Nociceptin Induces Hypophagia in the Perifornical and Lateral Hypothalamic Area

Nociceptin/orphanin FQ (N/OFQ) is known to induce food intake when administered into the lateral ventricle or certain brain areas. This is somewhat contradictory to its reward-suppressing role, as food is a strong rewarding stimulus. This discrepancy may be due to the functional diversity of N/OFQ’s target brain areas. N/OFQ has been shown to inhibit orexin and melanin-concentrating hormone (MCH) neurons, both of which are appetite-inducing cells. As the expression of these neurons is largely confined to the lateral hypothalamus/perifornical area (LH/PFA), we hypothesized that N/OFQ inhibits food intake by acting in this area. To test this hypothesis, we examined the effect of local N/OFQ infusion within the LH/PFA on food intake in the rat and found that N/OFQ decreased sugar pellet as well as chow intake. This effect was not seen when the injection site was outside of the LH/PFA, suggesting a site-specific effect. Next, to determine a possible cellular mechanism of N/OFQ action on food intake, whole cell patch clamp recordings were performed on rat orexin neurons. As previously reported in mice, N/OFQ induced a strong and long lasting hyperpolarization. Pharmacological study indicated that N/OFQ directly inhibited orexin neurons by activating ATP-sensitive potassium (KATP) channels. This effect was partially but significantly attenuated by the inhibitors of PI3K, PKC and PKA, suggesting that the N/OFQ signaling is mediated by these protein kinases. In summary, our results demonstrate a KATP channel-dependent N/OFQ signaling and that N/OFQ is a site-specific anorexic peptide

N/OFQ activates KATP channels in orexin neurons.

<p><i>A</i>: Current responses to voltage-ramps before (control; CTL) and during N/OFQ application in 2.5 mM extracellular potassium. B: Subtraction of currents recorded in two conditions (N/OFQ - CTL) reveals an N/OFQ-induced current (2.5 mM K⁺). Increasing the extracellular potassium concentration to 10 mM shifted the current-voltage relationship rightward. <i>C</i>. Grouped data showing that the reversal potential of the N/OFQ current is dependent on the concentration of extracellular potassium. *** p<0.005. <i>D-F</i>: N/OFQ responses are attenuated by BaCl₂ (<i>D</i>) and glibenclamide (Glib) (<i>E</i>) but not tertiapin Q (TQ) (<i>F</i>). Grouped data are shown in (G). *** p<0.005, n.s. non-significant vs. N/OFQ. Numbers in bars represent the number of cells examined in each group. <i>H</i>: Once N/OFQ current is induced, it is persistent and retains Ba⁺⁺ sensitivity even after a prolonged washout.</p

N/OFQ inhibits orexin neurons via NOP receptor activation in the rat.

<p><i>A</i>: N/OFQ hyperpolarizes orexin neurons. <i>B</i>: Representative voltage clamp trace showing a TTX-insensitive outward current induced by N/OFQ application. <i>C</i>: N/OFQ-induced effect is significantly attenuated by UFP-101. However, the effect persists in the presence of naloxone (E), indicating a specific activation of NOP receptors. D: N/OFQ is ineffective on orexin neurons patched with GDPβS in the recording pipette. E: Grouped data is shown. Numbers in bars represent the number of cells examined in each group. ** p<0.01, *** p<0.005 vs. N/OFQ.</p

N/OFQ does not consistently modulate excitatory transmission to orexin neurons.

<p><i>A</i>: mEPSC traces from a representative orexin neuron before (control: CTL) and during N/OFQ (0.3 µM, 5 min) application, showing a lack of effect. <i>B-C</i>: Cumulative frequency (freq.) graphs for mEPSC interevent interval (<i>C</i>) and amplitude (<i>D</i>) for the cell shown in <i>A</i>. Solid and broken lines represent CTL and N/OFQ conditions, respectively. <i>D-E</i>: Grouped data (n = 8) of mEPSC interevent interval (<i>D</i>) and amplitude (<i>E</i>) in control and N/OFQ.</p

N/OFQ-induced KATP channel activation is mediated by PI3K, PKA and PKC.

<p><i>A-E</i>: Representative recordings showing the effect of N/OFQ in the presence of specific inhibitors for PI3K (wortmannin; Wort), PKA (H89) or PKC (calphostin C; CalC), as indicated. Scale bars in <i>A</i> apply to all traces. <i>F</i>: Grouped data showing that kinase inhibitors attenuate the N/OFQ effect. Combined application of H89 and CalC did not have an additive effect. Numbers in bars represent the number of cells examined in each group. * p<0.05, *** p<0.001 vs. N/OFQ.</p

Intra-LH/PFA N/OFQ injection decreases palatable food intake.

<p><i>A</i>: Coronal brain maps depicting the location of injections. Each circle represents a rat used for the analysis. Filled and open circles were categorized as on- or off-target, respectively, relative to the orexin/MCH field. Numbers on the left of each map indicate the posterior distance from the bregma based on the Rat Brain Atlas by Paxinos and Watson <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0045350#pone.0045350-Paxinos1" target="_blank">[57]</a>. The brain maps were modified from the images in the Atlas. <i>B</i>: N/OFQ significantly reduced the sugar pellet intake during the first hour (1 h) following an injection into the LH/PFA (on-target) but not the 3h-total intake post-injection (filled bars). In contrast, N/OFQ injections outside of the LH/PFA (off-target) did not affect the sugar pellet consumption (open bars). <i>C</i>: N/OFQ significantly reduced chow intake during the first hour (1 h) following an injection into the LH/PFA (on-target) but not the 3h-total intake (filled bars). This effect was not seen when the injection was off-target. * p<0.05.</p

Rural Cooperatives Magazine, May/June 2013

Features - Start Me Up; Building Bridges; Indivisible Reserves; Birds of a Feather; Equity Elevator & Trading Co. joins century club; The Lure of Distant Shores; USDA funds help reopen town’s only grocery; Co-op food market planned in South Carolin

Impact of Providing a Tape Measure on the Provision of Lung-protective Ventilation

Introduction: Emergency department (ED) patients are frequently ventilated with excessively large tidal volumes for predicted body weight based on height, which has been linked to poorer patient outcomes. We hypothesized that supplying tape measures to respiratory therapists (RT) would improve measurement of actual patient height and adherence to a lung-protective ventilation strategy in an ED-intensive care unit (ICU) environment.Methods: On January 14, 2019, as part of a ventilator-associated pneumonia prevention bundle in our ED-based ICU, we began providing RTs with tape measures and created a best practice advisory reminding them to record patient height. We then retrospectively collected data on patient height and tidal volumes before and after the intervention.Results: We evaluated 51,404 tidal volume measurements in 1,826 patients over the 4 year study period; of these patients, 1,579 (86.5%) were pre-intervention and 247 (13.5%) were post-intervention. The intervention was associated with a odds of the patient’s height being measured were 10 times higher post-intervention (25.1% vs 3.2%, P &lt;0.05). After the bundle was initiated, we observed a significantly higher percentage of patients ventilated with mean tidal volumes less than 8 cubic centimeters per kilogram (93.9% vs 84.5% P &lt; 0.05).Conclusion: Patients in an ED-ICU environment were ventilated with a lung-protective strategy more frequently after an intervention reminding RTs to measure actual patient height and providing a tape measure to do so. A significantly higher percentage of patients had height measured rather than estimated after the intervention, allowing for more accurate determination of ideal body weight and calculation of lung-protective ventilation volumes. Measuring all mechanically ventilated patients’ height with a tape measure is an example of a simple, low-cost, scalable intervention in line with guidelines developed to improve the quality of care delivered to critically ill ED patients

Validation of the modified Bosniak classification system to risk stratify pediatric cystic renal masses : an international, multi-site study from the pediatric urologic oncology working group of the societies for pediatric urology

Background Pediatric cystic renal lesions are challenging to manage as little is known about their natural course. A modified Bosniak (mBosniak) classification system has been proposed for risk stratification in pediatric patients that takes ultrasound (US) and/or computed tomogram (CT) characteristics into account. However, literature validating this system remains limited. Objective To determine if the mBosniak classification system correlates with pathologic diagnoses. The hypothesis is that mBosniak classification can stratify the risk of malignancy in children with renal cysts. Study design Patients treated for cystic renal masses with available imaging and pathology between 2000 and 2019 from five institutions were identified. Clinical characteristics and pathology were obtained retrospectively. Characteristics from the most recent US, CT, and/or magnetic resonance imaging (MRI) were recorded. Reviewers assigned a mBosniak classification to each scan. mBosniak scores 1/2 were considered low-risk and 3/4 high-risk. These groups were compared with pathology (classified as benign, intermediate, malignant). Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (+LR), and negative likelihood ratio (-LR) were calculated to assess this categorization as a screening tool to guide surgical intervention. Agreement between imaging modalities was also explored. Results 99 patients were identified. High-risk imaging findings were correlated with malignant or intermediate pathology with a sensitivity of 88.3%, specificity of 84.6%, PPV of 89.8%, NPV of 82.5%, +LR of 5.7, and -LR of 0.14. The sensitivity for detecting malignant lesions only was 100%. There was substantial agreement between US/CT (n = 55; kappa = 0.66) and moderate agreement between US/MRI (n = 20; kappa = 0.52) and CT/MRI (n = 13; kappa = 0.47). Discussion The mBos classification system is a useful tool in predicting the likelihood of benign vs. intermediate or malignant pathology. The relatively high sensitivity and specificity of the system for prediction of high-risk lesions makes this classification applicable to clinical decision making. In addition, all malignant lesions were accurately identified as mBosniak 4 on imaging. This study adds substantial data to the relatively small body of literature validating the mBosniak system for risk stratifying pediatric cystic renal lesions. Conclusions Pediatric cystic renal lesions assigned mBosniak class 1/2 are mostly benign, whereas class 3/4 lesions are likely intermediate or malignant pathology. We observed that the mBosniak system correctly identified pathology appropriate for surgical management in 88% of cases and did not miss malignant pathologies. There is substantial agreement between CT and US scans concerning mBos classification