Upper Gastrointestinal Function in Morbidly Obese Adolescents Before and 6 Months After Gastric Banding.

BACKGROUND: The effects of laparoscopic adjustable gastric band (LAGB) placement on upper gastrointestinal tract function in obese adolescents are unknown. Therefore, our aim was to determine the short-term effects of LAGB on esophageal motility, gastroesophageal reflux, gastric emptying, appetite-regulatory hormones, and perceptions of post-prandial hunger and fullness. METHODS: This study was part of a prospective cohort study (March 2009-December 2015) in one tertiary referral hospital. The study included obese adolescents (14-18 years) with a body mass index (BMI) > 40 (or ≥ 35 with comorbidities). Gastric emptying was assessed by 13C-octanoic acid breath test, pharyngeal, and esophageal motor function by high-resolution manometry with impedance (HRIM), and appetite and other perceptions using 100-mm visual analogue scales. Dysphagia symptoms were scored using a Dakkak questionnaire. Data were compared pre- and post-LAGB placement and at a 6-month follow-up. RESULTS: Based upon analysis of 15 adolescents, at the 6-month follow-up, LAGB placement: (i) led to a significant reduction in weight and BMI; (ii) increased fullness and decreased hunger post-meal; (iii) increased symptoms of dysphagia after solid food; and, despite these effects, (iv) caused little or no changes to appetite hormones, while (v) effects on gastric emptying, esophageal motility, esophageal bolus transport, and esophageal emptying were not significant. CONCLUSION: In adolescents, LAGB improved BMI and altered the sensitivity to nutrients without significant effects on upper gastrointestinal tract physiology at the 6-month follow-up.

Vagal blocking improves glycemic control and elevated blood pressure in obese subjects with type 2 diabetes mellitus.

BACKGROUND: An active device that downregulates abdominal vagal signalling has resulted in significant weight loss in feasibility studies. OBJECTIVE: To prospectively evaluate the effect of intermittent vagal blocking (VBLOC) on weight loss, glycemic control, and blood pressure (BP) in obese subjects with DM2. METHODS: Twenty-eight subjects were implanted with a VBLOC device (Maestro Rechargeable System) at 5 centers in an open-label study. Effects on weight loss, HbA1c, fasting blood glucose, and BP were evaluated at 1 week to 12 months. RESULTS: 26 subjects (17 females/9 males, 51 ± 2 years, BMI 37 ± 1 kg/m(2), mean ± SEM) completed 12 months followup. One serious adverse event (pain at implant site) was easily resolved. At 1 week and 12 months, mean excess weight loss percentages (% EWL) were 9 ± 1% and 25 ± 4% (P < 0.0001), and HbA1c declined by 0.3 ± 0.1% and 1.0 ± 0.2% (P = 0.02, baseline 7.8 ± 0.2%). In DM2 subjects with elevated BP (n = 15), mean arterial pressure reduced by 7 ± 3 mmHg and 8 ± 3 mmHg (P = 0.04, baseline 100 ± 2 mmHg) at 1 week and 12 months. All subjects MAP decreased by 3 ± 2 mmHg (baseline 95 ± 2 mmHg) at 12 months. CONCLUSIONS: VBLOC was safe in obese DM2 subjects and associated with meaningful weight loss, early and sustained improvements in HbA1c, and reductions in BP in hypertensive DM2 subjects. This trial is registered with ClinicalTrials.gov NCT00555958.

Arousal-related reticular neurons during reduced oxygen tension: resilience and recovery of electrical activity.

Whole-cell patch clamp recordings of the electrical activity of large medullary reticular formation neurons, in nucleus gigantocellularis, were performed under control conditions and under conditions of hypoxia or anoxia. Neurons were discovered whose activity was remarkably resilient during and after the reduction or loss of oxygen. Such cells may relate to the ability of the newborn brain to survive hypoxia/anoxia, and also may demonstrate the preservation of neurons involved in generalized CNS arousal, as would be appropriate for activating behavioral responses to the reduction or loss of oxygen.

Thyroid hormone action: nongenomic modulation of neuronal excitability in the hippocampus.

Years of effort have failed to establish a generally-accepted mechanism of thyroid hormone (TH) action in the mature brain. Recently, both morphological and pharmacological evidence have supported a direct neuroactive role for the hormone and its triiodinated metabolites. However, no direct physiological validation has been available. We now describe electrophysiological studies in vivo in which we observed that local thyroxine (T4) administration promptly inhibited field excitatory postsynaptic potentials recorded in the dentate gyrus (DG) with stimulation of the medial perforant pathway, a result that was found to be especially pronounced in hypothyroid rats. In separate in vitro experiments, we observed more subtle but statistically significant responses of hippocampal slices to treatment with the hormone. The results demonstrate that baseline firing rates of CA1 pyramidal cells were modestly reduced by pulse-perfusion with T4. By contrast, administration of triiodothyronine (T3) was often noted to have modest enhancing effects on CA1 cell firing rates in hippocampal slices from euthyroid animals. Moreover, and more reliably, robust firing rate increases induced by norepinephrine were amplified when preceded by treatment with T3, whereas they were diminished by pretreatment with T4. These studies provide the first direct evidence for functional, nongenomic actions of TH leading to rapid changes in neuronal excitability in adult rat DG studied in vivo and highlight the opposing effects of T4 and T3 on norepinephrine-induced responses of CA1 cells studied in vitro.

Reverse engineering the lordosis behavior circuit.

Reverse engineering takes the facts we know about a device or a process and reasons backwards to infer the principles underlying the structure-function relations. The goal of this review is to apply this approach to a well-studied hormone-controlled behavior, namely the reproductive stance of female rodents, lordosis. We first provide a brief overview on the considerable amount of progress in the analysis of female reproductive behavior. Then, we propose an analysis of the mechanisms of this behavior from a reverse-engineering perspective with the goal of generating novel hypotheses about the properties of the circuitry elements. In particular, the previously proposed neuronal circuit modules, feedback signals, and genomic mechanisms are considered to make predictions in this manner. The lordosis behavior itself appears to proceed ballistically once initiated, but negative and positive hormonal feedback relations are evident in its endocrine controls. Both rapid membrane-initiated and slow genomic hormone effects contribute to the behavior's control. We propose that the value of the reverse-engineering approach is based on its ability to provide testable, mechanistic hypotheses that do not emerge from either traditional evolutionary or simple reductionistic perspectives, and several are proposed in this review. These novel hypotheses may generalize to brain functions beyond female reproductive behavior. In this way, the reverse-engineering perspective can further develop our conceptual frameworks for behavioral and systems neuroscience.

Intra-abdominal vagal blocking (VBLOC therapy): clinical results with a new implantable medical device.

BACKGROUND: A new medical device uses high-frequency electrical algorithms to create intermittent vagal blocking (VBLOC therapy). The aim is to assess the effects of vagal blocking on excess weight loss (EWL), safety, dietary intake, and vagal function. METHODS: An open-label, 3-center study was conducted in obese subjects (body mass index [BMI] 35-50 kg/m(2)). Electrodes were implanted laparoscopically on both vagi near the esophagogastric junction to provide electrical block. Patients were followed for 6 months for body weight, safety, electrocardiogram, dietary intake, satiation, satiety, and plasma pancreatic polypeptide (PP) response to sham feeding. To specifically assess device effects alone, no diet or exercise programs were instituted. RESULTS: Thirty-one patients (mean BMI, 41.2 +/- 1.4 kg/m(2)) received the device. Mean EWL at 4 and 12 weeks and 6 months after implant was 7.5%, 11.6%, and 14.2%, respectively (all P < .001); 25% of patients lost >25% EWL at 6 months (maximum, 36.8%). There were no deaths or device-related serious adverse events (AEs). Calorie intake decreased by >30% at 4 and 12 weeks and 6 months (all P 25 pg/mL (P = .02). Three patients had serious AEs that required brief hospitalization, 1 each for lower respiratory tract, subcutaneous implant site seroma, and Clostridium difficile diarrhea. CONCLUSIONS: Intermittent, intra-abdominal vagal blocking is associated with significant EWL and a desirable safety profile.

Presynaptic actions of opioid receptor agonists in ventromedial hypothalamic neurons in estrogen- and oil-treated female mice.

Estrogens act upon ventromedial hypothalamic (VMH) neurons, and their effects on female arousal and sexual behaviors mediated by VMH neurons involve several neurotransmitters and neuromodulators. Among these are opioid peptides which might be predicted to oppose estrogenic action on VMH because they tend to decrease CNS arousal. Spontaneous excitatory postsynaptic currents were recorded from VMH neurons from 17beta-estradiol- (E, 10 mug/0.1 ml) or oil-treated control ovariectomized (OVX) mice using whole-cell patch-clamp techniques. To examine the impact of opioidergic inputs, recordings of neurons from both treatment groups were obtained in the presence of the general opioid receptor agonist methionine enkephalin-Arg-Phe (MERF, 3 muM), or mu-receptor specific agonist [d-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO, 1 muM). Compared with oil, E treatment for 48 h significantly increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) without affecting their amplitude. MERF and DAMGO each abolished this E effect, causing significant reductions in sEPSCs. The effect of MERF was abolished by naltrexone (general opioid receptor antagonist, 3 muM) and the effect of DAMGO by d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP) (mu-opioid receptor selective antagonist, 1 muM); in contrast, kappa- and delta-opioid receptor agonists, U69593 (300 nM) and [d-Pen(2),d-Pen(5)]-enkephalin (DPDPE, 1 muM) respectively, had little effect on the sEPSCs compared with DAMGO. To consider presynaptic vs. postsynaptic effects of opioids, miniature excitatory postsynaptic currents (mEPSCs) were investigated in E- and oil-treated VMH neurons and opioid receptor antagonist effects on mEPSCs were observed. Both MERF and DAMGO reduced the frequency of mEPSCs, but had no effect on their amplitude. Our findings indicate that opioids suppress excitatory synaptic transmissions in VMH neurons primarily through mu-receptors and could thereby decrease sexual arousal in mice.

Voltage-dependent calcium channels in ventromedial hypothalamic neurones of postnatal rats: modulation by oestradiol and phenylephrine.

Oestradiol actions in the hypothalamus play an important role in reproductive behaviour. Oestradiol treatment in vivo induces alpha(1b)-adrenoceptor mRNA and increases the density of alpha(1B)-adrenoceptor binding in the hypothalamus. Oestradiol is also known to modulate neuronal excitability, in some cases by modulating calcium channels. We assessed the effects of phenylephrine, an alpha(1)-adrenergic agonist, on low-voltage-activated (LVA) and high-voltage-activated (HVA) calcium channels in ventromedial hypothalamic (VMN) neurones from vehicle- and oestradiol-treated female rats. Whole-cell and gramicidin perforated-patch recordings were obtained, with barium as the charge carrier. In the absence of phenylephrine, oestradiol treatment increased the magnitude of LVA currents compared to controls, but had no effect on HVA currents. Phenylephrine enhanced HVA currents in a significantly greater proportion of neurones from oestradiol-treated rats (76%) than from vehicle-treated (41%) rats. The L-channel blocker nifedipine abolished this oestradiol effect on phenylephrine-enhanced HVA currents. Preincubating slices with the N-type channel blocker omega-conotoxin GVIA completely blocked the phenylephrine response, suggesting that the N-type channel is essential. Phenylephrine also stimulated LVA currents in approximately two-thirds of neurones in slices from both vehicle- and oestradiol-treated rats. Our data show that oestradiol increases LVA currents in the VMN. Oestradiol also amplifies alpha(1)-adrenergic signalling by increasing the proportion of neurones showing phenylephrine-stimulated HVA currents mediated by N- and L-type calcium channels. In this way, oestradiol may increase excitatory responses to arousing adrenergic inputs to VMN neurones governing oestradiol-dependent reproductive behaviour.

Associates of change in liver fat content in the morbidly obese after laparoscopic gastric banding surgery.

AIM: Hepatic steatosis affects up to 30% of the population. After weight loss, monitoring of the change in hepatic steatosis is not routinely performed. This study aimed to define the closest associates of change in liver fat content in a population of obese females following laparoscopic gastric banding surgery. METHODS: Before and 3 months after surgery, proton magnetic resonance spectroscopy and magnetic resonance imaging were used to estimate the amount of lipid contained within the liver and abdominal subcutaneous and visceral compartments of 29 obese [mean body mass index (BMI) 39 +/- 5 kg/m(2)], non-diabetic women aged between 20 and 62 years. Liver enzymes, fasting plasma glucose and insulin were also measured as well as body weight, BMI and waist circumference. Insulin sensitivity was estimated using homeostasis model assessment insulin resistance index. RESULTS: Significant reductions occurred in body weight (p < 0.001), abdominal fat volumes (p < 0.001) and liver fat (p = 0.037) 3 months after surgery. Change in liver fat content more closely associated with change in serum gamma-glutamyl transferase (GGT; r = 0.71, p < 0.001) than with changes in weight (r = 0.10, p = 0.612) and waist circumference (r = 0.15, p = 0.468). CONCLUSIONS: Our findings suggest that obese non-diabetic female patients who have undergone significant weight loss over 3 months can be better assessed for the regression of excess liver fat content by monitoring changes in serum GGT levels rather than changes in simple anthropometry.

Hormonal induction of lordosis and ear wiggling in rat pups: gender and age differences.

To assess how early can estrogens induce female mating behaviors, rat pups 8-29 days old (D8-D29, respectively) were injected twice daily with estradiol benzoate (E) or oil (O) followed by progesterone (P) or oil, and then observed for the estrogen-dependent ear wiggling (EW) and lordosis in response to natural stimulation from male rats. In female pups treated with E + E + P, the incidence of EW appeared as early as D13 and increased gradually to reach maximum at D18, when all pups tested showed EW. EW also occurred in E + E + O females, but never in O + O + P females or in any E + E + P male. Lordosis in E + E + P, as well as E + E + O, female pups occurred later, starting at D15. O + O + P females or E + E + P males never display lordosis. To explore the possibilities that the age and gender differences are due to distribution and/or function of estrogen receptor-alpha (ERalpha) or progesterone receptor (PR), separate pups were used for immunocytochemical (ICC) staining of these receptors in the hypothalamic ventromedial nucleus (VMN). There was no age difference in female pups in the density of ERalpha or the induction of PR between D11/D12, when no sexual behavior was observed, and D19/D20, when almost all pups tested performed the behaviors. There were gender differences: male pups had less ERalpha than females at D19/D20, though not at D11/D12, and did not respond to E in the induction of PR in the VMN. These results show that ERs and their signaling systems in the VMN of rat pups are functional at least after D11 but only in females, and that the gender differences appeared to be due to differences in the molecular biology of ERalpha.

Acute estradiol application increases inward and decreases outward whole-cell currents of neurons in rat hypothalamic ventromedial nucleus.

Acute estradiol (E2) can potentiate the excitatory responses of hypothalamic ventromedial nucleus (VMN) neurons to neurotransmitters. To investigate the mechanism(s) underlying the potentiation, the whole-cell patch voltage clamp technique was used to study VMN neurons in hypothalamic slices prepared from female juvenile (3-5 weeks) rats. A voltage step and/or ramp was applied every 5 min to evoke whole-cell currents before, during and after a treatment with E2 (10 nM), corticosterone (10 nM) or vehicle for up to 20 min. Acute E2 increased inward currents in 38% of neurons tested. Their average peak inward current amplitudes started to increase within 5 min and reached the maximum of 163% of pretreatment level (Pre) at 20 min of treatment before recovering toward Pre. These increases are significantly greater than the Pre and corresponding vehicle controls and non-responsive neurons. Outward currents were decreased significantly by E2 in 27% of E2-treated cells, down to 60% of Pre levels. E2 also appeared to affect the kinetics of the inward and outward currents of estrogen-responsive neurons. Whenever observed, the effects of acute E2 were reversible after a 5- to 10-min washing. Probability analysis indicates that E2 affected the inward and the outward currents independently. The E2 effects are specific in that they were not produced by similar treatment with vehicle or corticosterone. Pharmacological characterizations using ion replacement and channel blockers showed that the inward currents were mediated practically all by Na(+) and the outward currents mainly by K(+). Thus, acute E2 can enhance inward Na(+) and attenuate outward K(+) currents. Since both effects will lead to an increase in neuronal excitability, they may explain our previous observation that E2 potentiates the excitation of VMN neurons.

Sex and estrogenic effects on coexpression of mRNAs in single ventromedial hypothalamic neurons.

Regulated gene expression in single neurons can be linked to biophysical events and behavior in the case of estrogen-regulated gene expression in neurons in the ventrolateral portion of the ventromedial nucleus (VMN) of the hypothalamus. These cells are essential for lordosis behavior. What genes are coexpressed in neurons that have high levels of mRNAs for estrogen receptors (ERs)? We have been able to isolate and measure certain mRNAs from individual VMN neurons collected from rat hypothalamus. Large numbers of neurons express mRNA for ERalpha, but these neurons are not identical with the population of VMN neurons expressing the likely gene duplication product, ERbeta. An extremely high proportion of neurons expressing either ER also coexpress mRNA for the oxytocin receptor (OTR). This fact matches the known participation of oxytocin binding and signaling in sexual and affiliative behaviors. In view of data that ER and OTR can signal through PKCs, we looked at coexpression of selected PKCs in the same individual neurons. The most discriminating analysis was for triple coexpression of ERs, OTR, and each selected PKC isoform. These patterns of triple coexpression were significantly different for male vs. female VMN neurons. Further, individual neurons expressing ERalpha could distribute their signaling across the various PKC isoforms differently in different cells, whereas the reverse was not true. These findings and this methodology establish the basis for systematic linkage of the brain's hormone-sensitive signaling pathways to biophysical and behavioral mechanisms in a well studied mammalian system.

Female oxytocin gene-knockout mice, in a semi-natural environment, display exaggerated aggressive behavior.

Compared to results from a generation of neuropharmacological work, the phenotype of mice lacking the oxytocin (OT) peptide gene was remarkably normal. An important component of the current experiments was to assay OT-knockout (OTKO) and wild-type (WT) littermate control mice living under controlled stressful conditions designed to mimic more closely the environment for which the mouse genome evolved. Furthermore, our experimental group was comprised of an all-female population, in contrast to previous studies which have focused on all-male populations. Our data indicated that aggressive behaviors initiated by OTKO during a food deprivation feeding challenge were considerably more intense and diverse than aggressive behaviors initiated by WT. From the measures of continuous social interaction in the intruder paradigm, it emerged that OTKO mice were more offensively aggressive (attacking rumps and tails) than WT. In a test of parental behaviors, OTKO mice were 100% infanticidal while WT were 16% infanticidal and 50% maternal. Finally, 'alpha females' (always OTKO) were identified in each experiment. They were the most aggressive, the first to feed and the most dominant at nesting behaviors. Semi-natural environments are excellent testing environments for elucidating behavioral differences between transgenic mice and their WT littermates which may not be ordinarily discernible. Future studies of mouse group behavior should include examining female groupings in addition to the more usual all-male groups.

Acute estrogen potentiates excitatory responses of neurons in rat hypothalamic ventromedial nucleus.

In a previous behavioral study, brief application of a membrane-limited estrogen to neurons in rat hypothalamic ventromedial nucleus (VMN) facilitated lordosis behavior-inducing genomic actions of estrogen. Here, electrophysiological recordings from single neurons were employed to characterize these membrane-initiated actions. From rat hypothalamic slices, electrical activity was recorded from neurons in the ventrolateral VMN, the cell group crucial for estrogen induction of lordosis. In addition to the resting activity, neuronal responses to histamine (HA) and N-methyl-d-aspartate (NMDA) were also recorded before, during, and after a brief (10-15 min) application of estradiol (E, 10 nM). These two transmitters were chosen because their actions are mediated by different mechanisms: HA through G protein-coupled receptors and NMDA by ligand-activated ion channels. Vehicle applications did not affect either resting activity or neuronal responses. In contrast, acute E exposure modulated neuronal responses to transmitters, with no significant effect on the resting activity. It potentiated excitatory responses to HAs (20 out of 48 cells tested) and to NMDA (10 out of 19 cells), but attenuated inhibitory responses to HA (3 out of 6 units). Both of these hormonal actions would increase VMN neuronal excitation. In separate experiments, neuronal excitation was found to be suppressed by anesthetics, which would block E's induction of lordosis when administered at the time of estrogen application. These data are consistent with the notion that increasing electrical excitation of VMN neurons can be a mechanism by which acute E exposure facilitates the lordosis-inducing genomic actions of estrogens.

Potentiation of the excitatory action of NMDA in ventrolateral periaqueductal gray by the mu-opioid receptor agonist, DAMGO.

Several lines of evidence have suggested that mu-opioids, generally regarded as inhibitory, also have effects that stimulate neural activity. To look for possible excitatory opioid action in the rat periaqueductal gray (PAG), we first re-examined data from a previous study and found that met-enkephalin could evoke a delayed, sluggish excitation, suggestive of modulation by the opioid on the action of certain excitants. This observation, coupled with other studies that show mu-opioids can modulate NMDA receptor activation, prompted us to perform extracellular recording of the responses of single ventrolateral PAG (vlPAG) neurons in brain slices to DAMGO, a mu-opioid, and to NMDA. When applied alone, DAMGO at nM concentrations, like met-enkephalin, often evoked the delayed excitation and occasionally an inhibition. When applied after a brief exposure to NMDA, DAMGO at doses as low as 0.1 nM potentiated the excitation produced by a subsequent pulse of NMDA. This occurred, depending on cell type, in 23-100% of vlPAG neurons. The potentiating action of DAMGO was blocked by naloxone, suggesting it was mediated by mu-opioid receptors. Characterization of these mu-opioid actions revealed that the potentiation and the delayed excitation, unlike the inhibition, was not blocked by another opioid antagonist, nalmefene, nor by an inhibitor of the G protein of the G(i) class, N-ethylmaleimide. Moreover, the potentiating action was distinct from the inhibition in that it was: (a) enhanced by repeated opioid applications, (b) exhibited low effective doses, (c) had a long time course (minutes to develop and last tens of minutes) and (d) was present in distinct though overlapping cell populations. These data reveal an unconventional action of opioids in PAG neurons, that is, a potentiation of excitation produced by NMDA. This effect appeared mechanistically distinct from opioid inhibition or disinhibition and may be related to established examples of direct opioid excitation. These observations may help understanding behaviorally important mechanisms linked to acute and chronic opioid functions in the vlPAG.

Brain glucose-sensing mechanisms: ubiquitous silencing by aglycemia vs. hypothalamic neuroendocrine responses.

Interest in brain glucose-sensing mechanisms is motivated by two distinct neuronal responses to changes in glucose concentrations. One mechanism is global and ubiquitous in response to profound hypoglycemia, whereas the other mechanism is largely confined to specific hypothalamic neurons that respond to changes in glucose concentrations in the physiological range. Although both mechanisms use intracellular metabolism as an indicator of extracellular glucose concentration, the two mechanisms differ in key respects. Global hyperpolarization (inhibition) in response to 0 mM glucose can be reversed by pyruvate, implying that the reduction in ATP levels acting through ATP-dependent potassium (K-ATP) channels is the key metabolic signal for the global silencing in response to 0 mM glucose. In contrast, neuroendocrine hypothalamic responses in glucoresponsive and glucose-sensitive neurons (either excitation or inhibition, respectively) to physiological changes in glucose concentration appear to depend on glucokinase; neuroendocrine responses also depend on K-ATP channels, although the role of ATP itself is less clear. Lactate can substitute for glucose to produce these neuroendocrine effects, but pyruvate cannot, implying that NADH (possibly leading to anaplerotic production of malonyl-CoA) is a key metabolic signal for effects of glucose on glucoresponsive and glucose-sensitive hypothalamic neurons.

Early membrane estrogenic effects required for full expression of slower genomic actions in a nerve cell line.

Interpretations of steroid hormone actions as slow, nuclear, transcriptional events have frequently been seen as competing against inferences of rapid membrane actions. We have discovered conditions where membrane-limited effects potentiate later transcriptional actions in a nerve cell line. Making use of a two-pulse hormonal schedule in a transfection system, early and brief administration of conjugated, membrane-limited estradiol was necessary but not sufficient for full transcriptional potency of the second estrogen pulse. Efficacy of the first pulse depended on intact signal transduction pathways. Surprisingly, the actions of both pulses were blocked by a classical estrogen receptor (ER) antagonist. Thus, two different modes of steroid hormone action can synergize.

A simple scoring system for predicting bile duct stones in patients with cholelithiasis.

A means of accurately predicting the presence of stones in the bile duct in patients undergoing laparoscopic cholecystectomy for gallbladder stones is lacking. With the use of a three-stage analysis, a predictive score was developed from seven common parameters. Initially the score was formulated by using data from a retrospective series of patients undergoing laparoscopic cholecystectomy; the system was then tested prospectively over a 1-year period in patients undergoing laparoscopic cholecystectomy for gallbladder stones. This simple scoring system demonstrated an ability to predict bile duct stones with a sensitivity in excess of 70%. The use of such a score may allow the development of preoperative strategies for treating patients undergoing laparoscopic cholecystectomy.

Minimally invasive management of bile leak after laparoscopic cholecystectomy.

BACKGROUND: Bile leakage is an uncommon complication of cholecystectomy.The bile may originate from the gallbladder bed, the cystic duct or rarely from injury to a major bile duct.This study aims to evaluate the efficacy of minimal access endoscopic and percutaneous techniques in treating symptomatic bile leak. PATIENTS AND METHODS: Twenty-one patients with symptomatic bile leak following laparoscopic cholecystectomy underwent assessment of the extent of the bile leak via ultrasound/CT and ERCP. Following diagnosis, the patients were treated by sphincterotomy and biliary drainage and, if necessary, percutaneous drainage of the bile collection. RESULTS: Only one patient required primary surgical treatment following diagnosis of a major duct injury.The other 20 were treated by a combination of sphincterotomy (including a stent in most) plus percutaneous drainage in six. In 19 of 20, this minimal access approach stopped the leak. DISCUSSION: Most patients who present with bile leakage after cholecystectomy can be managed successfully by means of ERCP with percutaneous drainage of any large bile collection.

Presynaptic and postsynaptic relations of mu-opioid receptors to gamma-aminobutyric acid-immunoreactive and medullary-projecting periaqueductal gray neurons.

The ventrolateral portion of the periaqueductal gray (PAG) is one brain region in which ligands of the mu-opioid receptor (MOR) produce analgesia. In the PAG, MOR ligands are thought to act primarily on inhibitory [e.g., gamma-aminobutyric acidergic (GABAergic)] neurons to disinhibit PAG output rather than directly on medullary-projecting PAG neurons. In this study, the ultrastructural localization of MOR immunolabeling was examined with respect to either GABAergic PAG neurons or PAG projection neurons that were labeled retrogradely from the rostral ventromedial medulla. Immunoreactivity for MOR and GABA often coexisted within dendrites. Dual-labeled profiles accounted for subpopulations of dendrites containing immunoreactivity for either MOR (65 of 145 dendrites; 45%) or GABA (65 of 183 dendrites; 35%). In addition, nearly half of PAG neuronal profiles (148 of 344 profiles) that were labeled retrogradely from the ventromedial medulla contained MOR immunoreactivity. MOR was distributed equally among retrogradely labeled neuronal profiles in the lateral and ventrolateral columns of the caudal PAG. With respect to the presynaptic distribution of MOR, approximately half of MOR-immunolabeled axon terminals (35 of 69 terminals) also contained GABA. Some MOR and GABA dual-immunolabeled axon terminals contacted unlabeled dendrites (11 of 35 terminals), whereas others contacted GABA-immunoreactive dendrites (15 of 35 terminals). Furthermore, axon terminals synapsing on medullary-projecting PAG neurons sometimes contained immunoreactivity for MOR. These data support the model that MOR ligands can act by inhibiting GABAergic neurons, but they also provide evidence that MOR ligands may act directly on PAG output neurons. In addition, MOR at presynaptic sites could affect both GABAergic neurons and output neurons. Thus, the disinhibitory model represents only partially the potential mechanisms by which MOR ligands can modulate output of the PAG.