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Item Activation and execution of the hepatic integrated stress response by dietary essential amino acid deprivation is amino acid specific(Wiley, 2022) Jonsson, William O.; Mirek, Emily T.; Wek, Ronald C.; Anthony, Tracy G.; Biochemistry and Molecular Biology, School of MedicineDietary removal of an essential amino acid (EAA) triggers the integrated stress response (ISR) in liver. Herein, we explored the mechanisms that activate the ISR and execute changes in transcription and translation according to the missing EAA. Wild‐type mice and mice lacking general control nonderepressible 2 (Gcn2) were fed an amino acid complete diet or a diet devoid of either leucine or sulfur amino acids (methionine and cysteine). Serum and liver leucine concentrations were significantly reduced within the first 6 h of feeding a diet lacking leucine, corresponding with modest, GCN2‐dependent increases in Atf4 mRNA translation and induction of selected ISR target genes (Fgf21, Slc7a5, Slc7a11). In contrast, dietary removal of the sulfur amino acids lowered serum methionine, but not intracellular methionine, and yet hepatic mRNA abundance of Atf4, Fgf21, Slc7a5, Slc7a11 substantially increased regardless of GCN2 status. Liver tRNA charging levels did not correlate with intracellular EAA concentrations or GCN2 status and remained similar to mice fed a complete diet. Furthermore, loss of Gcn2 increased the occurrence of ribosome collisions in liver and derepressed mechanistic target of rapamycin complex 1 signal transduction, but these changes did not influence execution of the ISR. We conclude that ISR activation is directed by intracellular EAA concentrations, but ISR execution is not. Furthermore, a diet devoid of sulfur amino acids does not require GCN2 for the ISR to execute changes to the transcriptome.Item Circadian entrainment by food and drugs of abuse(Elsevier, 2019-08-01) Gillman, Andrea G.; Rebec, George V.; Pecoraro, Norman C.; Kosobud, Ann E. K.; Neurology, School of MedicineCircadian rhythms organize behavior and physiological processes to be appropriate to the predictable cycle of daily events. These rhythms are entrained by stimuli that provide time of day cues (zeitgebers), such as light, which regulates the sleep-wake cycle and associated rhythms. But other events, including meals, social cues, and bouts of locomotor activity, can act as zeitgebers. Recent evidence shows that most organs and tissues contain cells that are capable of some degree of independent circadian cycling, suggesting the circadian system is more broadly and diffusely distributed. Within laboratory studies of behavior, circadian rhythms tend to be treated as a complication to be minimized, but they offer a useful model of predictable shifts in behavioral tendencies. In the present review, we summarize the evidence that formed the basis for a hypothesis that drugs of abuse can entrain circadian rhythms and describe the outcome of a series of experiments designed to test that hypothesis. We propose that such drug-entrained rhythms may contribute to demonstrated daily variations in drug metabolism, tolerance, and sensitivity to drug reward. Of particular importance, these rhythms may be evoked by a single episode of drug taking, strengthen with repeated episodes, and reemerge after long periods of abstinence, thereby contributing to drug abuse, addiction, and relapse.Item Drugs of Abuse Can Entrain Circadian Rhythms(Hindawi Publishing Corporation, 2007-11-02) Kosobud, Ann E.K.; Gillman, Andrea G.; Leffel, Joseph K., II; Pecoraro, Norman C.; Rebec, G.V.; Timberlake, William; Neurology, School of MedicineCircadian rhythms prepare organisms for predictable events during the Earth's 24-h day. These rhythms are entrained by a variety of stimuli. Light is the most ubiquitous and best known zeitgeber, but a number of others have been identified, including food, social cues, locomotor activity, and, most recently drugs of abuse. Given the diversity of zeitgebers, it is probably not surprising that genes capable of clock functions are located throughout almost all organs and tissues. Recent evidence suggests that drugs of abuse can directly entrain some circadian rhythms. We have report here that entrainment by drugs of abuse is independent of the suprachiasmatic nucleus and the light/dark cycle, is not dependent on direct locomotor stimulation, and is shared by a variety of classes of drugs of abuse. We suggest that drug-entrained rhythms reflect variations in underlying neurophysiological states. This could be the basis for known daily variations in drug metabolism, tolerance, and sensitivity to drug reward. These rhythms could also take the form of daily periods of increased motivation to seek and take drugs, and thus contribute to abuse, addiction and relapse.Item Feeding Performance and Outcomes in Infants With Robin Sequence Undergoing Mandibular Distraction Osteogenesis(Sage, 2024) McGhee, Heather; Gehle, Daniel; Shope, Chelsea; Wen, Chun-Che; Marston, Alexander P.; Discolo, Christopher; Pecha, Phayvanh P.; Otolaryngology -- Head and Neck Surgery, School of MedicineObjective: To describe perioperative feeding performance in infants with Robin sequence (RS) who underwent mandibular distraction osteogenesis (MDO). Design: A retrospective study of infants that underwent MDO from May 2010 to December 2019. Setting: Tertiary pediatric hospital. Patients: A total of 40 patients underwent MDO and 20 met inclusion criteria. Of the included infants, 6 had an associated syndrome and 80% were male. Main Outcome Measures: Time to full oral feeds, rate of G-tube placement, and change in weight percentile following MDO. Results: Average oral intake prior to MDO was 22.1% of individual goal feeds. Among the 15 (75%) children that did not require G-tube placement, mean time to full oral feeds after MDO was 11 days ± 5.7 days, with 80% of infants reaching full oral feeds within 2 weeks after extubation. The proportion of G-tube placement in patients with a syndrome was higher than in isolated RS (−0.6; 95% CI: −1.0, −0.2). Mean percentages of weight-for-age percentile decreased during the first 3 months after the procedure. This was followed by a mean upturn in weight starting after the third month after MDO with a recovery to preoperative mean weight-for-age percentiles by 6 months after surgery. Conclusions: This study suggests that infants with RS may achieve full oral feeds despite poor feeding performance before MDO. Infants with syndromic RS are more likely to require G-tube. These findings may be used to inform G-tube discussion and offer a timeline to work toward goal oral feeds for infants with RS after MDO.Item Gastric Tube Placement in Children 1-215 Months Old(Office of the Vice Chancellor for Research, 2010-04-09) Smith, Coral E.; Perkins, Susan M.; Lane, Kathleen A.; Ellett, Marsha L.Feeding by a nasogastric/orogastric (NG/OG) tube is preferred when the gastrointestinal system is functional and the need for assisted feeding is expected to be short-term. Preliminary studies in children show that between 21% and 44% of these tubes are placed incorrectly. When tubes are out of place, children can be seriously harmed, causing increased morbidity and occasionally death. The aims of this study were to determine the best method to predict the insertion distance for placing NG/OG tubes and to determine the best clinical methods of testing the location of NG/OG tubes once they were inserted. A randomized clinical trial was conducted. The three insertion-distance prediction methods tested were nose-ear-xiphoid (NEX); nose-ear-mid-umbilicus (NEMU); and age-related, height-based (ARHB). An abdominal radiograph was obtained immediately following tube insertion to determine the internal location of the tube tip and orifice(s). Based on data from 95 children age 1-220 months (M = 51.8, SD = 54.9, median = 33.4), both the ARHB and NEMU methods were superior to NEX in placing the tube in the stomach (p = .0064). ARHB and NEMU were not significantly different from each other. NEX was frequently too short (41.93% of tube insertions) leaving the tube tip and/or orifices in the esophagus. The three clinical methods of testing tube location were CO2 monitoring and measuring pH and bilirubin in tube aspirate. Measuring pH of tube aspirate was the superior clinical method of determining tube location. Aspirate was available for testing in 84 children (88.42%). Based on a pH cutoff of 5 (recommended by Metheny in fasting adults), the sensitivity was 26.67 (low), specificity was 80.60 (high), positive predictive value was 23.53 (low), and negative predictive value was 83.08 (high). Measuring the NEX distance is the method most commonly used by nurses in practice; therefore, based on the results of this study and studies of other researchers, a practice change to either ARHB or NEMU should improve the safety of enteral feeding in children. Because of the low sensitivity in predicting misplaced tubes using pH, the superior clinical method, obtaining an abdominal x-ray to ensure placement in the stomach at the time of tube insertion is recommended.Item Health Factors Associated With Development and Severity of Poststroke Dysphagia: An Epidemiological Investigation(American Heart Association, 2024) Krekeler, Brittany N.; Schieve, Heidi J. P.; Khoury, Jane; Ding, Lili; Haverbusch, Mary; Alwell, Kathleen; Adeoye, Opeolu; Ferioloi, Simona; Mackey, Jason; Woo, Daniel; Flaherty, Matthew; De Los Rios La Rosa, Felipe; Demel, Stacie; Star, Michael; Coleman, Elisheva; Walsh, Kyle; Slavin, Sabreena; Jasne, Adam; Mistry, Eva; Kleindorfer, Dawn; Kissela, Brett; Neurology, School of MedicineBackground: Dysphagia after stroke is common and can impact morbidity and death. The purpose of this population-based study was to determine specific epidemiological and health risk factors that impact development of dysphagia after acute stroke. Methods and results: Ischemic and hemorrhagic stroke cases from 2010 and 2015 were identified via chart review from the GCNKSS (Greater Cincinnati Northern Kentucky Stroke Study), a representative sample of ≈1.3 million adults from southwestern Ohio and northern Kentucky. Dysphagia status was determined on the basis of clinical assessments and necessity for alternative access to nutrition via nasogastric or percutaneous endoscopic gastrostomy tube placement. Comparisons between patients with and without dysphagia were made to determine differences in baseline characteristics and premorbid conditions. Multivariable logistic regression determined factors associated with increased risk of dysphagia. Dysphagia status was ascertained from 4139 cases (1709 with dysphagia). Logistic regression showed that increased age, Black race, higher National Institutes of Health Stroke Scale score at admission, having a hemorrhagic stroke (versus infarct), and right hemispheric stroke increased the risk of developing dysphagia after stroke. Factors associated with reduced risk included history of high cholesterol, lower prestroke modified Rankin Scale score, and white matter disease. Conclusions: This study replicated previous findings of variables associated with dysphagia (older age, worse stroke, right-sided hemorrhagic lesions), whereas other variables identified were without clear biological rationale (eg, Black race, history of high cholesterol, and presence of white matter disease) and should be investigated in future studies to determine biological relevance and potential influence in stroke recovery.