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A 74-year-old man with a history of chronic lymphocytic leukemia (CLL) presented with large salmon-colored patch lesions along the inferior fornix and superotemporal conjunctiva of the OS. The patient underwent an incisional biopsy of the lesions, which showed a CLL with areas of large B-cell lymphoma, consistent with Richter transformation. Following medical and radiation-based therapy of these lesions, the patient returned 3 months later with inferomedial preseptal swelling in the contralateral eye, which biopsy proved to be recurrent/resistant low-grade CLL with a posttreatment extranodal marginal zone B-cell lymphoma pattern. This case exemplifies a rare presentation of CLL with Richter transformation and a recurrent/resistant posttreatment orbital CLL with a marginal zone B-cell lymphoma-like pattern., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

The incidence of human papilloma virus-mediated oropharyngeal squamous cell carcinoma (OPSCC) has increased over the past 40 years, particularly among young individuals with a favorable prognosis; however, current therapy often leads to unfortunate side effects, such as dysphagia. Despite the emphasis on dysphagia in previous studies, there is an important research gap in understanding the correlation between neuronal changes and patient-reported and functional outcomes in patients with OPSCC. To address this issue, we examined pathologic tissue samples from patients with OPSCC using multiplex immunofluorescence staining and machine learning to correlate tumor-associated neuronal changes with prospectively collected patient-reported and functional outcomes. We found that tumor enrichment of adrenergic (TH + ) and CGRP + sensory-afferent nerves correlated with poorer swallowing outcomes. Functional electromyography recordings showed correlations between growing (GAP43 + ) and immature cholinergic (ChAT + DCX + ) nerves and denervation patterns in survivors of OPSCC. A murine model of radiation-induced dysphagia further confirmed that immature cholinergic and CGRP + nerves were correlated with impaired swallowing. Preclinical interventional studies also supported the independent contributions of CGRP + and cholinergic (ChAT + ) nerves to dysphagia in treated mouse models of OPSCC. Our results suggest that CGRP + and ChAT + neuronal signaling play distinct roles in tumor- and radiation-induced dysphagia in OPSCC and offer a comprehensive dataset on the neural landscape of OPSCC. These insights may guide early interventions for swallow preservation and the repurposing of neurology-related drugs, such as CGRP blockers, in clinical oncology and survivorship.

Purpose: Periocular lesions in pediatric patients usually require general anesthesia for surgical intervention. The US Food and Drug Administration (FDA) warns against multiple exposures to anesthesia in children younger than 3 years due to the increased risk of learning disabilities in this population. This study aimed to evaluate risk factors associated with chalazion recurrence after surgery., Methods: A retrospective chart review over a five-year period identified 649 patients at our institution undergoing surgical intervention for chalazion. The primary outcomes examined were as follows: (1) return to the operating room for additional surgical intervention and (2) recurrence of chalazion during convalescence from surgery and follow-up., Results: Fewer than one-third of patients suffered a recurrence after surgery. Multivariate logistic regression found younger age ( p  = 0.01), female sex ( p  = 0.01), and a greater number of chalazia drained ( p  < 0.001) were significantly correlated with recurrence of chalazia after surgery., Conclusions: Patients presenting at a younger age and with a greater number of chalazion were statistically more likely to have a recurrence of chalazion after surgery. Given recurrence is more likely in younger children, reconciling this with the risk-benefit ratio with regard to FDA guidelines on anesthesia in children under three years is a critical consideration for ophthalmologists.

Neuro-ophthalmologic diseases include a broad range of disorders affecting the afferent and efferent visual pathways. Recently, monoclonal antibody (mAb) therapies have emerged as a promising targeted approach in the management of several of these complex conditions. Here, we describe the mechanism-specific applications and advancements in neuro-ophthalmologic mAb therapies. The application of mAbs in neuro-ophthalmologic diseases highlights our increasing understanding of disease-specific mechanisms in autoimmune conditions such as neuromyelitis optica, thyroid eye disease, and myasthenia gravis. Due to the specificity of mAb therapies, applications in neuro-ophthalmologic diseases have yielded exceptional clinical outcomes, including both reduced rate of relapse and progression to disability, visual function preservation, and quality of life improvement. These advancements have not only expanded the range of treatable neuro-ophthalmologic diseases but also reduced adverse events and increased the response rate to treatment. Further research into neuro-ophthalmologic disease mechanisms will provide accurate and specific targeting of important disease mediators through applications of future mAbs. As our understanding of these diseases and the relevant therapeutic targets evolve, we will continue to build on our understanding of how mAbs interfere with disease pathogenesis, and how these changes improve clinical outcomes and quality of life for patients., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Saudi Journal of Ophthalmology.)

Competing Interests: The authors report no conflicts of interest.

Infratemporal fossa (ITF) tumors are difficult to access surgically due to anatomical constraints. Moreover, aggressive ITF carcinomas and sarcomas necessitate aggressive treatment strategies that, along with tumor-related symptoms, contribute to decreases in patient performance status. To assess factors that predict postoperative performance in patients undergoing surgery for ITF tumors. We reviewed medical records for all patients surgically treated for an ITF malignancy between January 1, 1999, and December 31, 2017, at our institution. We collected patient demographics, preoperative performance, tumor stage, tumor characteristics, treatment modalities, pathological data, and postoperative performance data. The 5-year survival rate was 62.2%. Higher preoperative Karnofsky Performance Status (KPS) score (n = 64; p < 0.001), short length of stay (p = 0.002), prior surgery at site (n = 61; p = 0.0164), and diagnosis of sarcoma (n = 62; p = 0.0398) were predictors of higher postoperative KPS scores. Percutaneous endoscopic gastrostomy (PEG) (n = 9; p = 0.0327), and tracheostomy tube placement (n = 20; p = 0.0436) were predictors of lower postoperative KPS scores, whereas age at presentation (p = 0.72), intracranial tumor spread (p = 0.8197), and perineural invasion (n = 40; p = 0.2195) were not. Male patients and patients with carcinomas showed the greatest decreases in KPS scores between pretreatment and posttreatment. Higher preoperative KPS score and short length of stay were the best predictors of higher postoperative KPS scores. This work provides treatment teams and patients with better information on outcomes for shared decision-making., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Environmental cues and internal states such as mood, reward, or aversion directly influence feeding behaviors beyond homeostatic necessity. The hypothalamus has been extensively investigated for its role in homeostatic feeding. However, many of the neural circuits that drive more complex, non-homeostatic feeding that integrate valence and sensory cues (such as taste and smell) remain unknown. Here, we describe a basal forebrain (BF)-to-lateral habenula (LHb) circuit that directly modulates non-homeostatic feeding behavior. Using viral-mediated circuit mapping, we identified a population of glutamatergic neurons within the BF that project to the LHb, which responds to diverse sensory cues, including aversive and food-related odors. Optogenetic activation of BF-to-LHb circuitry drives robust, reflexive-like aversion. Furthermore, activation of this circuitry suppresses the drive to eat in a fasted state. Together, these data reveal a role of basal forebrain glutamatergic neurons in modulating LHb-associated aversion and feeding behaviors by sensing environmental cues., (© 2022. The Author(s).)

Neural circuit plasticity and sensory response dynamics depend on forming new synaptic connections. Despite recent advances toward understanding the consequences of circuit plasticity, the mechanisms driving circuit plasticity are unknown. Adult-born neurons within the olfactory bulb have proven to be a powerful model for studying circuit plasticity, providing a broad and accessible avenue into neuron development, migration, and circuit integration. We and others have shown that efficient adult-born neuron circuit integration hinges on presynaptic activity in the form of diverse signaling peptides. Here, we demonstrate a novel oxytocin-dependent mechanism of adult-born neuron synaptic maturation and circuit integration. We reveal spatial and temporal enrichment of oxytocin receptor expression within adult-born neurons in the murine olfactory bulb, with oxytocin receptor expression peaking during activity-dependent integration. Using viral labeling, confocal microscopy, and cell type-specific RNA-seq, we demonstrate that oxytocin receptor signaling promotes synaptic maturation of newly integrating adult-born neurons by regulating their morphological development and expression of mature synaptic AMPARs and other structural proteins., (© 2022 Pekarek et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: The management of sub-totally resected sporadic vestibular schwannoma (VS) may include observation, re-resection or irradiation. Identifying the optimal choice can be difficult due to the disease's variable progression rate. We aimed to define an immune signature and associated transcriptomic fingerprint characteristic of rapidly-progressing VS to elucidate the underpinnings of rapidly progressing VS and identify a prognostic model for determining rate of progression., Methods: We used multiplex immunofluorescence to characterize the immune microenvironment in 17 patients with sporadic VS treated with subtotal surgical resection alone. Transcriptomic analysis revealed differentially-expressed genes and dysregulated pathways when comparing rapidly-progressing VS to slowly or non-progressing VS., Results: Rapidly progressing VS was distinctly enriched in CD4 + , CD8 + , CD20 + , and CD68 + immune cells. RNA data indicated the upregulation of anti-viral innate immune response and T-cell senescence. K - Top Scoring Pair analysis identified 6 pairs of immunosenescence-related genes (CD38-KDR, CD22-STAT5A, APCS-CXCR6, MADCAM1-MPL, IL6-NFATC3, and CXCL2-TLR6) that had high sensitivity (100%) and specificity (78%) for identifying rapid VS progression., Conclusion: Rapid progression of residual vestibular schwannoma following subtotal surgical resection has an underlying immune etiology that may be virally originating; and despite an abundant adaptive immune response, T-cell immunosenescence may be associated with rapid progression of VS. These findings provide a rationale for clinical trials evaluating immunotherapy in patients with rapidly progressing VS., (© 2022. The Author(s).)

Neural circuits and the cells that comprise them represent the functional units of the brain. Circuits relay and process sensory information, maintain homeostasis, drive behaviors, and facilitate cognitive functions such as learning and memory. Creating a functionally-precise map of the mammalian brain requires anatomically tracing neural circuits, monitoring their activity patterns, and manipulating their activity to infer function. Advancements in cell-type-specific genetic tools allow interrogation of neural circuits with increased precision. This review provides a broad overview of recombination-based and activity-driven genetic targeting approaches, contemporary viral tracing strategies, electrophysiological recording methods, newly developed calcium, and voltage indicators, and neurotransmitter/neuropeptide biosensors currently being used to investigate circuit architecture and function. Finally, it discusses methods for acute or chronic manipulation of neural activity, including genetically-targeted cellular ablation, optogenetics, chemogenetics, and over-expression of ion channels. With this ever-evolving genetic toolbox, scientists are continuing to probe neural circuits with increasing resolution, elucidating the structure and function of the incredibly complex mammalian brain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Swanson, Chin, Romero, Srivastava, Ortiz-Guzman, Hunt and Arenkiel.)

The lateral septal nucleus (LSN) is a highly interconnected region of the central brain whose activity regulates widespread circuitry. As such, the mechanisms that govern neuronal activity within the LSN have far-reaching implications on numerous brain-wide nuclei, circuits, and behaviors. We found that GABAergic neurons within the LSN express markers that mediate the release of acetylcholine (ACh). Moreover, we show that these vGAT LSN neurons release both GABA and ACh onto local glutamatergic LSN neurons. Using both short-term and long-term neuronal labeling techniques we observed expression of the cholinergic neuron marker Choline Acetyltransferase (ChAT) in vGAT LSN neurons. These findings provide evidence of cholinergic neurotransmission from vGAT LSN neurons, and provide an impetus to examine dynamic co-neurotransmission changes as a potential mechanism that contributes to neuronal and circuit-wide plasticity within the LSN., (© 2022 The Authors.)

Background: The functional understanding of genetic interaction networks and cellular mechanisms governing health and disease requires the dissection, and multifaceted study, of discrete cell subtypes in developing and adult animal models. Recombinase-driven expression of transgenic effector alleles represents a significant and powerful approach to delineate cell populations for functional, molecular, and anatomical studies. In addition to single recombinase systems, the expression of two recombinases in distinct, but partially overlapping, populations allows for more defined target expression. Although the application of this method is becoming increasingly popular, its experimental implementation has been broadly restricted to manipulations of a limited set of common alleles that are often commercially produced at great expense, with costs and technical challenges associated with production of intersectional mouse lines hindering customized approaches to many researchers. Here, we present a simplified CRISPR toolkit for rapid, inexpensive, and facile intersectional allele production., Results: Briefly, we produced 7 intersectional mouse lines using a dual recombinase system, one mouse line with a single recombinase system, and three embryonic stem (ES) cell lines that are designed to study the way functional, molecular, and anatomical features relate to each other in building circuits that underlie physiology and behavior. As a proof-of-principle, we applied three of these lines to different neuronal populations for anatomical mapping and functional in vivo investigation of respiratory control. We also generated a mouse line with a single recombinase-responsive allele that controls the expression of the calcium sensor Twitch-2B. This mouse line was applied globally to study the effects of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) on calcium release in the ovarian follicle., Conclusions: The lines presented here are representative examples of outcomes possible with the successful application of our genetic toolkit for the facile development of diverse, modifiable animal models. This toolkit will allow labs to create single or dual recombinase effector lines easily for any cell population or subpopulation of interest when paired with the appropriate Cre and FLP recombinase mouse lines or viral vectors. We have made our tools and derivative intersectional mouse and ES cell lines openly available for non-commercial use through publicly curated repositories for plasmid DNA, ES cells, and transgenic mouse lines., (© 2022. The Author(s).)

Olfactory impairment is a common clinical motif across neurodevelopmental disorders, suggesting olfactory circuits are particularly vulnerable to disease processes and can provide insight into underlying disease mechanisms. The mouse olfactory bulb is an ideal model system to study mechanisms of neurodevelopmental disease due to its anatomical accessibility, behavioral relevance, ease of measuring circuit input and output, and the feature of adult neurogenesis. Despite the clinical relevance and experimental benefits, olfactory testing across animal models of neurodevelopmental disease has been inconsistent and non-standardized. Here we performed a systematic literature review of olfactory function testing in mouse models of neurodevelopmental disorders, and identified intriguing inconsistencies that include evidence for both increased and decreased acuity in odor detection in various mouse models of Autism Spectrum Disorder (ASD). Based on our identified gaps in the literature, we recommend direct comparison of different mouse models of ASD using standardized tests for odor detection and discrimination. This review provides a framework to guide future olfactory function testing in mouse models of neurodevelopmental diseases., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Brain activity, the electrochemical signals passed between neurons, is determined by the connectivity patterns of neuronal networks, and from the morphology of processes and substructures within these neurons. As such, much of what is known about brain function has arisen alongside developments in imaging technologies that allow further insight into how neurons are organized and connected in the brain. Improvements in tissue clearing have allowed for high-resolution imaging of thick brain slices, facilitating morphological reconstruction and analyses of neuronal substructures, such as dendritic arbors and spines. In tandem, advances in image processing software provide methods of quickly analyzing large imaging datasets. This work presents a relatively rapid method of processing, visualizing, and analyzing thick slices of labeled neural tissue at high-resolution using CLARITY tissue clearing, confocal microscopy, and image analysis. This protocol will facilitate efforts toward understanding the connectivity patterns and neuronal morphologies that characterize healthy brains, and the changes in these characteristics that arise in diseased brain states.

Cancer neurobiology is an emerging discipline that inevitably unfurls new perspectives in oncology. The role that nerves play in cancer progression resonates with the long-reported dependency of tumors on neuro-molecular mechanisms that remain insufficiently elucidated. Whereas interactions between neurotrophic growth factors and receptors have been heavily studied in the nervous system, their expression in cancers and their impact on tumor cell growth and metastasis through their corresponding signaling pathways has been undervalued. Accumulating evidence suggests that trophic factors released by nerves strongly influence tumor development and that this neural contribution appears to not only play a stimulatory role but also function as an essential part of the tumor's microenvironment. This bidirectional communication between proliferating cells and tumor-infiltrating nerves drives axonogenesis and tumor growth and migration. Acquiring a better understanding of the trophic interactions between primary afferent neurons and invading tumors will guide clinically actionable strategies to prevent tumor-associated axonogenesis, disrupting the chemical crosstalk between neurons and tumors and ultimately decreasing tumor growth and spread., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Neurons in the tumor microenvironment release neurotransmitters, neuroligins, chemokines, soluble growth factors, and membrane-bound growth factors that solid tumors leverage to drive their own survival and spread. Tumors express nerve-specific growth factors and microRNAs that support local neurons and guide neuronal growth into tumors. The development of feed-forward relationships between tumors and neurons allows tumors to use the perineural space as a sanctuary from therapy. Tumor denervation slows tumor growth in animal models, demonstrating the innervation dependence of growing tumors. Further in vitro and in vivo experiments have identified many of the secreted signaling molecules (e.g., acetylcholine, nerve growth factor) that are passed between neurons and cancer cells, as well as the major signaling pathways (e.g., MAPK/EGFR) involved in these trophic interactions. The molecules involved in these signaling pathways serve as potential biomarkers of disease. Additionally, new treatment strategies focus on using small molecules, receptor agonists, nerve-specific toxins, and surgical interventions to target tumors, neurons, and immune cells of the tumor microenvironment, thereby severing the interactions between tumors and surrounding neurons. This article discusses the mechanisms underlying the trophic relationships formed between neurons and tumors and explores the emerging therapies stemming from this work.

Objective: Infratemporal fossa (ITF) tumors are unique in histological characteristics and difficult to treat. Predictors of patient outcomes in this context are not known. The objective of this study was to identify independent predictors of outcome and to characterize patterns of failure in patients with ITF carcinoma., Methods: All patients who had been surgically treated for anterolateral skull base malignancy between 1999 and 2017 at the authors' institution were retrospectively reviewed. Patient demographics, preoperative performance status, tumor stage, tumor characteristics, treatment modalities, and pathological data were collected. Primary outcomes were disease-specific survival (DSS) and local progression-free survival (LPFS) rates. Overall survival (OS) and patterns of progression were secondary outcomes., Results: Forty ITF malignancies with skull base involvement were classified as carcinoma. Negative margins were achieved in 23 patients (58%). Median DSS and LPFS were 32 and 12 months, respectively. Five-year DSS and OS rates were 55% and 36%, respectively. The 5-year LPFS rate was 69%. The 5-year overall PFS rate was 53%. Disease recurrence was noted in 28% of patients. Age, preoperative performance status, and margin status were statistically significant prognostic factors for DSS. Lower preoperative performance status and positive surgical margins increased the probability of local recurrence., Conclusions: The ability to achieve negative margins was significantly associated with improved tumor control rates and DSS. Cranial base surgical approaches must be considered in multimodal treatment regimens for anterolateral skull base carcinomas.

Context: Ultrasound (US) risk-stratification systems for investigation of thyroid nodules may not be as useful as anticipated., Objective: We aimed to assess the performance and costs of the American College of Radiology Thyroid Image Reporting And Data System (ACR-TIRADS)., Design Settings and Participants: We examined the data set upon which ACR-TIRADS was developed, and applied TR1 or TR2 as a rule-out test, TR5 as a rule-in test, or applied ACR-TIRADS across all nodule categories. We assessed a hypothetical clinical comparator where 1 in 10 nodules are randomly selected for fine needle aspiration (FNA), assuming a pretest probability of clinically important thyroid cancer of 5%., Results: The gender bias (92% female) and cancer prevalence (10%) of the data set suggests it may not accurately reflect the intended test population. Applying ACR-TIRADS across all nodule categories did not perform well, with sensitivity and specificity between 60% and 80% and overall accuracy worse than random selection (65% vs 85%). Test performance in the TR3 and TR4 categories had an accuracy of less than 60%. Using TR5 as a rule-in test was similar to random selection (specificity 89% vs 90%). Using TR1 and TR2 as a rule-out test had excellent sensitivity (97%), but for every additional person that ACR-TIRADS correctly reassures, this requires >100 ultrasound scans, resulting in 6 unnecessary operations and significant financial cost., Conclusions: Perhaps surprisingly, the performance ACR-TIRADS may often be no better than random selection. The management guidelines may be difficult to justify from a cost/benefit perspective. A prospective validation study that determines the true performance of TIRADS in the real-world is needed., (© Endocrine Society 2020.)

Background: The international guidelines for management of adrenal incidentalomas (AI) are becoming more conservative. These changes are based on the growing body of evidence suggesting that non-functioning adenomas have a low likelihood of becoming functional or malignant over time., Aims: To follow up at least 100 patients for 3 years who were originally found to have benign adrenal adenomas which were non-functional or had subclinical Cushing syndrome (SCS)., Methods: This study prospectively evaluated consecutive patients aged 18 years or older with benign adrenal incidentalomas (AI), not treated with adrenalectomy, which were non-functioning or had SCS. The initial and follow-up evaluation, including clinical assessment, hormonal investigations and imaging were coordinated via a standardised nurse-led AI clinic., Results: Of 233 patients referred to the AI clinic, 101 patients met the inclusion criteria and completed 3-year follow up. Most of those excluded were due to incomplete initial or follow-up evaluation or were not true AI. Most AI either remained stable or decreased in size on repeat imaging, while 5% of patients had AI enlargement of >5 mm diameter. No patient developed features suggesting adrenal carcinoma. Ninety-two patients had an initial diagnosis of non-functioning adenoma and nine patients had SCS. After 3 years (range 2.9-4.7 years), five of the nine patients with SCS showed normalisation of cortisol parameters (44%), and five of the 92 non-functional AI patients developed SCS (5%)., Conclusion: After 3 years of follow up, approximately half of patients with SCS normalised, while 5% of patients with initially non-functioning adenomas developed biochemical evidence of SCS. This study found a low likelihood of progressive hormonal excess with no evidence of malignancy developing on follow-up evaluation, providing support for the shift towards the more conservative approach to management of AI recommended in recent guidelines., (© 2019 Royal Australasian College of Physicians.)

An essential characteristic of nervous systems is their capacity to reshape functional connectivity in response to physiological and environmental cues. Endogenous signals, including neuropeptides, governs nervous system plasticity. Particularly, oxytocin has been recognized for its role in mediating activity-dependent circuit changes. These oxytocin-dependent changes occur at the synaptic level and consequently shape the cellular composition of circuits. Here we discuss recent advances that illustrate how oxytocin functions to reshape neural circuitry in response to environmental changes. Excitingly, recent findings pave the way for promising therapeutic applications of oxytocin to treat neurodevelopmental and neuropsychiatric diseases., (Copyright © 2020 Pekarek, Hunt and Arenkiel.)

Solid tumors are complex collections of cells surrounded by benign tissues that influence and are influenced by the tumor. These surrounding cells include vasculature, immune cells, neurons, and other cell types, and are collectively known as the tumor microenvironment. Tumors manipulate their microenvironment for the benefit of the tumor. Autonomic neurons innervate and drive malignant growth in a variety of solid tumors. However, the mechanisms underlying neuron-tumor relationships are not well understood. Recently, Amit et al. described that trophic relationships between oral cavity squamous cell carcinomas (OCSCCs) and nearby autonomic neurons arise through direct signaling between tumors and local neurons. An inducible tumor model in which 4NQO was introduced into the drinking water of Trp53 knockout mice was used to model OCSCC-microenvironment interactions. Using this model, this group discovered that loss of p53 expression in OCSCC tumors resulted in increased nerve density within these tumors. This neuritogenesis was controlled by tumor-derived microRNA-laden extracellular vesicles (EVs). Specifically, EV-delivered miR-34a inhibited neuritogenesis, whereas EV-delivered miR-21 and miR-324 increased neuritogenesis. The neurons innervating p53-deficient OCSCC tumors were predominantly adrenergic and arose through the transdifferentiation of trigeminal sensory nerve fibers to adrenergic nerve fibers. This transdifferentiation corresponded with increased expression of neuron-reprogramming transcription factors, including POU5F1, KLF4, and ASCL1, which were overexpressed in the p53-deficient samples, and are proposed targets of miR-34a-mediated regulation. Human OCSCC samples enriched in adrenergic neuron markers are associated strongly with poor outcomes, thus demonstrating the relevance of these findings to cancer patients., Competing Interests: Conflicts of interest The authors declare no conflict of interest.

Introduction : Deep brain stimulation (DBS) has emerged as an effective treatment for patients with severe treatment-refractory obsessive-compulsive disorder (OCD). Over the past two decades, several clinical trials with multiple years of follow-up have shown that DBS offers long-term symptom relief for individuals with severe OCD, though a portion of patients do not achieve an adequate response. Areas covered : This review sought to summarize the literature on the efficacy and long-term effectiveness of DBS for OCD, and to identify strategies that have the potential to improve treatment outcomes. Expert opinion : Although this literature is just emerging, a small number of DBS enhancement strategies have shown promising initial results. More posterior targets along the striatal axis and at the bed nucleus of the stria terminalis appear to offer greater symptom relief than more anterior targets. Research is also beginning to demonstrate the feasibility of maximizing treatment outcomes with target selection based on neural activation patterns during symptom provocation and clinical presentation. Finally, integrating DBS with post-surgery exposure and response prevention therapy appears to be another promising approach. Definitive conclusions about these strategies are limited by a low number of studies with small sample sizes that will require multi-site replication.

Inhibitory interneurons are integral to sensory processing, yet revealing their cell type-specific roles in sensory circuits remains an ongoing focus. To Investigate the mouse olfactory system, we selectively remove GABAergic transmission from a subset of olfactory bulb interneurons, EPL interneurons (EPL-INs), and assay odor responses from their downstream synaptic partners - tufted cells and mitral cells. Using a combination of in vivo electrophysiological and imaging analyses, we find that inactivating this single node of inhibition leads to differential effects in magnitude, reliability, tuning width, and temporal dynamics between the two principal neurons. Furthermore, tufted and not mitral cell responses to odor mixtures become more linearly predictable without EPL-IN inhibition. Our data suggest that olfactory bulb interneurons, through exerting distinct inhibitory functions onto their different synaptic partners, play a significant role in the processing of odor information.

Cellular heterogeneity within the mammalian brain poses a challenge toward understanding its complex functions. Within the olfactory bulb, odor information is processed by subtypes of inhibitory interneurons whose heterogeneity and functionality are influenced by ongoing adult neurogenesis. To investigate this cellular heterogeneity and better understand adult-born neuron development, we utilized single-cell RNA sequencing and computational modeling to reveal diverse and transcriptionally distinct neuronal and nonneuronal cell types. We also analyzed molecular changes during adult-born interneuron maturation and uncovered developmental programs within their gene expression profiles. Finally, we identified that distinct neuronal subtypes are differentially affected by sensory experience. Together, these data provide a transcriptome-based foundation for investigating subtype-specific neuronal function in the olfactory bulb (OB), charting the molecular profiles that arise during the maturation and integration of adult-born neurons and how they dynamically change in an activity-dependent manner., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Management of adrenal incidentalomas (AI) is becoming more conservative, based on international data showing a low incidence of functional or malignant lesions. The clinical characteristics of AI in New Zealand are unknown. Therefore, whether the AI guidelines apply to the New Zealand population is also unknown., Aims: To investigate the clinical characteristics of patients with AI presenting to a tertiary-care centre in New Zealand., Method: This study prospectively evaluated consecutive patients aged 18 or older with AI, 1 cm or larger, diagnosed in Canterbury, New Zealand. A standardised nurse-led dedicated AI clinic was used, including clinical assessment, hormonal evaluation and imaging., Results: From January 2010 to April 2016, 306 patients were referred to the AI clinic, 228 met the inclusion criteria. Most of those excluded were not true AI, due to imaging performed for known or suspected non-adrenal malignancy. The most common reason for imaging was abdominal pain (46%). Most cases were benign (96.5%) and 88.6% of all cases were non-functional. Of the functioning tumours (26 patients), 18 had subclinical Cushing syndrome, four had late-onset congenital adrenal hyperplasia, two had phaeochromocytoma and one had primary hyperaldosteronism. Three patients had primary adrenal cancer, one of whom was secreting excess cortisol. One adrenal metastasis was diagnosed., Conclusion: This study found a similar prevalence of functional and malignant AI as international centres, although mild cortisol excess and primary aldosteronism may be under-represented. Therefore, the conservative approach to management of AI recommended in current guidelines is likely to be applicable to New Zealand population., (© 2017 Royal Australasian College of Physicians.)

Addison's disease may be complicated by hypertension and less commonly by heart failure. We review the pathophysiology of the renin-angiotensin-aldosterone axis in Addison's disease and how this is altered in the setting of hypertension and heart failure. An essential first step in management in both conditions is optimizing glucocorticoid replacement and considering dose reduction if excessive. Following this, if a patient with Addison's disease remains hypertensive, the fludrocortisone dose should be reviewed and reduced if there are clinical and/or biochemical signs of mineralocorticoid excess. In the absence of such signs, where the renin is towards the upper end of the normal range or elevated, an angiotensin II (AII) receptor antagonist or angiotensin converting enzyme (ACE) inhibitor is the treatment of choice, and the fludrocortisone dose should remain unchanged. Dihydropyridine calcium channel blockers are clinically useful as second line agents, but diuretics should be avoided. In the setting of heart failure, there is an increase in total body sodium and water; therefore, it is appropriate to reduce and rarely consider ceasing the fludrocortisone. Loop diuretics may be used, but not aldosterone antagonists such as spironolactone or eplerenone. Standard treatment with ACE inhibitors, or as an alternative, AII receptor antagonists, are appropriate. Measurements of renin are no longer helpful in heart failure to determine the volume status but plasma levels of brain natriuretic peptide (BNP/proBNP) may help guide therapy., (© 2014 John Wiley & Sons Ltd.)

Context: Viral/bacterial infection is proposed as a trigger for the autoimmune thyroid diseases (AITD): Graves' disease (GD) and Hashimoto's thyroiditis (HT). Previous studies in European Caucasian AITD subjects found higher birth rates in the autumn/winter, suggesting those born in the autumn/winter experience increased viral/bacterial exposure after birth, impacting upon immune system development and predisposing to AITD later in life., Objective: Month of birth effects were investigated in three independent European Caucasian AITD datasets., Design: Variation in GD and HT onset was compared across months and seasons, with fluctuations across all 12 months analyzed using a Walter-Elwood test., Setting: The study was conducted at a research laboratory., Patients: National UK Caucasian AITD Case Control Collection (2746 GD and 502 HT compared with 1 423 716 UK births), National UK Caucasian GD Family Collection (239 GD and 227 unaffected siblings), and OXAGEN AITD Caucasian Family Collection (885 GD, 717 HT, and 794 unaffected siblings of European Caucasian decent)., Main Outcome Measures: Case-control and family-based association studies were measured., Results: No consistent month of birth effects were detected in GD females or males across all three collections. In HT females from the OXAGEN AITD Caucasian Family Collection, slightly higher birth rates were detected in autumn (Walter's test statistic = 7.47, P = .024) however, this was not seen in the HT females from the case-control cohort., Conclusion: Our results suggest in UK/Northern European Caucasian GD subjects, month of birth does not impact on AITD development. Although some month of birth effects for HT females in one collection cannot be excluded, only further work in larger European Caucasian AITD collections can confirm these effects.

Background: Endovenous radiofrequency ablation (RFA) is a safe and effective treatment for varicose veins caused by saphenous reflux. Deep venous thrombosis (DVT) is a known complication of this procedure. The purpose of this study is to describe the frequency of DVT after RFA and the associated predisposing factors., Methods: A retrospective analysis was performed using prospectively collected data from December 2008 to December 2011; a total of 277 consecutive office-based RFA procedures were performed at a single institution using the VNUS ClosureFast catheter (VNUS Medical Technologies, San Jose, CA). Duplex ultrasonography scans were completed 2 weeks postprocedure in all patients. Risk factors assessed for the development of DVT included: great versus small saphenous vein (SSV) treated, right versus left side treated, number of radiofrequency cycles used, hypercoagulable state, history of DVT, tobacco use, medications (i.e., oral contraceptives, aspirin, warfarin, and clopidogrel), and vein diameter at the junction of the superficial and deep systems., Results: Seventy-two percent of the patients were women, 56% were treated on the right side, and 86% were performed on the great saphenous vein (GSV). The mean age was 54 ± 14 years (range: 23-88 years). Three percent of patients had a preprocedure diagnosis of hypercoagulable state, and 8% had a history of previous DVT. On postprocedural ultrasound, thrombus protrusion into the deep system without occlusion (endovenous heat-induced thrombosis) was present in 11 patients (4%). DVT, as defined by thrombus protrusion with complete occlusion of the femoral or popliteal vein, was identified in 2 patients (0.7%). Previous DVT was the only factor associated with postprocedural DVT (P = 0.018). Although not statistically significant, there was a trend toward a higher risk of DVT in SSV-treated patients. Factors associated with endovascular heat-induced thrombosis alone were male sex (P = 0.02), SSV treatment (P = 0.05), aspirin use (P = 0.008), and factor V Leiden deficiency (P = 0.01)., Conclusions: The use of RFA to treat patients with symptoms caused by saphenous reflux involves a small but definite risk of DVT. This study shows that the risk of post-RFA DVT is greater in patients with previous DVT, with a trend toward an increased risk in patients having treatment of the SSV. Periprocedural anticoagulation may be considered in this subset to reduce the risk of DVT after RFA. Thrombus protrusion without DVT was found to be more likely in patients with hypercoagulability, male sex, SSV treatment, and aspirin use. Additional prospective studies are required to analyze these and other factors that may predict thrombotic events after endovenous RFA., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Genetic incompatibilities are commonly observed between hybridizing species. Although this type of isolating mechanism has received considerable attention, we have few examples describing how genetic incompatibilities evolve. We investigated the evolution of two loci involved in a classic example of a Bateson-Dobzhansky-Muller (BDM) incompatibility in Xiphophorus, a genus of freshwater fishes from northern Central America. Hybrids develop a lethal melanoma due to the interaction of two loci, an oncogene and its repressor. We cloned and sequenced the putative repressor locus in 25 Xiphophorus species and an outgroup species, and determined the status of the oncogene in those species from the literature. Using phylogenetic analyses, we find evidence that a repeat region in the proximal promoter of the repressor is coevolving with the oncogene. The data support a hypothesis that departs from the standard BDM model: it appears the alleles that cause the incompatibilities have coevolved simultaneously within lineages, rather than in allopatric or temporal isolation.

A 29-year-old female with a history of relapsing polychondritis (RP) and open repair of a proximal descending thoracic aneurysm presented with 2 areas of asymptomatic thoracic aortic aneurysmal dilatation. The patient returned 3 months later with symptomatic aneurysm expansion, and she underwent ascending aortic arch replacement. She subsequently underwent staged endovascular repair of the distal descending thoracic aorta. RP is a rare disorder with an incidence of 3.5 per million persons annually, 4% to 7% of whom develop aneurysmal disease. Because of the aneurysmal potential of this disease, it is important for vascular surgeons to be aware of its presentation and treatment. To our knowledge, this is the first reported case describing endovascular technique to treat such a patient.

Context: Plasma C-type natriuretic peptide (CNP) forms correlate with linear growth velocity in juveniles. In hyperthyroid children, plasma CNP products fall in parallel with height velocity and thyroid hormones (TH) as euthyroidism is restored. The effect of TH on CNP forms after completion of endochondral growth is unknown., Objective: To determine the effect of restoring euthyroidism on plasma CNP forms and bone turnover markers (BTMs) in hyperthyroid adults., Design and Setting: We performed a prospective observational study in 20 adults (19 women) with acquired hyperthyroidism before and during carbimazole treatment. INTERVENTION AND MAIN OUTCOMES: Blood levels of CNP, amino-terminal propeptide of CNP (NTproCNP), TH and BTMs - bone-specific alkaline phosphatase, osteocalcin, procollagen type 1 amino-terminal propeptide and type 1 collagen C-telopeptide (CTx) - were measured before and during the first 6 months of carbimazole treatment and correlations determined., Results: Both CNP and NTproCNP were significantly correlated with TH at baseline. As in children, decreases in CNP forms were closely associated with fall in TH. Significant associations were found between CNP forms and CTx., Conclusions: CNP production from tissues other than endochondral cartilage is responsive to TH. Strong temporal links with markers of bone resorption suggest that CNP may also participate in bone remodelling in the adult skeleton., (© 2012 Blackwell Publishing Ltd.)

Objective: Untreated Cushing's syndrome (CS) is associated with significant morbidity and mortality. However, recent operative series suggest low morbidity and mortality for CS, whereas population-based surveys report elevated mortality rates. We investigated the mortality and morbidity of CS in New Zealand., Design: A nationwide retrospective survey of patients with CS between 1960 and 2005 managed at the four main endocrinology services., Patients: A total of 253 patients with CS were identified, excluding adrenal carcinoma and malignant ectopic CS. MEASUREMENTS; The primary outcome was the standardized mortality ratio (SMR), comparing the observed number of deaths with the expected number for the population matched for age, sex and duration of follow-up. Secondary outcomes were the change in prevalence of co-morbidities at presentation and at final follow-up., Results: The approximate prevalence and incidence of CS was 79/million and 1·8/million/y. The mean age at presentation was 39 year, and median duration of follow-up was 6·4 year (range 0-46). Overall, 89% achieved biochemical cure at last follow-up, with >90% achieving biochemical cure for CS from adrenal adenoma and pituitary causes. Thirty-six patients died during follow-up compared with 8·8 expected deaths (SMR 4·1, 95%CI 2·9-5·6). While hypertension, sexual dysfunction, myopathy and mild psychiatric illness were significantly reduced after treatment, hypertension, diabetes mellitus, moderate or major psychiatric illness, and osteoporosis were common at final follow-up., Conclusion: CS is associated with both high mortality and a high prevalence of co-morbidities, even when biochemical cure rates are between 80% and 90%., (© 2011 Blackwell Publishing Ltd.)

Aim: To assess our experience in the management of juvenile thyrotoxicosis., Method: Retrospective review of thyroid clinic records of juvenile (<16 y) thyrotoxic (JT) patients treated at thyroid clinic between 1972 and 1999. Long-term (>8 y) treatment outcome was assessed., Results: During the 28-year period, 34 JT patients were diagnosed and treated--30 girls and 4 boys, median age 13 years (5.6-15.9 y). Thirty-two children had Graves' disease and two had toxic nodular goitre. All patients were initially treated with carbimazole, and no major adverse reactions occurred. One Graves' disease child later developed severe ophthalmopathy. During long-term follow-up, 12 of the 32 Graves' patients remain in remission after antithyroid drug treatment alone, but 4 of these 12 patients are currently receiving thyroxine replacement. Fifteen patients were surgically treated (median age 16 y), and six patients received radioiodine therapy (median age 18 y) including one patient with post-thyroidectomy relapse. The two patients with toxic nodular goitre were treated by thyroidectomy., Conclusion: Juvenile thyrotoxicosis is relatively rare and not always due to Graves' disease. More than a third of children with Graves' disease achieved long-term remission following antithyroid drug therapy, and remaining patients required definitive therapy.

Objective: To assess the performance of current clinical recommendations for the evaluation of an adrenal incidentaloma. DESIGN AND METHODS LITERATURE REVIEW: Electronic databases (Pubmed, Ovid and citation searches from key articles) from 1980 to 2008 were searched. Eligible studies were those deemed most applicable to the clinical scenario of a patient referred to an endocrinologist for assessment of an incidentally detected adrenal mass. Surgical series, histopathological series and oncological series were reviewed and most were excluded., Results: The prevalence of functional and malignant lesions presenting as adrenal incidentaloma was similar to that quoted in most reviews, other than a lower incidence of adrenal carcinoma (1.9 vs 4.7%) and metastases (0.7 vs 2.3%). The development of functionality or malignancy during follow-up was rare (<1% becoming functional and 0.2% becoming malignant). During follow-up, false-positive rates of the recommended investigations are typically 50 times greater than true positive rates. The average recommended computed tomography (CT) scan follow-up exposes each patient to 23 mSv of ionising radiation, equating to a 1 in 430 to 2170 chance of causing fatal cancer. This is similar to the chance of developing adrenal malignancy during 3-year follow-up of adrenal incidentaloma., Conclusion: Current recommendations for evaluation of adrenal incidentaloma are likely to result in significant costs, both financial and emotional, due to high false-positive rates. The dose of radiation involved in currently recommended CT scan follow-up confers a risk of fatal cancer that is similar to the risk of the adrenal becoming malignant. This argues for a review of current guidelines.

Context: Parenteral iron administration has been associated with hypophosphatemia. Fibroblast growth factor 23 (FGF23) has a physiological role in phosphate homeostasis via suppression of 25-hydroxyvitamin D [25(OH)D] activation and promotion of phosphaturia. We recently reported a case of iron-induced hypophosphatemic osteomalacia associated with marked FGF23 elevation., Objective: Our objective was to prospectively investigate the effect of parenteral iron polymaltose on phosphate homeostasis and to determine whether any observed change was related to alterations in circulating FGF23., Design, Setting, and Participants: Eight medical outpatients prescribed iv iron polymaltose were recruited. Plasma phosphate, 25(OH)D, 1,25-dihydroxyvitamin D [1,25(OH)(2)D], PTH, FGF23, and urinary tubular reabsorption of phosphate were measured prior to iron administration and then weekly for a minimum of 3 wk., Results: Plasma phosphate fell from 3.4 +/- 0.6 mg/dl at baseline to 1.8 +/- 0.6 mg/dl at wk 1 (P < 0.0001) associated with a fall in percentage tubular reabsorption of phosphate (90 +/- 4.8 to 68 +/- 13; P < 0.001) and 1,25(OH)(2)D (54 +/- 25 to 9 +/- 8 pg/ml; P < 0.001). These indices remained significantly suppressed at wk 2 and 3. 25(OH)D levels were unchanged. FGF23 increased significantly from 43.5 pg/ml at baseline to 177 pg/ml at wk 1 (P < 0.001) with levels correlating with both serum phosphate (R = -0.74; P <0.05) and 1,25(OH)(2)D (R = -0.71; P < 0.05)., Conclusion: Parenteral iron suppresses renal tubular phosphate reabsorption and 1alpha-hydroxylation of vitamin D resulting in hypophosphatemia. Our data suggest that this is mediated by an increase in FGF23.

Unlabelled: Context Patients with primary adrenal insufficiency (Addison's disease) receive more glucococorticoids than the normal endogenous production, raising concern about adverse effects on bone., Objective: To determine i) the effects of glucocorticoid replacement therapy on bone, and ii) the impact of glucocorticoid pharmacogenetics., Design, Setting and Participants: A cross-sectional study of two large Addison's cohorts from Norway (n=187) and from UK and New Zealand (n=105)., Main Outcome Measures: Bone mineral density (BMD) was measured; the Z-scores represent comparison with a reference population. Blood samples from 187 Norwegian patients were analysed for bone markers and common polymorphisms in genes that have been associated with glucocorticoid sensitivity., Results: Femoral neck BMD Z-scores were significantly reduced in the patients (Norway: mean -0.28 (95% confidence intervals (CI) -0.42, -0.16); UK and New Zealand: -0.21 (95% CI -0.36, -0.06)). Lumbar spine Z-scores were reduced (Norway: -0.17 (-0.36, +0.01); UK and New Zealand: -0.57 (-0.78, -0.37)), and significantly lower in males compared with females (P=0.02). The common P-glycoprotein (ABCB1) polymorphism C3435T was significantly associated with total BMD (CC and CT>TT P=0.015), with a similar trend at the hip and spine., Conclusions: BMD at the femoral neck and lumbar spine is reduced in Addison's disease, indicating undesirable effects of the replacement therapy. The findings lend support to the recommendations that 15-25 mg hydrocortisone daily is more appropriate than the higher conventional doses. A common polymorphism in the efflux transporter P-glycoprotein is associated with reduced bone mass and might confer susceptibility to glucocorticoid induced osteoporosis.

Graves' disease (GD) is a common autoimmune disease (AID) that shares many of its susceptibility loci with other AIDs. The thyroid stimulating hormone receptor (TSHR) represents the primary autoantigen in GD, in which autoantibodies bind to the receptor and mimic its ligand, thyroid stimulating hormone, causing the characteristic clinical phenotype. Although early studies investigating the TSHR and GD proved inconclusive, more recently we provided convincing evidence for association of the TSHR region with disease. In the current study, we investigated a combined panel of 98 SNPs, including 70 tag SNPs, across an extended 800 kb region of the TSHR to refine association in a cohort of 768 GD subjects and 768 matched controls. In total, 28 SNPs revealed association with GD (P < 0.05), with strongest SNP associations at rs179247 (chi(2) = 32.45, P = 8.90 x 10(-8), OR = 1.53, 95% CI = 1.32-1.78) and rs12101255 (chi(2) = 30.91, P = 1.95 x 10(-7), OR = 1.55, 95% CI = 1.33-1.81), both located in intron 1 of the TSHR. Association of the most associated SNP, rs179247, was replicated in 303 GD families (P = 7.8 x 10(-4)). In addition, we provide preliminary evidence that the disease-associated genotypes of rs179247 (AA) and rs12101255 (TT) show reduced mRNA expression ratios of flTSHR relative to two alternate TSHR mRNA splice variants.

Iron-induced renal phosphate wasting, hypophosphataemia and osteomalacia have previously been reported in a small number of Japanese patients receiving parenteral iron sucrose. We report the case history of a European male who, as a result of regular intravenous iron polymaltose, developed prolonged hypophosphataemia complicated by widespread insufficiency fractures. The pathogenesis of this complication remains unknown however our novel finding of a marked elevation in fibroblast growth factor 23 (FGF23), which normalized after ceasing parenteral iron, suggests an important and previously unreported effect of iron on FGF23 homeostasis.

Objective: Metabolic abnormalities in patients with bipolar disorder may be secondary to obesity, aspects of the disorder or its treatment. To investigate this further, the purpose the present study was to compare insulin resistance, components of the metabolic syndrome and adiponectin levels in a group of overweight bipolar patients taking sodium valproate and a group of non-psychiatric control subjects., Methods: Data were collected from 60 overweight bipolar patients who had experienced clinically significant weight gain thought to be related to sodium valproate treatment and from 60 control subjects without psychiatric illness matched for age, gender, body mass index and ethnicity., Results: The frequency of the metabolic syndrome was high in both groups (50% and 32%, respectively), although not significantly different between groups (p = 0.06). Similar frequencies of insulin resistance (HOMA-IR), abdominal obesity, hypertriglyceridaemia, hypertension and fasting hyperglycaemia were found in both groups. High-density lipoprotein cholesterol levels were lower in patients (p = 0.006), while adiponectin was unexpectedly higher than in control subjects (9.6+/-5.9 microg mL(-1) vs 7.4+/-4.3 microg mL(-1), p = 0.03). The frequencies of insulin resistance (HOMA-IR), the metabolic syndrome and its individual components were not significantly different in patients taking atypical antipsychotic medication and patients not on these medications., Conclusions: Frequencies of insulin resistance and the metabolic syndrome were similar in bipolar patients taking sodium valproate and matched control subjects, but dyslipidaemia was more frequent. Adiponectin levels were higher in patients. Further research is required to clarify the reasons for these findings.

Context: Dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) are the major circulating adrenal steroids and substrates for peripheral sex hormone biosynthesis. In Addison's disease, glucocorticoid and mineralocorticoid deficiencies require lifelong replacement, but the associated near-total failure of DHEA synthesis is not typically corrected., Objective and Design: In a double-blind trial, we randomized 106 subjects (44 males, 62 females) with Addison's disease to receive either 50 mg daily of micronized DHEA or placebo orally for 12 months to evaluate its longer-term effects on bone mineral density, body composition, and cognitive function together with well-being and fatigue., Results: Circulating DHEAS and androstenedione rose significantly in both sexes, with testosterone increasing to low normal levels only in females. DHEA reversed ongoing loss of bone mineral density at the femoral neck (P < 0.05) but not at other sites; DHEA enhanced total body (P = 0.02) and truncal (P = 0.017) lean mass significantly with no change in fat mass. At baseline, subscales of psychological well-being in questionnaires (Short Form-36, General Health Questionnaire-30), were significantly worse in Addison's patients vs. control populations (P < 0.001), and one subscale of SF-36 improved significantly (P = 0.004) after DHEA treatment. There was no significant benefit of DHEA treatment on fatigue or cognitive or sexual function. Supraphysiological DHEAS levels were achieved in some older females who experienced mild androgenic side effects., Conclusion: Although further long-term studies of DHEA therapy, with dosage adjustment, are desirable, our results support some beneficial effects of prolonged DHEA treatment in Addison's disease.