Suboptimal maternal nutrition, during early fetal liver development, promotes lipid accumulation in the liver of obese offspring.

Maternal nutrition during the period of early organ development can modulate the offspring's ability to metabolise excess fat as young adults when exposed to an obesogenic environment. This study examined the hypothesis that exposing offspring to nutrient restriction coincident with early hepatogenesis would result in endocrine and metabolic adaptations that subsequently lead to increased ectopic lipid accumulation within the liver. Pregnant sheep were fed either 50 or 100% of total metabolisable energy requirements from 30 to 80 days gestation and 100% thereafter. At weaning, offspring were made obese, and at ~1 year of age livers were sampled. Lipid infiltration and molecular indices of gluconeogenesis, lipid metabolism and mitochondrial function were measured. Although hepatic triglyceride accumulation was not affected by obesity per se, it was nearly doubled in obese offspring born to nutrient-restricted mothers. This adaptation was accompanied by elevated gene expression for peroxisome proliferator-activated receptor γ (PPARG) and its co-activator PGC1α, which may be indicative of changes in the rate of hepatic fatty acid oxidation. In contrast, maternal diet had no influence on the stimulatory effect of obesity on gene expression for a range of proteins involved in glucose metabolism and energy balance including glucokinase, glucocorticoid receptors and uncoupling protein 2. Similarly, although gene expressions for the insulin and IGF1 receptors were suppressed by obesity they were not influenced by the prenatal nutritional environment. In conclusion, excess hepatic lipid accumulation with juvenile obesity is promoted by suboptimal nutrition coincident with early development of the fetal liver.

Arrays of Ag split-ring resonators coupled to InGaAs single-quantum-well gain.

We study arrays of silver split-ring resonators operating at around 1.5-µm wavelength coupled to an MBE-grown single 12.7-nm thin InGaAs quantum well separated only 4.8 nm from the wafer surface. The samples are held at liquid-helium temperature and are pumped by intense femtosecond optical pulses at 0.81-µm center wavelength in a pump-probe geometry. We observe much larger relative transmittance changes (up to about 8%) on the split-ring-resonator arrays as compared to the bare quantum well (not more than 1-2%). We also observe a much more rapid temporal decay component of the differential transmittance signal of 15 ps for the case of split-ring resonators coupled to the quantum well compared to the case of the bare quantum well, where we find about 0.7 ns. These observations are ascribed to the evanescent coupling of the split-ring resonators to the quantum-well gain. All experimental results are compared with a recently introduced analytical toy model that accounts for this evanescent coupling, leading to excellent overall qualitative agreement.

Influence of prenatal nutrition and obesity on tissue specific fat mass and obesity-associated (FTO) gene expression.

The recent discovery of an association between body composition, energy intake and the fat mass and obesity-associated (FTO) gene represents a promising new therapeutic target in obesity prevention. In a well, pre-established large animal model, we investigated the regulation of FTO gene expression under conditions either leading to obesity or increased risk of obesity related disorders: i) a sedentary 'Western' lifestyle and ii) prenatal exposure to nutrient restriction. Pregnant sheep were either fed to fully meet their nutritional requirements throughout gestation or 50% of this amount from early-to-mid gestation. Following weaning, offspring were either made obese through exposure to a sedentary obesogenic environment or remained lean. A significant positive relationship between placental FTO gene expression and fetal weight was found at 110 days gestation. In both the newborn and adult offspring, the hypothalamus was the major site of FTO gene expression. Hypothalamic FTO gene expression was upregulated by obesity and was further increased by prenatal nutrient restriction. Importantly, we found a strong negative relationship between the hypothalamic FTO gene expression and food intake in lean animals only that may imply FTO as a novel controller of energy intake. In contrast, FTO gene expression in the heart was downregulated in obese offspring born to nutrient restricted mothers. In addition, FTO gene expression was unaffected by obesity or prenatal diet in insulin-dependent tissues, where it changed with age possibly reflecting adaptations in cellular energetic activity. These findings extend information gained from human epidemiology and provide new insights into the regulation of in vivo energy metabolism to prevent obesity.

Effects of maternal cold exposure and nutrient restriction on the ghrelin receptor, the GH-IGF axis, and metabolic regulation in the postnatal ovine liver.

Maternal cold exposure of pregnant sheep promotes fetal growth, whereas nutrient restriction (NR) can reverse this effect. The present study was designed to establish whether cold exposure induced by winter shearing of the mother at 70 days gestation (term=147 days), with or without NR (induced by a 50% reduction in maternal food intake from 110 days gestation), has specific effects on mRNA abundance of hepatic genes related to growth and liver energy metabolism that could regulate postnatal body and liver growth. Measurements of hepatic gene expression for the GH secretagog receptor-1a (GHSR-1A), peroxisome proliferator-activated receptor (PPAR)alpha, phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase activity together with glycogen content were made in the livers of offspring at 1 and 30 days of age. Maternal NR reduced liver mass at day 1, whereas offspring of cold-exposed mothers had larger livers at day 30 irrespective of maternal diet. Cold exposure resulted in the up-regulation of GHSR-1A mRNA abundance and reduced glucose-6-phosphatase activity at 1, but not 30 days of age, whereas IGF-II mRNA was decreased at 1 and 30 days. PPARalpha mRNA abundance was enhanced, while PEPCK was reduced in 30-day old offspring of cold-exposed mothers. NR caused reductions in IGF-I mRNA and, at 1-day postnatal age, down-regulated GHR, while, at 30 days, reduced GHSR-1A gene expression and hepatic glycogen content. In conclusion, we have shown that maternal cold exposure and NR have different effects on the hepatic GH-IGF and metabolic axis that may contribute to changes in liver growth over the first month of life.

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.

SETA is a multifunctional adapter protein with three SH3 domains that binds Grb2, Cbl, and the novel SB1 proteins.

Expression of the src homology 3 (SH3)-encoding, expressed in tumorigenic astrocytes (SETA) gene is associated with astrocyte transformation in culture and tumors in the adult brain. SETA binds to the apoptosis regulator apoptosis-linked gene 2 (ALG-2) interacting protein 1 (AIP1), and modulates apoptosis in astrocytes. The predicted protein structure of SETA revealed two SH3 domains, while related proteins were reported to have three. Here we report the identification of an additional SH3 domain N-terminal to the previously identified SETA sequence. Yeast two-hybrid screening of a p53(-/-) astrocyte cDNA library with this SH3 domain identified a novel gene, SETA binding protein 1 (SB1), with 55% amino acid identity to the renal tumor antigen, NY-REN-45. In vitro confrontation and co-immunoprecipitation experiments confirmed the binding of SB1 to SETA. Evidence that SETA binds to the CD2 protein, the proto-oncogene c-Cbl, and the signal transduction molecule Grb2, and can dimerize via its C-terminal coiled coil (CC) domain is also presented.

The cytoplasmic and nuclear populations of the eukaryote tRNA-isopentenyl transferase have distinct functions with implications in human cancer.

Mod5 is the yeast tRNA isopentenyl transferase, an enzyme that is conserved from bacteria to humans. Mod5 is primarily cytoplasmic where it modifies the A37 position of a few tRNAs, and the yeast enzyme has been shown capable of forming heritable, amyloid-like aggregates that confer a selective advantage in the presence of specific antifungal agents. A subpopulation of Mod5 is also found associated with nuclear tRNA genes, where it contributes tRNA-gene mediated (tgm) silencing of local transcription by RNA polymerase II. The tgm-silencing function of Mod5 has been observed in yeast and a Mod5-deletion in yeast can be complemented by the plant and human tRNA isopentenyl transferases, but not the bacterial enzymes, possibly due to the lack of an extended C-terminal domain found in eukaryotes. In light of this additional nuclear role for Mod5 we discuss the proposed role of the human homologue of Mod5, TRIT1, as a tumor suppressor protein.

The effects of ethanol on the efflux and release of norepinephrine and 5-hydroxytryptamine from slices of rat hypothalamus.

Studies were done to determine the effects of ethanol on release of norepinephrine, dopamine and 5-hydroxytryptamine from nerve terminals in the central nervous system. Superfused slices of rat hypothalamus were used in these studies and endogenous amines in the superfusate were quantitated using HPLC with electrochemical detection. In these experiments 'release' of transmitters was studied in the presence of amitriptyline to block neuronal uptake of amines, whereas 'efflux' was measured in its absence. A highly intoxicating concentration of ethanol (69.6 mM, 320 mg%) increased the K+-evoked release of norepinephrine, dopamine and serotonin without affecting basal release. Since this concentration of ethanol increased the basal efflux but not the basal release of 5-hydroxytryptamine, it appeared that neuronal uptake of 5-hydroxytryptamine under basal conditions may also be inhibited by intoxicating levels of ethanol.

Effect of multileaf collimator leaf width on physical dose distributions in the treatment of CNS and head and neck neoplasms with intensity modulated radiation therapy.

The purpose of this work is to examine physical radiation dose differences between two multileaf collimator (MLC) leaf widths (5 and 10 mm) in the treatment of CNS and head and neck neoplasms with intensity modulated radiation therapy (IMRT). Three clinical patients with CNS tumors were planned with two different MLC leaf sizes, 5 and 10 mm, representing Varian-120 and Varian-80 Millennium multileaf collimators, respectively. Two sets of IMRT treatment plans were developed. The goal of the first set was radiation dose conformality in three dimensions. The goal for the second set was organ avoidance of a nearby critical structure while maintaining adequate coverage of the target volume. Treatment planning utilized the CadPlan/Helios system (Varian Medical Systems, Milpitas CA) for dynamic MLC treatment delivery. All beam parameters and optimization (cost function) parameters were identical for the 5 and 10 mm plans. For all cases the number of beams, gantry positions, and table positions were taken from clinically treated three-dimensional conformal radiotherapy plans. Conformality was measured by the ratio of the planning isodose volume to the target volume. Organ avoidance was measured by the volume of the critical structure receiving greater than 90% of the prescription dose (V(90)). For three patients with squamous cell carcinoma of the head and neck (T2-T4 N0-N2c M0) 5 and 10 mm leaf widths were compared for parotid preservation utilizing nine coplanar equally spaced beams delivering a simultaneous integrated boost. Because modest differences in physical dose to the parotid were detected, a NTCP model based upon the clinical parameters of Eisbruch et al. was then used for comparisons. The conformality improved in all three CNS cases for the 5 mm plans compared to the 10 mm plans. For the organ avoidance plans, V(90) also improved in two of the three cases when the 5 mm leaf width was utilized for IMRT treatment delivery. In the third case, both the 5 and 10 mm plans were able to spare the critical structure with none of the structure receiving more than 90% of the prescription dose, but in the moderate dose range, less dose was delivered to the critical structure with the 5 mm plan. For the head and neck cases both the 5 and 10 x 2.5 mm beamlets dMLC sliding window techniques spared the contralateral parotid gland while maintaining target volume coverage. The mean parotid dose was modestly lower with the smaller beamlet size (21.04 Gy v 22.36 Gy). The resulting average NTCP values were 13.72% for 10 mm dMLC and 8.24% for 5 mm dMLC. In conclusion, five mm leaf width results in an improvement in physical dose distribution over 10 mm leaf width that may be clinically relevant in some cases. These differences may be most pronounced for single fraction radiosurgery or in cases where the tolerance of the sensitive organ is less than or close to the target volume prescription.

Prognostic implications of early multimodality evoked potentials in severely head-injured patients. A prospective study.

Results of multimodality evoked potential (MEP) studies recorded from 100 comatose patients soon after severe head injury were analyzed prospectively, using a previously established grading system, to assess the prognostic value of MEP's with respect to patient outcome, to evaluate the effect of clinically relevant sequelae of head injury on the prediction of outcome by MEP's and to describe time to clinical recovery as a function of initial MEP grade. Graded MEP's when recorded in the first few days after head injury, could predict patient outcome at 1 year with approximately 80% accuracy. Exclusion from the analysis of patients who died from causes unrelated to the brain and those with severe systemic complications that occurred after the evoked potentials were recorded improved the accuracy of outcome prediction to nearly 100%. The presence of a mass lesion requiring surgery reduces the probability if good to moderate outcome for a given MEP grade by approximately 25% to 40% from the seen in patients without mass lesions. The clinical outcome predicted shortly after head injury by MEP grades may not be realized for many months. Patients with mild MEP abnormality (Grade I or II) generally reach their outcome by 3 to 6 months, whereas those with more severe deficits (Grade III) may not show improvement for at least 1 year.

The dynamics of neuronal dysfunction and recovery following severe head injury assessed with serial multimodality evoked potentials.

Serial studies of visual, auditory, and somatosensory evoked potentials (EP's) obtained from 139 severely head-injured patients up to 1 year after trauma were analyzed to ascertain whether or nor EP's can be used to monitor neurological recovery or deterioration following secondary insults. The EP data were analyzed using a grading system of abnormality developed previously, and patients were grouped by the most severe EP abnormality found in any modality during an early study (mean Day 3). The findings showed differential recovery trends depending on the severity of EP abnormality obtained on the initial study and presence of secondary insult. If EP's were normal early after injury, they remained so for up to 1 year, and these patients did well clinically. The EP's that were absent did not improve, and the patients had poor outcomes. Secondary insults did not affect the EP's or the outcomes of patients in these two groups. When EP's that were initially mildly abnormal became normal or remained no worse than mildly abnormal, patients had favorable outcomes in spite of complications. In contrast, deterioration of EP's with secondary insult indicated poor patient outcome. Severe EP abnormalities which improved over time led to favorable outcomes. However, persistence or deterioration of severe abnormalities indicated a poor outcome. Changes in EP's over time were better indicators of outcome than the presence or absence of complications. The results suggest that EP's may be used to assess neural recovery and the consequences of secondary insults to the brain. Four case reports are included to exemplify results.

Effects of estradiol on the basal and evoked efflux of norepinephrine and 5-hydroxytryptamine from slices of rat hypothalamus.

17-beta-Estradiol, at a concentration (100 ng/ml) approaching plasma levels found in pregnant women, inhibited the K+-evoked efflux of endogenous norepinephrine from superfused slices of rat hypothalamus. The same concentration of estradiol increased slightly the basal efflux of serotonin. Since estradiol crosses the blood-brain barrier with ease it is suggested that the inhibition of norepinephrine release from central neurons may contribute to the depression and emotional lability sometimes associated with estradiol therapy.

The use of midazolam for hypnosedative interviews.

The authors describe three cases in which midazolam was successfully used in diagnostic hypnosedative interviews. A discussion comparing and contrasting midazolam to other intravenous hypnosedatives is presented. The authors suggest that midazolam is an effective agent for diagnostic hypnosedative interviews and may be preferable to other agents when posthypnotic recollection of interview content is undesirable.

Volume and surface three-dimensional displays of Tc-99m HMPAO brain SPECT imaging in a chronic hypnosedative abuser.

An alcohol- and diazepam-abusing patient underwent brain CT and SPECT imaging studies. The CT scan showed mild brain atrophy, whereas SPECT imaging using Tc-99m HMPAO showed a large lesion in the left cerebral hemisphere. The extent of lesion involvement was appreciated by three-dimensional displays. This finding was associated with a clinical presentation of hypnosedative withdrawal delirium (disorientation, impaired memory, rambling speech with loose associations, paranoia, ideation, restlessness, poor judgment). Tc-99m HMPAO SPECT may provide objective documentation of regional cerebral neurochemical alteration associated with hypnosedative abuse or hypnosedative withdrawal states, whereas surface and volume three-dimensional displays simplify and enhance brain SPECT image interpretation.

Operational and scientific notes.

Published information on the distribution of Aedes albopictus in South Carolina is limited and fragmentary. This paper draws on various published and unpublished sources and presents synoptic information on the occurrence of the mosquito in 17 counties. Additional surveys are required to establish the infestation status of the other 29 counties in the state.

Malathion resistance in mosquitoes from Charleston and Georgetown counties of coastal South Carolina.

Susceptibility tests were conducted using the World Health Organization diagnostic test procedure on strains of Aedes taeniorhynchus, Aedes sollicitans, Aedes vexans, and Culex nigripalpus collected from several localities in Charleston and Georgetown counties of South Carolina. Aedes taeniorhynchus was resistant to malathion (mortality 1.0-54.4%) but not to propoxur, permethrin, or fenitrothion. There also were indications that Ae. sollicitans and Cx. nigripalpus were resistant to malathion, but to a lesser extent than Ae. taeniorhynchus (mortalities: 72.1-81.0%, and 46.2%, respectively). Aedes vexans was susceptible to malathion (mortality 98.6%). In field tests using ULV application of malathion and field-collected Ae. taeniorhynchus, and susceptible Ae. aegypti and Ae. taeniorhynchus, a noticeably lower mortality also was obtained in the wild mosquitoes.

Maternal parity and its effect on adipose tissue deposition and endocrine sensitivity in the postnatal sheep.

Maternal parity influences size at birth, postnatal growth and body composition with firstborn infants being more likely to be smaller with increased fat mass, suggesting that adiposity is set in early life. The precise effect of parity on fat mass and its endocrine sensitivity remains unclear and was, therefore, investigated in the present study. We utilised an established sheep model in which perirenal-abdominal fat mass (the major fat depot in the neonatal sheep) increases approximately 10-fold over the first month of life and focussed on the impact of parity on glucocorticoid sensitivity and adipokine expression in the adipocyte. Twin-bearing sheep of similar body weight and adiposity that consumed identical diets were utilised, and maternal blood samples were taken at 130 days of gestation. One offspring from each twin pair was sampled at 1 day of age, coincident with the time of maximal recruitment of uncoupling protein 1 (UCP1), whilst its sibling was sampled at 1 month, when UCP1 had disappeared. Plasma leptin was lower in nulliparous mothers than in multiparous mothers, and offspring of nulliparous mothers possessed more adipose tissue with increased mRNA abundance of leptin, glucocorticoid receptor and UCP2, adaptations that persisted up to 1 month of age when gene expression for interleukin-6 and adiponectin was also raised. The increase in fat mass associated with firstborn status is therefore accompanied by a resetting of the leptin and glucocorticoid axis within the adipocyte. Our findings emphasise the importance of parity in determining adipose tissue development and that firstborn offspring have an increased capacity for adipogenesis which may be critical in determining later adiposity.