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Objective: The mechanistic target of rapamycin (mTOR) pathway has been implicated in promoting epileptogenesis in animal models of acquired epilepsy, such as posttraumatic epilepsy (PTE) following traumatic brain injury (TBI). However, the specific anatomical regions and neuronal populations mediating mTOR's role in epileptogenesis are not well defined. In this study, we tested the hypothesis that mTOR activation in dentate gyrus granule cells promotes neuronal death, mossy fiber sprouting, and PTE in the controlled cortical impact (CCI) model of TBI. Methods: An adeno‐associated virus (AAV)‐Cre viral vector was injected into the hippocampus of Rptorflox/flox (regulatory‐associated protein of mTOR) mutant mice to inhibit mTOR activation in dentate gyrus granule cells. Four weeks after AAV‐Cre or AAV‐vehicle injection, mice underwent CCI injury and were subsequently assessed for mTOR pathway activation by Western blotting, neuronal death, and mossy fiber sprouting by immunopathological analysis, and posttraumatic seizures by video‐electroencephalographic monitoring. Results: AAV‐Cre injection primarily affected the dentate gyrus and inhibited hippocampal mTOR activation following CCI injury. AAV‐Cre‐injected mice had reduced neuronal death in dentate gyrus detected by Fluoro‐Jade B staining and decreased mossy fiber sprouting by ZnT3 immunostaining. Finally, AAV‐Cre‐injected mice exhibited a decrease in incidence of PTE. Significance: mTOR pathway activation in dentate gyrus granule cells may at least partly mediate pathological abnormalities and epileptogenesis in models of TBI and PTE. Targeted modulation of mTOR activity in this hippocampal network may represent a focused therapeutic approach for antiepileptogenesis and prevention of PTE. [ABSTRACT FROM AUTHOR]

Objective: Tuberous sclerosis complex (TSC) is a genetic disorder, characterized by tumor formation in the brain and other organs, and severe neurological symptoms, such as epilepsy. Abnormal vascular endothelial growth factor (VEGF) expression may promote angiogenesis in kidney and lung tumors in TSC and has been identified in brain specimens from TSC patients, but the role of VEGF and vascular abnormalities in neurological manifestations of TSC is poorly defined. In this study, we investigated abnormalities in brain VEGF expression, cerebral blood vessel anatomy, and blood–brain barrier (BBB) structure and function in a mouse model of TSC. Methods: Tsc1GFAPCKO mice were used to investigate VEGF expression and vascular abnormalities in the brain by Western blotting and immunohistochemical analysis of vascular and BBB markers. In vivo two‐photon imaging was used to assess BBB permeability to normally impenetrable fluorescently labeled compounds. The effect of mechanistic target of rapamycin (mTOR) pathway inhibitors, VEGF receptor antagonists (apatinib), or BBB stabilizers (RepSox) was assessed in some of these assays, as well as on seizures by video‐electroencephalography. Results: VEGF expression was elevated in cortex of Tsc1GFAPCKO mice, which was reversed by the mTOR inhibitor rapamycin. Tsc1GFAPCKO mice exhibited increased cerebral angiogenesis and vascular complexity in cortex and hippocampus, which were reversed by the VEGF receptor antagonist apatinib. BBB permeability was abnormally increased and BBB‐related tight junction proteins occludin and claudin‐5 were decreased in Tsc1GFAPCKO mice, also in an apatinib‐ and RepSox‐dependent manner. The BBB stabilizer (RepSox), but not the VEGF receptor antagonist (apatinib), decreased seizures and improved survival in Tsc1GFAPCKO mice. Significance: Increased brain VEGF expression is dependent on mTOR pathway activation and promotes cerebral vascular abnormalities and increased BBB permeability in a mouse model of TSC. BBB modulation may affect epileptogenesis and represent a rational treatment for epilepsy in TSC. [ABSTRACT FROM AUTHOR]

Objective: Neurostimulation is an emerging treatment for patients with drug‐resistant epilepsy, which is used to suppress, prevent, and terminate seizure activity. Unfortunately, after implantation and despite best clinical practice, most patients continue to have persistent seizures even after years of empirical optimization. The objective of this study is to determine optimal spatial and amplitude properties of neurostimulation in inhibiting epileptiform activity in an acute hippocampal seizure model. Methods: We performed high‐throughput testing of high‐frequency focal brain stimulation in the acute intrahippocampal kainic acid mouse model of status epilepticus. We evaluated combinations of six anatomic targets and three stimulus amplitudes. Results: We found that the spike‐suppressive effects of high‐frequency neurostimulation are highly dependent on the stimulation amplitude and location, with higher amplitude stimulation being significantly more effective. Epileptiform spiking activity was significantly reduced with ipsilateral 250 μA stimulation of the CA1 and CA3 hippocampal regions with 21.5% and 22.2% reductions, respectively. In contrast, we found that spiking frequency and amplitude significantly increased with stimulation of the ventral hippocampal commissure. We further found spatial differences with broader effects from CA1 versus CA3 stimulation. Significance: These findings demonstrate that the effects of therapeutic neurostimulation in an acute hippocampal seizure model are highly dependent on the location of stimulation and stimulus amplitude. We provide a platform to optimize the anti‐seizure effects of neurostimulation, and demonstrate that an exploration of the large electrical parameter and location space can improve current modalities for treating epilepsy. Plain Language Summary: In this study, we tested how electrical pulses in the brain can help control seizures in mice. We found that the electrode's placement and the stimulation amplitude had a large effect on outcomes. Some brain regions, notably nearby CA1 and CA3, responded positively with reduced seizure‐like activities, while others showed increased activity. These findings emphasize that choosing the right spot for the electrode and adjusting the strength of electrical pulses are both crucial when considering neurostimulation treatments for epilepsy. [ABSTRACT FROM AUTHOR]

Gaeumannomyces tritici, an ascomycete soilborne fungus, causes a devastating root disease in wheat. Carabrone, a botanical bicyclic sesquiterpenic lactone, is a promising fungicidal agent that can effectively control G. tritici. However, the mechanism of action of carabrone against G. tritici remains largely unclear. Here, we used immunogold for subcellular localization of carabrone and the results showed that carabrone is subcellularly localized in the mitochondria of G. tritici. We then explored the functional analysis of genes GtCytc1, GtCytb, and GtIsp of the mitochondrial respiratory chain cytochrome bc1 complex in G. tritici by RNA silencing as a possible target of carabrone. The results showed that the silenced mutant ∆GtIsp is less sensitive to carabrone compared to ∆GtCytc1 and ∆GtCytb. Compared with the control, the activities of complex III in all the strains, except ∆GtIsp and carabrone‐resistant isolate 24‐HN‐1, were significantly decreased following treatment with carabrone at EC20 and EC80 in vitro (40%–50% and 70%–80%, respectively). The activities of mitochondrial respiratory chain complex III and the mitochondrial respiration oxygen consumption rates in all the strains, except ∆GtIsp and 24‐HN‐1, were higher with respect to the control when treated with carabrone at EC20 in vivo. The rates of mitochondrial respiration of all strains, except ∆GtIsp, were significantly inhibited following treatment with carabrone at EC80 (ranging from 57% to 81%). This study reveals that the targeting of the iron–sulphur protein encoded by GtIsp is highly sensitive to carabrone and provides a direction for the research of carabrone's target. [ABSTRACT FROM AUTHOR]

Summary: Objective: Microglial abnormalities have been reported in pathologic specimens from patients with tuberous sclerosis complex (TSC), a genetic disorder characterized by epilepsy, intellectual disability, and autism. However, the pathogenic role of microglia in epilepsy in TSC is poorly understood, particularly whether microglia defects may be a primary contributor to epileptogenesis or are secondary to seizures or simply epiphenomena. In this study, we tested the hypothesis that Tsc1 gene inactivation in microglia is sufficient to cause epilepsy in mouse models of TSC. Methods: Using a chemokine receptor, Cx3cr1, to target microglia, conventional Tsc1Cx3cr1‐CreCKO (conditional knockout) mice and postnatal‐inducible Tsc1Cx3cr1‐CreERCKO mice were generated and assessed for molecular and histopathologic evidence of microglial abnormalities, mechanistic target of rapamycin 1 (mTORC1) pathway activation, and epilepsy. Results: Tsc1Cx3cr1‐CreCKO mice exhibited a high efficiency of microglia Tsc1 inactivation, mTORC1 activation, increased microglial size and number, and robust epilepsy, which were rapamycin‐dependent. However, Cre reporter studies demonstrated that constitutive Cx3cr1 expression affected not only microglia, but also a large percentage of cortical neurons, confounding the role of microglia in epileptogenesis in Tsc1 Cx3cr1‐CreCKO mice. In contrast, postnatal inactivation of Tsc1 utilizing a tamoxifen‐inducible Cx3cr1‐CreER resulted in a more‐selective microglia Tsc1 inactivation with high efficiency, mTORC1 activation, and increased microglial size and number, but no documented epilepsy. Significance: Microglia abnormalities may contribute to epileptogenesis in the context of neuronal involvement in TSC mouse models, but selective Tsc1 gene inactivation in microglia alone may not be sufficient to cause epilepsy, suggesting that microglia have more supportive roles in the pathogenesis of seizures in TSC. [ABSTRACT FROM AUTHOR]

Objective Tuberous sclerosis complex (TSC) is a genetic disorder, characterized by tumor formation in multiple organs and severe neurologic manifestations, including epilepsy, intellectual disability, and autism. Abnormalities of both neurons and astrocytes have been implicated in contributing to the neurologic phenotype of TSC, but the role of microglia in TSC has not been investigated. The objectives of this study were to characterize microglial activation in a mouse model of TSC, involving conditional inactivation of the Tsc1 gene predominantly in glial cells ( Tsc1GFAPCKO mice), and to test the hypothesis that microglial activation contributes to epileptogenesis in this mouse model. Methods Microglial and astrocyte activation was examined in Tsc1GFAPCKO mice by ionized calcium binding adaptor molecule 1 and glial fibrillary acidic protein immunohistochemistry. Cytokine and chemokine expression was evaluated with quantitative polymerase chain reaction. Seizures were monitored by video-electroencephalography (EEG). The effect of minocycline in inhibiting microglial and astrocyte activation, cytokine expression, and seizures was tested. Results Microglial cell number and size were increased in cortex and hippocampus of 3- to 4-week-old Tsc1GFAPCKO mice, which correlated with the onset of seizures. Minocycline treatment prevented the increase in number and cell size of microglia in 4-week-old Tsc1GFAPCKO mice. However, minocycline treatment had no effect on astrocyte proliferation and cytokine/chemokine expression and the progression of seizures in Tsc1GFAPCKO mice. Significance Microglia cell number and size are abnormal in Tsc1GFAPCKO mice, and minocycline treatment inhibits this microglia activation, but does not suppress seizures. Microglia may play a role in the neurologic manifestations of TSC, but additional studies are needed in other models and human studies to determine whether microglia are critical for epileptogenesis in TSC. [ABSTRACT FROM AUTHOR]

Objective Inhibitors of the mechanistic target of rapamycin (m TOR) pathway have antiepileptogenic effects in preventing epilepsy and pathologic and molecular mechanisms of epileptogenesis in mouse models of tuberous sclerosis complex ( TSC). However, long-term treatment with m TOR inhibitors may be required to maintain efficacy and potentially has chronic side effects, such as immunosuppression. Attempts to minimize drug exposure will facilitate translational efforts to develop m TOR inhibitors as antiepileptogenic agents for patients with TSC. In this study, we tested intermittent dosing paradigms of m TOR inhibitors for antiepileptogenic properties in a TSC mouse model. Methods Western blot analysis of phosphorylation of S6 protein was used to assess the dose- and time-dependence of m TOR inhibition by rapamycin in control mice and conditional knockout mice with inactivation of the Tsc1 gene in glial fibrillary acidic protein ( GFAP)-expressing cells ( Tsc1 GFAPCKO mice). Based on the Western blot studies, different dosing paradigms of rapamycin starting at postnatal day 21 were tested for their ability to prevent epilepsy or pathologic abnormalities in Tsc1 GFAPCKO mice: 4 days of rapamycin only (4-∞), 4 days on-24 days off (4-24), and 4 days on-10 days off (4-10). Results m TOR activity was inhibited by rapamycin in a dose-dependent fashion and recovered to baseline by about 10 days after the last rapamycin dose. The 4-10 and 4-24 dosing paradigms almost completely prevented epilepsy and the 4-10 paradigm inhibited glial proliferation and megalencephaly in Tsc1 GFAPCKO mice. Significance Intermittent dosing of rapamycin, with drug holidays of more than 3 weeks, maintains significant antiepileptogenic properties in mouse models of TSC. These findings have important translational applications in developing m TOR inhibitors as antiepileptogenic agents in TSC patients by minimizing drug exposure and potential side effects. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the advantages and disadvantages of the retention and removal of silicone oil in the treatment of complicated retinal detachments. Methods: The records of 344 patients (348 eyes) that underwent vitrectomy and silicone oil injection for complicated retinal detachments were abstracted and analysed. The anatomical and functional results, complications and influencing factors are discussed. The outcome in eyes after removal of the silicone oil was compared with the outcome in a comparable group of eyes in which the silicone oil was retained. Results: The overall retinal reattachment rate was 63% (220/348). The final vision of 5/300 or better was 52% (115/220) in those eyes with totally attached retinas. The silicone oil-related complications included keratopathy (23%) and secondary glaucoma (11%). Comparing removal of silicone oil with retention of silicone oil, we found: (i) there was no statistical difference in the redetachment rate (19 vs 17%); (ii) Oil-removed eyes had a better final vision ( P < 0.05); and (iii) keratopathy (13 vs 23%), secondary glaucoma (11 vs 25%) and optic nerve atrophy (4 vs 18%) were significantly lower in oil-removed eyes. Conclusion: Silicone oil injection is useful in the treatment of complicated retinal detachments. For reducing the incidence of complications, early removal of silicone oil is recommended in those cases in which the retina is attached, all breaks adequately closed and traction relieved. [ABSTRACT FROM AUTHOR]

Purpose: To report a typical case of nanophthalmos with uveal effusion and local serous retinal detachment followed for 1 year. Methods: Clinical ocular examinations included vision, refraction, corneal diameter; anterior chamber depth, intraocular pressure, fundoscopy, A/B scan ultrasonography and gonioscopy. Results: Both eyes were hypermetropic with small corneas and shallow anterior chambers. Decreased axial length and thickened sclera were also found. There were peripheral choroidal effusions and local serous retinal detachments as well. The patient declined any surgery that was offered. No significant change in either eye was found after I year follow-up. Conclusion: This case illustrates that the progress of choroidal effusion and retinal detachment in nanophthalmos may be very slow and even non-progressive for at least 1 year. In these cases sclerectomy and or sclerotomy may be delayed without undue immediate risk to the vision. [ABSTRACT FROM AUTHOR]