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Key Points: Increased dupilumab utilization coincided with decreased ESS in patients with CRSwNP between 2019 and 2021. One potential confounder was the concurrent COVID-19 pandemic, which may have negatively impacted surgery utilization rates., (© 2024 ARS‐AAOA, LLC.)

Reflective supervision and consultation (RS/C) is regarded as best practice within the infant/early childhood mental health field. Benefits of RS/C on the early childhood workforce and children and families have been demonstrated through case studies, conceptual pieces, and individual research studies. However, findings across studies have not been summarized using gold-standard methodology, thus the state of existing empirical support for RS/C is unclear. This systematic review examined the collective evidence for RS/C across diverse early childhood-serving programs. Electronic databases were searched to identify studies investigating associations between RS/C and professionals' reflective capacity and well-being, child/family outcomes, and implementation factors. Twenty-eight papers were identified. Studies showed positive associations between RS/C and early childhood-serving professionals' reflective capacity and well-being, with qualitative studies reporting more consistent results than studies using quantitative methods. Many methodological limitations were identified, including incomplete reporting of study designs and participant characteristics, variability in outcome measures, and lack of randomization and comparison groups. Furthermore, few studies examined child and family outcomes. Therefore, while RS/C shows great promise, it was difficult to ascertain its overall effectiveness from an empirical standpoint. Establishing RS/C as an empirically supported approach will be possible with more rigorous research., (© 2023 Michigan Association for Infant Mental Health.)

Microscopy by Achromatic X-rays With Emission of Laminar Light (MAXWELL) is a new X-ray/visible technique with attractive characteristics including isotropic resolution in all directions, large-volume imaging and high throughput. An ultrathin, laminar X-ray beam produced by a Wolter type I mirror irradiates the sample stimulating the emission of visible light by scintillating nanoparticles, captured by an optical system. Three-dimensional (3D) images are obtained by scanning the specimen with respect to the laminar beam. We implemented and tested the technique with a high-brightness undulator at SPring-8, demonstrating its validity for a variety of specimens. This work was performed under the Synchrotrons for Neuroscience-an Asia-Pacific Strategic Enterprise (SYNAPSE) collaboration., (© 2022. The Author(s).)

Objective: To identify social determinants of health care that are associated with poorer pediatric well-differentiated thyroid cancer (WDTC) outcomes and increased stage at presentation., Study Design: Using the SEER database (Surveillance, Epidemiology, and End Results), we retrospectively gathered data on pediatric WDTC across the United States between 1973 and 2015., Setting: All patients between 0 and 19 years old with a diagnosis of WDTC were included., Methods: Patient variables were analyzed for relationships to AJCC stage at presentation (American Joint Committee on Cancer), overall survival, and disease-specific survival., Results: Among 3913 patients with pediatric thyroid cancer, 3185 were female (81.4%), 3366 had papillary thyroid cancer (85.3%), and 367 had follicular thyroid cancer (9.4%). Two- and 5-year overall and disease-specific survival approached 100%. However, when outcomes were analyzed by specific populations, male sex, non-Caucasian race, poverty, and language isolation were linked to worse overall survival. Male sex and poverty were associated with poorer disease-specific survival. Regarding overall AJCC stage at presentation, male sex and Black race were related to higher overall presenting AJCC stage. Later AJCC T stage at presentation was seen in male, Hispanic, Asian, and Black patients. There were no variables significantly related to following through with recommended surgery., Conclusion: Pediatric WDTC continues to carry an excellent prognosis in the United States. However, when we consider specific populations, the social determinants of health care affect survival and disease burden at presentation: male sex, poverty, language isolation, and race affected survival and/or AJCC stage at presentation in pediatric WDTC.

The pituitary gland is a small gland at the base of the skull controlling many physiologic processes through its regulation of primary endocrine glands. Pathologies of the pituitary gland and sellar space are wide ranging and most commonly include pituitary adenomas but can also encompass pituitary hyperplasia, other benign nonadenomatous tumors, cysts, and primary and metastatic malignancy. At present, the endoscopic approach has been established as a safe and effective approach to surgical management of pituitary pathology. A detailed understanding of the sella and parasellar anatomy from an endoscopic approach is imperative to performing safe endoscopic surgery in this area., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To comprehensively review the recent published literature to characterize current trends of burnout and well-being among otolaryngology trainees., Methods: Study design: systematic review and meta-analysis. A comprehensive literature review from 2000 to 2021 of studies related to otolaryngology resident burnout and well-being, as well as the general topic of well-being among surgical residents was completed. All included studies were summarized qualitatively. For the quantitative analysis, only articles reporting a Maslach burnout inventory (MBI), modified MBI or Mini-Z- Burnout assessment were included., Results: Twenty-five articles were included in the qualitative summary and nine articles in the quantitative analysis. In the qualitative summary, trainees were reported to have increased levels of distress and emotional hardening compared to attending otolaryngologists. Total hours worked per week and female gender were associated with worsened well-being. Residency program strategies to improve trainee well-being include program-sponsored wellness activities, dedicated wellness champions, and assistance with clerical burden. Implementation of protected nonclinical time has been shown to decrease burnout and increase well-being among trainees. Moreover, formal trainee mentorship programs have also been shown to reduce trainee burnout and stress. In the quantitative analysis, rates of trainee burnout ranged from 29.7% to 86% with an overall trend towards reduced rates of burnout from 2006 to 2021. Utilizing a weighted average, the overall burnout among otolaryngology residents was 58.6%., Conclusions: Rates of burnout remain high among otolaryngology trainees. Implementing formal mentorship programs and providing protected time during regular work hours appear to be effective tools to improve resident well-being., Competing Interests: The authors declare no conflicts of interest.This systematic review and meta‐analysis was considered exempt from IRB review. Skye K. Lawlor: idea generation, study design, data collection, analysis, manuscript drafting, manuscript approval; Christopher M. Low: idea generation, study design, data collection, analysis, manuscript drafting, manuscript approval; Matthew L. Carlson: idea generation, study design, analysis, manuscript drafting, manuscript approval; Karthik Rajasekaran: idea generation, study design, data analysis, manuscript drafting, manuscript approval; Garret Choby: idea generation, study design, data collection, analysis, manuscript drafting, manuscript approval., (© 2022 The Authors. World Journal of Otorhinolaryngology ‐ Head and Neck Surgery published by John Wiley & Sons Ltd on behalf of Chinese Medical Association.)

Objective: To provide a comprehensive state-of-the-art review of the emerging role of urine leukotriene E4 (uLTE4) as a biomarker in the diagnosis of chronic rhinosinusitis (CRS), aspirin-exacerbated respiratory disease (AERD), and asthma., Data Sources: Ovid MEDLINE(R), Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus., Review Methods: A state-of-the-art review was performed investigating the role of uLTE4 as a diagnostic biomarker, predictor of disease severity, and potential marker of selected therapeutic efficacy., Conclusions: uLTE4 has been shown to be a reliable and clinically relevant biomarker for CRS, AERD, and asthma. uLTE4 is helpful in ongoing efforts to better endotype patients with CRS and to predict disease severity., Implications for Practice: Aside from being a diagnostic biomarker, uLTE4 is also able to differentiate aspirin-tolerant patients from patients with AERD and has been associated with objective disease severity in patients with CRS with nasal polyposis. uLTE4 levels have also been shown to predict response to medical therapy, particularly leukotriene-modifying agents.

Background: Myriad open and endoscopic approaches are employed to resect maxillary sinus lesions, each with associated advantages and disadvantages. The inferior and anterior portion of the sinus remains a challenging space to access., Objectives: To describe the extended anterior inferior approach to endoscopic medial maxillectomy (EAMM) as a novel and valuable addition to a stepwise approach for minimizing surgical morbidity without compromising tumor outcomes. To report the outcomes of patients treated with this approach., Methods: A retrospective case series study of 9 patients who underwent EAMM between 2016 and 2019 at a tertiary care referral center was performed. The endoscopic technique is described. The duration of follow-up ranged from 1 to 53 months. Intraoperative steps, including transection of the nasolacrimal duct and execution of an intraoperative dacryocystorhinostomy, were reviewed. Postoperative outcomes, including patient symptoms at follow-up and tumor recurrence, were recorded., Results: Adequate exposure with gross total tumor resection or margin-negative tumor resection was achieved in all cases. Sparing of the nasolacrimal duct was achieved in 2 patients. No patients reported persistent epiphora, empty nose syndrome, or changes in cosmesis such as alar or nasal tip collapse. One patient reported unilateral V2 hypoesthesia at 6 months postoperatively that had resolved by his next follow-up 18 months after surgery. Postoperative tumor surveillance was achieved by endoscopic examinations in all patients and there was no evidence of tumor recurrence at a median follow-up of 22 months., Conclusions: The EAMM provides improved access to the inferior-posterior-medial maxillary sinus. This approach minimizes the risk of hypoesthesia and change in cosmesis present in other approaches, and obviates division of the nasolacrimal duct for inferior, posterior-medial attached lesions. This progressive escalation of approach for maxillary sinus lesions minimizes injury to nasal and nasolacrimal structures without compromising tumor outcomes.

Background: Sinonasal adenocarcinoma (SNAC) is a rare tumor. The impact of health disparities on survival, stage at presentation, and utilization of surgery is not well understood in patients with SNAC., Methods: The Surveillance, Epidemiology, and End Results database was queried for cases of SNAC from 1973 to 2015. Cases were analyzed to assess for disparities in presentation, treatment, and survival., Results: SNAC was identified in 630 patients. In a multivariate model of overall survival, an age increase of 10 years (Hazard Ratio (HR) = 1.37, p < 0.001), male sex (HR = 1.26, p = 0.045), and more recent decade of diagnosis (HR = 0.74, p < 0.001) were significantly related to time-to-death. There is a higher rate of SNAC-related death in counties with more rural populations (p = 0.027)., Conclusion: Future interventions targeting rural and less well-educated populations may improve care with the goal of increasing the span of healthy life and reducing survival disparities related to SNAC., (© 2021 Wiley Periodicals LLC.)

Many physiologic effects of l-glutamate, the major excitatory neurotransmitter in the mammalian central nervous system, are mediated via signaling by ionotropic glutamate receptors (iGluRs). These ligand-gated ion channels are critical to brain function and are centrally implicated in numerous psychiatric and neurologic disorders. There are different classes of iGluRs with a variety of receptor subtypes in each class that play distinct roles in neuronal functions. The diversity in iGluR subtypes, with their unique functional properties and physiologic roles, has motivated a large number of studies. Our understanding of receptor subtypes has advanced considerably since the first iGluR subunit gene was cloned in 1989, and the research focus has expanded to encompass facets of biology that have been recently discovered and to exploit experimental paradigms made possible by technological advances. Here, we review insights from more than 3 decades of iGluR studies with an emphasis on the progress that has occurred in the past decade. We cover structure, function, pharmacology, roles in neurophysiology, and therapeutic implications for all classes of receptors assembled from the subunits encoded by the 18 ionotropic glutamate receptor genes. SIGNIFICANCE STATEMENT: Glutamate receptors play important roles in virtually all aspects of brain function and are either involved in mediating some clinical features of neurological disease or represent a therapeutic target for treatment. Therefore, understanding the structure, function, and pharmacology of this class of receptors will advance our understanding of many aspects of brain function at molecular, cellular, and system levels and provide new opportunities to treat patients., (U.S. Government work not protected by U.S. copyright.)

The new Brain Imaging Beamline (BIB) of the Taiwan Photon Source (TPS) has been commissioned and opened to users. The BIB and in particular its endstation are designed to take advantage of bright unmonochromatized synchrotron X-rays and target fast 3D imaging, ∼1 ms exposure time plus very high ∼0.3 µm spatial resolution. A critical step in achieving the planned performances was the solution to the X-ray induced damaging problems of the detection system. High-energy photons were identified as their principal cause and were solved by combining tailored filters/attenuators and a high-energy cut-off mirror. This enabled the tomography acquisition throughput to reach >1 mm 3  min -1 , a critical performance for large-animal brain mapping and a vital mission of the beamline.

Objective  The objective of this study is to describe the clinical presentation, tumor characteristics, natural history, and treatment patterns of sinonasal osteosarcoma. Methods  Fourteen patients who had been treated for osteosarcoma of the nasal cavity and paranasal sinuses at a tertiary care center were reviewed. In addition, a systematic review of the literature for osteosarcoma of the sinonasal cavity was performed. Results  In a systematic review, including 14 patients from the authors' institution, 53 total studies including 88 patients were assessed. Median follow-up was 18 months (interquartile range: 8-39 months). The most common presenting symptoms were facial mass or swelling (34%), and nasal obstruction (30%). The most common paranasal sinus involved by tumor was the maxillary sinus (64%), followed by the ethmoid sinuses (52%). The orbit (33%), dura (13%) and infratemporal fossa (10%) were the most common sites of local invasion. The majority of patients underwent surgery followed by adjuvant therapy (52.4%). Increasing age was associated with decreased overall survival rate (unit risk ratio [95% confidence interval (CI)] = 1.02 [1.003-1.043]; p  = 0.0216) and T4 disease was associated with decreased disease-specific survival rate (hazard ratio [HR] = 2.87; p  = 0.0495). The 2- and 5-year overall survival rates were 68 and 40%, respectively, while 2- and 5-year disease-specific survival rates were 71% and 44%, respectively. Conclusion  Sinonasal osteosarcomas are uncommon tumors and can pose a significant therapeutic challenge. Increasing age and T4 disease are associated with worse prognosis. This disease usually warrants consultation by a multidisciplinary team and consideration of multimodality therapy., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Orbital hemangiomas are the most common primary neoplasm of the orbit and manifest as two distinct pathologic entities: infantile hemangiomas and cavernous hemangiomas. In this article, both infantile and cavernous hemangiomas are reviewed, with special attention paid to the natural history, clinical presentation, and management teams and approaches involved. An example case of each type of hemangioma is presented along with pearls and tips a reader can take away after reading this article., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Background: Minimal information has been reported on the effect of distant and nodal metastases at the time of diagnosis on survival in patients with sinonasal adenocarcinoma (SNAC)., Methods: The Surveillance, Epidemiology, and End Results database was utilized to compare overall survival (OS) and disease-specific survival (DSS)., Results: Of the 325 patients with SNAC identified, 5-year and 10-year OS for all included patients was 64% and 58%, respectively. On multivariate analysis, the presence of distant metastases (P < .0001), maxillary and frontal sinus primary tumors (P = .0042, P = .0006), and increasing age (P = .007) were risk factors for worsened DSS. The presence of regional spread to multiple cervical nodal basins (OS RR 3.26, P = .002; DSS RR 2.51, P = .013) and a single nodal basin (DSS RR 2.19, P = .046) was associated with worsened survival compared to no regional spread., Conclusion: Survival in SNAC was significantly worsened with increasing age, tumor site of origin, and distant metastatic disease., (© 2020 Wiley Periodicals LLC.)

Objective: This study aims to describe presenting characteristics of patients diagnosed with non-invasive chronic rhinosinusitis (CRS) following liver or kidney transplant and determine factors associated with disease-related complications, selection of endoscopic sinus surgery (ESS), and disease resolution in this population., Study Design: Retrospective chart review., Setting: An academic tertiary care center (Mayo Clinic, Rochester, Minnesota)., Subjects and Methods: Liver and kidney transplant recipients evaluated by Mayo Clinic otolaryngologists for CRS between 1998 and 2018 were identified. Univariate and multivariate logistic regression analyses were used to determine patient factors and treatment modalities associated with developing complications, selection of ESS, and disease resolution., Results: Fifty-seven patients met inclusion criteria. No patients developed intraorbital or intracranial complications of their CRS. Multivariate modeling demonstrated that the presence of polyps ( P  = 0.036) was associated with undergoing ESS within one year of presentation. A higher Lund-Mackay (LM) computed tomography score ( P  = 0.023) and older age ( P  = 0.018) were significantly associated with decreased disease resolution. No other factors were significantly associated with the use of endoscopic sinus surgery within one year of otolaryngology presentation or resolution of CRS in this cohort., Conclusion: The risk of developing CRS-related intraorbital or intracranial complications in this immunecompromised patient cohort may be lower than originally thought. For liver- and kidney-recipients stable on immunosuppressive medication for many years, prognostic factors for CRS may mirror those for immunocompetent patients., (© 2020 The Authors.)

Background: Chronic osteoarthritic pain is not well understood in terms of its pathophysiological mechanism. Activated glial cells are thought to play a role in the maintenance of chronic pain. T98G glioblastoma cell line was previously observed to release higher amounts of interleukin-6 (IL-6) when treated with cerebrospinal fluid (CSF) from patients with another chronic pain condition, post-herpetic neuralgia. In this study, we investigated the ability of CSF from patients diagnosed with knee osteoarthritis suffering from chronic pain, to trigger the release of pro-inflammatory cytokines, IL-6, IL-1beta and tumour necrosis factor alpha (TNF-α) from T98G. Characterization of upstream signalling was also explored., Methods: Fifteen osteoarthritis patients undergoing total knee replacement due to chronic knee pain and 15 patients without pain undergoing other surgeries with spinal anaesthesia were prospectively recruited. CSF was collected during anaesthesia. CSF were added to cultured T98G cells in the presence of lipopolysaccharide. IL-6, IL-1β and TNF-α release from T98G cells were measured using enzyme immunoassay. Antibody array and western blotting were performed using CSF-triggered T98G cell lysates to identify possible signalling targets. Age, gender and pain scores were recorded. Mann-Whitney U test was used to compare IL-6 release and protein expression between groups. Association between IL-6 and pain score was analysed using linear regression., Results: Significant higher levels of IL-6 were released by T98G cells when induced by osteoarthritis patients' CSF in the presence of LPS. The IL-6 levels showed positive association with pain score (adjusted B estimate = 10.1 (95% Confidence Interval 4.3-15.9); p = 0.001). Antibody array conducted with 6 pooled T98G cell lysate induced with osteoarthritis pain patient CSF identified greater than 2-fold proteins including STE20-related kinase adaptor protein and spleen tyrosine kinase. Further validation done using western blotting of individual CSF-triggered T98G cell lysate showed non-significant increase., Conclusion: Higher IL-6 release from T98G when triggered by OA-CSF, in the presence of LPS, suggest the presence of "unknown molecule" in CSF that may be crucial in the maintenance phase of chronic pain in our osteoarthritis population. Further studies on the signalling pathways involved in pain and relevance of IL-6 release from T98G cells in other pain models are needed.

Objectives/hypothesis: Sinonasal mucosal melanoma (SNMM) is a rare malignant neoplasm. No study to date has analyzed the impact that nodal metastases and distant metastases at diagnosis have on overall survival (OS) and disease-specific survival (DSS)., Study Design: Retrospective database review., Methods: The Surveillance, Epidemiology, and End Results database was queried for cases of SNMM. Descriptive statistics were used analyze patient demographic and clinicopathologic variables. The Kaplan-Meier model was used to analyze survival, and the Cox proportional hazards model was used for multivariate analysis., Results: Three hundred twenty-eight cases of SNMM were identified. The most frequent sinonasal anatomic location was the nasal cavity in 279 (73.0%) patients, followed by the maxillary sinus in 60 (15.7%) patients. Regional nodal metastases at diagnosis occurred in 33 (8.6%) patients, whereas distant metastases at diagnosis occurred in 41 (10.7%) patients. Five-year OS was 22.7%, and 5-year DSS was 26.8%. The presence of positive nodes at diagnosis (OS P < .0001, DSS P < .0001), distant metastases at diagnosis (OS P = .0442, DSS P = .0442), primary tumor site (OS P < .0001, DSS P < .0001), and increasing age (OS P = .0012, DSS P = .0016) were found to be significant as negative predictors of OS and DSS., Conclusions: SNMM is a rare pathologic entity with a poor prognosis. The presence of nodal and distant metastases at diagnosis are negative prognostic factors in OS and DSS. These factors can be used in the development of new models of risk stratification and to inform treatment strategies and surveillance patterns., Level of Evidence: NA Laryngoscope, 130:622-627, 2020., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: In this study we aim to describe presenting characteristics and identify prognostic factors for disease resolution in patients with chronic rhinosinusitis (CRS) in the setting of eosinophilic granulomatosis with polyangiitis (EGPA)., Methods: Patients evaluated at a tertiary care center with diagnoses of EGPA and CRS were identified. Descriptive statistics were obtained. Univariate analysis was used to search for prognostic factors associated with higher Lund-Mackay score at presentation and disease resolution., Results: Forty-four patients were included with a mean age of 52.7 (standard deviation, 14) years. Twenty-one patients (47.7%) were female, all had a diagnosis of asthma, and 36 (83.7%) had eosinophils >10%. Common presenting symptoms for CRS included nasal discharge (87.9%) followed by nasal congestion (83.9%) and facial pain and pressure (83.8%). Medical management of CRS included systemic corticosteroids (93.2%) and systemic antibiotics (75%). Surgical intervention occurred in 29 patients (67%). Nine patients (20.5%) had resolution of sinus symptoms, including 4 with imaging confirmation. Fourteen patients (31.8%) had continued CRS, but with improved symptoms, whereas 9 patients (20.5%) had continued CRS with no improvement in symptoms. Eleven patients (25%) were lost to follow-up and 4 (9.1%) died. Univariate analysis did not show antineutrophil cytoplasmic antibody positivity, presence of peripheral eosinophilia, gender, age, or absence of systemic therapy to be predictive of higher Lund-Mackay score at presentation or predictive of disease resolution., Conclusion: CRS in patients with EGPA is often refractory to medical and surgical management. Treatment of these patients should occur in a multidisciplinary setting., (© 2019 ARS-AAOA, LLC.)

Background: The anatomy of the frontal sinus can pose a challenge for many neuroradiolgists and otolaryngologists, especially trainees. While much of resident education occurs in didactics, self-study or in the operating room, studies suggest that some trainees prefer hands-on learning. Three-dimensional (3D) printing technology provides users the opportunity to make customizable low-cost objects that provide tactile learning-a learning modality that may be preferable in education., Methods: Three-dimensional printed models of frontal sinus anatomy based on selected patient computed tomography scans that represent various air cells according to the International Frontal Sinus Classification (IFAC) as different colored solid structures were printed using binder jetting., Results: Seven unique de-identified patient scans were selected as the basis for the models so that all frontal cell types described in the IFAC scheme are represented between all 3D printed models., Conclusion: This paper describes the technology and process necessary to create these models.

Rapid advances in sequencing technology have led to an explosive increase in the number of genetic variants identified in patients with neurological disease and have also enabled the assembly of a robust database of variants in healthy individuals. A surprising number of variants in the GRIN genes that encode N -methyl-D-aspartate (NMDA) glutamatergic receptor subunits have been found in patients with various neuropsychiatric disorders, including autism spectrum disorders, epilepsy, intellectual disability, attention-deficit/hyperactivity disorder, and schizophrenia. This review compares and contrasts the available information describing the clinical and functional consequences of genetic variations in GRIN2A and GRIN2B. Comparison of clinical phenotypes shows that GRIN2A variants are commonly associated with an epileptic phenotype but that GRIN2B variants are commonly found in patients with neurodevelopmental disorders. These observations emphasize the distinct roles that the gene products serve in circuit function and suggest that functional analysis of GRIN2A and GRIN2B variation may provide insight into the molecular mechanisms, which will allow more accurate subclassification of clinical phenotypes. Furthermore, characterization of the pharmacological properties of variant receptors could provide the first opportunity for translational therapeutic strategies for these GRIN -related neurological and psychiatric disorders., Competing Interests: Competing interests: SFT is PI on a research grant from Allergan and Janssen and Emory University School of Medicine, is a member of the SAB for Sage Therapeutics, is co-founder of NeurOp Inc, and receives royalties for software. SFT and SJM are co-inventors on Emory-owned Intellectual Property that includes allosteric modulators of NMDAR function.No competing interests were disclosed.No competing interests were disclosed., (Copyright: © 2019 Myers SJ et al.)

Objective: To examine the impact of 2-dimensional (2D) illustrations and 3-dimensonal (3D)-printed anatomic models of the frontal sinuses according to the International Frontal Sinus Anatomy Classification in the education of otolaryngology and radiology residents., Study Design: A crossover study design with half of the study participants randomized to the 2D illustration intervention first and the other half randomized to the 3D-printed model first., Setting: Regularly scheduled resident didactic lectures at a tertiary care center., Subjects and Methods: Forty-one otolaryngology and radiology residents were assessed with pre- and postintervention questionnaires that included subjective and objective methods of assessment., Results: Overall, there was a statistically significant improvement in total number of answers correct and in confidence score between the pre- and postintervention assessments ( P < .0001). The primary outcome of order of intervention (ie, 2D → 3D vs 3D → 2D) did not result in statistically significant differences in postevaluation scores. In regard to the secondary outcome of learner preference for educational modality, radiology residents favored the 2D illustrations to understand anatomic relationships, while otolaryngology residents preferred the 3D model to be more helpful in surgical planning ( P = .0075)., Conclusion: There is no difference between 2D-illustrated and 3D-printed International Frontal Sinus Anatomy Classification anatomic models in overall educational outcome, despite the preference of learners. Together, these models can be used as helpful tools in frontal sinus education for otolaryngology and radiology trainees.

The detection of delirium in acutely ill older patients is challenging with the lack of informants and the necessity to identify subtle and fluctuating signs. We conducted a cross-sectional study among older patients admitted to a university hospital in Malaysia to determine the presence, characteristics, and mortality outcomes of delirium. Consecutive patients aged ≥65years admitted to acute medical wards were recruited from August to September 2016. Cognitive screening was performed using the mini-mental test examination (MMSE) and the Confusion Assessment Method (CAM). The CAM-Severity (CAM-S) score was also performed in all patients. Of 161 patients recruited, 43 (26.7%) had delirium. At least one feature of delirium from the CAM-S short and long severity scores were present in 48.4% and 67.1%, respectively. Older age (OR: 1.07, 95% CI: 1.01-1.14), immobility (OR: 3.16, 95% CI: 1.18-8.50), cognitive impairment (OR: 5.04, 95% CI: 2.07-12.24), and malnutrition (OR: 3.37; 95% CI: 1.15-9.85) were significantly associated with delirium. Older patients with delirium had a higher risk of mortality (OR: 7.87, 95% CI: 2.42-25.57). Delirium is common among older patients in our setting. A large proportion of patients had altered mental status on admission to hospital although they did not fulfill the CAM criteria of delirium. This should prompt further studies on strategies to identify delirium and the use of newer, more appropriate assessment tools in this group of vulnerable individuals., Competing Interests: All authors declare no conflict of interest.

Objectives: Determine the effect of endoscopic skull base surgery (ESBS) on long-term olfactory outcomes after surgery., Methods: An English-language search was conducted using the Cochrane, MEDLINE, Scopus, and Embase databases from January 2000 to October 2017 for adult patients undergoing ESBS with subjective and objective olfaction outcomes. Two authors independently examined articles to identify those meeting inclusion criteria. Studies examining objective olfactory outcomes after ESBS were included in the meta-analysis. A random-effects meta-analysis of patients undergoing sellar and parasellar ESBS was conducted to compare preoperative and postoperative olfactory outcomes using the University of Pennsylvania Smell Identification Test (UPSIT) and Cross-Cultural Smell Identification Test (CCSIT)., Results: Among 339 eligible articles, 29 articles met inclusion criteria. Twenty-five of these focused on sellar and parasellar tumors. Individual articles not meeting criteria for meta-analysis were qualitatively reported. Meta-analysis showed there was no difference in preoperative and postoperative olfactory function after sellar and parasellar ESBS based on the UPSIT (five studies, mean difference [MD] = -1.03; 95% CI: -3.98, 1.93; P = .50) and the CCIST (three studies, MD = -0.77; 95% CI: -3.03, 1.49; P = .50). A pooled overall meta-analysis revealed similar results (eight studies, effect size = -0.30; 95% CI: -0.79, 0.18; P = .22). However, heterogeneity for all meta-analyses was high (I 2 > 95%, P < .01), suggesting significant variation in the included studies., Conclusions: Based on published objective olfaction outcomes after sellar and parasellar ESBS, there was no significant difference between preoperative and postoperative olfaction. Further prospective studies using validated objective measures of olfaction are required to improve our understanding on this subject., Level of Evidence: 2a Laryngoscope, 129:1998-2007, 2019., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives: Rectovaginal fistulas can occur from both obstetric and nonobstetric (eg, inflammatory bowel disease, iatrogenic, or traumatic) etiologies. Current data on factors contributing to rectovaginal repair success or failure are limited, making adequate patient counseling difficult. Our objective was to compare outcomes of transperineal rectovaginal fistula repair performed in a single referral center on women with obstetric and nonobstetric causes., Methods: We performed a retrospective cohort study of women who had a transperineal rectovaginal fistula repair performed by a urogynecologist at the University of Michigan from 2005 to 2015. Data were obtained by chart review and included demographics, medical comorbidities, fistula etiology, history of a prior fistula repair, failure of current repair, time to failure, and operative details. Repair failure was defined as fistula symptoms with presence of recurrent fistula on exam or imaging in the postoperative follow-up period. Comparisons between the obstetric and nonobstetric cohorts were performed using χ, Fisher exact, and Wilcoxon rank sum tests. Relative risks were calculated to identify predictors of failure., Results: Eighty-eight women were included-53 obstetric and 35 nonobstetric fistulas. The overall fistula repair failure rate was 22.7% (n = 20). Median follow-up was 157.0 days (range, 47.5-402.0). Of all the factors, only nonobstetric etiology was significantly associated with an increased risk of repair failure (relative risk, 3.53 [range, 1.50-8.32]; P = 0.004., Conclusions: Nonobstetric rectovaginal fistulas have a nearly 4-fold increased risk of repair failure compared with obstetric fistulas. Our results will help surgeons adequately counsel patients on potential outcomes of surgical repair of obstetric versus nonobstetric rectovaginal fistulas.

Despite widespread belief in the early childhood field of the benefits of reflective supervision, there has been limited empirical evidence to support the effectiveness of reflective supervision for home visitors and the children and families they serve. The present study examined the psychometric properties of four adapted self-report measures assessing supervisors' reflective supervision capacities; the study also investigated whether these measures captured change in reflective capacity over time as supervisors participated in professional development activities focused on reflective supervision. Results from 33 participants (home visiting supervisors and program managers) suggested that three of the four measures demonstrated acceptable internal consistency, and these three measures were correlated with each other. Two of these measures also captured significant change over time. Finally, there was some evidence that those with less education demonstrated more substantial improvement in their reflective supervision capacities than did those with an advanced degree. Findings provide initial evidence for reliable, efficient, and cost-effective supervisor self-report measures that could be used in research and program evaluation to assess change in supervisor reflective capacity over time., (© 2018 Michigan Association for Infant Mental Health.)

The present study explored the role of the medial septal region (MS) in experimental neuropathic pain. For the first time, we found that the MS sustains nociceptive behaviors in rodent models of neuropathic pain, especially in the chronic constriction injury (CCI) model and the paclitaxel model of chemotherapy-induced neuropathic pain. For example, inactivation of the MS with intraseptal muscimol (2 μg/μl, 0.5 μl), a GABA mimetic, reversed peripheral hypersensitivity (PH) in the CCI model and induced place preference in a conditioned place preference task, a surrogate measure of spontaneous nociception. The effect of intraseptal muscimol on PH was comparable to that seen with microinjection of the local anesthetic, lidocaine, into rostral ventromedial medulla which is implicated in facilitating experimental chronic nociception. Cellular analysis in the CCI model showed that the MS region sustains nociceptive gain with CCI by facilitating basal nociceptive processing and the amplification of stimulus-evoked neural processing. Indeed, consistent with the idea that excitatory transmission through MS facilitates chronic experimental pain, intraseptal microinjection of antagonists acting at AMPA and NMDA glutamate receptors attenuated CCI-induced PH. We propose that the MS is a central monitor of bodily nociception which sustains molecular plasticity triggered by persistent noxious insult.

Cytosolic phospholipase A 2 (cPLA 2 ) is an enzyme that releases arachidonic acid (AA) for the synthesis of eicosanoids and lysophospholipids which play critical roles in the initiation and modulation of oxidative stress and neuroinflammation. In the central nervous system, cPLA 2 activation is implicated in the pathogenesis of various neurodegenerative diseases that involves neuroinflammation, thus making it an important pharmacological target. In this paper, a new class of arachidonic acid (AA) analogues was synthesized and evaluated for their ability to inhibit cPLA 2 . Several compounds were found to inhibit cPLA 2 more strongly than arachidonyl trifluoromethyl ketone (AACOCF 3 ), an inhibitor that is commonly used in the study of cPLA 2 -related neurodegenerative diseases. Subsequent experiments concluded that one of the inhibitors was found to be cPLA 2 -selective, non-cytotoxic, cell and brain penetrant and capable of reducing reactive oxygen species (ROS) and nitric oxide (NO) production in stimulated microglial cells. Computational studies were employed to understand how the compound interacts with cPLA 2 .

Cholinergic mechanisms in supramammillary nucleus (SuM), especially the lateral SuM (lSuM) modulates septo-hippocampal neural activity. The lSuM, as compared to the contiguous medial SuM (mSuM) has relatively dense projections to hippocampus and cingulate cortex (Cg). In the present study, we have investigated whether the effects of cholinergic activation of SuM on hippocampal and cortical neural activities involve a cooperative interaction with the medial septum (MS). Microinjection of the broad-spectrum cholinergic agonist, carbachol, or the cholinergic-nicotinic receptor agonist, nicotine, into the lSuM and the mSuM in urethane anesthetized rat evoked a similar pattern of hippocampal theta rhythm. Despite that, only the lSuM microinjections resulted in an increase in expression of c-Fos-like immunoreactivity (c-Fos-ir) in neurons, including interneurons, of the ipsilateral hippocampus with a very dense expression in dentate gyrus. Likewise, a robust induction of c-Fos-ir was also observed in the ipsilateral Cg. Inhibition of the MS with muscimol pre-treatment attenuated both carbachol-evoked c-Fos-ir and theta activation. The findings indicate that cholinergic-nicotinic mechanisms in lSuM evoke not only neural activation via the ascending synchronizing pathway but also an MS-modulated expression of the plasticity-related molecule c-Fos in cortical regions that are strongly innervated by the lSuM.

Arachidonic acid derivatives equipped with either one or two fluorescent groups attached to the tip of the alkyl chains were synthesized and shown to function as inhibitor and substrate probes of cPLA 2 . The inhibitor probe was demonstrated to perform dual functions of inhibition and imaging while the substrate probe could be used for activity assay.

Several studies have indicated that neuroinflammation is indeed associated with neurodegenerative disease pathology. However, failures of recent clinical trials of anti-inflammatory agents in neurodegenerative disorders have emphasized the need to better understand the complexity of the neuroinflammatory process in order to unravel its link with neurodegeneration. Deregulation of Cyclin-dependent kinase 5 (Cdk5) activity by production of its hyperactivator p25 is involved in the formation of tau and amyloid pathology reminiscent of Alzheimer's disease (AD). Recent studies show an association between p25/Cdk5 hyperactivation and robust neuroinflammation. In addition, we recently reported the novel link between the p25/Cdk5 hyperactivation-induced inflammatory responses and neurodegenerative changes using a transgenic mouse that overexpresses p25 (p25Tg). In this study, we aimed to understand the effects of early intervention with a potent natural anti-inflammatory agent, curcumin, on p25-mediated neuroinflammation and the progression of neurodegeneration in p25Tg mice. The results from this study showed that curcumin effectively counteracted the p25-mediated glial activation and pro-inflammatory chemokines/cytokines production in p25Tg mice. Moreover, this curcumin-mediated suppression of neuroinflammation reduced the progression of p25-induced tau/amyloid pathology and in turn ameliorated the p25-induced cognitive impairments. It is widely acknowledged that to treat AD, one must target the early-stage of pathological changes to protect neurons from irreversible damage. In line with this, our results demonstrated that early intervention of inflammation could reduce the progression of AD-like pathological outcomes. Moreover, our data provide a rationale for the potential use of curcuminoids in the treatment of inflammation associated neurodegenerative diseases.

N-methyl-d-aspartate receptors (NMDARs) are ionotropic glutamatergic receptors that have been implicated in learning, development, and neuropathological conditions. They are typically composed of GluN1 and GluN2A-D subunits. Whereas a great deal is known about the role of GluN2A- and GluN2B-containing NMDARs, much less is known about GluN2D-containing NMDARs. Here we explore the subunit composition of synaptic NMDARs on hippocampal interneurons. GluN2D mRNA was detected by single-cell PCR and in situ hybridization in diverse interneuron subtypes in the CA1 region of the hippocampus. The GluN2D subunit was detectable by immunoblotting and immunohistochemistry in all subfields of the hippocampus in young and adult mice. In whole-cell patch-clamp recordings from acute hippocampal slices, (+)-CIQ, the active enantiomer of the positive allosteric modulator CIQ, significantly enhanced the amplitude of the NMDAR component of miniature excitatory postsynaptic currents (mEPSCs) in CA1 interneurons but not in pyramidal cells. (+)-CIQ had no effect in slices from Grin2d-/- mice, suggesting that GluN2D-containing NMDARs participate in excitatory synaptic transmission onto hippocampal interneurons. The time course of the NMDAR component of the mEPSC was unaffected by (+)-CIQ potentiation and was not accelerated in slices from Grin2d-/- mice compared with wild-type, suggesting that GluN2D does not detectably slow the NMDAR EPSC time course at this age. (+)-CIQ increased the activity of CA1 interneurons as detected by the rate and net charge transfer of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from CA1 pyramidal cells. These data provide evidence that interneurons contain synaptic NMDARs possessing a GluN2D subunit, which can influence interneuron function and signal processing., (U.S. Government work not protected by U.S. copyright.)

Background: There is some evidence to suggest that ginseng and Ginkgo biloba can improve cognitive performance, however, very little is known about the mechanisms associated with such improvement. Here, we tested whether cardiovascular reactivity to a task is associated with cognitive improvement., Methodology/principal Findings: Using a double-blind, placebo controlled, crossover design, participants (N = 24) received two doses of Panax Ginseng (500, 1000 mg) or Ginkgo Biloba (120, 240 mg) (N = 24), and underwent a series of cognitive tests while systolic, diastolic, and heart rate readings were taken. Ginkgo Biloba improved aspects of executive functioning (Stroop and Berg tasks) in females but not in males. Ginseng had no effect on cognition. Ginkgo biloba in females reversed the initial (i.e. placebo) increase in cardiovascular reactivity (systolic and diastolic readings increased compared to baseline) to cognitive tasks. This effect (reversal) was most notable after those tasks (Stroop and Iowa) that elicited the greatest cardiovascular reactivity during placebo. In males, although ginkgo also decreased cardiovascular readings, it did so from an initial (placebo) blunted response (i.e. decrease or no change from baseline) to cognitive tasks. Ginseng, on the contrary, increased cardiovascular readings compared to placebo., Conclusions/significance: These results suggest that cardiovascular reactivity may be a mechanism by which ginkgo but not ginseng, in females is associated with certain forms of cognitive improvement., Trial Registration: ClinicalTrials.gov NCT02386852.

N-Methyl-D-aspartate receptors are localized to synaptic and extrasynaptic sites of dendritic spines and shafts. Here, the ontogenic profiles of GluN3A and GluN3B subunits in the rat brain were determined. A developmental switch from GluN3A to GluN3B proteins was detected within the first two postnatal weeks of crude synaptosomes prepared from forebrain and midbrain. Further fractionation of crude synaptosomes revealed the preferential localization of GluN3B to synaptic regions from P7 onwards. Immunolabeling and biochemical fractionation of rat P7 cultured hippocampal neurons showed that GluN3B was predominantly at synaptic sites. Unlike GluN2A and GluN2B, both GluN3 subunits were mostly associated with peripheral components of the postsynaptic density (PSD) rather than its core. When considering the non-PSD fraction, the overall extrasynaptic/synaptic spatial profile of GluN3B differed from GluN3A. Heterologous expression of GluN3B with GluN1 in HEK293FT cells could not be co-immunoprecipitated with PSD-95 unless co-expressed with a PSD-95-interacting GluN2 subunit, suggesting that anchoring of GluN3B at synaptic sites may require co-assembly with another scaffold-interacting NMDAR subunit.

The present study explored the functional details of the influence of medial septal region (MSDB) on spectrum of nociceptive behaviours by manipulating intraseptal GABAergic mechanisms. Results showed that formalin-induced acute nociception was not affected by intraseptal microinjection of bicuculline, a GABAA receptor antagonist, or on selective lesion of septal GABAergic neurons. Indeed, the acute nociceptive responses were dissociated from the regulation of sensorimotor behaviour and generation of theta-rhythm by the GABAergic mechanisms in MSDB. The GABAergic lesion attenuated formalin-induced unconditioned cellular response in the anterior cingulate cortex (ACC) and blocked formalin-induced conditioned place avoidance (F-CPA), and as well as the contextual fear induced on conditioning with brief footshock. The effects of lesion on nociceptive-conditioned cellular responses were, however, variable. Interestingly, the lesion attenuated the conditioned representation of experimental context in dorsal hippocampus field CA1 in the F-CPA task. Collectively, the preceding suggests that the MSDB is a nodal centre wherein the GABAergic neurons mediate nociceptive affect-motivation by regulating cellular mechanisms in ACC that confer an aversive value to the noxious stimulus. Further, in conjunction with a modulatory influence on hippocampal contextual processing, MSDB may integrate affect with context as part of associative learning in the F-CPA task.

The advent of whole exome/genome sequencing and the technology-driven reduction in the cost of next-generation sequencing as well as the introduction of diagnostic-targeted sequencing chips have resulted in an unprecedented volume of data directly linking patient genomic variability to disorders of the brain. This information has the potential to transform our understanding of neurologic disorders by improving diagnoses, illuminating the molecular heterogeneity underlying diseases, and identifying new targets for therapeutic treatment. There is a strong history of mutations in GABA receptor genes being involved in neurologic diseases, particularly the epilepsies. In addition, a substantial number of variants and mutations have been found in GABA receptor genes in patients with autism, schizophrenia, and addiction, suggesting potential links between the GABA receptors and these conditions. A new and unexpected outcome from sequencing efforts has been the surprising number of mutations found in glutamate receptor subunits, with the GRIN2A gene encoding the GluN2A N-methyl-d-aspartate receptor subunit being most often affected. These mutations are associated with multiple neurologic conditions, for which seizure disorders comprise the largest group. The GluN2A subunit appears to be a locus for epilepsy, which holds important therapeutic implications. Virtually all α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor mutations, most of which occur within GRIA3, are from patients with intellectual disabilities, suggesting a link to this condition. Similarly, the most common phenotype for kainate receptor variants is intellectual disability. Herein, we summarize the current understanding of disease-associated mutations in ionotropic GABA and glutamate receptor families, and discuss implications regarding the identification of human mutations and treatment of neurologic diseases., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)

The effect of ApoE on NMDAR-dependent ERK/CREB signaling is isoform-dependent, and ApoE4 accelerates memory decline in ageing. However, this isoform-dependent function on neuronal signaling during ageing is unclear. In this study, we have examined NMDAR-associated ERK/CREB signal transduction in young and aged huApoE3 and huApoE4 targeted replacement (TR) mice. At 12 weeks huApoE4 mouse brain, increased NR1-S896 phosphorylation was linked to higher protein kinase C (PKC) activation. This up-regulation was accompanied by higher phosphorylation of AMPA GluR1-S831, CaMKII, ERK1/2 and CREB. But at 32 weeks, there was no significant difference between huApoE3 and huApoE4 TR mice on NMDAR-associated ERK/CREB signaling. Interestingly, in 72-week-old huApoE4 TR mice, protein phosphorylation that were increased in younger mice were significantly reduced. Lower NR1-S896 phosphorylation was linked to reduced PKC, GluR1-S831, CaMKII, ERK1/2 and CREB phosphorylation in huApoE4 TR mice as compared to huApoE3 TR mice. Furthermore, we have consistently detected lower ApoE levels in young and aged huApoE4 TR mouse brain, and this was associated with reduced expression of the ApoE receptor, LRP1 and NR2A-Y1246 phosphorylation. These results suggest age-specific, isoform-dependent effects of ApoE on neuronal signaling.

Chronic intractable pain caused by postherpetic neuralgia (PHN) can be alleviated by intrathecal (i.t.) steroid therapy. We investigated the possibility that interleukin-6 (IL-6) release in an in vitro system could be a potential marker for evaluating the effectiveness of i.t. steroid therapy in PHN patients. We studied 32 patients who received a course of i.t. injection of water-soluble dexamethasone. Their therapeutic index was calculated as such: ((Pain score before treatment - Pain score after treatment)÷Pain score before treatment)×100%, and they were divided into two groups, therapy effective (index>50%) and ineffective (index<50%). Cerebrospinal fluid (CSF) from the patients was used to stimulate cultures of T98G glioblastoma cells, and the subsequent IL-6 release was measured by enzyme-linked immunosorbent assay (ELISA). Our results showed that the CSF triggered IL-6 release from T98G cells in a volume-dependent manner. IL-6 release was significantly lower when using CSF from the therapy effective patient group (p<0.001) compared to the therapy ineffective group. In particular, therapy effective patients had less IL-6 release even before treatment as compared to therapy ineffective patients. In the therapy effective group, in vitro steroid treatment suppressed the CSF's IL-6 releasing effect almost completely, whereas in the therapy ineffective group, the IL-6 release was significantly reduced but remained detectable. These in vitro tests may provide an objective evaluation on the efficacy of i.t. steroid therapy administered to PHN patients., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The association constants for formation a 1:1 complex between 4-phenyl azophenol and tri-n-butylphosphine oxide were measured in mixtures of n-octane and n-decanol, n-octane and n-hexanoic acid, and n-octane and 2-ethylhexyl acetamide. The experiments provide insight into the competition between solvent self-association and solvent-solute interactions in these systems. The solvation properties of the three polar solvents are quite different from one another and from polar solvents that do not self-associate. Carboxylic acids form dimers in concentrated solution (>1 mM in alkanes). Carboxylic acid dimers have exposed H-bond acceptor sites that solvate H-bond donor solutes with a similar binding affinity to carboxylic acid monomers. The carboxylic acid H-bond donor site is inaccessible in the dimer and is not available to solvate H-bond acceptor solutes. The result is that solvation of H-bond acceptor solutes is in competition with solvent dimerization, whereas solvation of H-bond donor solutes is not. Secondary amides form linear polymers in concentrated solution (>10 mM in alkanes). The solvation properties of the secondary amide aggregates are similar to those of carboxylic acid dimers. Solvation of H-bond acceptor solutes must compete with solvent self-association, because the amide H-bond donor site is not accessible in the middle of a polymeric aggregate. However, the amide aggregates have exposed H-bond acceptor sites, which solvate H-bond donor solutes with similar binding affinity to amide monomers. Alcohols form cyclic tetramers at concentrations of 100 mM in alkanes, and these cyclic aggregates are in equilibrium with linear polymeric aggregates at concentrations above 1 M. The alcohol aggregates have exposed H-bond acceptor sites that solvate H-bond donor solutes with similar binding affinity to alcohol monomers. Although the alcohol H-bond donor sites are involved in H-bond interactions with other alcohols in the aggregates, these sites are sufficiently exposed to form a second bifurcated H-bond with H-bond acceptor solutes, and these interactions have a similar binding affinity to alcohol monomers. The result is that self-association of alcohols does not compete with solvation of solutes, and alcohols are significantly more polar solvents than expected based on the properties of alcohol monomers.

The forebrain cholinergic neurons project to cortex, including the hippocampus and the cingulate cortex (Cg). However, the relative influence of these neurons on behavior-linked neural processing in the two cortical areas remains unclear. We have now examined the effect of destruction of the cholinergic neurons with microinjection of the immunotoxin 192 IgG-saporin into the medial septum on the induction of c-Fos protein, an index of neuronal synaptic excitation, in the two forebrain areas to varied episodic experiences. Separate groups of rats were (a) re-exposed to the laboratory where they had previously undergone a surgery for intraseptal microinjection or (b) exposed to a novel environment. Re-exposure evoked a differential increase in the number of c-Fos positive neurons in dorsal CA1 compared to novelty, while a robust increase was observed in the Cg selectively in the novel environment. Both the differential and the selective increases were strongly attenuated by the cholinergic destruction with intraseptal-immunotoxin. These findings suggest that the cholinergic modulation of the neural processing in the two forebrain areas varies partly in an environment-dependent fashion affecting CA1 neural activation on repeat exposure to an environment where they had a relatively complex aversive experience while favoring Cg neural activation more during novelty., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Abnormalities in glutamate signaling and glutamate toxicity are thought to be important in the pathophysiology of bipolar disorder (BD). Whilst previous studies have found brain white matter changes in BD, there is paucity of data about how glutamatergic genes affect brain white matter integrity in BD. Based on extant neuroimaging data, we hypothesized that GRIN2B risk allele is associated with reductions of brain white matter integrity in the frontal, parietal, temporal, and occipital regions and cingulate gyrus in BD. Fourteen patients with BD and 22 healthy controls matched in terms of age, gender and handedness were genotyped using blood samples and underwent diffusion tensor imaging. Compared to G allele, brain FA values were significantly lower in BD patients with risk T allele in left frontal region (P = 0.001), right frontal region (P = 0.002), left parietal region (P = 0.001), left occipital region (P = 0.001), right occipital region (P < 0.001), and left cingulate gyrus (P = 0.001). Further elucidation of the interactions between different glutamate genes and their relationships with such structural, functional brain substrates will enhance our understanding of the link between dysregulated glutamatergic neurotransmission and neuroimaging endophenotypes in BD.

The association constants for formation of 1:1 complexes between a H-bond acceptor, tri-n-butylphosphine oxide, and a H-bond donor, 4-phenylazophenol, have been measured in a range of different solvent mixtures. Binary mixtures of n-octane and a more polar solvent (ether, ester, ketone, nitrile, sulfoxide, tertiary amide, and halogenated and aromatic solvents) have been investigated. Similar behavior was observed in all cases. When the concentration of the more polar solvent is low, the association constant is identical to that observed in pure n-octane. Once a threshold concentration of the more polar solvent in reached, the logarithm of the association constant decreases in direct proportion to the logarithm of the concentration of the more polar solvent. This indicates that one of the two solutes is preferentially solvated by the more polar solvent, and it is competition with this solvation equilibrium that determines the observed association constant. The concentration of the more polar solvent at which the onset of preferential solvation takes place depends on solvent polarity: 700 mM for toluene, 60 mM for 1,1,2,2-tetrachloroethane, 20 mM for the ether, ester, ketone, and nitrile, 0.2 mM for the tertiary amide, and 0.1 mM for the sulfoxide solvents. The results can be explained by a simple model that considers only pairwise interactions between specific sites on the surfaces of the solutes and solvents, which implies that the bulk properties of the solvent have little impact on solvation thermodynamics.