Higher plasma motilin levels in obese patients decrease after Roux-en-Y gastric bypass surgery and regulate hunger.

OBJECTIVE: Motilin-induced phase III contractions of the migrating motor complex (MMC) signal hunger in healthy volunteers. The current aim was to study the role of motilin as a hunger-inducing factor in obese patients and to evaluate the effect of Roux-en-Y gastric bypass (RYGB) surgery on plasma motilin levels and hunger scores. DESIGN: Motilin and ghrelin plasma levels were determined during a complete MMC cycle in controls and obese patients selected for RYGB before, 6 months and 1 year after surgery. 20 min after the end of the second phase III, obese patients received an intravenous infusion of 40 mg erythromycin. Hunger was scored every 5 min. Hedonic hunger was assessed in obese patients with the Power of Food Scale questionnaire. RESULTS: Obesity caused a switch in the origin of phase III from antrum to duodenum. Obese patients had significantly higher motilin levels compared with controls during the MMC but tended to lack the motilin peak prior to phase III necessary to trigger hunger. Hunger scores during phase III were significantly lower in obese patients, but could be restored to control levels through the administration of a low dose of the motilin agonist, erythromycin. After RYGB surgery motilin, but not ghrelin, levels decreased in parallel with hedonic hunger scores. CONCLUSIONS: Motilin may be an important regulator involved in the pathogenesis of obesity.

Low cytochrome oxidase 4I1 links mitochondrial dysfunction to obesity and type 2 diabetes in humans and mice.

OBJECTIVES: Cytochrome oxidase (COX) dysfunction is associated with mitochondrial oxidative stress. We determined the association between COX expression, obesity and type 2 diabetes. SUBJECTS/METHODS: COX4I1 and COX10 genes were measured in monocytes of 24 lean controls, 31 glucose-tolerant and 67 diabetic obese patients, and 17 morbidly obese patients before and after bariatric surgery. We investigated the effect of caloric restriction and peroxisome proliferator-activated receptor (PPAR) agonist treatment on Cox in obese diabetic mice, and that of diet-induced insulin resistance in Streptozotocin-treated mice. RESULTS: Low COX4I1 was associated with type 2 diabetes in obese patients, adjusting for age, gender, smoking, interleukin-6 and high-sensitivity C-reactive protein, all related to metabolic syndrome (MetS; odds ratio: 6.1, 95% confidence interval: 2.3-16). In contrast, COX10 was low in glucose-tolerant and diabetic obese patients. In morbidly obese patients, COX4I1 was lower in visceral adipose tissue collected at bariatric surgery. In their monocytes, COX4I1 decreased after bariatric surgery, and low COX4I1 at 4 months was associated with MetS at 7 years. In leptin-deficient obese diabetic mice, Cox4i1 was low in white visceral adipose tissue (n=13; P<0.001) compared with age-matched lean mice (n=10). PPARγ-agonist treatment (n=13), but not caloric restriction (n=11), increased Cox4i1 (P<0.001). Increase in Cox4i1 depended on the increase in glucose transporter 4 (Glut4) expression and insulin sensitivity, independent of the increase in blood adiponectin. In streptozotocin-treated mice (three groups of seven mice, diet-induced insulin resistance decreased Cox4i1 and Glut4 (P<0.001 for both). CONCLUSION: COX4I1 depression is related to insulin resistance and type 2 diabetes in obesity. In peripheral blood monocytes, it may be a diagnostically useful biomarker.

Effect of obesity on gastrointestinal transit, pressure and pH using a wireless motility capsule.

BACKGROUND: Despite the increasing prevalence and medical burden of obesity, the understanding of gastrointestinal physiology in obesity is scarce, which hampers drug development. AIM: To investigate the effect of obesity and food intake on gastrointestinal transit, pressure and pH. MATERIAL AND METHODS: An exploratory cross-sectional study using a wireless motility capsule (SmartPill©) was performed in 11 participants with obesity and 11 age- and gender-matched participants with normal weight (group) in fasted and fed state (visit). During the first visit, the capsule was ingested after an overnight fast. During a second visit, the capsule was ingested after a nutritional drink to simulate fed state. Linear mixed models were constructed to compare segmental gastrointestinal transit, pressure and pH between groups (obesity or control) and within every group (fasted or fed). RESULTS: Food intake slowed gastric emptying in both groups (both P < 0.0001), though food-induced gastric contractility was higher in participants with obesity compared to controls (P = 0.02). In the small intestine, a higher contractility (P = 0.001), shorter transit (P = 0.04) and lower median pH (P = 0.002) was observed in participants with obesity compared to controls. No differences were observed for colonic measurements. CONCLUSION: Obesity has a profound impact on gastrointestinal physiology, which should be taken into account for drug development.

Laparoscopic totally stapled entero-enterostomy: a safe and reproducible new technique.

BACKGROUND: Laparoscopic gastric bypass for morbid obesity is a technically demanding procedure partially because of the necessity to construct two anastomoses. In this study, a new technique to perform the entero-enterostomy is presented. METHODS: We evaluated the procedure in a consecutive series of 100 patients who underwent laparoscopic gastric bypass. Intra- and postoperative complications were analyzed. RESULTS: No complications in relation to the construction of the entero-enterostomy occurred. No leakage, kinking, or stenosis was observed during a mean follow-up of 13.5 months (range 6-20 months). CONCLUSION: This new technique for a totally stapled entero-enterostomy can be recommended.

Laparoscopic totally stapled entero-enterostomy: a safe and reproducible new technique.

BACKGROUND: Laparoscopic gastric bypass for morbid obesity is a technically demanding procedure, partially because of the necessity to construct two anastomoses. In this study, a new technique to perform the entero-enterostomy is presented. METHODS: We evaluated the procedure in a consecutive series of 100 patients who underwent laparoscopic gastric bypass. Intra- and postoperative complications were analyzed. RESULTS: No complications in relation to the construction of the entero-enterostomy occurred. No leakage, kinking, or stenosis were observed during a mean follow-up of 13.5 months (range 6-20 months). CONCLUSION: This new technique for a totally stapled entero-enterostomy can be recommended.

Thermionic cooling devices based on resonant-tunneling AlGaAs/GaAs heterostructure.

We study by means of full quantum simulations the operating principle and performance of a semiconductor heterostructure refrigerator combining resonant tunneling filtering and thermionic emission. Our model takes into account the coupling between the electric and thermal currents by self-consistently solving the transport equations within the non-equilibrium Green's function framework and the heat equation. We show that the device can achieve relatively high cooling power values, while in the considered implementation, the maximum lattice temperature drop is severely limited by the thermal conductivity of the constituting materials. In such an out-of-equilibrium structure, we then emphasize the significant deviation of the phonon temperature from its electronic counterpart which can vary over several hundred Kelvin. The interplay between those two temperatures and the impact on the electrochemical potential is also discussed. Finally, viable options toward an optimization of the device are proposed.

Periventricular morphology in the diencephalon of antarctic notothenioid teleosts.

We have examined the subependymal region of the diencephalic third ventricle in notothenioid perciforms and report a pattern of neuropil expansions that appears to be phyletically derived for notothenioids and their outgroups but that is otherwise unique among vertebrates. We recognize five types of expansions based on their composition (from less dense neuropil to sacs) and width or protrusion into the third ventricle. In the species with the most elaborate morphology, Trematomus bernacchii, bilateral subependymal expansions fuse along the midline to form a single sac within the ventricular cavity. The extent of these expansions loosely corresponds with phyletic position but also (and perhaps more importantly) is correlated with the habitation of cold water (r2 = 0.48; P = 0.012). Furthermore, subependymal expansion type is positively correlated with the maximum size of the soma of neurons in two hypothalamic nuclei, the preopticus magnocellularis (r2 = 0.54; P = 0.006) and the lateralis tuberis (r2 = 0.40; P = 0.038). These nuclei project to the pituitary and contain cerebrospinal fluid-contacting neurons. In considering the functional consequences of this morphology, we cannot dismiss the possibility that these structures form a specialized enteroceptive system tied to the monitoring of cerebrospinal and extracellular fluid components, including antifreeze glycopeptides and inorganic ions.

Interspecific variation in the projection of primary afferents onto the electrosensory lateral line lobe of weakly electric teleosts: different solutions to the same mapping problem.

We demonstrate that preterminal axons composing the primary afferent projection onto the four somatotopically organized electrosensory lateral line lobe (ELL) segments in weakly electric gymnotiform teleosts course in fundamentally different directions in the most commonly studied species. Afferents enter the deep fiber layer (dfl) of the ELL and course in variable, but species-specific, directions within a horizontal plane before turning dorsally to terminate within the deep neuropil layer of the ELL (dnl). Among the species considered here, apteronotids exhibit the tightest projection pattern. Afferents enter the rostral ELL from the anterior lateral line nerve ganglion (ALLNG) in a nonsomatotopic fashion. As they course horizontally, these fibers undergo a rostrocaudal somatotopic sorting along the ventrolateral border of the dfl, then turn within a horizontal plane to course medially across the ELL segments. These medially coursing horizontal fibers are sorted: they form sublaminae according to the nerve branch containing their peripheral axon. Horizontal axons then turn dorsally, form fascicles, and terminate within the dnl. Within the dorsal fascicles, axons run directly into the dnl with little deviation, and their terminal fields exhibit no appreciable spread. In sternopygids, dfl horizontal fibers course in directions orthogonal to those in apteronotids. Fibers enter the rostral ELL and course medially across segments before turning caudally within segments. Unlike apteronotids, sternopygid horizontal fibers do not sort tightly by nerve branch. As horizontal axons turn dorsally they also form tight fascicles. But rather than terminating directly and without spreading, as in apteronotids, sternopygid fibers disperse from these fascicles and become sorted horizontally a second time prior to terminating in the dnl.(ABSTRACT TRUNCATED AT 250 WORDS)

Collateral sprouting in the electrosensory lateral line lobe of weakly electric teleosts (gymnotiformes) following ricin ablation.

Sprouted collateral axons were observed in the electrosensory lateral line lobe (ELL) of gymnotiform teleosts (Apteronotus leptorhynchus) following the ablation of the supraorbital branch of the anterior lateral line nerve. Ablation was accomplished by using microinjections of the toxic lectin ricin. Sprouted axons were followed for up to 26 weeks postablation. Ricin exposure severely reduced axonal numbers and the peripheral electroreceptors in the region innervated by these fibers. To visualize sprouted fibers, intact lateral line afferent nerve branches were anterogradely labelled with the neuronal tract tracers horseradish peroxidase or cobalt chloride, or the monoclonal antibody Q26A3. Within the four somatotopically organized ELL segments, sprouted collaterals were first observed two weeks after ricin injection in the medial and centromedial segments, and four weeks postinjection in the centrolateral and lateral segments. Sprouting involved intrasegmental, horizontally directed axons from adjacent nerve branch terminal fields, and mixed intra- and extrasegmental, dorsally directed axons from the ELL deep fiber layer. The sprouting response was robust but variable in its timing, peaking between 6 and 12 weeks. Subsequently, the intrasegmental, horizontally directed fibers were retained but the mixed dorsally directed fibers, including all extrasegmental axons, were retracted. Therefore, this sprouting response appears to consist of a collateral overproduction followed by a selective axonal retraction. In our view, the most likely explanation for this axonal retraction is that the descending inputs from the isthmus and the cerebellum, as well as commissural fibers from the contralateral ELL, maintain established somatotopic relationships by eliminating somatotopically mismatched sprouted collaterals.

Development of the electrosensory nervous system in Eigenmannia (Gymnotiformes): I. The peripheral nervous system.

The nerves of the anterior lateral line system in embryonic and larval stages of the weakly electric gymnotiform fish Eigenmannia were visualized by injection of the fluorescent marker DiI into the primordium of the anterior (ALLN) and posterior (PLLN) lateral line nerves. Examination of developmental series reveals that the nerve fibers that innervate the electrosensory and mechanosensory components of the anterior lateral line system are present before the first mechanoreceptors and electroreceptors have differentiated. This suggests that nerve fibers might induce the formation of lateral line receptors. Whereas the innervation of the mechanoreceptive system is already established at an early stage, the afferent innervation of electroreceptors continues to arborize in the periphery, presumably by following pioneer axon pathways. The earliest recognizable stage of the anterior lateral line nerve ganglion (ALLNG) is evident 2 days after spawning. The ganglion shows two germinal cell masses that develop into the supraorbital-infraorbital and the hyomandibular placodes. The supraorbital-infraorbital placode forms the dorsal part of the ALLNG; the hyomandibular placode forms the ventral part of the ALLNG. Counts of ALLNG cells in embryonic, larval, and adult stages of Eigenmannia show that, at each stage examined, the number of ganglion cells is always significantly larger than the number of mechanoreceptors and electroreceptor units in the periphery. During development, the distribution of ALLNG cell diameters shifts from a unimodal distribution in juveniles to a bimodal distribution in adults, peaking at 8 microns and 18 microns. These results suggest that tuberous electroreceptive organs, which are innervated by the large ALLNG cells, may not be functional prior to day 18. Our results further suggest that the number of ALLNG cells correlates with the rate of induction of lateral line receptors in the periphery.

Development of the electrosensory nervous system of Eigenmannia (gymnotiformes): II. The electrosensory lateral line lobe, midbrain, and cerebellum.

The somatotopically and functionally organized electrosensory system of gymnotiform teleosts provides a model for the study of the formation of ordered nerve connections. This paper describes the development of the major electrosensory nuclei within the hind- and midbrain. All three main electrosensory nuclei--the electrosensory lateral line lobe (ELL), dorsal torus semicircularis (torus), and tectum--grow by adding cells at their caudolateral borders. Toral and tectal germinal zones arise from lateral ventricular outpocketings that either completely or partially close by maturity. In the ELL before day 5 postspawning, germinal cells form from an initial periventricular germinal zone, then migrate to the caudolateral border of the hindbrain and begin dividing. The ELL grows from two main germinal zones, one for the medial segment, and one for the three lateral tuberous segments. Within each ELL germinal zone, newly formed cells arise from two areas: granular cells arise from a ventral subzone, pyramidal cells are generated more dorsally. Granular cells remain in situ, whereas pyramidal cells may migrate rostromedially. Cells begin differentiating as soon as they are formed. Spherical and pyramidal cells send ascending axons into the internal plexiform layer by day 14-18 and the ELL gradually begins to assume its mature laminar appearance. The ELL grows caudally, preceding the caudal lobe of the cerebellum, which will eventually lie over and fuse with it. Primary electrosensory afferents enter the ELL by day 6; incoming afferents form four fascicles within the ELL, suggesting the formation of separate ELL segments. Unlabelled projections between labelled fields from a single nerve branch filled with HRP on day 7 suggest that somatotopic order is already present at this early age. In the periphery, receptor addition is unordered, occurring along nerve branch pathways. Meanwhile the ELL adds cells in an orderly fashion at its caudolateral border. This suggests that primary afferents shift position caudally with growth to maintain their somatotopic relationships. Because all three central nuclei are in topographic register and grow by adding cells caudally, during growth ELL efferents to the torus and toral efferents to the tectum may utilize passive mechanisms, such as fiber-fiber interactions, to guide axons.

Ganglion cell arrangement and axonal trajectories in the anterior lateral line nerve of the weakly electric fish Apteronotus leptorhynchus (Gymnotiformes).

To determine the organizational principles underlying the peripheral electrosensory nervous system of weakly electric gymnotiform teleosts we labelled each of the four anterior lateral line nerve branches with HRP. We determined the position of labelled cell bodies within the ganglion and followed anterogradely filled fibers to their termination sites in one of the four somatotopic maps in the electroreceptive lateral line lobe (ELL). Within the ganglion, cell bodies exhibit a loose somatotopy based on nerve branch position: trunk electroreceptors have their cell bodies located in the caudal ganglion; cell bodies to the head receptors are rostral. Cell bodies to the head exhibit a rough dorsoventral polarity, supraorbital cells tend to be located dorsally, infraorbital cells centrally, and mandibular cells ventrally. Despite this general somatotopy there is substantial overlap (up to 30%) of cell bodies among regions. There appears to be no rostrocaudal topography within nerve branch regions. Iontophoretic WGA-HRP injected into the medial segment of the ELL retrogradely labelled cell bodies that innervate ampullary organs. These cell bodies were dispersed throughout the ganglion, indicating that cell bodies do not cluster by receptor type. Peripherally directed axons from the ganglion appear to undergo an active reorganization in order to form the nerve branches. Within nerve branches, axons to a particular area of skin do not cluster together. Centrally from the ganglion, axons retain the position of their cell body until they reach the ELL border. Once in the ELL, fibers become sorted in the deep fiber layer according to receptor type and the map they terminate in. This reorganization involves rearrangement of fascicles and axons within fascicles. In toto, proceeding from peripheral to central, the electrosensory periphery loses at least a portion of its receptor topography in the distal nerve and ganglion and then acquires both a functional and somatotopic organization after reaching the ELL; conceptually it is torn down and rebuilt again. From an ontogenetic perspective, axonal growth occurs from the ganglion outward; the fact that ganglion cell bodies are not highly organized while the receptors they innervate and their central processes are suggests that active axonal guidance mechanisms are involved.

Zebrin II immunoreactivity in the rat and in the weakly electric teleost Eigenmannia (gymnotiformes) reveals three modes of Purkinje cell development.

Monoclonal antibody (mab) anti-zebrin II recognizes a single 36-kD polypeptide in Purkinje cells in the rat and fish cerebellum. In the adult rat, zebrin II+ Purkinje cells form, in each hemicerebellum, seven parasagittal bands interposed by zebrin II- bands. We show that, in rats, immunoreactivity first appears caudally at postnatal day 5 and spreads; all Purkinje cells are labelled by postnatal day 12. Subsequently, immunoreactivity is selectively lost so that by day 18 the adult pattern of zebrin II+/-immunoreactive bands is created. This pattern indicates two types of Purkinje cells according to developmental trajectory, zebrin II-/+/-. In the adult gymnotiform teleost Eigenmannia, Purkinje cells in the corpus cerebelli (CCb), lateral valvula cerebelli (VCbl), and eminentia granularis anterior (EGa) are zebrin II+. Purkinje cells in the eminentia granularis posterior (EGp) and medialis (EGm) and the medial valvula cerebelli (VCbm) are zebrin II-. Zebrin II antigenicity is first present at 6 days postspawning (P6) in the EGa and at P8 in the CCb. In the valvula, labelling does not appear until P29. Immunoreactivity in the CCb, VCBl, and the EGa persists in the adult, whereas in the VCbm Purkinje cells become zebrin II- before reaching adulthood. These developmental histories (zebrin II-/+ and zebrin II-/+/-) correspond to the patterns of Purkinje cell development in mammals. Additionally, Eigenmannia has a third class of Purkinje cells, in the EGp and EGm, that never express zebrin II immunoreactivity, indicating that zebrin II expression is not an obligatory feature of Purkinje cell development in all vertebrates.

Strategies for assessing the implications of malformed frogs for environmental health.

The recent increase in the incidence of deformities among natural frog populations has raised concern about the state of the environment and the possible impact of unidentified causative agents on the health of wildlife and human populations. An open workshop on Strategies for Assessing the Implications of Malformed Frogs for Environmental Health was convened on 4-5 December 1997 at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina. The purpose of the workshop was to share information among a multidisciplinary group with scientific interest and responsibility for human and environmental health at the federal and state level. Discussions highlighted possible causes and recent findings directly related to frog deformities and provided insight into problems and strategies applicable to continuing investigation in several areas. Possible causes of the deformities were evaluated in terms of diagnostics performed on field amphibians, biologic mechanisms that can lead to the types of malformations observed, and parallel laboratory and field studies. Hydrogeochemistry must be more integrated into environmental toxicology because of the pivotal role of the aquatic environment and the importance of fates and transport relative to any potential exposure. There is no indication of whether there may be a human health factor associated with the deformities. However, the possibility that causal agents may be waterborne indicates a need to identify the relevant factors and establish the relationship between environmental and human health in terms of hazard assessment.

Excitonic and quasiparticle gaps in Si nanocrystals

We present calculations of the one- and two-particle excitations in silicon nanocrystals. The one-particle properties are handled in the GW approximation, and the excitonic gap is obtained from the Bethe-Salpeter equation. We develop a tight binding version of these methods to treat clusters up to 275 atoms. The self-energy and Coulomb corrections almost exactly cancel each other for crystallites with radius larger than 0.6 nm. The result of this cancellation is that one-particle calculations give quite accurate values for the excitonic gap of crystallites in the most studied range of sizes.

Monoclonal antibody anti-type I and anti-zebrin II labelling in siluriform fishes: the role of shared lineage versus shared function in polypeptide co-distributions.

Two monoclonal antibodies (mabs), the newly generated mab anti-type I and the previously described mab anti-zebrin II, were reacted with brainstem sections of two ostariophysan siluriforms, the gymnotoid Rhamphichthys rostratus and the siluroid Ictalurus punctatus. Mab anti-type I recognizes a 47 kDa polypeptide present in the dendrites and soma of projection neurons. Mab anti-zebrin II recognizes a 36 kDa polypeptide present throughout the neuronal cytoplasm, including the axon. Strongly type I immunopositive cells include: all cerebellar Purkinje cells; pyramidal cells of the nucleus medialis, electrosensory lateral line lobe and tectum; pacemaker relay cells; Mauthner neurons; lateral line ganglion cells; cells of the inferior olive; and large neurons of the reticular formation and lateral reticular nucleus. Weakly reactive type I cells include: neurons in the torus semicircularis, medial and efferent octavolateralis nuclei, the magnocellular and lateral tegmental nuclei; and the motor neurons of the Vth, VIIth and Xth cranial nerves. Most type I positive cells are brainstem projection neurons. Zebrin II expression is restricted to subsets of two cell types which also express the type I antigen - Purkinje cells and acousticolateralis pyramidal cells. Both of these neuronal types develop from the region of the rhombic lip. While the mutual expression of the type I antigen can be explained by the shared function of projection neurons, the common expression of the zebrin II antigen is most likely due to a shared embryological and/or phylogenetic lineage.

Zebrin II distinguishes the ampullary organ receptive map from the tuberous organ receptive maps during development in the teleost electrosensory lateral line lobe.

In weakly electric gymnotiform teleosts, monoclonal antibody anti-zebrin II recognizes developing pyramidal cells in the ampullary organ-receptive medial segment of the medullary electrosensory lateral line lobe (ELL) and in the mechanoreceptive nucleus medialis. Developing pyramidal cells in the remaining three tuberous organ-receptive lateral ELL segments are unreactive. These results suggest that certain biochemical features of the ELL ampullary organ-receptive medial segment are more similar to the nucleus medialis than to the tuberous organ-receptive ELL segments, and support the hypothesis that the ampullary system evolved from mechanosensory precursors.

A search for primitive Purkinje cells: zebrin II expression in sea lampreys (Petromyzon marinus).

Zebrin II/aldolase C is a 36 kDa polypeptide expressed by Purkinje cells in the cerebellum of elasmobranchs, teleosts, birds, and mammals, and by octavolateralis pyramidal cells in developing teleosts. To better understand the evolution of these two systems we determined if zebrin II is expressed (1) in previously described primitive Purkinje cells, and (2) in octavolateralis pyramidal cells of sea lampreys (Petromyzon marinus). Ammocete and adult stages were reacted with mab anti-zebrin II. In ammocetes the large pyramidal cells of the anterior octavomotor nucleus (AON) were mab anti-zebrin II immunoreactive, but immunoreactivity was not detected in the cerebellar plate. In adults there was no immunoreactivity in any portion of the brain, including the cerebellar plate and the AON. The data indicate that zebrin II immunoreactivity may prove valuable in studying the development of the octavolateralis system across vertebrates. Three explanations are proposed to account for the absence of zebrin II+ Purkinje cells: aldolase C is expressed in Purkinje cells but the zebrin II epitope has not yet evolved; the zebrin II epitope was present in ancestral lampreys but has since been lost; or sea lampreys do not have Purkinje cells. The evolutionary implications of these results are briefly reviewed.