Inositol pyrophosphates inhibit Akt signaling, thereby regulating insulin sensitivity and weight gain.

The inositol pyrophosphate IP7 (5-diphosphoinositolpentakisphosphate), formed by a family of three inositol hexakisphosphate kinases (IP6Ks), modulates diverse cellular activities. We now report that IP7 is a physiologic inhibitor of Akt, a serine/threonine kinase that regulates glucose homeostasis and protein translation, respectively, via the GSK3ß and mTOR pathways. Thus, Akt and mTOR signaling are dramatically augmented and GSK3ß signaling reduced in skeletal muscle, white adipose tissue, and liver of mice with targeted deletion of IP6K1. IP7 affects this pathway by potently inhibiting the PDK1 phosphorylation of Akt, preventing its activation and thereby affecting insulin signaling. IP6K1 knockout mice manifest insulin sensitivity and are resistant to obesity elicited by high-fat diet or aging. Inhibition of IP6K1 may afford a therapeutic approach to obesity and diabetes.

Dietary-induced binge-like eating impairs acoustic startle responses to acute nisoxetine in male mice.

Sensorimotor gating disruptions have been noted in several psychiatric and neurodegenerative disorders. However, the involvement of sensorimotor gating processes in eating disorders has not been well characterized. Our objective was to examine the sensorimotor gating of the acoustic startle response following dietary-induced binge eating and high-fat diet (HFD) induced weight gain in male C57B/6J mice. Acute administration of the norepinephrine reuptake inhibitor, nisoxetine (0.5 and 5 mg/kg), and a dopamine reuptake inhibitor, GBR 12783 (1.6 and 16 mg/kg), were either given alone or in combination to assess norepinephrine and dopamine alterations, respectively. Male mice with repeated bouts of calorie restriction (Restrict) and with limited access to a sweetened fat food (Binge) demonstrated an escalation of intake over 2.5 weeks under standard chow conditions. Restrict Binge (RB) mice had a reduced startle response to the startle pulse (110 dB) compared with the Naive control group at 5 mg/kg nisoxetine. There was an overall effect of nisoxetine (0.5 and 5 mg/kg) to increase percent inhibition at pre-pulse (74 dB), %PP74. Under HFD conditions, the RB group did not demonstrate a binge-like eating phenotype. The RB group on HFD had a higher response to 74 dB with nisoxetine (5.0 mg/kg) compared with a combinational dose of nisoxetine (5.0 mg/kg) and GBR 12783 (1.6 mg/kg). These findings suggest that dietary conditions that promote binge-like eating can influence the central noradrenergic and dopaminergic controls of the acoustic startle response and potentially influence sensorimotor gating.

High-fat diet attenuates morphine withdrawal effects on sensory-evoked locus coeruleus norepinephrine neural activity in male obese rats.

Objective: These experiments sought to characterize the effects of obesity propensity and obesogenic diet on locus coeruleus (LC) norepinephrine (NE) activity and determine the effects of obesity on LC neural responses to morphine withdrawal.Methods: In vivo single-unit LC electrophysiological activity was measured in obese prone (OP) and obese resistant (OR) male SD rats following high-fat (HFD: 45% fat) or low-fat (LFD; 10% fat) feeding. A separate cohort of LFD and HFD rats underwent in vivo LC recording on day 3 of spontaneous morphine withdrawal following an escalation dose paradigm (5-15 mg/kg; SQ twice daily).Results: OP (LFD: 34 cells/7 rats; HFD: 32 cells/6 rats) had higher spontaneous and tonic activity, and lower sensory-evoked activity compared with OR (LFD: 31 cells/6 rats; HFD: 41 cells/7 rats). Interacting effect of diet x strain status was observed on signal-to-noise ratio with OR-LFD having higher ratio than OP-LFD and OP-HFD. Morphine treatment decreased body weights. Withdrawal increased sensory-evoked rate in LFD (morphine; 20 cells/10 rats; saline 24 cells/6 rats) but not HFD (saline: 22 cells/7 rats; morphine: 21 cells/5 rats) rats. In a separate group of age-matched SD rats, a similar weight loss (5-7%) in response to the morphine did not alter sensory-evoked rate but decreased signal-to-noise ratio (Control: 22 cells/8 rats; Weight-matched: 23 cells/8 rats).Discussion: Taken together, our findings suggest that obesity and diet alter the sensory-evoked LC-NE neural responses, which could have implication for emotional stress and opioid-withdrawal behaviors.

Stargardt misdiagnosis: How ocular genetics helps.

Ocular Genetics at Wills Eye Hospital sees a wide range of rare disorders for accurate diagnosis. To demonstrate how focused consultation and genetic testing results in precise diagnoses, we investigated false diagnosis rates for patients referred with a diagnosis of Stargardt disease. This is a retrospective review of patients over a 3 year period referred to our Ocular Genetics clinic for possible Stargardt disease, or already holding a diagnosis of Stargardt disease. Results of diagnostic and genetic testing were compared to standard definition of Stargardt. Of 40 patients, 14 (35%) had been misdiagnosed. Four had non-Stargardt phenotype of which three had ABCA4 pathogenic variants with phenotypes inconsistent with Stargardt disease. Two of those with pathogenic ABCA4 variants were related. Nine had pathogenic variants in other different genes with overlapping features of Stargardt disease. One had Thioridazine maculopathy. Our study highlights the essential role of the subspecialty field of ocular genetics in obtaining accurate diagnoses for the delivery of correct counseling and interventional trial eligibility assessment.

Identification of Dihydromyricetin and Metabolites in Serum and Brain Associated with Acute Anti-Ethanol Intoxicating Effects in Mice.

Dihydromyricetin is a natural bioactive flavonoid with unique GABAA receptor activity with a putative mechanism of action to reduce the intoxication effects of ethanol. Although dihydromyricetin's poor oral bioavailability limits clinical utility, the promise of this mechanism for the treatment of alcohol use disorder warrants further investigation into its specificity and druggable potential. These experiments investigated the bioavailability of dihydromyricetin in the brain and serum associated with acute anti-intoxicating effects in C57BL/6J mice. Dihydromyricetin (50 mg/kg IP) administered 0 or 15-min prior to ethanol (PO 5 g/kg) significantly reduced ethanol-induced loss of righting reflex. Total serum exposures (AUC0→24) of dihydromyricetin (PO 50 mg/kg) via oral (PO) administration were determined to be 2.5 µM × h (male) and 0.7 µM × h (female), while intraperitoneal (IP) administration led to 23.8-fold and 7.2- increases in AUC0→24 in male and female mice, respectively. Electrophysiology studies in α5ß3γ2 GABAA receptors expressed in Xenopus oocytes suggest dihydromyricetin (10 µM) potentiates GABAergic activity (+43.2%), and the metabolite 4-O-methyl-dihydromyricetin (10 µM) negatively modulates GABAergic activity (-12.6%). Our results indicate that administration route and sex significantly impact DHM bioavailability in mice, which is limited by poor absorption and rapid clearance. This correlates with the observed short duration of DHM's anti-intoxicating properties and highlights the need for further investigation into mechanism of DHM's potential anti-intoxicating properties.

Presynaptic Regulation of Leptin in a Defined Lateral Hypothalamus-Ventral Tegmental Area Neurocircuitry Depends on Energy State.

Synaptic transmission controls brain activity and behaviors, including food intake. Leptin, an adipocyte-derived hormone, acts on neurons located in the lateral hypothalamic area (LHA) to maintain energy homeostasis and regulate food intake behavior. The specific synaptic mechanisms, cell types, and neural projections mediating this effect remain unclear. In male mice, using pathway-specific retrograde tracing, whole-cell patch-clamp recordings and post hoc cell type identification, we found that leptin reduces excitatory synaptic strength onto both melanin-concentrating hormone- and orexin-expressing neurons projecting from the LHA to the ventral tegmental area (VTA), which may affect dopamine signaling and motivation for feeding. A presynaptic mechanism mediated by distinct intracellular signaling mechanisms may account for this regulation by leptin. The regulatory effects of leptin depend on intact leptin receptor signaling. Interestingly, the synaptic regulatory function of leptin in the LHA-to-VTA neuronal pathway is highly sensitive to energy states: both energy deficiency (acute fasting) and excessive energy storage (high-fat diet-induced obesity) blunt the effect of leptin. These data revealed that leptin may regulate synaptic transmission in the LHA-to-VTA neurocircuitry in an inverted "U-shape" fashion dependent on plasma glucose levels and related to metabolic states.SIGNIFICANCE STATEMENT The lateral hypothalamic area (LHA) to ventral tegmental area (VTA) projection is an important neural pathway involved in balancing whole-body energy states and reward. We found that the excitatory synaptic inputs to both orexin- and melanin-concentrating hormone expressing LHA neurons projecting to the VTA were suppressed by leptin, a peptide hormone derived from adipocytes that signals peripheral energy status to the brain. Interestingly, energy states seem to affect how leptin regulates synaptic transmission since both the depletion of energy induced by acute food deprivation and excessive storage of energy by high-fat diet feeding dampen the suppressive effect of leptin on synaptic transmission. Together, these data show that leptin regulates synaptic transmission and might be important for maintaining energy homeostasis.

Sex-Specific Effects on Total Body Fat Gain with 4-Week Daily Dosing of Raspberry Ketone [4-(4-Hydroxyphenyl)-2-butanone] and Ketogenic Diet in Mice.

Background: Raspberry ketone (RK: [4-(4-Hydroxyphenyl)-2-butanone]) is a dietary supplement marketed for weight control. RK is structurally unrelated to the ketone bodies elevated with a ketogenic diet (KD). This study aims to determine whether RK oral supplementation with KD improves the weight loss outcomes in high-fat diet (HFD; 45% fat)-fed mice. Methods: Male and female C57BL/6J mice were HFD-fed for 9 weeks and switched to KD (80% fat) or a control diet (CD; 10% fat) or continued with the HFD for 4 weeks. Coincident with the diet switch, each diet group received oral RK (200 mg/kg/day) or a vehicle. Results: In male KD-fed mice, oral RK reduced body weight by ~6% (KD_Veh: -9.2 ± 1% vs. KD_RK: -15.1 ± 1%) and fat composition by ~18% (KD_Veh: -16.0 ± 4% vs. KD_RK: -34.2 ± 5%). HFD and KD feeding induced glucose intolerance in both male and female mice. Oral RK decreased the glucose area under the curve in female mice by ~6% (KD_Veh: 44,877 ± 957 vs. KD_RK: 42,040 ± 675 mg*min/dl). KD also had gut microbiota alterations with higher alpha diversity in males and more beta diversity with RK. These findings suggest sex-specific weight loss effects with RK and KD in mice.

Metabolic gene signature in white adipose tissue of oral doses raspberry ketone [4-(4-hydroxyphenyl)-2-butanone] that prevent diet-induced weight gain and induce loss of righting reflex.

Raspberry ketone (RK; [4-(4-hydroxyphenyl)-2-butanone]) is a synthetic flavoring agent and dietary supplement for weight control. This study investigated the metabolic signature of oral doses of RK that prevent weight gain or promote loss of righting reflex (LORR) in C57Bl/6J mice. Daily RK 200 mg/kg prevented high-fat diet (HFD; 45% Kcal fat) fed weight gain (∼8% reduction) over 35 days. RNA-seq of inguinal white adipose tissue (WAT) performed in males revealed 12 differentially expressed genes. Apelin (Apln) and potassium voltage-gated channel subfamily C member (Kcnc3) expression were elevated with HFD and normalized with RK dosing, which was confirmed by qPCR. Acute RK 640 mg/kg produced a LORR with a <5 min onset with a >30 min duration. Acute RK 200 mg/kg increased gene expression of Apln, Kcnc3, and nuclear factor erythroid 2-related factor 2 (Nrf2), but reduced acetyl-COA carboxylase (Acc1) and NAD(P)H quinone dehydrogenase 1 (Nqo1) in inguinal WAT. Acute RK 640 mg/kg elevated interleukin 6 (Il 6) and heme oxygenase 1 (Hmox1) expression, but reduced Nrf2 in inguinal and epididymal WAT. Our findings suggest that RK has a dose-dependent metabolic signature in WAT associated with either weight control or LORR.

TWO CASES OF CRB1-RELATED RETINAL DYSTROPHY ASSOCIATED WITH RETINAL MASSES.

BACKGROUND/PURPOSE: Mutations in CRB1 are associated with variable severity in expression leading to apparent phenotypic diversity. We present two retinal findings. METHODS: We present two unrelated children with CRB1-related retinal dystrophy with a solitary mass visualized on fundoscopy. Both underwent a complete ophthalmologic examination including visual acuity assessment, optical coherence tomography, intravenous fluorescein angiography, and fundus autofluorescence. RESULTS: In one child, a gliotic mass was observed on the superior temporal vessel away from disk. On optical coherence tomography, the mass appeared to be located in the superficial retina and contained discrete internal moth-eaten optically empty spaces as previously reported in the astrocytic hamartomas of tuberous sclerosis. Fundus autofluorescence showed speckled hyperautofluorescence of the lesion. In the other child, there was a calcified mass within the nerve fiber layer just temporal to the optic nerve. On optical coherence tomography, this mass appeared irregular in shape, encapsulated, and had a heterogeneous disorganized interior with hyperreflective areas. CONCLUSION: In this report, we detail two presentations of CRB1-related retinal dystrophy: retinal astrocytic hamartoma and another form of superficial retinal hamartoma. We believe this may represent a manifestation of CRB1 mutations. Recognition of this finding may prevent unnecessary evaluation for tumor cause in patients with CRB1-related retinal dystrophy.

Mutations in AGBL5 associated with Retinitis pigmentosa.

BACKGROUND: Retinitis pigmentosa (RP) is the leading cause of heritable retinal visual impairment. Clinically, it is characterized by a variable onset of progressive night blindness and visual field constriction. RP is characterized by wide genetic heterogeneity with a broad range of potential genes involved in the genesis of this disease. Very few cases have been reported of RP due to pathogenic variants in AGBL5. MATERIALS AND METHODS: We report two patients with RP and bilallelic pathogenic variants in AGBL5. RESULTS: Genetic sequencing showed one homozygous AGBL5 missense variant in one patient and a homozygous nonsense variant in the other. These patients presented with progressive peripheral vision loss and nyctalopia. Their RP phenotypes were similar to previous reports in literature. CONCLUSION: These two cases provide further evidence regarding the relationship of pathogenic variants in AGBL5 as a cause of autosomal recessive RP.

Systematic Review of Binge Eating Rodent Models for Developing Novel or Repurposing Existing Pharmacotherapies.

Recent advances in developing and screening candidate pharmacotherapies for psychiatric disorders have depended on rodent models. Eating disorders are a set of psychiatric disorders that have traditionally relied on behavioral therapies for effective long-term treatment. However, the clinical use of Lisdexamfatamine for binge eating disorder (BED) has furthered the notion of using pharmacotherapies for treating binge eating pathologies. While there are several binge eating rodent models, there is not a consensus on how to define pharmacological effectiveness within these models. Our purpose is to provide an overview of the potential pharmacotherapies or compounds tested in established rodent models of binge eating behavior. These findings will help provide guidance for determining pharmacological effectiveness for potential novel or repurposed pharmacotherapies.

Lateral hypothalamus hypocretin/orexin glucose-inhibited neurons promote food seeking after calorie restriction.

OBJECTIVE: The present study tests the hypothesis that changes in the glucose sensitivity of lateral hypothalamus (LH) hypocretin/orexin glucose-inhibited (GI) neurons following weight loss leads to glutamate plasticity on ventral tegmental area (VTA) dopamine neurons and drives food seeking behavior. METHODS: C57BL/6J mice were calorie restricted to a 15% body weight loss and maintained at that body weight for 1 week. The glucose sensitivity of LH hypocretin/orexin GI and VTA dopamine neurons was measured using whole cell patch clamp recordings in brain slices. Food seeking behavior was assessed using conditioned place preference (CPP). RESULTS: 1-week maintenance of calorie restricted 15% body weight loss reduced glucose inhibition of hypocretin/orexin GI neurons resulting in increased neuronal activation with reduced glycemia. The effect of decreased glucose on hypocretin/orexin GI neuronal activation was blocked by pertussis toxin (inhibitor of G-protein coupled receptor subunit Gαi/o) and Rp-cAMP (inhibitor of protein kinase A, PKA). This suggests that glucose sensitivity is mediated by the Gαi/o-adenylyl cyclase-cAMP-PKA signaling pathway. The excitatory effect of the hunger hormone, ghrelin, on hcrt/ox neurons was also blocked by Rp-cAMP suggesting that hormonal signals of metabolic status may converge on the glucose sensing pathway. Food restriction and weight loss increased glutamate synaptic strength (indexed by increased AMPA/NMDA receptor current ratio) on VTA dopamine neurons and the motivation to seek food (indexed by CPP). Chemogenetic inhibition of hypocretin/orexin neurons during caloric restriction and weight loss prevented these changes in glutamate plasticity and food seeking behavior. CONCLUSIONS: We hypothesize that this change in the glucose sensitivity of hypocretin/orexin GI neurons may drive, in part, food seeking behavior following caloric restriction.

Use of the World Health Organization primary eye care protocol to investigate the ocular health status of school children in Rwanda.

PURPOSE: To assess the ocular health status of primary and secondary schoolchildren in Rwanda and to explore the use of the World Health Organization (WHO) primary eye care screening protocol. METHODS: This was a cross-sectional population-based study across 19 schools in Rwanda. Initial screening was carried out using the WHO screening protocol, whereby visual acuity was measured using a tumbling E Snellen chart (6/60 and 6/12). Abnormal ocular features were identified using a flashlight and history against a checklist. All children with abnormal screening were referred to an on-site ophthalmic clinic for full examination. Those who could not be treated on-site were referred to an ophthalmologist at a hospital for specialist care. RESULTS: A total of 24,892 children underwent ocular health screening. Of those, 1,865 (7.5%) failed the primary screening; 658 (2.6%) were false positives (35.3% of those who failed screening), and 1,207 (4.8%) true positives. The most frequently observed ocular diagnoses were allergic conjunctivitis (3.11%) and strabismus (0.26%). Refractive error was very rare (0.18%). CONCLUSIONS: The WHO primary eye care curriculum provides existing health personnel with an approach to school-based vision screening that uses a standardized checklist and low-cost resources. In our study cohort, results indicated a low frequency of refractive error; the overwhelming majority of ocular problems could be identified on visual inspection.

Factors Affecting the Perception of Strabismus Among Pediatric Ophthalmologists.

PURPOSE: To define potential factors that influence the perceived urgency of strabismus surgery with a specific focus on the contributions of gender, degree of strabismus, and direction of strabismus. METHODS: An electronic survey was sent to members of the American Association for Pediatric Ophthalmology and Strabismus (AAPOS). Respondents provided demographic information and ranked eight photographs of adults digitally altered to create varying degrees of strabismus according to perceived urgency for surgery. RESULTS: Pediatric ophthalmologists ranked deviations of increasing size with increasing treatment urgency. Men were perceived with higher urgency for treatment compared to women in the smaller angles of strabismus. No consistent preference for type of deviation was found. CONCLUSIONS: The gender of the patient and the amount of misalignment may influence the urgency of surgical management among strabismus surgeons. [J Pediatr Ophthalmol Strabismus. 2023;60(4):257-262.].

Grape Polyphenols May Prevent High-Fat Diet-Induced Dampening of the Hypothalamic-Pituitary-Adrenal Axis in Male Mice.

Context : Chronic high-fat diet (HFD) consumption causes obesity associated with retention of bile acids (BAs) that suppress important regulatory axes, such as the hypothalamic-pituitary-adrenal axis (HPAA). HFD impairs nutrient sensing and energy balance due to a dampening of the HPAA and reduced production and peripheral metabolism of corticosterone (CORT). Objective: We assessed whether proanthocyanidin-rich grape polyphenol (GP) extract can prevent HFD-induced energy imbalance and HPAA dysregulation. Methods: Male C57BL6/J mice were fed HFD or HFD supplemented with 0.5% w/w GPs (HFD-GP) for 17 weeks. Results: GP supplementation reduced body weight gain and liver fat while increasing circadian rhythms of energy expenditure and HPAA-regulating hormones, CORT, leptin, and PYY. GP-induced improvements were accompanied by reduced mRNA levels of Il6, Il1b, and Tnfa in ileal or hepatic tissues and lower cecal abundance of Firmicutes, including known BA metabolizers. GP-supplemented mice had lower concentrations of circulating BAs, including hydrophobic and HPAA-inhibiting BAs, but higher cecal levels of taurine-conjugated BAs antagonistic to farnesoid X receptor (FXR). Compared with HFD-fed mice, GP-supplemented mice had increased mRNA levels of hepatic Cyp7a1 and Cyp27a1, suggesting reduced FXR activation and more BA synthesis. GP-supplemented mice also had reduced hepatic Abcc3 and ileal Ibabp and Ostß, indicative of less BA transfer into enterocytes and circulation. Relative to HFD-fed mice, CORT and BA metabolizing enzymes (Akr1d1 and Srd5a1) were increased, and Hsd11b1 was decreased in GP supplemented mice. Conclusion: GPs may attenuate HFD-induced weight gain by improving hormonal control of the HPAA and inducing a BA profile with less cytotoxicity and HPAA inhibition, but greater FXR antagonism.

A vitamin D deficient diet increases weight gain and compromises bone biomechanical properties without a reduction in BMD in adult female mice.

Vitamin D contributes to the development and maintenance of bone. Evidence suggests vitamin D status can also alter energy balance and gut health. In young animals, vitamin D deficiency (VDD) negatively affects bone mineral density (BMD) and bone microarchitecture, and these effects may also occur due to chronic ethanol intake. However, evidence is limited in mature models, and addressing this was a goal of the current study. Seven-month-old female C57BL/6 mice (n = 40) were weight-matched and randomized to one of four ad libitum diets: control, alcohol (Alc), vitamin D deficient (0 IU/d), or Alc+VDD for 8 weeks. A purified (AIN-93) diet was provided with water or alcohol (10 %) ad libitum. Body weight and food intake were recorded weekly, and feces were collected at 0, 4, and 8 weeks. At the age of 9 months, intestinal permeability was assessed by oral gavage of fluorescein isothiocyanate-dextran. Thereafter, bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. The microarchitecture of the distal femur was assessed by micro-computed tomography and biomechanical properties were evaluated by cyclic reference point indentation. VDD did not affect BMD or most bone microarchitecture parameters, however, the polar moment of inertia (p < 0.05) was higher in the VDD groups compared to vitamin D sufficient groups. VDD mice also had lower whole bone water content (p < 0.05) and a greater average unloading slope (p < 0.01), and energy dissipated (p < 0.01), indicating the femur displayed a brittle phenotype. In addition, VDD caused a greater increase in energy intake (p < 0.05), weight gain (p < 0.05), and a trend for higher intestinal permeability (p = 0.08). The gut microbiota of the VDD group had a reduction in alpha diversity (p < 0.05) and a lower abundance of ASVs from Rikenellaceae, Clostridia_UCG-014, Oscillospiraceae, and Lachnospiraceae (p < 0.01). There was little to no effect of alcohol supplementation on outcomes. Overall, these findings suggest that vitamin D deficiency causes excess weight gain and reduces the biomechanical strength of the femur as indicated by the higher average unloading slope and energy dissipated without an effect on BMD in a mature murine model.

Practice Patterns of Pediatric Ophthalmologists During the COVID-19 Pandemic.

PURPOSE: To report the use of protective personal equipment (PPE) during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: A 12-question multiple-choice survey was posted on a discussion board used by members of the American Association for Pediatric Ophthalmology and Strabismus (AAPOS). Respondents provided information about their experience, PPE use, office equipment, and approach to care during the COVID-19 pandemic. RESULTS: One hundred twenty-eight pediatric ophthalmologists completed the survey. Eighty-seven (68.0%) identified as in private practice, whereas 41 (32.0%) identified as in an academic setting. Sixty-nine pediatric ophthalmologists (53.9%) reported routinely using N95 respirators, 72 (56.3%) reported wearing medical scrubs, 41 (32.0%) reported using disposable gloves, 33 (25.7%) reported wearing goggles, and 12 (9.4%) reported using face shields during office examinations. One hundred twenty-one pediatric ophthalmologists (94.5%) reported having slit lamps with plastic shields and 52 (40.6%) reported having phoropters with plastic shields. Ninety-nine (77.3%) responded that they would see a patient older than 2 years who refused to wear a mask for a nonemergency visit. CONCLUSIONS: Practice patterns of pediatric ophthalmologists have varied during the COVID-19 pandemic. [J Pediatr Ophthalmol Strabismus. 2022;59(3):145-150.].

Weight-gain propensity and morphine withdrawal alters locomotor behavior and regional norepinephrine-related gene expression in male and female mice.

Interactions between obesity and opioid use are poorly understood. The objective of this study was to determine whether phenotypic differences in diet-induced weight gain altered morphine withdrawal responses. Male and female C57BL/6J mice were characterized as obese prone (OP) or obese resistant (OR) based on median split in body weights following exposure to high-fat diet (45% fat). After classification into OP or OR, all mice were fed a low-fat diet (10% fat) for the remainder of the study (≥5 weeks) to remain weight matched. Mice were treated with a 7-day escalating dosing scheme of morphine (20-100 mg/kg; IP) or saline and underwent a spontaneous withdrawal. Morphine-induced weight loss was restored by withdrawal day 7. On withdrawal day 8, male OP demonstrated less total time mobile in the open field test (OFT). In females, OR-morphine traveled less distance than OR-saline, and OR-morphine spent less time mobile compared with all other groups in the OFT. Female OP also increased time spent in the center of the apparatus, regardless of treatment. On withdrawal day 8, relative gene expression was measured by qPCR. For males, expression of dopamine beta-hydroxylase (dbh), alpha-adrenergic receptor 2 a (adra2a), and orexin receptor 1 (orx1) were increased in the locus coeruleus (LC) region of OP mice, regardless of treatment. In comparison, in females, dbh and adra2a were decreased in the LC region of OP mice, regardless of treatment. Also, in the LC region of females, OP-morphine had lower expression of alpha-adrenergic receptor 1 a (adra1a) than OR-morphine and OP-saline. In the hypothalamic paraventricular nucleus (PVN) of females, adra2a was increased in OP-morphine compared with OP-saline and OR-morphine. Our findings suggest morphine withdrawal responses and regional expression of noradrenergic-related genes are differentially influenced by weight gain propensity.

Resolution of traumatic mydriasis and accommodative dysfunction eight years after sweetgum ball ocular injury.

Purpose: To present a case of traumatic mydriasis (MD) and accommodative dysfunction (AD) secondary to a sweetgum ball ocular injury that resolved 8 years after the inciting trauma. Observations: A 6-year-old female presented with left eye ocular trauma after being hit with a sweetgum ball. Sweetgum balls are the small, spiky fallen fruits of the American Sweetgum tree (Liquidambar styraciflua). Due to their size and shape, children often use them as projectiles during play. On presentation, the patient had a partial thickness corneal laceration, traumatic mydriasis (TM), and accommodative dysfunction (AD). Her corneal laceration was repaired. Her TM and AD persisted. She was treated with bifocal spectacles and patching. At her 7-year follow-up visit, her TM and AD showed minimal signs of improvement. Eight years post-injury, her TM and AD had both improved significantly. Conclusion and Importance: Sweetgum balls, when used as projectiles, pose a risk of serious ocular injury. Pupillary and accommodative function in TM may improve much later than previously appreciated. Young age may contribute to parasympathetic neuroregeneration. Patching may have prevented amblyopia in this case, allowing her left eye to achieve its full visual potential once her pupillary and accommodative function returned.