Paradoxical Temporal Enlargement: An Expansion of Superficial Temporal Fat Pad Following Interfacial Technique for Pterional Craniotomy.

OBJECTIVE: Contour irregularities in the temporal region have been reported previously after procedures involving temporal dissection. In this study, we report paradoxical temporal enlargement (PTE) following interfascial pterional craniotomy. METHODS: A retrospective review of patients who underwent a unilateral transcranial procedure with frontotemporal approach at our institution between September 2013 and December 2017 was performed. Patients with a previous craniotomy or bilateral craniotomy were excluded. Radiological imaging series including computed tomography and magnetic resonance imaging were utilized to calculate temporal soft tissue volumes both preoperatively and postoperatively by using advanced software technology. Relative soft tissue volume differences between the operative side and the contralateral side were calculated at different time-points including preoperative, 3-months follow-up (3M), 12-months (12M) follow-up, and the last follow-up (LFU, over 1-year). RESULTS: Forty-three patients were included. Mean age was 52.7 ± 4.5 years. Mean follow-up was 27.9 ± 15.8 months. Significant changes of temporal fat pad relative-volume difference were observed between the preoperative and the corresponding 3M (t [82] = -2.8865, P = 0.0050); 12M (t [77] = -4.4321, P < 0.0001), and LFU (t [74] = -4.9862, P < 0.0001) postoperative time points. No significant change of the temporalis muscle was observed between the preoperative and the corresponding 3M (P = 0.3629), 12M (P = 0.1553), or LFU (P = 0.0715). Soft tissue volume showed a significant increase on the operative side between the preoperative and the corresponding LFU (t [74] = -2.5866, P =  0.0117). CONCLUSIONS: Paradoxical temporal enlargement with more than 10% volumetric change was observed in 24% of the patients at their LFU (>1-year). This change was not due to temporalis muscle changes. Paradoxical temporal enlargement was due to hypertrophy of the superficial temporal fat pad. Before surgical correction of postoperative temporal contour changes, it is important to obtain imaging and characterize the etiology of the deformity.

An Assessment of Globe Position Dynamics following Transcranial Lateral and Superior Orbital Wall Resections without Rigid Reconstruction: A Case Series of 55 Patients.

Background There is no consensus exists regarding which reconstructive approach, if any, should be used after performing transcranial lateral orbital wall resections. Rigid reconstruction is often done to prevent enophthalmos; however, it is not clear if this is a risk with extensive orbital wall resections for transcranial surgery. Objective To assess globe position dynamics in patients that underwent transcranial lateral and superior orbital wall resections without rigid reconstruction to determine if enophthalmos is a significant risk. Methods Preoperative (PO) and postoperative data were retrospectively collected from the electronic medical records of 55 adult patients undergoing lateral and superior orbital wall resections as part of a skull base approach. The globe positions were assessed radiologically at all available time points and used to track relative globe displacements over time. Results An evaluation of PO variables identified a relationship between maximum lesion diameters and globe positions dynamics. The composition of globe position presentations in the population remained relatively stable over time, with only 1 out of 55 patients (1.81%) developing postoperative enophthalmos. An assessment of mean globe displacements revealed improvements in the patients presenting with PO exophthalmos, and stability in the patients presenting with normal PO globe positions. Conclusions Excellent results in long-term postoperative globe position dynamics can be achieved without the use of rigid reconstruction after transcranial lateral and superior orbital wall resections, regardless of the PO globe positioning.

Glucocorticoids Target Ependymal Glia and Inhibit Repair of the Injured Spinal Cord.

Following injury, the mammalian spinal cord forms a glial scar and fails to regenerate. In contrast, vertebrate fish spinal cord tissue regenerates significantly to restore function. Cord transection in zebrafish (Danio rerio) initially causes paralysis and neural cell death. Subsequently, ependymal glia proliferate, bipolar glia extend across the lesion, and new neurons are born; axons from spared and nascent neurons extend along trans-lesional glial bridges to restore functional connectivity. Here we report that glucocorticoids, used in the clinical management of spinal cord injury, directly inhibit neural repair by targeting ependymal glia independently of hematogenous cells and microglia. After transecting injury, the glucocorticoid receptor in ependymal glia is regulated differentially in zebrafish (becoming inactive) vs. the rat (becoming active). Glucocorticoid blockade of neural regeneration via a direct effect on ependymal glia has important therapeutic implications for the putative benefit of corticosteroids in early management of spinal cord injury.

Apoplectic Silent Crooke Cell Adenoma with Adjacent Pseudoaneurysms: Causation or Bystander?

BACKGROUND: Crooke cell adenomas (CCAs) are rare and potentially aggressive pituitary tumors that often invade the cavernous sinuses. Although clinical presentations of pituitary tumors may include the development of accompanying intracranial aneurysms, there are no documented cases of coexistent intracranial aneurysms and CCAs to date. Herein we describe an apoplectic silent CCA that presented with adjacent cavernous internal carotid artery (ICA) aneurysms. CASE DESCRIPTION: A 45-year old male patient presented for evaluation of headaches and diplopia. Subsequent imaging series revealed a hemorrhagic pituitary macroadenoma that had invaded the left cavernous sinus and circumferentially involved the ICA. Two pseudoaneurysms were visualized along regions of the ICA directly attached to the tumor. A transnasal transsphenoidal endoscopic approach was used for resection of the tumor, which was identified histologically as a CCA. Endocrine evaluations characterized the tumor as nonfunctional. The patient experienced an excellent recovery with resolution of related symptoms. A pseudoaneurysm was treated with a Pipeline embolization device; however, it persisted at last follow-up. CONCLUSIONS: CCAs are a poorly characterized and rare pituitary tumor type. In this case, an apoplectic silent CCA invaded the left cavernous sinus and presented with pseudoaneurysms along its involvement of the ICA. Accordingly, the authors speculated that the invasive qualities of this silent corticotroph adenoma may have directly contributed to the development of these aneurysms.

Novel zebrafish behavioral assay to identify modifiers of the rapid, nongenomic stress response.

When vertebrates face acute stressors, their bodies rapidly undergo a repertoire of physiological and behavioral adaptations, which is termed the stress response. Rapid changes in heart rate and blood glucose levels occur via the interaction of glucocorticoids and their cognate receptors following hypothalamic-pituitary-adrenal axis activation. These physiological changes are observed within minutes of encountering a stressor and the rapid time domain rules out genomic responses that require gene expression changes. Although behavioral changes corresponding to physiological changes are commonly observed, it is not clearly understood to what extent hypothalamic-pituitary-adrenal axis activation dictates adaptive behavior. We hypothesized that rapid locomotor response to acute stressors in zebrafish requires hypothalamic-pituitary-interrenal (HPI) axis activation. In teleost fish, interrenal cells are functionally homologous to the adrenocortical layer. We derived eight frameshift mutants in genes involved in HPI axis function: two mutants in exon 2 of mc2r (adrenocorticotropic hormone receptor), five in exon 2 or 5 of nr3c1 (glucocorticoid receptor [GR]) and two in exon 2 of nr3c2 (mineralocorticoid receptor [MR]). Exposing larval zebrafish to mild environmental stressors, acute changes in salinity or light illumination, results in a rapid locomotor response. We show that this locomotor response requires a functioning HPI axis via the action of mc2r and the canonical GR encoded by nr3c1 gene, but not MR (nr3c2). Our rapid behavioral assay paradigm based on HPI axis biology can be used to screen for genetic and environmental modifiers of the hypothalamic-pituitary-adrenal axis and to investigate the effects of corticosteroids and their cognate receptor interactions on behavior.

The endocannabinoid gene faah2a modulates stress-associated behavior in zebrafish.

The ability to orchestrate appropriate physiological and behavioral responses to stress is important for survival, and is often dysfunctional in neuropsychiatric disorders that account for leading causes of global disability burden. Numerous studies have shown that the endocannabinoid neurotransmitter system is able to regulate stress responses and could serve as a therapeutic target for the management of these disorders. We used quantitative reverse transcriptase-polymerase chain reactions to show that genes encoding enzymes that synthesize (abhd4, gde1, napepld), enzymes that degrade (faah, faah2a, faah2b), and receptors that bind (cnr1, cnr2, gpr55-like) endocannabinoids are expressed in zebrafish (Danio rerio). These genes are conserved in many other vertebrates, including humans, but fatty acid amide hydrolase 2 has been lost in mice and rats. We engineered transcription activator-like effector nucleases to create zebrafish with mutations in cnr1 and faah2a to test the role of these genes in modulating stress-associated behavior. We showed that disruption of cnr1 potentiated locomotor responses to hyperosmotic stress. The increased response to stress was consistent with rodent literature and served to validate the use of zebrafish in this field. Moreover, we showed for the first time that disruption of faah2a attenuated the locomotor responses to hyperosmotic stress. This later finding suggests that FAAH2 may be an important mediator of stress responses in non-rodent vertebrates. Accordingly, FAAH and FAAH2 modulators could provide distinct therapeutic options for stress-aggravated disorders.

Elucidating cannabinoid biology in zebrafish (Danio rerio).

The number of annual cannabinoid users exceeds 100,000,000 globally and an estimated 9% of these individuals will suffer from dependency. Although exogenous cannabinoids, like those contained in marijuana, are known to exert their effects by disrupting the endocannabinoid system, a dearth of knowledge exists about the potential toxicological consequences on public health. Conversely, the endocannabinoid system represents a promising therapeutic target for a plethora of disorders because it functions to endogenously regulate a vast repertoire of physiological functions. Accordingly, the rapidly expanding field of cannabinoid biology has sought to leverage model organisms in order to provide both toxicological and therapeutic insights about altered endocannabinoid signaling. The primary goal of this manuscript is to review the existing field of cannabinoid research in the genetically tractable zebrafish model-focusing on the cannabinoid receptor genes, cnr1 and cnr2, and the genes that produce enzymes for synthesis and degradation of the cognate ligands anandamide and 2-arachidonylglycerol. Consideration is also given to research that has studied the effects of exposure to exogenous phytocannabinoids and synthetic cannabinoids that are known to interact with cannabinoid receptors. These results are considered in the context of either endocannabinoid gene expression or endocannabinoid gene function, and are integrated with findings from rodent studies. This provides the framework for a discussion of how zebrafish may be leveraged in the future to provide novel toxicological and therapeutic insights in the field of cannabinoid biology, which has become increasingly significant given recent trends in cannabis legislation.

An automated climbing apparatus to measure chemotherapy-induced neurotoxicity in Drosophila melanogaster.

We have developed a novel model system in Drosophila melanogaster to study chemotherapy-induced neurotoxicity in adult flies. Neurological deficits were measured using a manual geotactic climbing assay. The manual assay is commonly used; however, it is laborious, time-consuming, subject to human error and limited to observing one sample at a time. We have designed and built a new automated fly-counting apparatus that uses a "video capture-particle counting technology" to automatically measure 10 samples at a time, with 20 flies per sample. Climbing behavior was assessed manually, as in our previous studies, and with the automated apparatus within the same experiment yielding statistically similar results. Both climbing endpoints as well as the climbing rate can be measured in the apparatus, giving the assay more versatility than the manual assay. Automation of our climbing assay reduces variability, increases productivity and enables high throughput drug screens for neurotoxicity.

In vivo genome editing using a high-efficiency TALEN system.

The zebrafish (Danio rerio) is increasingly being used to study basic vertebrate biology and human disease with a rich array of in vivo genetic and molecular tools. However, the inability to readily modify the genome in a targeted fashion has been a bottleneck in the field. Here we show that improvements in artificial transcription activator-like effector nucleases (TALENs) provide a powerful new approach for targeted zebrafish genome editing and functional genomic applications. Using the GoldyTALEN modified scaffold and zebrafish delivery system, we show that this enhanced TALEN toolkit has a high efficiency in inducing locus-specific DNA breaks in somatic and germline tissues. At some loci, this efficacy approaches 100%, including biallelic conversion in somatic tissues that mimics phenotypes seen using morpholino-based targeted gene knockdowns. With this updated TALEN system, we successfully used single-stranded DNA oligonucleotides to precisely modify sequences at predefined locations in the zebrafish genome through homology-directed repair, including the introduction of a custom-designed EcoRV site and a modified loxP (mloxP) sequence into somatic tissue in vivo. We further show successful germline transmission of both EcoRV and mloxP engineered chromosomes. This combined approach offers the potential to model genetic variation as well as to generate targeted conditional alleles.