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This article compares the presentation and outcomes of surgically treated acromegaly in New Zealand (NZ) and the United States (US) to evaluate the impact of health care access on tumor size and associated comorbidities. The study found that the average size of GH-secreting pituitary tumors at presentation did not significantly differ between the two health care systems. Additionally, there were no significant differences in age, gender distribution, or the occurrence of cardiovascular and metabolic comorbidities. However, the study acknowledges the limitations of a small sample size and suggests further research to compare the presentation of functioning and nonfunctioning tumors across different health care systems. [Extracted from the article]

This article, published in the Journal of Neurological Surgery, explores the use of a random forest algorithm to predict functional outcomes following microvascular decompression (MVD) for trigeminal neuralgia (TN). TN is a painful disorder caused by blood vessel compression, and MVD is considered the most effective treatment. The study reviewed 225 cases of TN and trained a random forest algorithm to predict postoperative pain outcomes. The algorithm demonstrated 88% accuracy in predicting average postoperative pain, with sleep and mood found to be important predictors. The study highlights the potential of machine learning in identifying meaningful associations for rare conditions like TN. [Extracted from the article]

This article explores the impact of patient demographics and socioeconomic status on surgical outcomes in endonasal endoscopic pituitary surgery. The study reviewed 187 patients who underwent this surgery between 2017 and 2019. The findings revealed that male patients were more likely to have larger tumors and higher comorbidity scores, while Hispanic patients had smaller tumors and lower comorbidity scores. Black patients experienced longer hospital stays, higher costs, and higher rates of readmission, regardless of income. These results suggest that racial health disparities are not solely due to socioeconomic status and emphasize the importance of considering social determinants of health in clinical practice. [Extracted from the article]

An increasing body of evidence points to mitochondrial dysfunction as a contributor to the molecular pathogenesis of neurodegenerative diseases such as Parkinson's disease (1). Recent studies of the Parkinson's disease associated genes PINK1 (ref. 2) and parkin (PARK, ref. 3) indicate that they may act in a quality control pathway preventing the accumulation of dysfunctional mitochondria (4-8). Here we elucidate regulators that have an impact on parkin translocation to damaged mitochondria with genome-wide small interfering RNA (siRNA) screens coupled to high-content microscopy. Screening yielded gene candidates involved in diverse cellular processes that were subsequently validated in low-throughput assays. This led to characterization of TOMM7 as essential for stabilizing PINK1 on the outer mitochondrial membrane following mitochondrial damage. We also discovered that HSPA1L (HSP70 family member) and BAG4 have mutually opposing roles in the regulation of parkin translocation. The screens revealed that SIAH3, found to localize to mitochondria, inhibits PINK1 accumulation after mitochondrial insult, reducing parkin translocation. Overall, our screens provide a rich resource to understand mitochondrial quality control., Following the loss of mitochondrial membrane potential, PINK1 and parkin coordinate a ubiquitination (9), proteasomal activation (10) and autophagic (mitophagy) (5) response that may attenuate cell death (11). As mitophagy [...]

α-Synuclein (α-Syn) accumulation is a pathological hallmark of Parkinson's disease. Duplications and triplications of SNCA, the gene coding for α-Syn, cause genetic forms of the disease, which suggests that increased α-Syn dosage can drive PD. To identify the proteins that regulate α-Syn, we previously performed a screen of potentially druggable genes that led to the identification of 60 modifiers. Among them, Doublecortin-like kinase 1 (DCLK1), a microtubule binding serine threonine kinase, emerged as a promising target due to its potent effect on α-Syn and potential druggability as a neuron-expressed kinase. In this study, we explore the relationship between DCLK1 and α-Syn in human cellular and mouse models of PD. First, we show that DCLK1 regulates α-Syn levels post-transcriptionally. Second, we demonstrate that knockdown of Dclk1 reduces phosphorylated species of α-Syn and α-Syn-induced neurotoxicity in the SNc in two distinct mouse models of synucleinopathy. Last, silencing DCLK1 in human neurons derived from individuals with SNCA triplications reduces phosphorylated and total α-Syn, thereby highlighting DCLK1 as a potential therapeutic target to reduce pathological α-Syn in disease. [ABSTRACT FROM AUTHOR]

Astrocytes are the most abundant cell type in the central nervous system (CNS) and have a multitude of functions that include maintenance of CNS homeostasis, trophic support of neurons, detoxification, and immune surveillance. It has only recently been appreciated that astrocyte dysfunction is a primary cause of many neurological disorders. Despite their importance in disease very little is known about global gene expression for human astrocytes. We have performed a microarray expression analysis of human fetal astrocytes to identify genes and signaling pathways that are important for astrocyte development and maintenance. Our analysis confirmed that the fetal astrocytes express high levels of the core astrocyte marker GFAP and the transcription factors from the NFI family which have been shown to play important roles in astrocyte development. A group of novel markers were identified that distinguish fetal astrocytes from pluripotent stem cell-derived neural stem cells (NSCs) and NSC-derived neurons. As in murine astrocytes, the Notch signaling pathway appears to be particularly important for cell fate decisions between the astrocyte and neuronal lineages in human astrocytes. These findings unveil the repertoire of genes expressed in human astrocytes and serve as a basis for further studies to better understand astrocyte biology, especially as it relates to disease. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a debilitating neurodegenerative disease characterized primarily by the selective death of dopaminergic (DA) neurons in the substantia nigra pars compacta of the midbrain. Although several genetic forms of PD have been identified, the precise molecular mechanisms underlying DA neuron loss in PD remain elusive. In recent years, microRNAs (miRNAs) have been recognized as potent post-transcriptional regulators of gene expression with fundamental roles in numerous biological processes. Although their role in PD pathogenesis is still a very active area of investigation, several seminal studies have contributed significantly to our understanding of the roles these small non-coding RNAs play in the disease process. Among these are studies which have demonstrated specific miRNAs that target and down-regulate the expression of PD-related genes as well as those demonstrating a reciprocal relationship in which PD-related genes act to regulate miRNA processing machinery. Concurrently, a wealth of knowledge has become available regarding the molecular mechanisms that unify the underlying etiology of genetic and sporadic PD pathogenesis, including dysregulated protein quality control by the ubiquitin-proteasome system and autophagy pathway, activation of programmed cell death, mitochondrial damage and aberrant DA neurodevelopment and maintenance. Following a discussion of the interactions between PD-related genes and miRNAs, this review highlights those studies which have elucidated the roles of these pathways in PD pathogenesis. We highlight the potential of miRNAs to serve a critical regulatory role in the implicated disease pathways, given their capacity to modulate the expression of entire families of related genes. Although few studies have directly linked miRNA regulation of these pathways to PD, a strong foundation for investigation has been laid and this area holds promise to reveal novel therapeutic targets for PD. [ABSTRACT FROM AUTHOR]

Objective: The goal of this study was to describe the clinical presentation associated with atypical schwannoma of the cerebellopontine angle, characterize the pathologic findings and describe the long-term outcome., Materials and Methods: The study design was retrospective case review of patients with the histopathologic diagnosis of atypical and benign schwannoma of the cerebellopontine angle diagnosed at the study institution over a 10-year period., Setting: Tertiary referral center., Main Outcomes Measure: Demographic data of the cohort were recorded. Findings on pathology were evaluated. Initial treatment and post-operative course was recorded. Main outcome measures were clinical presentation, including cranial nerve deficits at the time of presentation, complication and recurrence rates., Results: At presentation, a somewhat accelerated course of cranial nerve deficit was noted among patients with atypical schwannoma as compared to benign schwannoma. In the immediate post-operative period, there were no differences noted in the complication rate. Atypical schwannomas appear to have higher recurrence rate compared to benign schwannomas., Conclusions: Atypical schwannoma is an intermediate disease process with an accelerated clinical course and higher recurrence rate as compared to vestibular schwannoma. Traditional operative approaches may be employed without increased concern for post-operative complications. Thorough counseling and close follow-up should be offered to these patients given the higher recurrence rate. Larger studies are required to determine if these patients need more frequent MRIs for long-term surveillance., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Parkin, an E3 ubiquitin ligase, is a central mediator of mitochondrial quality control and is linked to familial forms of Parkinson's disease (PD). Removal of dysfunctional mitochondria from the cell by Parkin is thought to be neuroprotective, and pharmacologically increasing Parkin levels may be a novel therapeutic approach. We used genome-editing to integrate a coincidence reporter into the PARK2 gene locus of a neuroblastoma-derived cell line and developed a quantitative high-throughput screening (qHTS) assay capable of accurately detecting subtle compound-mediated increases in endogenous PARK2 expression. Interrogation of a chemogenomic library revealed diverse chemical classes that up-regulate the PARK2 transcript, including epigenetic agents, drugs controlling cholesterol biosynthesis, and JNK inhibitors. Use of the coincidence reporter eliminated wasted time pursuing reporter-biased false positives accounting for ∼2/3 of the actives and, coupled with titration-based screening, greatly improves the efficiency of compound selection. This approach represents a strategy to revitalize reporter-gene assays for drug discovery.

CD4 Th cells are critical to the development of coordinated immune responses to infections and tumors. Th cells are activated through interactions of the TCR with MHC class II complexed with peptide. T cell activation is dependent on the density of MHC peptide complexes as well as the duration of interaction of the TCR with APCs. In this study, we sought to determine whether MHC class II peptides could be modified with amino acid sequences that facilitated uptake and presentation with the goal of improving Th cell activation in vitro and in vivo. A model epitope derived from the murine folate receptor α, a self- and tumor Ag, was modified at its carboxyl terminus with the invariant chain-derived Ii-Key peptide and at its N terminus with a peptide that enhances uptake of Ag by APC. Modification of a peptide resulted in enhanced generation of high-avidity murine folate receptor α T cells that persisted in vivo and homed to sites of Ag deposition. The nesting approach was epitope and species independent and specifically excluded expansion of CD4 regulatory T cells. The resulting Th cells were therapeutic, enhanced in vivo helper activity and had an increased ability to resist tolerizing immune microenvironments. In addition to improved immunoadjuvants, this epitope modification strategy may be useful for enhancing ex vivo and in vivo generation of Th cells for preventing and treating diseases.