the notch and antinotch sites, respectively, and this was thought to be the reason for the differences in switching behaviour observed. However, for the simple nanorods and plates investigated here, no differences in the electric field distributions are expected. To rationalise the functional measurements, domain development during switching was imaged directly by piezoresponse force microscopy. A two-stage process was identified, in which narrow needle-like reverse domains initially form across the entire interelectrode gap and then subsequently coarsen through domain wall propagation perpendicular to the applied electric field. To be consistent with the electrical switching data, we suggest that the initial formation of needle domains occurs more readily in the nanorods than in the plates.

Obesity and Weight Loss Result in Increased Adipose Tissue ABCG1 Expression in Db/db Mice

The prevalence of obesity has reached epidemic proportions and is associated with several co-morbid conditions including diabetes, dyslipidemia, cancer, atherosclerosis and gallstones. Obesity is associated with low systemic inflammation and an accumulation of adipose tissue macrophages (ATMs) that are thought to modulate insulin resistance. ATMs may also modulate adipocyte metabolism and take up lipids released during adipocyte lipolysis and cell death. We suggest that high levels of free cholesterol residing in adipocytes are released during these processes and contribute to ATM activation and accumulation during obesity and caloric restriction. Db/db mice were studied for extent of adipose tissue inflammation under feeding conditions of ad libitum (AL) and caloric restriction (CR). The major finding was a marked elevation in epididymal adipose ABCG1 mRNA levels with obesity and CR (6-fold and 16-fold, respectively) over that seen for lean wild-type mice. ABCG1 protein was also elevated for CR as compared to AL adipose tissue. ABCG1 is likely produced by cholesterol loaded ATMs since this gene is not highly expressed in adipocytes and ABCG1 expression is sterol mediated. Our data supports the concept that metabolic changes in adipocytes due to demand lipolysis and cell death lead to cholesterol loading of ATMs. Based on finding cholesterol-loaded peritoneal leukocytes with elevated levels of ABCG1 in CR as compared to AL mice, we suggest that pathways for cholesterol trafficking out of adipose tissue involve ATM egress as well as ABCG1 mediated cholesterol efflux. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).

A Compilation of Strategies for Implementing Clinical Innovations in Health and Mental Health

Efforts to identify, develop, refine, and test strategies to disseminate and implement evidence-based treatments have been prioritized in order to improve the quality of health and mental health care delivery. However, this task is complicated by an implementation science literature characterized by inconsistent language use and inadequate descriptions of implementation strategies. This article brings more depth and clarity to implementation research and practice by presenting a consolidated compilation of discrete implementation strategies, based on a review of 205 sources published between 1995 and 2011. The resulting compilation includes 68 implementation strategies and definitions, which are grouped according to six key implementation processes: planning, educating, financing, restructuring, managing quality, and attending to the policy context. This consolidated compilation can serve as a reference to stakeholders who wish to implement clinical innovations in health and mental health care and can facilitate the development of multifaceted, multilevel implementation plans that are tailored to local contexts.

Stepping Down and Stepping In: Youth's Perspectives on Making the Transition from Residential Treatment to Treatment Foster Care

Older youth preparing to emancipate from the foster care system are often served in residential treatment settings where they have limited opportunities to practice skills for independent living in a community setting. Stepping these youth down to less restrictive environments such as treatment foster care is a growing trend, especially for youth with mental health issues. Yet, few studies have explored the youth's perspective on making this transition. This study utilized qualitative interviews with youths who were participating in a treatment foster care intervention study (n=8) to gain their perspectives on the process of transitioning from residential care. Youths were interviewed right before they exited residential care and two months after placement in the new foster home. Youths reported hopes for gaining family in the new home as well as fears of placement disruption. Findings point to the need to enlist youths in discussion and problem solving about difficulties they anticipate in the new home and expectations for their relationship with the new foster parents. In addition, the struggles described after two months in the home point to the need for youths to build specific skills to better manage ongoing relationships with foster parents and for foster parent training on how to help build these skills.

Deficiency of Lymphotoxin-α Does Not Exacerbate High-fat Diet-induced Obesity but Does Enhance Inflammation in Mice

Lymphotoxin-α (LTα) is secreted by lymphocytes and acts through tumor necrosis factor-α receptors and the LTβ receptor. Our goals were to determine whether LT has a role in obesity and investigate whether LT contributes to the link between obesity and adipose tissue lymphocyte accumulation. LT deficient (LT(-/-)) and wild-type (WT) mice were fed standard pelleted rodent chow or a high-fat/high-sucrose diet (HFHS) for 13 wk. Body weight, body composition, and food intake were measured. Glucose tolerance was assessed. Systemic and adipose tissue inflammatory statuses were evaluated by quantifying plasma adipokine levels and tissue macrophage and T cell-specific gene expression in abdominal fat. LT(-/-) mice were smaller (20%) and leaner (25%) than WT controls after 13 wk of HFHS diet feeding. LT(-/-) mice showed improved glucose tolerance, suggesting that, in WT mice, LT may impair glucose metabolism. Surprisingly, adipose tissue from rodent chow- and HFHS-fed LT(-/-) mice exhibited increased T lymphocyte and macrophage infiltration compared with WT mice. Despite the fact that LT(-/-) mice exhibited an enhanced inflammatory status at the systemic and tissue level even when fed rodent chow, they were protected from enhanced diet-induced obesity and insulin resistance. Thus, LT contributes to body weight and adiposity and is required to modulate the accumulation of immune cells in adipose tissue.

Hydrothermal Synthesis and Comparative Coordination Chemistry of New Rare-earth V4+ Compounds

Several new hydrated rare earth vanadates and rare earth oxy-vanadates have been synthesized using hydrothermal techniques and characterized using single crystal and powder X-ray diffraction and infrared and UV-vis absorption spectroscopies. The hydrated rare earth vanadates adopt the space group P2(1)/m with general formula A(3)VO(5)(OH)(3) (A = Y (1), Dy (2), or La (3)) and contain anionic distorted square pyramidal [VO(5)](-6) units and AO(7) and AO(8) polyhedra. The oxy-vanadates with the general formula A(2)O(VO(4)) (A = Y (4), Dy (5; 6), or Yb (7)) form two polymorphs in either P2(1)/c or C2/c space groups and contain anionic tetrahedral [VO(4)](-4) units and nonvanadium bonded O(2-) anions in distorted [OA(4)] tetrahedra. In all cases, the vanadium ion is in the tetravalent oxidation state, and its original source was the trace V(4+) impurities in YVO(4). The observed vanadyl and equatorial vanadium-oxygen bond lengths about the square pyramid in compounds 1-3 and the tetrahedral vanadium coordination found in compounds 4-7 are unusual for V(4+). The electronic and vibrational spectra are also reported and correlated with the appropriate coordination environment.

Two Novel Acentric Borate Fluorides: M3B6O11F2 (M = Sr, Ba)

Two novel, noncentrosymmetric borate fluorides, Sr(3)B(6)O(11)F(2) and Ba(3)B(6)O(11)F(2), have been synthesized hydrothermally and their structures determined. The compounds are isostructural, crystallizing in space group P2(1), having lattice parameters of a = 6.4093 (13) Å, b = 8.2898 (17) Å, c = 9.3656 (19) Å, and β = 101.51 (3)° for Sr(3)B(6)O(11)F(2) and a = 6.5572 (13) Å, b = 8.5107 (17) Å, c = 9.6726 (19) Å, and β = 101.21 (3)° for Ba(3)B(6)O(11)F(2). The structure consists of a complex triple-ring borate framework having aligned triangular [BO(3)] groups that impart polarity. Fluorine atoms are bound only to the alkaline-earth metals and are not part of the borate framework, resulting in a vastly different structure from those of the hydrated borates Sr(3)B(6)O(11)(OH)(2) and Ba(3)B(6)O(11)(OH)(2) with similar formulas. The title compounds are transparent to nearly 200 nm, making them potentially useful for deep-ultraviolet nonlinear-optical applications.

Hydrothermal Synthesis and Crystal Structure of Two New Hydrated Alkaline Earth Metal Borates Sr3B6O11(OH)2 and Ba3B6O11(OH)2

Two new hydrated borates Sr(3)B(6)O(11)(OH)(2) (1) and Ba(3)B(6)O(11)(OH)(2) (2) were hydrothermally synthesized. Their structures were determined by single-crystal X-ray diffraction and further characterized by IR, powder XRD, and DSC/TGA. Compound 1 crystallizes in the triclinic space group P-1 with unit cell parameters of a = 6.6275(13) Å, b = 6.6706(13) Å, c = 11.393(2) Å, α = 91.06(3)°, β = 94.50(3)°, and γ = 93.12(3)°, while compound 2 crystallizes in the noncentrosymmetric monoclinic space group Pc with a = 6.958(14) Å, b = 7.024(14) Å, c = 11.346(2) Å, and β = 90.10(3)°. In spite of the differences in symmetry and packing of the borate chains, both structures consist of the same fundamental building block (FBB) of a [B(6)O(11)(OH)(2)](-6) unit and three unique alkaline earth metal atoms.

Detection of Infectious Influenza Virus in Cough Aerosols Generated in a Simulated Patient Examination Room

The potential for aerosol transmission of infectious influenza virus (ie, in healthcare facilities) is controversial. We constructed a simulated patient examination room that contained coughing and breathing manikins to determine whether coughed influenza was infectious and assessed the effectiveness of an N95 respirator and surgical mask in blocking transmission.

Indacaterol: a Novel Long-acting β(2) -agonist

Bronchodilator drugs are the foundation for the treatment of chronic obstructive pulmonary disease. The principal inhaled bronchodilator treatments used are β(2) -agonists and anticholinergics, either alone or in combination. Currently available β(2) -agonists are of either short duration and used multiple times/day, or of long duration, which requires twice-daily administration. Indacaterol is considered an ultra-long-acting β(2) -agonist and was recently approved for use in the United States. Its duration of action is approximately 24 hours, allowing for once-daily administration. Cough was the most commonly reported adverse effect with use of indacaterol. Cough usually occurred within 15 seconds of inhalation of the drug, lasted around 6 seconds, was not associated with bronchospasm, and did not cause discontinuation of the drug. Otherwise, the drug's safety profile was similar to that of other bronchodilators. Based on similar improvement in spirometric measurements compared with other bronchodilator drugs and the convenience of its once-daily dosing, indacaterol may be beneficial in the management of mild-to-moderate chronic obstructive pulmonary disease, either alone or in combination with anticholinergic drugs administered once/day.

Ultrafast Laser Fabrication of Low-loss Waveguides in Chalcogenide Glass with 0.65 DB/cm Loss

This Letter reports on the fabrication of low-loss waveguides in gallium-lanthanum-sulfide chalcogenide glasses using an ultrafast laser. Spatial beam shaping and temporal pulse width tuning were used to optimize the guided mode profiles and optical loss of laser-written waveguides. Highly symmetric single-mode waveguides guiding at 1560 nm with a loss of 0.65  dB/cm were fabricated using 1.5 ps laser pulses. This Letter suggests a pathway to produce high quality optical waveguides in substrates with strong nonlinearity using the ultrafast laser direct writing technique.

Use of Emerging Tobacco Products in the United States

This paper provides the first nationally representative estimates for use of four emerging products. Addressing the issue of land-line substitution with cell phones, we used a mixed-mode survey to obtain two representative samples of US adults. Of 3,240 eligible respondents contacted, 74% completed surveys. In the weighted analysis, 13.6% have tried at least one emerging tobacco product; 5.1% snus; 8.8% waterpipe; 0.6% dissolvable tobacco products; 1.8% electronic nicotine delivery systems (ENDS) products. Daily smokers (25.1%) and nondaily smokers (34.9%) were the most likely to have tried at least one of these products, compared to former smokers (17.2%) and never smokers (7.7%), P<.001. 18.2% of young adults 18-24 and 12.8% of those >24 have tried one of these products, P<.01. In multivariable analysis, current daily (5.5, 4.3-7.6), nondaily (6.1, 4.0-9.3), and former smoking status (2.7, 2.1-3.6) remained significant, as did young adults (2.2, 1.6-3.0); males (3.5, 2.8-4.5); higher educational attainment; some college (2.7, 1.7-4.2); college degree (2.0, 1.3-3.3). Use of these products raises concerns about nonsmokers being at risk for nicotine dependence and current smokers maintaining their dependence. Greater awareness of emerging tobacco product prevalence and the high risk demographic user groups might inform efforts to determine appropriate public health policy and regulatory action.

Maintaining Quality of Care 24/7 in a Nontrauma Surgical Intensive Care Unit

Most surgical critical care literature reflects practices at trauma centers and tertiary hospitals. Surgical critical care needs and practices may be quite different at nontrauma center teaching hospitals. As acute care surgery develops as a component of surgical critical care and trauma, the opportunities and challenges of the nontrauma centers should be considered.

The Joint Commission's New Tobacco-cessation Measures

Copper Chelation by Tetrathiomolybdate Inhibits Vascular Inflammation and Atherosclerotic Lesion Development in Apolipoprotein E-deficient Mice

Endothelial activation, which is characterized by upregulation of cellular adhesion molecules and pro-inflammatory chemokines and cytokines, and consequent monocyte recruitment to the arterial intima are etiologic factors in atherosclerosis. Redox-active transition metal ions, such as copper and iron, may play an important role in endothelial activation by stimulating redox-sensitive cell signaling pathways. We have shown previously that copper chelation by tetrathiomolybdate (TTM) inhibits LPS-induced acute inflammatory responses in vivo. Here, we investigated whether TTM can inhibit atherosclerotic lesion development in apolipoprotein E-deficient (apoE-/-) mice. We found that 10-week treatment of apoE-/- mice with TTM (33-66 ppm in the diet) reduced serum levels of the copper-containing protein, ceruloplasmin, by 47%, and serum iron by 26%. Tissue levels of "bioavailable" copper, assessed by the copper-to-molybdenum ratio, decreased by 80% in aorta and heart, whereas iron levels of these tissues were not affected by TTM treatment. Furthermore, TTM significantly attenuated atherosclerotic lesion development in whole aorta by 25% and descending aorta by 45% compared to non-TTM treated apoE-/- mice. This anti-atherogenic effect of TTM was accompanied by several anti-inflammatory effects, i.e., significantly decreased serum levels of soluble vascular cell and intercellular adhesion molecules (VCAM-1 and ICAM-1); reduced aortic gene expression of VCAM-1, ICAM-1, monocyte chemotactic protein-1, and pro-inflammatory cytokines; and significantly less aortic accumulation of M1 type macrophages. In contrast, serum levels of oxidized LDL were not reduced by TTM. These data indicate that TTM inhibits atherosclerosis in apoE-/- mice by reducing bioavailable copper and vascular inflammation, not by altering iron homeostasis or reducing oxidative stress.

Early Origins of Heart Disease: Low Birth Weight and the Role of the Insulin-like Growth Factor System in Cardiac Hypertrophy

Epidemiological studies indicate that poor growth before birth is associated with left ventricular hypertrophy and an increased risk of death from heart disease later in life. In fetal life, the insulin-like growth factor (IGF) system has been implicated in physiological growth of the heart, whereas in postnatal life IGFs can be involved in both physiological and pathological cardiac hypertrophy. A reduction in substrate supply in fetal life, resulting in chronic hypoxaemia and intrauterine growth restriction, results in increased cardiac IGF-1R, IGF-2 and IGF-2R gene expression; and there is also evidence for a role of the IGF-2 receptor in the ensuing cardiac hypertrophy. The persistent high level of cardiac IGF-2R gene expression from fetal to postnatal life may be due to epigenetic changes in key cardiac hypertrophy regulatory pathways.

Out of Control Little-used Clinical Assets Are Draining Healthcare Budgets

To improve utilization and reduce the cost of maintaining mobile clinical equipment, healthcare organization leaders should do the following: Select an initial asset group to target. Conduct a physical inventory. Evaluate the organization's asset "ecosystem." Optimize workflow processes. Phase in new processes, and phase out inventory. Devote time to change management. Develop a replacement strategy.

Expression Analysis of MIR182 and Its Associated Target Genes in Advanced Ovarian Carcinoma

BRCA1/BRCA2 mutations are common and the hallmarks of high-grade serous ovarian carcinoma. We found that MIR182, a negative BRCA1 regulator, is significantly overexpressed in high-grade serous ovarian carcinoma. To examine whether overexpression of MIR182 and its target genes, including BRCA1, HMGA2 (high-mobility group A2), FOXO3 and MTSS1, are associated with high-grade serous ovarian carcinoma tumor types and clinical outcome, we studied MIR182 by in situ hybridization and its target gene expression by immunohistochemistry in 117 cases of advanced ovarian cancer. We found that high-grade serous ovarian carcinoma had significantly higher MIR182 (P=0.0003) and HMGA2 (P=0.04) expression, and significantly lower BRCA1 (P<0.0001) and FOXO3 (P<0.001) expression than normal controls. MIR182 is significantly correlated with MTSS1 expression (r=0.31; P<0.001), whereas other target genes did not show a significant correlation with MIR182, indicating a complicated regulatory mechanisms of these genes in high-grade serous ovarian carcinoma. Among the examined MIR182 target genes, only HMGA2 was significantly associated with serous type carcinomas (P<0.01), ascites (P<0.01) and high death rate (P=0.02). FOXO3 expression was associated with lower-stage disease (P=0.04) and solid growth pattern (P=0.03). MIR182 expression is significantly higher in high-grade serous ovarian carcinoma than in fallopian tubes.

Assessing Secondhand Smoke Exposure with Reported Measures

Non-smokers are exposed to tobacco smoke from the burning cigarette and the exhaled smoke from smokers. In spite of decades of development of approaches to assess secondhand smoke exposure (SHSe), there are still unresolved methodological issues. This manuscript summarises the scientific evidence on the use of SHSe reported measures and their methods, objectives, strengths and limitations; and discusses best practices for assessing behaviour leading to SHSe for lifetime and immediate or current SHSe. Recommendations for advancing measurement science of SHSe are provided. Behavioural measures of SHSe commonly rely on self-reports from children and adults. Most commonly, the methodology includes self, proxy and interview-based reporting styles using retrospective recall or diary-style reporting formats. The reporting method used will vary based upon the subject of interest, assessment objectives and cultural context. Appropriately implemented, reported measures of SHSe provide an accurate, timely and cost-effective method for assessing exposure time, location and quantity in a wide variety of populations.

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