bluuebunny/crossref_metadata_2025 huggingface dataset:
Neural Representations of Individual Stimuli in Humans Revealed by Gamma-Band Electrocorticographic Activity
Authors: Jacobs Joshua , Kahana Michael J.
Published: August 2009

A fundamental question in neuroscience concerns how the human brain represents perceptual and conceptual information. Traditionally, researchers probed this issue by identifying single neurons that increased their firing rate when an animal encountered certain stimuli. Here we provide evidence of a complementary scheme in which gamma-band (25–128 Hz) electrocorticographic (ECoG) activity— a phenomenon involving large groups of neurons—encodes the active cognitive representation. We analyzed intracranial brain recordings from neurosurgical patients while they studied lists of visually presented letters and found that the amplitude of gamma-band activity encoded the identity of the current letter. These letter-specific patterns occurred during periods of overall increased gamma amplitude and were linked to the phase of simultaneous theta (4–8 Hz) oscillations. In occipital cortex, these patterns sometimes reflected the shape of the viewed letter, but, in other brain regions, this phenomenon was not related to letter form. Our findings show that gamma-band activity encodes a range of perceptual and conceptual information, suggesting that ECoG recordings can reveal neural correlates of specific human cognitive representations.
Neocortical Networks Entrain Neuronal Circuits in Cerebellar Cortex
Authors: Roš Hana , Sachdev Robert N. S. , Yu Yuguo , Šestan Nenad , McCormick David A.
Published: August 2009

Activity in neocortex is often characterized by synchronized oscillations of neurons and networks, resulting in the generation of a local field potential (LFP) and electroencephalogram. Do the neuronal networks of the cerebellum also generate synchronized oscillations and are they under the influence of those in the neocortex? Here we show that, in the absence of any overt external stimulus, the cerebellar cortex generates a slow oscillation that is correlated with that of the neocortex. Disruption of the neocortical slow oscillation abolishes the cerebellar slow oscillation, whereas blocking cerebellar activity has no overt effect on the neocortex. We provide evidence that the cerebellar slow oscillation results in part from the activation of granule, Golgi, and Purkinje neurons. In particular, we show that granule and Golgi cells discharge trains of single spikes, and Purkinje cells generate complex spikes, during the “up” state of the slow oscillation. Purkinje cell simple spiking is weakly related to the cerebellar and neocortical slow oscillation in a minority of cells. Our results indicate that the cerebellum generates rhythmic network activity that can be recorded as an LFP in the anesthetized animal, which is driven by synchronized oscillations of the neocortex. Furthermore, we show that correlations between neocortical and cerebellar LFPs persist in the awake animal, indicating that neocortical circuits modulate cerebellar neurons in a similar manner in natural behavioral states. Thus, the projection neurons of the neocortex collectively exert a driving and modulatory influence on cerebellar network activity.
Calpain Mediates Proteolysis of the Voltage-Gated Sodium Channel α-Subunit
Authors: von Reyn Catherine R. , Spaethling Jennifer M. , Mesfin Mahlet N. , Ma Marek , Neumar Robert W. , Smith Douglas H. , Siman Robert , Meaney David F.
Published: August 2009

Alterations in the expression, molecular composition, and localization of voltage-gated sodium channels play major roles in a broad range of neurological disorders. Recent evidence identifies sodium channel proteolysis as a key early event after ischemia and traumatic brain injury, further expanding the role of the sodium channel in neurological diseases. In this study, we investigate the protease responsible for proteolytic cleavage of voltage-gated sodium channels (NaChs). NaCh proteolysis occurs after protease activation in rat brain homogenates, pharmacological disruption of ionic homeostasis in cortical cultures, and mechanical injury using anin vitromodel of traumatic brain injury. Proteolysis requires Ca2+and calpain activation but is not influenced by caspase-3 or cathepsin inhibition. Proteolysis results in loss of the full-length α-subunits, and the creation of fragments comprising all domains of the channel that retain interaction even after proteolysis. Cell surface biotinylation after mechanical injury indicates that proteolyzed NaChs remain in the membrane before noticeable evidence of neuronal death, providing a mechanism for altered action potential initiation, propagation, and downstream signaling events after Ca2+elevation.
Characterization of a Nicotine-Sensitive Neuronal Population in Rat Entorhinal Cortex
Authors: Tu Bin , Gu Zhenglin , Shen Jian-xin , Lamb Patricia W. , Yakel Jerrel L.
Published: August 2009

The entorhinal cortex (EC) is a part of the hippocampal complex that is essential to learning and memory, and nicotine affects memory by activating nicotinic acetylcholine receptors (nAChRs) in the hippocampal complex. However, it is not clear what types of neurons in the EC are sensitive to nicotine and whether they play a role in nicotine-induced memory functions. Here, we have used voltage-sensitive dye imaging methods to locate the neuronal populations responsive to nicotine in entorhino-hippocampal slices and to clarify which nAChR subtypes are involved. In combination with patch-clamp methods, we found that a concentration of nicotine comparable to exposure during smoking depolarized neurons in layer VI of the EC (ECVI) by acting through the non-α7 subtype of nAChRs. Neurons in the subiculum (Sb; close to the deep EC layers) also contain nicotine-sensitive neurons, and it is known that Sb neurons project to the ECVI. When we recorded evoked EPSCs (eEPSCs) from ECVI neurons while stimulating the Sb near the CA1 region, a low dose of nicotine not only enhanced synaptic transmission (by increasing eEPSC amplitude) but also enhanced plasticity by converting tetanus stimulation-induced short-term potentiation to long-term potentiation; nicotine enhanced synaptic transmission and plasticity of ECVI synapses by acting on both the α7 and non-α7 subtypes of nAChRs. Our data suggest that ECVI neurons are important regulators of hippocampal function and plasticity during smoking.
An Ultra-Short Dopamine Pathway Regulates Basal Ganglia Output
Authors: Zhou Fu-Wen , Jin Ying , Matta Shannon G. , Xu Ming , Zhou Fu-Ming
Published: August 2009

Substantia nigra pars reticulata (SNr) is a key basal ganglia output nucleus critical for movement control. Its GABA-containing projection neurons intermingle with nigral dopamine (DA) neuron dendrites. Here we show that SNr GABA neurons coexpress dopamine D1and D5receptor mRNAs and also mRNA for TRPC3 channels. Dopamine induced an inward current in these neurons and increased their firing frequency. These effects were mimicked by D1-like agonists, blocked by a D1-like antagonist. D1-like receptor blockade reduced SNr GABA neuron firing frequency and increased their firing irregularity. These D1-like effects were absent in D1or D5receptor knock-out mice and inhibited by intracellularly applied D1or D5receptor antibody. These D1-like effects were also inhibited when the tonically active TRPC3 channels were inhibited by intracellularly applied TRPC3 channel antibody. Furthermore, stimulation of DA neurons induced a direct inward current in SNr GABA neurons that was sensitive to D1-like blockade. Manipulation of DA neuron activity and DA release and inhibition of dopamine reuptake affected SNr GABA neuron activity in a D1-like receptor-dependent manner. Together, our findings indicate that dendritically released dopamine tonically excites SNr GABA neurons via D1–D5receptor coactivation that enhances constitutively active TRPC3 channels, forming an ultra-short substantia nigra pars compacta → SNr dopamine pathway that regulates the firing intensity and pattern of these basal ganglia output neurons.
Temporal Filtering of Nociceptive Information by Dynamic Activation of Endogenous Pain Modulatory Systems
Authors: Yelle Marc D. , Oshiro Yoshitetsu , Kraft Robert A. , Coghill Robert C.
Published: August 2009

Endogenous pain control mechanisms have long been known to produce analgesia during “flight or fight” situations and to contribute to cognitively driven pain modulation, such as placebo analgesia. Afferent nociceptive information can also directly activate supraspinal descending modulatory systems, suggesting that these mechanisms may participate in feedback loops that dynamically alter the processing of nociceptive information. The functional significance of these feedback loops, however, remains unclear. The phenomenon of offset analgesia—disproportionately large decreases in pain ratings evoked by small decreases in stimulus intensity—suggests that dynamic activation of endogenous pain inhibition may contribute to the temporal filtering of nociceptive information. The neural mechanisms that mediate this phenomenon remain currently unknown. Using functional magnetic resonance imaging, we show that several regions of the midbrain and brainstem are differentially activated during offset analgesia. These activations are consistent with the location of areas such as the periaqueductal gray (PAG), rostral ventral medulla, and locus ceruleus that have substantial roles in descending inhibition of pain. This transient analgesia contributes to the temporal filtering of nociceptive information by producing a perceptual amplification of the magnitude and duration of decreases in noxious stimulus intensity. Together with the involvement of PAG and associated brainstem mechanisms in cognitively generated analgesia, the present observations suggest that the fundamental role of endogenous pain modulatory mechanisms is to dynamically shape the processing of nociceptive signals to best fit with the ever-changing demands of the environment.
Cushing's syndrome associated with a nested stromal epithelial tumor of the liver: hormonal, immunohistochemical, and molecular studies
Authors: Rod Anne , Voicu Manuela , Chiche Laurence , Bazille Céline , Mittre Hervé , Louiset Estelle , Reznik Yves
Published: August 2009

Context

Ectopic ACTH syndrome (EAS) is principally associated with aggressive malignant tumors but also with neuroendocrine tumors of good prognosis. Recently, rare nonhepatocytic nested stromal and epithelial tumors (NSET) were characterized by their possible association with Cushing's syndrome of which biochemical and physiopathological features were still incompletely studied.

Objective

To describe the clinical and hormonal characteristics of an EAS originating from a liver NSET and further understand the mechanism of cortisol overproduction.

Design and setting

This is a clinical case report from the Endocrinology Department of Caen University Hospital, France.

Patient and intervention

A 17-year-old female patient was found to have a large liver NSET with mild Cushingoid clinical features and intense biological hypercortisolism but moderate ACTH secretion. Resection of the tumor was curative with a 30-month follow-up.

Results

The epithelial component of the tumor coexpressed ACTH mildly, corticotropin-releasing hormone (CRH) strongly, and 11β-hydroxysteroid dehydrogenase at a level comparable with normal human hepatocytes.

Conclusions

Liver NSET is a new cause of EAS, which may evoke hypercortisolism by multiple biochemical pathways.
Hyperinsulinism–hyperammonaemia syndrome: novel mutations in the GLUD1 gene and genotype–phenotype correlations
Authors: Kapoor Ritika R , Flanagan Sarah E , Fulton Piers , Chakrapani Anupam , Chadefaux Bernadette , Ben-Omran Tawfeg , Banerjee Indraneel , Shield Julian P , Ellard Sian , Hussain Khalid
Published: August 2009

Background

Activating mutations in the GLUD1 gene (which encodes for the intra-mitochondrial enzyme glutamate dehydrogenase, GDH) cause the hyperinsulinism–hyperammonaemia (HI/HA) syndrome. Patients present with HA and leucine-sensitive hypoglycaemia. GDH is regulated by another intra-mitochondrial enzyme sirtuin 4 (SIRT4). Sirt4 knockout mice demonstrate activation of GDH with increased amino acid-stimulated insulin secretion.

Objectives

To study the genotype–phenotype correlations in patients with GLUD1 mutations. To report the phenotype and functional analysis of a novel mutation (P436L) in the GLUD1 gene associated with the absence of HA.

Patients and methods

Twenty patients with HI from 16 families had mutational analysis of the GLUD1 gene in view of HA (n=19) or leucine sensitivity (n=1). Patients negative for a GLUD1 mutation had sequence analysis of the SIRT4 gene. Functional analysis of the novel P436L GLUD1 mutation was performed.

Results

Heterozygous missense mutations were detected in 15 patients with HI/HA, 2 of which are novel (N410D and D451V). In addition, a patient with a normal serum ammonia concentration (21 μmol/l) was heterozygous for a novel missense mutation P436L. Functional analysis of this mutation confirms that it is associated with a loss of GTP inhibition. Seizure disorder was common (43%) in our cohort of patients with a GLUD1 mutation. No mutations in the SIRT4 gene were identified.

Conclusion

Patients with HI due to mutations in the GLUD1 gene may have normal serum ammonia concentrations. Hence, GLUD1 mutational analysis may be indicated in patients with leucine sensitivity; even in the absence of HA. A high frequency of epilepsy (43%) was observed in our patients with GLUD1 mutations.
VHL inactivation is an important pathway for the development of malignant sporadic pancreatic endocrine tumors
Authors: Schmitt A M , Schmid S , Rudolph T , Anlauf M , Prinz C , Klöppel G , Moch H , Heitz P U , Komminoth P , Perren A
Published: August 2009

A small subset of familial pancreatic endocrine tumors (PET) arises in patients with von Hippel–Lindau syndrome and these tumors may have an adverse outcome compared to other familial PET. Sporadic PET rarely harbors somatic VHL mutations, but the chromosomal location of the VHL gene is frequently deleted in sporadic PET. A subset of sporadic PET shows active hypoxia signals on mRNA and protein level. To identify the frequency of functionally relevant VHL inactivation in sporadic PET and to examine a possible prognostic significance we correlated epigenetic and genetic VHL alterations with hypoxia signals. VHL mutations were absent in all 37 PETs examined. In 2 out of 35 informative PET (6%) methylation of the VHL promoter region was detected and VHL deletion by fluorescence in situ hybridization was found in 14 out of 79 PET (18%). Hypoxia inducible factor 1α (HIF1-α), carbonic anhydrase 9 (CA-9), and glucose transporter 1 (GLUT-1) protein was expressed in 19, 27, and 30% of the 152 PETs examined. Protein expression of the HIF1-α downstream target CA-9 correlated significantly with the expression of CA-9 RNA (P<0.001), VHL RNA (P<0.05), and VHL deletion (P<0.001) as well as with HIF1-α (P<0.005) and GLUT-1 immunohistochemistry (P<0.001). These PET with VHL alterations and signs of hypoxia signalling were characterized by a significantly shortened disease-free survival. We conclude that VHL gene impairment by promoter methylation and VHL deletion in nearly 25% of PET leads to the activation of the HIF-pathway. Our data suggest that VHL inactivation and consecutive hypoxia signals may be a mechanism for the development of sporadic PET with an adverse outcome.
Cytotoxic drugs in drinking water: A prediction and risk assessment exercise for the thames catchment in the United Kingdom
Authors: Rowney Nicole C. , Johnson Andrew C. , Williams Richard J.
Published: August 2009

Cytotoxic, also known as antineoplastic, drugs remain an important weapon in the fight against cancer. This study considers the water quality implications for the Thames catchment (United Kingdom) arising from the routine discharge of these drugs after use, down the drain and into the river. The review focuses on 13 different cytotoxic drugs from the alkylating agent, antimetabolite, and anthracycline antibiotic families. A geographic-information-system-based water quality model was used in the present study. The model was informed by literature values on consumption, excretion, and fate data to predict raw drinking water concentrations at the River Thames abstraction points at Farmoor, near Oxford, and Walton, in West London. To discover the highest plausible values, upper boundary values for consumption and excretion together with lower removal values for sewage treatment were used. The raw drinking water cytotoxic drug maximum concentrations at Walton (the higher of the two) representative of mean and low flow conditions were predicted to be 11 and 20 ng/L for the five combined alkylating agents, 2 and 4 ng/L for the three combined antimetabolites, and 0.05 and 0.10 ng/L the for two combined anthracycline antibiotics, respectively. If they were to escape into tap water, then the highest predicted concentrations would still be a factor of between 25 and 40 below the current recommended daily doses of concern. Although the risks may be negligible for healthy adults, more concern may be associated with special subgroup populations, such as pregnant women, their fetuses, and breast-feeding infants, due to their developmental vulnerability.
Variation in Biofilm Structure and Activity Along the Length of a Rising Main Sewer
Authors: Mohanakrishnan Janani , Sharma Keshab Raj , Meyer Rikke Louise , Hamilton Geoff , Keller Jurg , Yuan Zhiguo
Published: August 2009

Sewers systems are dynamic in nature, with periodic variation of hydraulic flow and wastewater substrate concentrations. While various models are currently available for predicting hydrogen sulfide (H 2S) production in rising mains, they assume constant biofilm activities along the length and ignore the effect of substrate availability on biofilm development. To investigate variation in rising main biofilm structure and activity, detailed studies were carried out on a Robbins device setup, which was established in parallel to a real rising main that it simulated. The changes in wastewater characteristics, as wastewater traveled through both the experimental setup and the real sewer system, were monitored. The study revealed that the biofilm activities varied significantly with locations, with biofilm corresponding to the start of the rising main capable of greater sulfide and volatile fatty acid production than biofilm downstream. Analysis of microbial community composition of these biofilms showed a difference in diversity and abundance, both with regard to general bacterial populations and sulfate reducers. These differences were hypothesized to be a consequence of varying substrate types and availability along the sewer line. The results suggest that the biofilm structure and activity may vary considerably along the length of rising mains and should be taken into consideration for improved sewer modeling and when considering the overall effect of different hydrogen sulfide management options.
Interleukin-10 Prevents Diet-Induced Insulin Resistance by Attenuating Macrophage and Cytokine Response in Skeletal Muscle
Authors: Hong Eun-Gyoung , Ko Hwi Jin , Cho You-Ree , Kim Hyo-Jeong , Ma Zhexi , Yu Tim Y. , Friedline Randall H. , Kurt-Jones Evelyn , Finberg Robert , Fischer Matthew A. , Granger Erica L. , Norbury Christopher C. , Hauschka Stephen D. , Philbrick William M. , Lee Chun-Geun , Elias Jack A. , Kim Jason K.
Published: August 2009

OBJECTIVE

Insulin resistance is a major characteristic of type 2 diabetes and is causally associated with obesity. Inflammation plays an important role in obesity-associated insulin resistance, but the underlying mechanism remains unclear. Interleukin (IL)-10 is an anti-inflammatory cytokine with lower circulating levels in obese subjects, and acute treatment with IL-10 prevents lipid-induced insulin resistance. We examined the role of IL-10 in glucose homeostasis using transgenic mice with muscle-specific overexpression of IL-10 (MCK-IL10).

RESEARCH DESIGN AND METHODS

MCK-IL10 and wild-type mice were fed a high-fat diet (HFD) for 3 weeks, and insulin sensitivity was determined using hyperinsulinemic-euglycemic clamps in conscious mice. Biochemical and molecular analyses were performed in muscle to assess glucose metabolism, insulin signaling, and inflammatory responses.

RESULTS

MCK-IL10 mice developed with no obvious anomaly and showed increased whole-body insulin sensitivity. After 3 weeks of HFD, MCK-IL10 mice developed comparable obesity to wild-type littermates but remained insulin sensitive in skeletal muscle. This was mostly due to significant increases in glucose metabolism, insulin receptor substrate-1, and Akt activity in muscle. HFD increased macrophage-specific CD68 and F4/80 levels in wild-type muscle that was associated with marked increases in tumor necrosis factor-α, IL-6, and C-C motif chemokine receptor-2 levels. In contrast, MCK-IL10 mice were protected from diet-induced inflammatory response in muscle.

CONCLUSIONS

These results demonstrate that IL-10 increases insulin sensitivity and protects skeletal muscle from obesity-associated macrophage infiltration, increases in inflammatory cytokines, and their deleterious effects on insulin signaling and glucose metabolism. Our findings provide novel insights into the role of anti-inflammatory cytokine in the treatment of type 2 diabetes.
Nutrient Stress Activates Inflammation and Reduces Glucose Metabolism by Suppressing AMP-Activated Protein Kinase in the Heart
Authors: Ko Hwi Jin , Zhang Zhiyou , Jung Dae Young , Jun John Y. , Ma Zhexi , Jones Kelly E. , Chan Sook Y. , Kim Jason K.
Published: August 2009

OBJECTIVE

Heart failure is a major cause of mortality in diabetes and may be causally associated with altered metabolism. Recent reports indicate a role of inflammation in peripheral insulin resistance, but the impact of inflammation on cardiac metabolism is unknown. We investigated the effects of diet-induced obesity on cardiac inflammation and glucose metabolism in mice.

RESEARCH DESIGN AND METHODS

Male C57BL/6 mice were fed a high-fat diet (HFD) for 6 weeks, and heart samples were taken to measure insulin sensitivity, glucose metabolism, and inflammation. Heart samples were also examined following acute interleukin (IL)-6 or lipid infusion in C57BL/6 mice and in IL-6 knockout mice following an HFD.

RESULTS

Diet-induced obesity reduced cardiac glucose metabolism, GLUT, and AMP-activated protein kinase (AMPK) levels, and this was associated with increased levels of macrophages, toll-like receptor 4, suppressor of cytokine signaling 3 (SOCS3), and cytokines in heart. Acute physiological elevation of IL-6 suppressed glucose metabolism and caused insulin resistance by increasing SOCS3 and via SOCS3-mediated inhibition of insulin receptor substrate (IRS)-1 and possibly AMPK in heart. Diet-induced inflammation and defects in glucose metabolism were attenuated in IL-6 knockout mice, implicating the role of IL-6 in obesity-associated cardiac inflammation. Acute lipid infusion caused inflammation and raised local levels of macrophages, C-C motif chemokine receptor 2, SOCS3, and cytokines in heart. Lipid-induced cardiac inflammation suppressed AMPK, suggesting the role of lipid as a nutrient stress triggering inflammation.

CONCLUSIONS

Our findings that nutrient stress activates cardiac inflammation and that IL-6 suppresses myocardial glucose metabolism via inhibition of AMPK and IRS-1 underscore the important role of inflammation in the pathogenesis of diabetic heart.
Atf4 Regulates Obesity, Glucose Homeostasis, and Energy Expenditure
Authors: Seo Jin , Fortuno Edgardo S. , Suh Jae Myoung , Stenesen Drew , Tang Wei , Parks Elizabeth J. , Adams Christopher M. , Townes Tim , Graff Jonathan M.
Published: August 2009

OBJECTIVE

We evaluate a potential role of activating transcription factor 4 (Atf4) in invertebrate and mammalian metabolism.

RESEARCH DESIGN AND METHODS

With two parallel approaches—a fat body–specific green fluorescent protein enhancer trap screen in D. melanogaster and expression profiling of developing murine fat tissues—we identified Atf4 as expressed in invertebrate and vertebrate metabolic tissues. We assessed the functional relevance of the evolutionarily conserved expression by analyzing Atf4 mutant flies and Atf4 mutant mice for possible metabolic phenotypes.

RESULTS

Flies with insertions at the Atf4 locus have reduced fat content, increased starvation sensitivity, and lower levels of circulating carbohydrate. Atf4 null mice are also lean, and they resist age-related and diet-induced obesity. Atf4 null mice have increased energy expenditure potentially accounting for the lean phenotype. Atf4 null mice are hypoglycemic, even before substantial changes in fat content, indicating that Atf4 regulates mammalian carbohydrate metabolism. In addition, the Atf4 mutation blunts diet-induced diabetes as well as hyperlipidemia and hepatosteatosis. Several aspects of the Atf4 mutant phenotype resemble mice with mutations in components of the target of rapamycin (TOR) pathway. Consistent with the phenotypic similarities, Atf4 null mice have reduced expression of genes that regulate intracellular amino acid concentrations and lower intracellular concentration of amino acids, a key TOR input. Further, Atf4 mutants have reduced S6K activity in liver and adipose tissues.

CONCLUSIONS

Atf4 regulates age-related and diet-induced obesity as well as glucose homeostasis in mammals and has conserved metabolic functions in flies.
Natriuretic Peptides/cGMP/cGMP-Dependent Protein Kinase Cascades Promote Muscle Mitochondrial Biogenesis and Prevent Obesity
Authors: Miyashita Kazutoshi , Itoh Hiroshi , Tsujimoto Hirokazu , Tamura Naohisa , Fukunaga Yasutomo , Sone Masakatsu , Yamahara Kenichi , Taura Daisuke , Inuzuka Megumi , Sonoyama Takuhiro , Nakao Kazuwa
Published: August 2009

OBJECTIVE

Natriuretic peptides (NPs) have been characterized as vascular hormones that regulate vascular tone via guanylyl cyclase (GC), cyclic GMP (cGMP), and cGMP-dependent protein kinase (cGK). Recent clinical studies have shown that plasma NP levels were lower in subjects with the metabolic syndrome. The present study was conducted to elucidate the roles for NP/cGK cascades in energy metabolism.

RESEARCH DESIGN AND METHODS

We used three types of genetically engineered mice: brain NP (BNP) transgenic (BNP-Tg), cGK-Tg, and guanylyl cyclase-A (GCA) heterozygous knockout (GCA+/−) mice and analyzed the metabolic consequences of chronic activation of NP/cGK cascades in vivo. We also examined the effect of NPs in cultured myocytes.

RESULTS

BNP-Tg mice fed on high-fat diet were protected against diet-induced obesity and insulin resistance, and cGK-Tg mice had reduced body weight even on standard diet; surprisingly, giant mitochondria were densely packed in the skeletal muscle. Both mice showed an increase in muscle mitochondrial content and fat oxidation through upregulation of peroxisome proliferator–activated receptor (PPAR)-γ coactivator (PGC)-1α and PPARδ. The functional NP receptors, GCA and guanylyl cyclase-B, were downregulated by feeding a high-fat diet, while GCA+/− mice showed increases in body weight and glucose intolerance when fed a high-fat diet. NPs directly increased the expression of PGC-1α and PPARδ and mitochondrial content in cultured myocytes.

CONCLUSIONS

The findings together suggest that NP/cGK cascades can promote muscle mitochondrial biogenesis and fat oxidation, as to prevent obesity and glucose intolerance. The vascular hormone, NP, would contribute to coordinated regulation of oxygen supply and consumption.
Placental Structure in Type 1 Diabetes
Authors: Nelson Scott M. , Coan Philip M. , Burton Graham J. , Lindsay Robert S.
Published: August 2009

OBJECTIVE

Alteration of placental structure may influence fetal overgrowth and complications of maternal diabetes. We examined the placenta in a cohort of offspring of mothers with type 1 diabetes (OT1DM) to assess structural changes and determine whether these were related to maternal A1C, fetal hematocrit, fetal hormonal, or metabolic axes.

RESEARCH DESIGN AND METHODS

Placental samples were analyzed using stereological techniques to quantify volumes and surface areas of key placental components in 88 OT1DM and 39 control subjects, and results related to maternal A1C and umbilical cord analytes (insulin, leptin, adiponectin, IGF-I, hematocrit, lipids, C-reactive protein, and interleukin-6).

RESULTS

Intervillous space volume was increased in OT1DM (OT1DM 250 ± 81 cm3 vs. control 217 ± 65 cm3; P = 0.02) with anisomorphic growth of villi (P = 0.025). The placentas showed a trend to increased weight (OT1DM 690 ± 19 g; control 641 ± 22 g; P = 0.08), but villous, nonparenchymal, trophoblast, and capillary volumes did not differ. Villous surface area, capillary surface area, membrane thickness, and calculated morphometric diffusing capacity were also similar in type 1 diabetic and control subjects. A1C at 26–34 weeks associated with birth weight (r = 0.27, P = 0.03), placental weight (r = 0.41, P = 0.0009), and intervillous space volume (r = 0.38, P = 0.0024). In multivariate analysis of cord parameters in OT1DM, fetal IGF-I emerged as a significant correlate of most components (intervillous space, villous, trophoblast, and capillary volumes, all P < 0.01). By contrast, fetal insulin was only independently associated with capillary surface area (positive, r2 = 6.7%; P = 0.02).

CONCLUSIONS

There are minimal placental structural differences between OT1DM and control subjects. Fetal IGF-I but not fetal insulin emerges as a key correlate of placental substructural volumes, thereby facilitating feedback to the placenta regarding fetal metabolic demand.
Troponin T and Pro–B-Type Natriuretic Peptide in Fetuses of Type 1 Diabetic Mothers
Authors: Russell Noirin E. , Higgins Mary F. , Amaruso Michael , Foley Michael , McAuliffe F.M.
Published: August 2009

OBJECTIVE

Cardiomyopathy is noted in up to 40% of infants of diabetic mothers, and the exact mechanisms are unknown. The aim of this study was to determine whether fetal serum markers of cardiac function differ between normal and type 1 diabetic pregnancies and to examine the relationship between these markers and fetal cardiac structure and function.

RESEARCH DESIGN AND METHODS

This was a prospective observational study of 45 type 1 diabetic pregnancies and 39 normal pregnancies. All participants had concentrations of fetal pro–B-type natriuretic peptide (proBNP) and troponin-T (TnT) measured at the time of delivery. All patients with type 1 diabetes had Doppler evaluation of the umbilical artery, middle cerebral artery, and ductus venosus in the third trimester, and a subset (n = 21) had detailed fetal echocardiograms performed in each trimester.

RESULTS

Fetal proBNP and TnT concentrations were higher in the diabetic cohort than in the normal cohort (P < 0.05). ProBNP correlated positively with interventricular septum thickness (P < 0.05) but not with cardiac function indexes in the third trimester. In patients with poor glycemic control, there was a significant positive correlation (P < 0.05) between fetal TnT and the third trimester umbilical artery pulsatility index. There were also increased levels of fetal TnT in infants with poor perinatal outcome (P < 0.05).

CONCLUSIONS

Biochemical markers of cardiac dysfunction are elevated in infants of diabetic mothers, especially those with cardiomyopathy or poor perinatal outcome. Hyperglycemia in early pregnancy may affect myocardial and placental development, thus contributing to the susceptibility to hypoxia seen in these infants.
Retinal Vascular Fractal Dimension and Risk of Early Diabetic Retinopathy
Authors: Lim Shueh Wen , Cheung Ning , Wang Jie J. , Donaghue Kim C. , Liew Gerald , Islam F.M. Amirul , Jenkins Alicia J. , Wong Tien Y.
Published: August 2009

OBJECTIVE

To examine the prospective association of retinal vascular fractal dimension with diabetic retinopathy risk in young people with type 1 diabetes.

RESEARCH DESIGN AND METHODS

This was a hospital-based prospective study of 590 patients aged 12–20 years with type 1 diabetes free of retinopathy at baseline. All patients had seven-field retinal photographs taken of both eyes. Incident retinopathy was ascertained from retinal photographs taken at follow-up visits. Fractal dimension was measured from baseline photographs using a computer-based program following a standardized protocol.

RESULTS

Over a mean ± SD follow-up period of 2.9 ± 2.0 years, 262 participants developed mild nonproliferative diabetic retinopathy (15.0 per 100 person-years). After adjusting for age, sex, diabetes duration, A1C, and other risk factors, we found no association between retinal vascular fractal dimension and incident retinopathy.

CONCLUSIONS

Retinal vascular fractal dimension was not associated with incident early diabetic retinopathy in this sample of children and adolescents with type 1 diabetes.
Safety Analysis of Interchanges
Authors: Torbic Darren J. , Harwood Douglas W. , Gilmore David K. , Richard Karen R. , Bared Joe G.
Published: August 2009

As the U.S. freeway system ages and becomes more congested, many parts of the system, particularly interchanges, need reconstruction or rehabilitation. In addition, new development and expanding urbanization often require new interchanges to be constructed along existing freeways. Because interchange projects are typically among highway agencies’ highest-cost projects, it is important that they be planned wisely. Improved safety should be a key justification for interchange improvement projects, but engineers lack a suitable tool for examining the safety performance of existing interchanges and anticipating the safety performance of new or rebuilt interchanges. The objectives of this research are to synthesize the current state of knowledge concerning the safety assessment of interchanges, develop a spreadsheet-based computational tool for performing safety assessments of interchanges, and identify gaps in knowledge concerning interchange safety assessment and future research needed to fill those gaps. This paper summarizes safety data related to interchanges, discusses the use of safety performance functions within the Interchange Safety Analysis Tool (ISAT) (the spreadsheet-based tool developed in this research), describes the scope and capabilities of ISAT, and identifies substantive gaps in the current state of knowledge that limit the ability of ISAT to provide all of the capabilities desired by potential users.
Evaluation of Pavement Strain Gauge Repeatability
Authors: Gokhale Salil , Byron Tom , Iyer Shivprakash , Choubane Bouzid
Published: August 2009

Pavement instrumentation gauges have been in use for a long time and have typically been used to measure and evaluate the response of a pavement system. Although information related to the installation of these gauges and the methodology for data collection and analysis have been well-documented, literature on the repeatability of these measurements is limited. Since the response from these instrumentation gauges plays an important part in modeling pavement systems, it is necessary to have a high degree of confidence in their measurements. The Florida Department of Transportation conducted this parametric experiment to evaluate the repeatability of strain gauges currently used in its accelerated pavement testing facility. Strain measurements using 28 strain gauges were made at five different pavement temperatures, three levels of load, three levels of tire pressure, and three levels of speed. The loading was applied to the pavement test section with the heavy vehicle simulator, and five replicate load passes were made at each combination of variables. Statistical analysis of the measured strain data showed that the surface strain gauges were repeatable under various conditions of temperature, load, speed, and tire pressure. The results of this study also showed that strain measurements did not vary significantly with a change in the internal tire pressure. This paper presents a description of the testing program, data collection efforts, subsequent analysis, and preliminary results obtained under accelerated pavement testing.
Predicting Remaining Strength of Flexible Pavement and Overlay Design Thickness with Stochastic Modeling
Authors: Abaza Khaled A. , Murad Maher M.
Published: August 2009

A pavement's remaining strength is predicted from initial pavement strength by means of layer structural capacity adjustment factors. “Initial pavement strength” is defined as the total structural capacity associated with the asphalt concrete and underlying granular layers estimated by appropriate relative strength indicators such as the gravel equivalent or structural number. The pavement's future remaining strength is estimated as the product sum of multiplying the initial layer strength by the corresponding adjustment factor. The structural adjustment factor represents the percentage of remaining strength for a particular pavement layer at a specified service time ( t). The structural capacity adjustment factor associated with the asphalt layer is the principal factor estimated from a project performance curve generated with stochastic modeling. The discrete time Markov model is used to predict pavement distress ratings for a particular project over a specified service life ( T). A simplified approach is presented for estimating a project transition matrix using only initial and terminal transition probabilities. The predicted distress ratings are used to construct a project performance curve. The area falling under the performance curve has long been recognized as a direct measure of the pavement relative strength. Therefore, the principal structural capacity adjustment factor is defined as the ratio of the area under the performance curve for the remaining service period ( T - t) and the area under the entire performance curve for a service life ( T). A sample application is provided with results used to generate empirical models to aid in developing rehabilitation strategies and management policies at the network level.
Backcalculated and Laboratory-Measured Resilient Modulus Values
Authors: Dawson Tyler A. , Baladi Gilbert Y. , Sessions Colin P. , Haider Syed Waqar
Published: August 2009

The resilient modulus ( MR) of roadbed soils is a necessary parameter in pavement design. The MR of roadbed soils is dependent on the soil type, water content, dry density, particle gradation, Atterberg limits, and stress states. Several procedures can be used for the determination of the MR: laboratory testing, backcalculation with nondestructive deflection testing (NDT) data, and correlations to other soil parameters such as the California bearing ratio, density, and water content. The first procedure is time-consuming and expensive and requires substantial resources to cover the various roadbed soils under the road network. The second is relatively inexpensive and fast and can be designed to cover representative soils under the pavement network. The third procedure is approximate and may be used for the Level 2 design of the Mechanistic–Empirical Pavement Design Guide. The Michigan Department of Transportation (MDOT) sponsored a research project for the development of a systematic procedure to determine the MR values for all soil types encountered under the pavement network in the state of Michigan. The procedure includes laboratory testing of representative disturbed and undisturbed soil samples, NDT with the MDOT falling weight deflectometer, and developing correlations between the MR values obtained from the two tests and between the MR values and other soil parameters that can be obtained using simple tests. The developed correlation equations between the MR measured values and the other soil parameters are presented elsewhere, whereas the correlations between the laboratory-obtained and the backcalculated MR values are discussed in this paper.
Measuring Curvature in Concrete Slabs and Connecting the Data to Slab Modeling Theory
Authors: Byrum Christopher R.
Published: August 2009

Slab curling, warping, and load deflection basins are analyzed by quantifying slab curvature. Warping and curling curvature can cause the edges or midslab regions of slabs to lift off the foundation, with increases in slab-bending stress and deflections caused by loading. This paper provides an overview and comparison of methods for measuring slab curvature from curling and warping. Methods described include the end-slope, string-line, and straight-edge methods, best-fit polynomials, and shape functions. In addition, for multiple slabs, a rapid traveling profiler method is described: the profiler uses thousands of closely spaced data points and a generalized analysis of variation of curvature known as the road profile curvature index. To show key differences, the methods are compared by means of a test slab. The three primary ways of matching measured slab shape data to theoretical models are matching on the basis of the mean value theorem for integrals for continuous functions, matching on the basis of a best-fit or least squares error approach for the full slab length, or matching the difference in magnitude of the elevation between the ends and middle portions of the slabs. It is shown that fitting methods based on the mean value theorem for integrals are the most accurate and theoretically correct and will closely match the end of slab slope conditions near joints and overall average slab curvature simultaneously. On the basis of the mean value theorem for integrals, how to fit theoretical equations by Westergaard or any finite element method solution to the site average slab curvature measurement is described.
Semi-Automated Faulting Measurement for Rigid Pavements
Authors: Nazef Abdenour , Mraz Alexander , Iyer Shivprakash , Choubane Bouzid
Published: August 2009

Faulting measurements have traditionally been conducted manually by means of fault meters. However, operating any manual device such as a fault meter close to vehicular traffic is hazardous to both the operator and the traveling public. Automated methods, such as those associated with high-speed profilers, offer a safer, more efficient, and cost-effective alternative. Therefore, there is a need to develop an automated method for measuring joint faulting with longitudinal profiles from high-speed profilers. A study was initiated with the primary objective of determining an appropriate profiler sampling interval to accurately locate transverse joints. A secondary objective was to determine how well faulting estimated from profile elevation compares with faulting measured with a Georgia fault meter. An algorithm was developed: it can accurately detect on average 95% of transverse joints from profile data collected at highway speed with a 0.68-in. (17.3-mm) sampling interval. This algorithm was also adapted to estimate faulting measured with a Georgia fault meter (AASHTO R36-04). Although the algorithm results are repeatable, the algorithm overestimated the faulting at joints by 0.05 in. (1.3 mm) to 0.06 in. (1.5 mm) compared with faulting measured with the Georgia fault meter.
Evaluation of International Friction Index Coefficients for Various Devices
Authors: Flintsch Gerardo W. , Izeppi Edgar de León , McGhee Kevin K. , Roa Julio Alberto
Published: August 2009

This paper presents a research effort to compare and harmonize measurements of texture and skid resistance taken with various devices at the Virginia Smart Road in May 2008 by the members of the Virginia Consortium for Pavement Surface Properties. There have been numerous efforts by different countries and agencies to understand better the relationship and behavior of different friction-testing devices and the influence of texture, speed, and other external conditions on these measurements. Measurements obtained with different types of equipment on 24 pavement sections with a wide range of textures were compared, and the relationship between friction and speed for the different pavement sections and devices was studied. Data were collected with two locked-wheel skid trailers, a Griptester, and a dynamic friction tester. Nine asphalt sections were tested; six were Superpave® mixes, two were stone matrix asphalt, and one was an open-graded friction course. The concrete sections tested included one continuously reinforced concrete pavement with tined finishing and two epoxy overlays. Even though all steps included in the specifications derived from the experiments by the Permanent International Association of Road Congresses (PIARC) were followed, the results obtained were not satisfactory. From a theoretical standpoint, all the values computed with the international friction index (IFI) F60 should be equal, but this was not the case. Discrepancies in the IFI values calculated for the different devices suggest that the original coefficients determined during the PIARC experiment may need to be adjusted for the devices evaluated, before the IFI can be implemented by the participating agencies.
Crash Analysis of Roundabouts at High-Speed Rural Intersections
Authors: Isebrands Hillary
Published: August 2009

Federal, state, and local agencies have identified increased intersection safety as an achievable objective in their campaigns for safer highways. Roundabouts could reduce the number of fatal and severe crashes. Roundabouts have been successful in Europe and Australia in both urban and rural environments for decades. The documented safety benefits associated with roundabouts address numerous concerns surrounding injury crashes at intersections; however, applications of roundabouts on two-lane, high-speed (40+ mph) rural highways have not been explored to the extent that urban roundabouts have in the United States. This research conducted a safety analysis of 17 intersections on high-speed rural roadways in the United States that were converted to roundabouts. The findings show the average injury crash frequency was reduced by 84%, average injury crash rate was reduced by 89%, angle crashes were reduced by 86%, and fatal crashes were reduced by 100%.
Turbo Roundabouts
Authors: Fortuijn Lambertus G. H.
Published: August 2009

While concentric two-lane roundabouts have a higher capacity than single-lane roundabouts, they have the disadvantage of a higher driving speed through the roundabout. They also reintroduce the possibility of lane changing on the roundabout and hence raise the risk of accidents. The author developed the turbo roundabout in 1996 in an attempt to deal with these drawbacks. This type of roundabout has the following features: no lane changing on the roundabout, no need to yield to traffic on more than two lanes, and low driving speed through the roundabout because of raised lane dividers. This paper discusses the concept of the turbo roundabout and the details determining success. Studies have shown that the risk of accidents associated with injury is greatly reduced on turbo roundabouts: an 80% reduction has been measured. In view of the known safety trends on single-lane roundabouts, it is recommended that a slightly lower reduction in the accident rate (70%) should be assumed in the long term. Another great advantage of the turbo roundabout is the fact that the traffic flow can be divided over the lanes of the roundabout in a much more balanced way. Since 2000, 70 turbo roundabouts have been built in the Netherlands. The Dutch Information and Technology Platform (CROW) published its guidelines on turbo roundabouts in April 2008.