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Open Access Publications from the University of California

Scholarly Works (13 results)

  • Article
  • Peer Reviewed
UC San Francisco Previously Published Works (2007)

Interleukin- 6 ( IL- 6) may play multiple roles in angiogenesis and vascular remodeling. Our previous study showed that a promoter polymorphism ( 174G > C) in IL- 6 is associated with brain arteriovenous malformation hemorrhage; tissue expression is related to genotype. In this study, we investigated the effects of IL- 6 on human cerebral smooth muscle cells ( HCSMCs) and smooth muscle cells isolated from brain arteriovenous malformation surgical specimens ( AVM SMCs) and surgical controls ( control HCSMCs - from structurally normal temporal lobe taken during surgical treatment of epilepsy patients). We found that IL- 6 ( 1.16 +/- 0.27 versus 0.376 +/- 0.04 pg/ mL, n= 5, P < 0.05) and endogenous vascular endothelial growth factor ( VEGF) receptor II ( kinase domain- containing receptor ( KDR), 15 +/- 3 versus 1.5 +/- 3 pg/ mL, n= 5, P < 0 .05) were increased in brain AVM SMCs compared with control HCSMCs. Further research revealed that IL- 6 could stimulate SMC proliferation, VEGF release, and KDR activation in control HCSMCs. It could also stimulate KDR phosphorylation in control HCSMCs, further confirming a unique role of IL- 6 in the triggering of KDR. Interleukin- 6 could increase matrix metalloproteinase- 9 ( MMP- 9) secretion through activating KDR in control HCSMCs ( P < 0.05 versus control). Inhibiting IL- 6- induced KDR could reduce MMP- 9 activity at least 50% compared with the control group ( P < 0.05). Increased MMP- 9 activity was accompanied by increased control HCSMC proliferation, and blocking MMP- 9 activity significantly reduced IL- 6- induced control HCSMC proliferation ( P < 0.05). Collectively, our results show that IL- 6 could activate, amplify, and maintain the angiogenic cascade in HCSMCs. A novel role of IL- 6 during HCSMC proliferation is upregulating KDR expression and phosphorylation. The results may contribute to the angiogenic phenotype of human brain vascular diseases, such as brain AVM.

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Cover page: Interleukin-6 upregulates expression of KDR and stimulates proliferation of human cerebrovascular smooth muscle cells
  • Article
  • Peer Reviewed
UC San Francisco Previously Published Works (2018)
Stereotactic radiosurgery (SRS) is a promising treatment for medically intractable mesial temporal lobe epilepsy. SRS for epilepsy has had an acceptable safety profile with reports of radiation-induced vascular malformations confined to central nervous system pathologies with prominent angiogenesis - namely, primary brain tumors, metastases, and arteriovenous malformations. Theoretical risks for radiation-induced lesions following radiosurgery for epilepsy have yet to be established. Of 13 patients treated in a pilot trial for medial temporal lobe epilepsy, one developed multiple delayed radiation-induced cavernous malformations following radiosurgery. This patient received a prescription dose of 20 Gy delivered to the amygdala, anterior hippocampus, and parahippocampal gyrus. Eight years following treatment, computed tomography imaging demonstrated an evolving hyperdensity in the mesial temporal lobe. Magnetic resonance imaging confirmed multiple T2 hypointense lesions with a mixed-signal intensity core in the left parahippocampal gyrus and anterior temporal lobe. The patient was initially managed conservatively. However, recurrent hemorrhage ultimately caused an acute deterioration in mental status, aphasia, and hemiparesis, necessitating surgical resection. Pathology confirmed radiation-induced cavernous malformations. This represents the first case of a radiation-induced vascular lesion as a long-term sequela of radiosurgery for epilepsy and illustrates the potential for this complication even when low doses are used in patients without angiogenic lesions. Optimal timing and indications for surgical resection of radiation-induced cavernous malformations prior to the development of neurologic symptoms warrant further refinement. Long-term vigilance and clinical monitoring are required.
    Cover page: Radiation-induced Cavernous Malformation as a Late Sequelae of Stereotactic Radiosurgery for Epilepsy.
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2010)
    Speech perception requires the rapid and effortless extraction of meaningful phonetic information from a highly variable acoustic signal. A powerful example of this phenomenon is categorical speech perception, in which a continuum of acoustically varying sounds is transformed into perceptually distinct phoneme categories. We found that the neural representation of speech sounds is categorically organized in the human posterior superior temporal gyrus. Using intracranial high-density cortical surface arrays, we found that listening to synthesized speech stimuli varying in small and acoustically equal steps evoked distinct and invariant cortical population response patterns that were organized by their sensitivities to critical acoustic features. Phonetic category boundaries were similar between neurometric and psychometric functions. Although speech-sound responses were distributed, spatially discrete cortical loci were found to underlie specific phonetic discrimination. Our results provide direct evidence for acoustic-to-higher order phonetic level encoding of speech sounds in human language receptive cortex.
      Cover page: Categorical speech representation in human superior temporal gyrus
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2006)

      Abnormal vascular remodeling mediated by inflammatory cells has been identified as a key pathologic component of various vascular diseases, including abdominal aortic aneurysms, brain arteriovenous malformations and atherosclerosis. Based on findings from observational studies that analysed human intracranial aneurysms and experimental studies that utilized animal models, an emerging concept suggests that a key component of the pathophysiology of intracranial aneurysms is sustained abnormal vascular remodeling coupled with inflammation. This concept may provide a new treatment strategy to utilize agents to inhibit inflammation or cytokines produced by inflammatory cells such as matrix metalloproteinases. Such an approach would aim to stabilize these vascular lesions and prevent future expansion or rupture.

        Cover page: Intracranial aneurysms: links among inflammation, hemodynamics and vascular remodeling
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2009)
        Seizures are common in patients with gliomas, and phenytoin (PHT) is frequently used to control tumor-related seizures. PHT, however, has many undesirable side effects (SEs) and drug interactions with glioma chemotherapy. Levetiracetam (LEV) is a newer antiepileptic drug (AED) with fewer SEs and essentially no drug interactions. We performed a pilot study testing the safety and feasibility of switching patients from PHT to LEV monotherapy for postoperative control of glioma-related seizures. Over a 13-month period, 29 patients were randomized in a 2:1 ratio to initiate LEV therapy within 24 h of surgery or to continue PHT therapy. 6 month follow-up data were available for 15 patients taking LEV and for 8 patients taking PHT. In the LEV group, 13 patients (87%) were seizure-free. In the PHT group, 6 patients (75%) were seizure-free. Reported SEs at 6 months was as follows (%LEV/%PHT group): dizziness (0/14), difficulty with coordination (0/29), depression (7/14) lack of energy or strength (20/43), insomnia (40/43), mood instability (7/0). The pilot data presented here suggest that it is safe to switch patients from PHT to LEV monotherapy following craniotomy for supratentorial glioma. A large-scale, double-blinded, randomized control trial of LEV versus PHT is required to determine seizure control equivalence and better assess differences in SEs.
          Cover page: Safety and feasibility of switching from phenytoin to levetiracetam monotherapy for glioma-related seizure control following craniotomy: a randomized phase II pilot study.
          • Article
          • Peer Reviewed
          Seizures are common in patients with gliomas, and phenytoin (PHT) is frequently used to control tumor-related seizures. PHT, however, has many undesirable side effects (SEs) and drug interactions with glioma chemotherapy. Levetiracetam (LEV) is a newer antiepileptic drug (AED) with fewer SEs and essentially no drug interactions. We performed a pilot study testing the safety and feasibility of switching patients from PHT to LEV monotherapy for postoperative control of glioma-related seizures. Over a 13-month period, 29 patients were randomized in a 2:1 ratio to initiate LEV therapy within 24 h of surgery or to continue PHT therapy. 6 month follow-up data were available for 15 patients taking LEV and for 8 patients taking PHT. In the LEV group, 13 patients (87%) were seizure-free. In the PHT group, 6 patients (75%) were seizure-free. Reported SEs at 6 months was as follows (%LEV/%PHT group): dizziness (0/14), difficulty with coordination (0/29), depression (7/14) lack of energy or strength (20/43), insomnia (40/43), mood instability (7/0). The pilot data presented here suggest that it is safe to switch patients from PHT to LEV monotherapy following craniotomy for supratentorial glioma. A large-scale, double-blinded, randomized control trial of LEV versus PHT is required to determine seizure control equivalence and better assess differences in SEs.
            Cover page: Safety and feasibility of switching from phenytoin to levetiracetam monotherapy for glioma-related seizure control following craniotomy: a randomized phase II pilot study
            • Article
            • Peer Reviewed
            UC Berkeley Previously Published Works (2007)

            The spatiotemporal dynamics of cortical oscillations across human brain regions remain poorly understood because of a lack of adequately validated methods for reconstructing such activity from noninvasive electrophysiological data. We present a novel adaptive spatial filtering algorithm optimized for robust source time-frequency reconstruction from magnetoencephalography (MEG) and electroencephalography (EEG) data. The efficacy of the method is demonstrated with real MEG data from a self-paced finger movement task. The algorithm reliably reveals modulations both in the beta band (12-30 Hz) and a high gamma band (65-90 Hz) in sensorimotor cortex. The performance is validated by both across-subjects statistical comparisons and by intracranial electrocorticography (ECoG) data from two epilepsy patients. We also revealed observed high gamma activity in the cerebellum. The proposed algorithm is highly parallelizable and runs efficiently on modern high performance computing clusters. This method enables noninvasive five-dimensional imaging of space, time, and frequency activity in the brain and renders it applicable for widespread studies of human cortical dynamics.

              Cover page: Spatial localization of cortical time-frequency dynamics
              • Article
              • Peer Reviewed
              UC San Francisco Previously Published Works (2015)
              MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally control the expression of their target genes via RNA interference. There is increasing evidence that expression of miRNAs is dysregulated in neuronal disorders, including epilepsy, a chronic neurological disorder characterized by spontaneous recurrent seizures. Mesial temporal lobe epilepsy (MTLE) is a common type of focal epilepsy in which disease-induced abnormalities of hippocampal neurogenesis in the subgranular zone as well as gliosis and neuronal cell loss in the cornu ammonis area are reported. We hypothesized that in MTLE altered miRNA-mediated regulation of target genes could be involved in hippocampal cell remodeling. A miRNA screen was performed in hippocampal focal and non-focal brain tissue samples obtained from the temporal neocortex (both n=8) of MTLE patients. Out of 215 detected miRNAs, two were differentially expressed (hsa-miR-34c-5p: mean increase of 5.7 fold (p=0.014), hsa-miR-212-3p: mean decrease of 76.9% (p=0.0014)). After in-silico target gene analysis and filtering, reporter gene assays confirmed RNA interference for hsa-miR-34c-5p with 3'-UTR sequences of GABRA3, GRM7 and GABBR2 and for hsa-miR-212-3p with 3'-UTR sequences of SOX11, MECP2, ADCY1 and ABCG2. Reporter gene assays with mutated 3'-UTR sequences of the transcription factor SOX11 identified two different binding sites for hsa-miR-212-3p and its primary transcript partner hsa-miR-132-3p. Additionally, there was an inverse time-dependent expression of Sox11 and miR-212-3p as well as miR-132-3p in rat neonatal cortical neurons. Transfection of neurons with anti-miRs for miR-212-3p and miR-132-3p suggest that both miRNAs work synergistically to control Sox11 expression. Taken together, these results suggest that differential miRNA expression in neurons could contribute to an altered function of the transcription factor SOX11 and other genes in the setting of epilepsy, resulting not only in impaired neural differentiation, but also in imbalanced neuronal excitability and accelerated drug export.
                Cover page: SOX11 identified by target gene evaluation of miRNAs differentially expressed in focal and non-focal brain tissue of therapy-resistant epilepsy patients
                • Article
                • Peer Reviewed
                UC San Francisco Previously Published Works (2012)
                Brain arteriovenous malformation (BAVM), a rare but important cause of intracranial hemorrhage, has increased angiogenesis and inflammation as key components of the nidus of abnormal vessels and stroma that form the resected surgical specimen. Accordingly, both vascular endothelial growth factor (VEGF) and transforming growth factor-β have been implicated in the pathology of BAVM for their proangiogenic and vascular-regulating roles. The C-terminal fragment of the extracellular matrix component perlecan (domain V, DV) has been shown to be increased and through the α5β1 integrin, to increase VEGF levels in and around areas of cerebral ischemic injury, another proangiogenic condition. We aimed to determine whether the concentrations of DV, DV's proangiogenic receptor α5β1 integrin, or DV's antiangiogenic receptor α2β1 integrin are elevated in human BAVM tissue. DV levels were increased in BAVM compared with control brain tissue from epileptic resection, as was α5β1 integrin. In addition, α5β1 integrin was preferentially increased and localized to endothelial cells compared with α2β1 integrin. VEGF and transforming growth factor-β levels were also increased in BAVM compared with control tissue. Furthermore, increases in all components were strongly correlated. Excessive generation of proangiogenic DV in BAVM suggests that DV may participate in its pathology and may represent a future therapeutic target.
                  Cover page: Perlecan domain V is upregulated in human brain arteriovenous malformation and could mediate the vascular endothelial growth factor effect in lesional tissue
                  • Article
                  • Peer Reviewed
                  UC San Francisco Previously Published Works (2013)

                  Purpose

                  Gamma knife radiosurgery (RS) may be an alternative to open surgery for mesial temporal lobe epilepsy (MTLE), but morbidities and the anticonvulsant mechanisms of RS are unclear. Examination of visual field defects (VFDs) after RS may provide evidence of the extent of a postoperative fixed lesion. VFDs occur in 52-100% of patients following open surgery for MTLE.

                  Methods

                  This multicenter prospective trial of RS enrolled patients with unilateral hippocampal sclerosis and concordant video-electroencephalography (EEG) findings. Patients were randomized to low (20 Gy) or high (24 Gy) doses delivered to the amygdala, hippocampal head, and parahippocampal gyrus. Postoperative perimetry were obtained at 24 months after RS. Visual field defect ratios (VFDRs) were calculated to quantify the degree of VFDs. Results were contrasted with age, RS dose and 50% isodose volume, peak volume of radiation-induced change at the surgical target, quality of life measurements, and seizure remission.

                  Key findings

                  No patients reported visual changes and no patients had abnormal bedside visual field examinations. Fifteen (62.5%) of 24 patients had postoperative VFDs, all homonymous superior quadrantanopsias. None of the VFDs were consistent with injury to the optic nerve or chiasm. Clinical diagnosis of VFDs correlated significantly with VFDRs (p = 0.0005). Patients with seizure remission had smaller (more severe) VFDRs (p = 0.04). No other variables had significant correlations.

                  Significance

                  VFDs appeared after RS in proportions similar to historical comparisons from open surgery for MTLE. The nature of VFDs was consistent with lesions of the optic radiations. The findings support the hypothesis that the mechanism of RS involves some degree of tissue damage and is not confined entirely to functional changes in neuromodulation.
                    Cover page: Visual field defects after radiosurgery for mesial temporal lobe epilepsy
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