Adrenalectomy exacerbates stress-induced impairment in fear discrimination: A causal role for kynurenic acid?

Impaired activity of the hypothalamic-pituitary axis and reduced blood levels of glucocorticoids (GCs) are signature features of stress-related maladies. Recent evidence suggests a possible role of the tryptophan metabolite kynurenic acid (KYNA) in this context. Here we investigated possible causal relationships in adult male rats, using stress-induced fear discrimination as a translationally relevant behavioral outcome measure. One week following adrenalectomy (ADX) or sham surgery, animals were for 2 h either physically restrained or exposed to a predator odor, which caused a much milder stress response. Extracellular KYNA levels were determined before, during and after stress by in vivo microdialysis in the prefrontal cortex. Separate cohorts underwent a fear discrimination procedure starting immediately after stress termination. Different auditory conditioned stimuli (CS) were either paired with a foot shock (CS+) or non-reinforced (CS-). One week later, fear was assessed by re-exposing the animals to each CS. Separate groups of rats were treated with the KYNA synthesis inhibitor BFF-816 prior to stress initiation to test a causal role of KYNA in fear discrimination. Restraint stress raised extracellular KYNA levels by ∼85 % in ADX rats for several hours, and these animals were unable to discriminate between CS+ and CS-. Both effects were prevented by BFF-816 and were not observed after exposure to predator odor or in sham-operated rats. These findings suggest that a causal connection exists between adrenal function, stress-induced KYNA increases, and behavioral deficits. Pharmacological inhibition of KYNA synthesis may therefore be an attractive, novel option for the treatment of stress-related disorders.

Activation of alpha7 nicotinic and NMDA receptors is necessary for performance in a working memory task.

RATIONALE: Working memory deficits are present in schizophrenia (SZ) but remain insufficiently resolved by medications. Similar cognitive dysfunctions can be produced acutely in animals by elevating brain levels of kynurenic acid (KYNA). KYNA's effects may reflect interference with the function of both the α7 nicotinic acetylcholine receptor (α7nAChR) and the glycineB site of the NMDA receptor. OBJECTIVES: The aim of the present study was to examine, using pharmacological tools, the respective roles of these two receptor sites on performance in a delayed non-match-to-position working memory (WM) task (DNMTP). METHODS: DNMTP consisted of 120 trials/session (5, 10, and 15 s delays). Rats received two doses (25 or 100 mg/kg, i.p.) of L-kynurenine (KYN; bioprecursor of KYNA) or L-4-chlorokynurenine (4-Cl-KYN; bioprecursor of the selective glycineB site antagonist 7-Cl-kynurenic acid). Attenuation of KYN- or 4-Cl-KYN-induced deficits was assessed by co-administration of galantamine (GAL, 3 mg/kg) or PAM-2 (1 mg/kg), two positive modulators of α7nAChR function. Reversal of 4-Cl-KYN-induced deficits was examined using D-cycloserine (DCS; 30 mg/kg), a partial agonist at the glycineB site. RESULTS: Both KYN and 4-Cl-KYN administration produced dose-related deficits in DNMTP accuracy that were more severe at the longer delays. In KYN-treated rats, these deficits were reversed to control levels by GAL or PAM-2 but not by DCS. In contrast, DCS eliminated performance deficits in 4-Cl-KYN-treated animals. CONCLUSIONS: These experiments reveal that both α7nAChR and NMDAR activity are necessary for normal WM accuracy. They provide substantive new support for the therapeutic potential of positive modulators at these two receptor sites in SZ and other major brain diseases.

Demographic Differences Among Patients Undergoing Blepharoplasty Based on Surgeon Training in New York State.

PURPOSE: To evaluate whether patient demographics and surgical metrics varied among differently trained surgeons performing blepharoplasty. METHODS: The Statewide Planning and Research Cooperative System database was used to identify patients who underwent blepharoplasty in New York State. Surgeons were grouped based on residency training as listed in the New York State Physician Profile. Multivariate regression analysis was used to determine predictors of patient characteristics based on surgeon training. RESULTS: There were 361 surgeons who performed 39,932 cases of blepharoplasty in New York State from 2008 to 2016. When aggregated by surgeon training, there were significant differences among procedure times and total charges for blepharoplasty. On average, cases performed by ophthalmologists took 66.7 minutes and patients were charged $6,860; cases performed by otolaryngologists took 158.2 minutes and patients were charged $9,084; and cases performed by plastic surgeons took 131.8 minutes and patients were charged $11,028. Unlike plastic surgeons or otolaryngologists, ophthalmologists tended to have older patients and more male patients. Ophthalmologists were more likely to operate on patients with comorbidities as well as non-white patients (p < 0.0001). They were also significantly more likely to have patients with insurance coverage than self-pay (p < 0.0001). CONCLUSIONS: Demographic and surgical metrics of blepharoplasty cases performed by surgeons trained in otolaryngology and plastic surgery are similar. Ophthalmology-trained surgeons performed blepharoplasty on patients that were more likely to be older, male, non-white, and had insurance coverage. Ophthalmologist procedure time for blepharoplasty was also less than half of the procedure time of otolaryngologists and plastic surgeons.Blepharoplasty is a surgical procedure commonly performed by ophthalmologists, otolaryngologists, and plastic surgeons to address cosmetic concerns or visual impairment related to the eyelids.

The Impact of Submental Deoxycholic Acid Injections on Neck Surgery

Non-invasive procedures targeting the submental fat or "double chin" have undergone a surge in popularity. Injections of deoxycholic acid, a secondary bile acid, have recently received FDA-approval for fat reduction in this area. With appropriate patient selection, this preparation of 10 mg/mL of sodium deoxycholate (Kybella®, Kythera Biopharmaceuticals, Westlake Village, CA) leads to aesthetic improvement of moderate-to-severe convexity or fullness associated with submental fat in adults.

The Aesthetic Oculoplastic Surgery Video Teleconference Consult.

BACKGROUND: Skype video telemedicine consults are gaining popularity to evaluate patients from distant locations. No study has analyzed the utility of this means of patient evaluation in a cosmetic oculoplastic patient population. OBJECTIVES: The authors sought to provide an evidence-based analysis of the utility of Skype video consults in a cosmetic oculoplastic surgery patient population with regards to patient demographics, reasons for consult, and procedural conversion rate. METHODS: A 1-year retrospective chart review (May 2016 to May 2017) of patients who underwent aesthetic oculoplastic Skype consults from 2 authors' practices was performed. The authors analyzed patient demographics, referral source, chief complaint, location of residence, length of consult, and conversion to face-to-face consultation and intervention. RESULTS: Seventy-nine patients (60 women and 19 men) underwent Skype evaluations. Mean age was 49 years. Sixty-four consults (81%) lasted 15 minutes or less. Referral sources included the internet (67%), another physician (19%), self-referral (7.5%), referred by former patients (4%), and social media sites (2.5%). Consultations were obtained for revision (49%), or first-time (30%) eyelid/eyebrow surgery, cosmetic ptosis surgery (6%), laser skin procedures (5%), cosmetic orbital decompression (5%), and lower eyelid fat prolapse (5%). Twenty patients (25%) followed-up with in-person consultation. Sixteen of these patients (80%) had surgical (56%) or nonsurgical (44%) interventions. CONCLUSIONS: Skype consults are an efficient, in-office modality to increase patient flow through the office, expand patient base, and generate income. In this report, 25% of Skype contacts followed-up with formal in-person consultations, of which 80% had surgical or nonsurgical interventions.

In Vitro Evaluation of Preinjection Aspiration for Hyaluronic Fillers as a Safety Checkpoint.

BACKGROUND: Hyaluronic acid (HA) fillers have increased in popularity. Although complications are rare, knowledge regarding their prevention and management are crucial. The utility of preinjection aspiration has become controversial. OBJECTIVE: Our study investigated the utility of preinjection aspiration as a safety checkpoint for HA fillers through comparison of physiochemical and rheological properties in an in vitro model. MATERIALS AND METHODS: Whole blood was drawn from vacutainers using syringes containing 10 commonly used HA fillers. Each HA filler was examined with the plunger pulled back at volumes of 0.2 and 0.5 cc. The time required to visualize a flash was recorded. Data were compared using physiochemical and rheological properties, pullback volumes, and needle gauges. RESULTS: Using a multivariable regression model, HA concentration, elastic modulus (G'), viscous modulus (G″), and complex modulus (G*) had significant relationships with time to flash, whereas needle gauge and pullback volume did not. However, when comparing pullback volume using an appropriate paired analysis, 0.5 cc pullback volume had a significantly decreased mean time to flash than 0.2 cc. CONCLUSION: Preinjection aspiration may have utility as a safety checkpoint for HA fillers. Practitioners may have to adjust pullback volume and waiting time to visualize the flash based on physiochemical and rheological properties.

Attenuating Nicotine Reinforcement and Relapse by Enhancing Endogenous Brain Levels of Kynurenic Acid in Rats and Squirrel Monkeys.

The currently available antismoking medications have limited efficacy and often fail to prevent relapse. Thus, there is a pressing need for newer, more effective treatment strategies. Recently, we demonstrated that enhancing endogenous levels of kynurenic acid (KYNA, a neuroinhibitory product of tryptophan metabolism) counteracts the rewarding effects of cannabinoids by acting as a negative allosteric modulator of α7 nicotinic receptors (α7nAChRs). As the effects of KYNA on cannabinoid reward involve nicotinic receptors, in the present study we used rat and squirrel monkey models of reward and relapse to examine the possibility that enhancing KYNA can counteract the effects of nicotine. To assess specificity, we also examined models of cocaine reward and relapse in monkeys. KYNA levels were enhanced by administering the kynurenine 3-monooxygenase (KMO) inhibitor, Ro 61-8048. Treatment with Ro 61-8048 decreased nicotine self-administration in rats and monkeys, but did not affect cocaine self-administration. In rats, Ro 61-8048 reduced the ability of nicotine to induce dopamine release in the nucleus accumbens shell, a brain area believed to underlie nicotine reward. Perhaps most importantly, Ro 61-8048 prevented relapse-like behavior when abstinent rats or monkeys were reexposed to nicotine and/or cues that had previously been associated with nicotine. Ro 61-8048 was also effective in monkey models of cocaine relapse. All of these effects of Ro 61-8048 in monkeys, but not in rats, were reversed by pretreatment with a positive allosteric modulator of α7nAChRs. These findings suggest that KMO inhibition may be a promising new approach for the treatment of nicotine addiction.

Tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase 1 make separate, tissue-specific contributions to basal and inflammation-induced kynurenine pathway metabolism in mice.

BACKGROUND: In mammals, the majority of the essential amino acid tryptophan is degraded via the kynurenine pathway (KP). Several KP metabolites play distinct physiological roles, often linked to immune system functions, and may also be causally involved in human diseases including neurodegenerative disorders, schizophrenia and cancer. Pharmacological manipulation of the KP has therefore become an active area of drug development. To target the pathway effectively, it is important to understand how specific KP enzymes control levels of the bioactive metabolites in vivo. METHODS: Here, we conducted a comprehensive biochemical characterization of mice with a targeted deletion of either tryptophan 2,3-dioxygenase (TDO) or indoleamine 2,3-dioxygenase (IDO), the two initial rate-limiting enzymes of the KP. These enzymes catalyze the same reaction, but differ in biochemical characteristics and expression patterns. We measured KP metabolite levels and enzyme activities and expression in several tissues in basal and immune-stimulated conditions. RESULTS AND CONCLUSIONS: Although our study revealed several unexpected downstream effects on KP metabolism in both knockout mice, the results were essentially consistent with TDO-mediated control of basal KP metabolism and a role of IDO in phenomena involving stimulation of the immune system.

Reduced kynurenine pathway metabolism and cytokine expression in the prefrontal cortex of depressed individuals.

BACKGROUND: Neuroinflammatory processes are increasingly believed to participate in the pathophysiology of a number of major psychiatric diseases, including depression. Immune activation stimulates the conversion of the amino acid tryptophan to kynurenine, leading to the formation of neuroactive metabolites, such as quinolinic acid and kynurenic acid. These compounds affect glutamatergic neurotransmission, which plays a prominent role in depressive pathology. Increased tryptophan degradation along the kynurenine pathway (KP) has been proposed to contribute to disease etiology. METHODS: We used postmortem brain tissue from the ventrolateral prefrontal cortex (VLPFC) to assess tissue levels of tryptophan and KP metabolites, the expression of several KP enzymes and a series of cytokines as well as tissue pathology, including microglial activation. Tissue samples came from nonpsychiatric controls (n = 36) and individuals with depressive disorder not otherwise specified (DD-NOS, n = 45) who died of natural causes, homicide, accident, or suicide. RESULTS: We found a reduction in the enzymatic conversion of tryptophan to kynurenine, determined using the kynurenine:tryptophan ratio, and reduced messenger RNA expression of the enzymes indoleamine-2,3-dioxygenase 1 and 2 and tryptophan-2,3-dioxygenase in depressed individuals irrespective of the cause of death. These findings correlated with reductions in the expression of several cytokines, including interferon-γ and tumour necrosis factor-α. Notably, quinolinic acid levels were also lower in depressed individuals than controls. LIMITATIONS: Information on the use of antidepressants and other psychotropic medications was insufficient for statistical comparisons. CONCLUSION: Contrary to expectations, the present results indicate that depression, in the absence of medical illness or an overt inflammatory process, is associated with compromised, rather than increased, KP metabolism in the VLPFC.

Extranodal Rosai-Dorfman Disease of the Orbit: Clinical Features of 8 Cases.

PURPOSE: To report on the presentation, radiography, histology, and treatment of 8 cases of extranodal Rosai-Dorfman disease involving the orbit. METHODS: Multicenter retrospective case series. RESULTS: Five males and 3 females had a median age of 10 years (range 2-78 years). Presenting signs and symptoms included proptosis, periorbital pain, palpable mass, blepharoptosis, decreased vision, diplopia, impaired extraocular motility, and afferent pupillary defect. Four patients had bilateral orbital disease, while 4 had unilateral disease. Six cases were extraconal, 1 was intraconal, and 1 was both intra- and extra-conal. Four cases had only extranodal disease without lymphadenopathy (3 of which had localized orbital disease). Diagnosis was confirmed by exam, orbital, and/or systemic radiography, and biopsy in all cases. Treatment strategies included excision or debulking, systemic corticosteroids, chemotherapy, radiotherapy, observation or a combination thereof. At last follow up, 4 patients were disease free, while 4 had residual improved disease. CONCLUSIONS: Rosai-Dorfman disease of the orbit is a rare clinical entity. Purely extranodal disease is rare, with isolated orbital disease being exceedingly rare. This study is unique in that 4 of 8 patients had strictly isolated extranodal disease of the orbit. A large majority of the cases had disease in the extraconal space, contrasting with previous reports. In addition, lacrimal gland disease, particularly bilateral involvement, was prominent in the current study. Although there is no consensus on treatment, surgical excision should be attempted if plausible in symptomatic patients especially if the orbit represents a localized site of disease.

Upper Eyelid Fractional CO2 Laser Resurfacing With Incisional Blepharoplasty.

PURPOSE: Laser resurfacing, performed at the same time as blepharoplasty, has most commonly been applied to the lower eyelid skin but can effectively be used on the upper eyelid to reduce rhytidosis and improve skin quality. The authors evaluate the safety and efficacy of this procedure. METHODS: Fractional CO2 laser resurfacing was performed in conjunction with incisional upper blepharoplasty. The ultrapulsed laser energy was applied to the sub-brow skin, the upper medial canthal skin, and the pretarsal skin in 30 patients. Photos were obtained preoperatively and at 3 months. RESULTS: All patients demonstrated reduction in upper eyelid rhytidosis without any serious complications. Independent rhytidosis grading (0-4) showed a mean improvement of 42%. One patient experienced wound dehiscence that satisfactorily resolved without intervention. CONCLUSIONS: Upper eyelid laser resurfacing is effective and can be safely performed at the same time as upper blepharoplasty. This approach reduces or eliminates the need for medial incisions to address medial canthal skin redundancy and rhytidosis and it directly treats upper eyelid wrinkles on residual eyelid and infra-brow skin during blepharoplasty.

Stop Blaming the Septum.

PURPOSE: To identify if isolated surgical violation of the orbital septum predisposes to "middle lamellar" scarring and subsequent postblepharoplasty lower eyelid retraction. METHODS: A retrospective review of patients who underwent transconjunctival blepharoplasty in either a postseptal (orbital septum undisturbed) or preseptal (septal incision required) plane was performed. Patients undergoing skin excision, orbicularis muscle plication, and canthal suspension were excluded. The presence of clinically apparent postoperative lower eyelid retraction and limitation of forced superior eyelid excursion (forced traction testing) were assessed. RESULTS: Two hundred eighty-eight patients (576 eyelids) were evaluated. One hundred fifty-eight patients (316 eyelids, 55%) had transconjunctival blepharoplasty performed in a postseptal plane and 130 patients (260 eyelids, 45%) in a preseptal plane. Two hundred two patients (404 eyelids, 70%) had forced traction testing performed postoperatively. After surgery, there were no patient complaints of change in lower eyelid position, subjective physician assessment of clinically apparent lower eyelid retraction, and only 1 case (0.5%) of a positive forced traction test in a patient with conjunctival scarring after significant postoperative infection. CONCLUSIONS: Lower eyelid scars leading to eyelid retraction after blepharoplasty are not likely related to "isolated" orbital septal scars (middle lamellar scars). Their designation as a "multilamellar scar" is more appropriate.

Complications of lower blepharoplasty and midface lifting.

Lower eyelid blepharoplasty and midface lifting share a complex anatomy, which should be mastered before attempting these types of surgeries. In recent years, there have been significant contributions to rejuvenating this area. A thorough understanding of the rejuvenative approaches and their outcomes is imperative. Thus, the problem must be preoperatively evaluated to offer the appropriate technique and minimize complications.

Management of postblepharoplasty lower eyelid retraction.

Future advances in the treatment of lower eyelid retraction will likely focus on new synthetic graft materials that are inert and stable with minimal potential for reabsorption. Other advances may focus on biomodulating agents that reduce the risk of retraction at the time of cosmetic eyelid surgery or reverse existing exuberant scarring. Nonsurgical options are viable for modest cases, and these conservative measures may continue to improve, but, for severe retraction, surgery still offers the best promise of correction.

A case of congenital myofibroma of the orbit presenting at birth.

PURPOSE: The purpose of this report is to highlight a rare cause of congenital proptosis. METHODS: This is a case report. RESULTS: We present a case of a baby girl born with a large myofibroma in the right retrobulbar space. This case is unusual because it presented from birth and was in a critical location. A prenatal ultrasound performed two days prior to birth did not reveal this mass to the technician or obstetrician. At birth, the tumor induced severe proptosis, with the eyelids unable to close around the globe. Deterioration of the ocular surface secondary to exposure was evident immediately after birth. One week after birth, the mass was excised by the Oculoplastics service in conjunction with a Neurosurgical team using a transcranial approach. The tumor was diagnosed by histopathology and immunologic staining as a myofibroma, a rare condition. CONCLUSIONS: Orbital myofibroma is a rare cause of congenital proptosis presenting at birth.

Cancer of the orbit and adnexa.

The diagnosis and treatment of orbital and periorbital malignancies are challenging. These tumors can result in blindness, death, and significant cosmetic deformities. Herein, we present the most common ocular malignancies and a systematic approach to diagnosis. Further, we integrate the seventh edition American Joint Committee on Cancer staging system, biomarkers, and multidisciplinary approaches to treatment.

Periocular abscesses following brow epilation.

PURPOSE: The aim of this article was to report the clinical presentation, radiography, culture results, treatment modalities, and outcomes of periocular abscesses associated with brow epilation. METHODS: This was a retrospective case series including 26 patients referred for periocular abscess following brow epilation. RESULTS: Twenty-six female patients with a median age of 20.5 (range, 12-73) years were referred for oculoplastic evaluation of periocular abscesses related to recent brow epilation. All patients were treated with incision and drainage along with systemic antibiotics. Culture results revealed 16 cases of methicillin-resistant Staphylococcus aureus, 3 of methicillin-sensitive Staphylococcus aureus, and 7 cultures that showed no growth. All patients had resolution of their abscesses at 1-month follow-up visits without progression to orbital cellulitis. CONCLUSIONS: Periocular abscess formation after brow epilation has been previously described in only a single case report in the literature. The authors believe this entity is underreported given their current report describing 26 such cases. Given the high prevalence of cosmetic brow epilation in females, the authors believe a careful history regarding brow epilation in any patient presenting with a periocular abscess or preseptal cellulitis is essential to explore the possible cause of their infection. The majority of patients in the current study's cohort had methicillin-resistant Staphylococcus aureus-related abscesses, and treatment with antibiotics with methicillin-resistant Staphylococcus aureus coverage may be a prudent first line choice in such patients.

Gas chromatography/tandem mass spectrometry detection of extracellular kynurenine and related metabolites in normal and lesioned rat brain.

We describe here a gas chromatography-tandem mass spectrometry (GC/MS/MS) method for the sensitive and concurrent determination of extracellular tryptophan and the kynurenine pathway metabolites kynurenine, 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN) in rat brain. This metabolic cascade is increasingly linked to the pathophysiology of several neurological and psychiatric diseases. Methodological refinements, including optimization of MS conditions and the addition of deuterated standards, resulted in assay linearity to the low nanomolar range. Measured in samples obtained by striatal microdialysis in vivo, basal levels of tryptophan, kynurenine, and QUIN were 415, 89, and 8 nM, respectively, but 3-HK levels were below the limit of detection (<2 nM). Systemic injection of kynurenine (100 mg/kg, i.p.) did not affect extracellular tryptophan but produced detectable levels of extracellular 3-HK (peak after 2-3 h: ~50 nM) and raised extracellular QUIN levels (peak after 2h: ~105 nM). The effect of this treatment on QUIN, but not on 3-HK, was potentiated in the N-methyl-D-aspartate (NMDA)-lesioned striatum. Our results indicate that the novel methodology, which allowed the measurement of extracellular kynurenine and 3-HK in the brain in vivo, will facilitate studies of brain kynurenines and of the interplay between peripheral and central kynurenine pathway functions under physiological and pathological conditions.