12 research outputs found
Internal auditory canal exostosis: A technical case report
Background: Exostoses of the internal auditory canal is a rare finding that may present with disabling symptoms of dizziness, hearing loss, and vestibular dysfunction based on the extent of cranial nerve compression. The purpose of this case report is to discuss the presentation and outcomes in a patient who presented with this disorder.
Case Description: A 19-year-old female presented to the neurotologist with left ear discomfort, pain with left lateral gaze, and dizziness. She underwent extensive evaluation including audiometric testing, videonystagmography, and neuroimaging, which confirmed left auditory and vestibular hypofunction and compression of the contents of the internal auditory canal from the exostosis. After extensive counseling, the patient elected to undergo a suboccipital craniectomy to remove the internal auditory canal exostosis. She experienced complete resolution of symptoms.
Conclusions: Exostoses of the internal auditory canal, although rare, can present with severe symptoms of dizziness, hearing loss, and vestibular hypofunction based on the extent of cranial nerve compression. Imaging, particularly with thin-cut computed tomography, is invaluable in making the correct diagnosis. Severe cases can be treated successfully with surgery with minimal or no complications and excellent outcome
Protein Phosphatase 2A Mediates Dormancy of Glioblastoma Multiforme-Derived Tumor Stem-Like Cells during Hypoxia
The hypoxic microenvironment of glioblastoma multiforme (GBM) is thought to increase resistance to cancer therapies. Recent evidence suggests that hypoxia induces protein phosphatase 2A (PP2A), a regulator of cell cycle and cell death. The effects of PP2A on GBM tumor cell proliferation and survival during hypoxic conditions have not been studied.Expression of PP2A subunits and HIF-α proteins was measured in 65 high-grade astrocytoma and 18 non-neoplastic surgical brain specimens by western blotting. PP2A activity was measured by an immunoprecipitation assay. For in vitro experiments, GBM-derived tumor stem cell-like cells (TSCs) were exposed to severe hypoxia produced by either CoCl₂ or 1% O₂. PP2A activity was inhibited either by okadaic acid or by shRNA depletion of the PP2A C subunit. Effects of PP2A activity on cell cycle progression and cell survival during hypoxic conditions were assessed using flow cytometry.In our patient cohort, PP2A activity was positively correlated with HIF-1∝ protein expression (P = 0.002). Patients with PP2A activity levels above 160 pMP had significantly worse survival compared to patients with levels below this threshold (P = 0.002). PP2A activity was an independent predictor of survival on multivariable analysis (P = 0.009). In our in vitro experiments, we confirmed that severe hypoxia induces PP2A activity in TSCs 6 hours after onset of exposure. PP2A activity mediated G1/S phase growth inhibition and reduced cellular ATP consumption in hypoxic TSCs. Conversely, inhibition of PP2A activity led to increased cell proliferation, exhaustion of intracellular ATP, and accelerated P53-independent cell death of hypoxic TSCs.Our results suggest that PP2A activity predicts poor survival in GBM. PP2A appears to reduce the metabolic demand of hypoxic TSCs and enhances tumor cell survival. Modulation of PP2A may be a potential target for cancer therapy
Internal auditory canal exostosis: A technical case report
Background: Exostoses of the internal auditory canal is a rare finding that may present with disabling symptoms of dizziness, hearing loss, and vestibular dysfunction based on the extent of cranial nerve compression. The purpose of this case report is to discuss the presentation and outcomes in a patient who presented with this disorder.
Case Description: A 19-year-old female presented to the neurotologist with left ear discomfort, pain with left lateral gaze, and dizziness. She underwent extensive evaluation including audiometric testing, videonystagmography, and neuroimaging, which confirmed left auditory and vestibular hypofunction and compression of the contents of the internal auditory canal from the exostosis. After extensive counseling, the patient elected to undergo a suboccipital craniectomy to remove the internal auditory canal exostosis. She experienced complete resolution of symptoms.
Conclusions: Exostoses of the internal auditory canal, although rare, can present with severe symptoms of dizziness, hearing loss, and vestibular hypofunction based on the extent of cranial nerve compression. Imaging, particularly with thin-cut computed tomography, is invaluable in making the correct diagnosis. Severe cases can be treated successfully with surgery with minimal or no complications and excellent outcome
Successful Vim targeting for mixed essential and parkinsonian tremor using intraoperative MRI
Functional Neuroanatomy of Secondary Self-Injurious Behavior
BACKGROUND: Secondary self-injurious behavior (SSIB) is underreported and predominantly not associated with suicide. In both adults and children, SSIB can cause intractable self-harm and is associated with a variety of clinical disorders, particularly those involving dysfunctional motor control.
METHODS: We performed a literature review evaluating the clinical efficacy of deep-brain stimulation (DBS) as modulating SSIB observations and review current progress in preclinical SSIB animal studies.
RESULTS: Neuromodulation is an effective therapeutic option for several movement disorders. Interestingly, this approach is emerging as a potentially effective treatment for movement disorder-associated SSIB (secondary); however, it is important to understand the neuroanatomy, clinical appraisal, and outcome data when considering surgical therapy for SSIB.
CONCLUSION: The current review examines the literature encompassing animal models and human case studies while identifying existing hypotheses from cytoarchitectonic-based targeting to neurotransmitter-based pathways. This review also highlights the need for awareness of an underrecognized pathology that may be amenable to DBS
PP2A inhibition enhances cell death of hypoxic TSCs.
<p>(A) Examples of Annexin/PI stainings of TSCs grown for seven days in either normal culturing conditions or in media supplemented with 200 µM of CoCl<sub>2</sub>. Addition of 1 nM of OA has no significant effect on cells propagated in normal culturing conditions, but significantly increases the number of Annexin V+/PI+ cells in hypoxic conditions. (B) Photographs of TSCs <i>in vitro</i> following one week of culture during normoxia or hypoxia with or without inhibition of PP2A. Viable cells are stained by formazan dye. Few viable cells (black, arrows) are seen in hypoxic cells exposed to OA. (C) While neither 0.5 nM nor 1 nM of OA exerts a significant effect on the death of TSCs in routine culturing conditions, OA significantly increases the amount of Annexin V+/PI+ TSCs during hypoxic conditions. Bars represent the mean value of 6 independent experiments ± SEM. (D) Depletion of the PP2A-C causes an almost two-fold increase of cell death during hypoxic conditions. Importantly, enhancement of PP2A activity by PME-1 depletion reduces death of hypoxic TSCs to levels comparable to normoxia. (E) Inhibition of PP2A in TSCs exposed to hypoxic conditions for 3 days leads to increased phosphorylation of PLK and AKT.</p
Hypoxia increases cyclin G2 expression and PP2A activity in TSCs.
<p>(A) At 2, 4, 6, 8, 12, and 24 hours following addition of CoCl<sub>2</sub> to culture media, HIF-1α protein is detected in TSCs while cells grown in standard conditions lack expression. Increased cyclin G2 levels are detected in TSCs six hours following exposure to CoCl<sub>2</sub>. Expression levels of the PP2A C subunit remain stable throughout the experiment. Bar graph depicts marked increase of PP2A activity following exposure of TSCs to CoCl<sub>2</sub>. Thus, PP2A activity levels are nine times higher in TSCs propagated in CoCl<sub>2</sub> for six hours compared to TSCs grown in standard conditions. Bars represent the mean value of 3 independent experiments ± SEM. (B) To determine whether PP2A directly interacts with cyclin G2, PP2A was immunoprecipitated in cell lysates from control TSCs and TSCs exposed to six hours of CoCl<sub>2</sub>. In both conditions, the PP2A C subunit forms a complex with cyclin G2.</p
PP2A reduces ATP consumption and inhibits growth of TSCs during hypoxic conditions.
<p>(A) Effect of PP2A inhibition on ATP consumption of TSCs during normoxia and hypoxia. Intracellular ATP was measured in TSCs 1 hour following substrate depletion (D5030 media) with our without PP2A inhibition. PP2A inhibition leads to significantly higher ATP consumption during hypoxic conditions. The ATP content was measured and normalized to the lysate protein content. Bars represent the mean values of 8 independent experiments ± SEM. (B) 24 hours following plating, TSCs are exposed to CoCl<sub>2</sub> and/or OA for additional 24 hours. Hypoxia leads to G1/S phase growth inhibition in TSCs. Representative examples of cell cycle analysis experiments. (C) Summary of six independent experiments reveals that hypoxia-mediated G1/S phase arrest is partially reversed by OA in a dose-dependent fashion. Accordingly, PP2A inhibition allows for significantly more hypoxic TSCs to progress into the S-phase. (D) In line with pharmacological inhibition of PP2A, depletion of PP2A by shRNA alleviates G1/S cell cycle arrest in TSCs propagated in CoCl<sub>2</sub>. Given the longer duration of PP2A inhibition in PP2A-depleted cells (48 h) compared to OA-treated cells (24 h [C]), more PP2A-depleted cells progress to G2 phase. Increasing PP2A activity by depletion of the endogenous PP2A inhibitor PME-1 has the opposite effect. Western blots reveal depletion of PP2A-C and PME-1 in TSCs by shRNA.</p