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Background: Trauma exposure is a risk factor for substance use disorders (SUD) among women. This study explores written content from an expressive writing (EW) intervention conducted within a residential SUD program to examine themes across trauma experiences and characterize their deep insight into such experiences. Materials and Methods: This qualitative study is a secondary data analysis of written content of the first writing session from women (n?=?44) randomized to an EW condition while in residential SUD treatment. Results: Nearly all participants (72.7% African American; mean age 37.3 years) reported a significant trauma event (93.2%) with an average of 3.7 types of trauma events (54.4% had a current posttraumatic stress disorder diagnosis). Four primary themes emerged: (1) trauma across the lifespan; (2) loss of safety; (3) altered self-concept; and (4) desire to move on. Most participants identified interpersonal trauma, especially at an early age, as well as parental neglect and physical and/or sexual violence. These themes indicate a pattern of interpersonal betrayal and paint a picture of trauma and the subsequent ?rippling effect? such that the physical, mental, and emotional consequences were often as impactful as the event itself. However, there was also a desire to move on and gain a sense of normalcy. Conclusions: Findings highlight the importance of the written word and addressing underlying trauma in addiction treatment to facilitate healing and the woman's desire to move on.

Sternal fractures are rare and are typically caused by major trauma such as motor vehicle collisions. However, sternal insufficiency fractures can occur with minimal to no trauma in patients with exaggerated thoracic kyphosis from multiple thoracic compression fractures, especially in the setting of osteoporosis. We describe a case of a sternal insufficiency fracture that presented as chest pain resembling a myocardial infarction. As sternal insufficiency fractures may vary in clinical presentation, this case demonstrates that radiologists should carefully evaluate the sternum, especially when risk factors are present. Furthermore, awareness and identification of these fractures can prevent unnecessary cardiac workups.

.Abstract: In the present work, nickel-titanium (NiTi) shape memory alloys (SMAs) is joined to 304 stainless steel (SS) using friction stir welding (FSW) using process parameters of 400 rpm and a constant tool translation speed of 75 mm/min. The macrostructure of the dissimilar weld showed some surface tunneling defects but there were regions of the weld that were defect free and without evidence of intermetallics at the interface. The weld stir zone (SZ) showed grain refinement compared to both base materials (BM). NiTi side of the joint showed very fine thermomechanical affected zone (TMAZ) and absence of a distinct heat affected (HAZ) zone, resulting in very little variation in microhardness. SS side of the weld showed typical FSW microstructural zones with higher microhardness in the SZ (270 HV) compared to BM (185 HV). Tensile testing of the weld showed a small initial plateau region, characteristic of shape memory alloys (SMAs) arising from NiTi part of the weld. Importantly, the transformation temperatures of NiTi, measured by differential scanning calorimetry (DSC) from different weld zones, varied by no more than 4 °C. Corrosion properties of the weld zone investigated in 3.5 wt. % NaCl solution showed moderately inferior corrosion resistance of dissimilar weld, compared to individual base metals, as characterized by the surface film impedance and corrosion current density. The decreased corrosion resistance was attributed to inhomogeneous passive film formed across the weld due to zonal heterogeneities. The predicted and measured galvanic parameters of the galvanically coupled base metals suggested that there appeared to be negligible galvanic effects. The results from the study show that with further development, FSW can be successfully utilized to create dissimilar joints between NiTi and stainless steel.

In this study, friction stir welding (FSW) process is utilized to join equiatomic nickel-titanium (NiTi) shape memory alloys as a solid-state welding alternative to fusion welding. In the studied range of process parameters (spindle speeds – 350 – 450 rpm and constant translation speed 75 mm/min), combination of 400 rpm spindle speed and 75 mm/min tool translation speed produced a defect-free joint without any discernable voids. The weld microstructure consisted of a typical stir zone with fine grains; a rather small thermo-mechanically affected zone and heat affected zone. Vickers microhardness measurements after appropriate thermal cycling, showed uniform hardness across the weld zone, indicating a joint free of detrimental precipitates. The transformation temperatures measured by differential scanning calorimetry, showed little to no change across the weld zones. Under tensile loading, at ambient temperature a maximum joint efficiency of 93% was obtained in the martensitic phase while at elevated temperature a joint efficiency of 84% was obtained in the austenitic phase. The welded specimen showed martensitic detwinning plateau, characteristic of SMAs tested in martensitic phase, indicating that martensitic detwinning was the dominant mode of deformation at low strains, even within the weld zone. The weld zone showed comparatively lower corrosion resistance than the base material, owing to less dense TiO2 passive layer formation. Galvanic effect between the weld zone and base materials was negligible, indicating good compatibility between the different weld zones. Our results show that friction stir welding can be successfully applied for joining NiTi SMAs sheets.

Background: The use of 5-aminolevulinic acid (5-ALA) for intraoperative protoporphyrin IX fluorescent imaging in the resection of malignant gliomas has been demonstrated to improve tumor visualization, increase the extent of resection, and extend progression-free survival. The current technique for visualization of 5-ALA consists of excitation and emission filters built into the operating microscope. However, there are notable limitations to this process, including low quantum yield, expense, and masking of surrounding anatomy., Methods: We present 3 cases in which 3 separate methods were employed for visualizing fluorescence. The devices reported are 1) a low-cost blue light flashlight, 2) a low-cost headlamp, and 3) the first reported case of the new Designs for Vision REVEAL Fluorescence-Guided Surgery (FGS) 5-ALA fluorescent headlight and loupes. The aim of the study is to provide confirmation that tumor fluorescence can be observed using commercially available products other than the microscope., Results: We demonstrate through 3 intraoperative cases that a variety of devices can produce visible fluorescence of the high-grade tumor and allow for simultaneous real-time visualization of the adjacent brain parenchyma and vasculature. The REVEAL FGS system appears to offer increased fluorescence emission compared with all other methods, including the microscope., Conclusions: Our study demonstrates the feasibility of using blue/ultraviolet light supplied by a commercially available, inexpensive flashlight or headlamp to visualize 5-ALA fluorescence in high-grade gliomas. We also provide the first documentation of the intraoperative use of the new Designs for Vision REVEAL FGS 5-ALA fluorescent headlight and loupes and report on the experience. Lack of an operative microscope capable of fluorescent illumination should not be a limiting factor in performing fluorescent-guided glioma resection., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Technical limitations and clinical challenges have historically limited the diagnostic tools and treatment methods available for surgical approaches to the management of epilepsy. By contrast, recent technological innovations in several areas hold significant promise in improving outcomes and decreasing morbidity. We review innovations in the neurosurgical management of epilepsy in several areas, including wireless recording and stimulation systems (particularly responsive neurostimulation [NeuroPace]), conformal electrodes for high-resolution electrocorticography, robot-assisted stereotactic surgery, optogenetics and optical imaging methods, novel positron emission tomography ligands, and new applications of focused ultrasonography. Investigation into genetic causes of and susceptibilities to epilepsy has introduced a new era of precision medicine, enabling the understanding of cell signaling mechanisms underlying epileptic activity as well as patient-specific molecularly targeted treatment options. We discuss the emerging path to individualized treatment plans, predicted outcomes, and improved selection of effective interventions, on the basis of these developments., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Though frequently effective in the management of medically refractory seizures, epilepsy surgery presents numerous challenges. Selection of the appropriate candidate patients who are likely to benefit from surgery is critical to achieving seizure freedom and avoiding neurocognitive morbidity. Identifying the seizure focus and mapping epileptogenic networks involves an interdisciplinary team dedicated to formulating a safe and effective surgical plan. Various strategies can be employed either to eliminate the epileptic focus or to modulate network activity, including resection of the focus with open surgery or laser interstitial thermal therapy; modulation of epileptogenic firing patterns with responsive neurostimulation, deep brain stimulation, or vagus nerve stimulation; or non-invasive disconnection of epileptic circuits with focused ultrasound, which is also discussed in greater detail in the subsequent chapter in our series. We review several challenges of epilepsy surgery that must be thoughtfully addressed in order to ensure its success., (Copyright © 2020 Elsevier Inc. All rights reserved.)

mTORopathies are a heterogeneous group of neurological disorders characterized by malformations of cortical development (MCD), enhanced cellular mechanistic target of rapamycin (mTOR) signaling, and epilepsy that results from mutations in mTOR pathway regulatory genes. Homozygous mutations (del exon 9-13) in the pseudokinase STE20-related kinase adaptor alpha ( STRAD-α ; STRADA ), an mTOR modulator, are associated with Pretzel Syndrome (PS), a neurodevelopmental disorder within the Old Order Mennonite Community characterized by megalencephaly, intellectual disability, and intractable epilepsy. To study the cellular mechanisms of STRADA loss, we generated CRISPR-edited Strada mouse N2a cells, a germline mouse Strada knockout (KO-/-) strain, and induced pluripotent stem cell (iPSC)-derived neurons from PS individuals harboring the STRADA founder mutation. Strada KO in vitro leads to enhanced mTOR signaling and iPSC-derived neurons from PS individuals exhibit enhanced cell size and mTOR signaling activation, as well as subtle alterations in electrical firing properties e.g., increased input resistance, a more depolarized resting membrane potential, and decreased threshold for action potential (AP) generation. Strada -/- mice exhibit high rates of perinatal mortality and out of more than 100 litters yielding both WT and heterozygous pups, only eight Strada -/- animals survived past P5. Strada -/- mice are hypotonic and tremulous. Histopathological examination ( n = 5 mice) revealed normal gross brain organization and lamination but all had ventriculomegaly. Ectopic neurons were seen in all five Strada -/- brains within the subcortical white matter mirroring what is observed in human PS brain tissue. These distinct experimental platforms demonstrate that STRADA modulates mTOR signaling and is a key regulator of cell size, neuronal excitability, and cortical lamination., (Copyright © 2020 Dang, Glanowska, Iffland, Barnes, Baybis, Liu, Patino, Vaid, Streicher, Parker, Kim, Moon, Henry, Murphy, Sutton, Parent and Crino.)

Intramedullary spinal cord tumors (IMSCT) comprise a rare subset of CNS tumors that have distinct management strategies based on histopathology. These tumors often present challenges in regards to optimal timing for surgery, invasiveness, and recurrence. Advances in microsurgical techniques and technological adjuncts have improved extent of resection and outcomes with IMSCT. Furthermore, adjuvant therapies including targeted immunotherapies and image-guided radiation therapy have witnessed rapid development over the past decade, further improving survival for many of these patients. In this review, we provide an overview of types, epidemiology, imaging characteristics, surgical management strategies, and future areas of research for IMSCT., Competing Interests: Disclosure M.H. Bilsky receives royalties from Globus and DePuy/Synthes and is on the Speaker’s Bureau for Brainlab and Varian. The other authors have nothing to disclose., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: The authors tested the feasibility of magnetic resonance-guided focused ultrasound (MRgFUS) ablation of mesial temporal lobe epilepsy (MTLE) seizure circuits. Up to one-third of patients with mesial temporal sclerosis (MTS) suffer from medically refractory epilepsy requiring surgery. Because current options such as open resection, laser ablation, and Gamma Knife radiosurgery pose potential risks, such as infection, hemorrhage, and ionizing radiation, and because they often produce visual or neuropsychological deficits, the authors developed a noninvasive MRgFUS ablation strategy for mesial temporal disconnection to mitigate these risks., Methods: The authors retrospectively reviewed 3-T MRI scans obtained with diffusion tensor imaging (DTI). The study group included 10 patients with essential tremor (ET) who underwent pretreatment CT and MRI prior to MRgFUS, and 2 patients with MTS who underwent MRI. Fiber tracking of the fornix-fimbria pathway and inferior optic radiations was performed, ablation sites mimicking targets of open posterior hippocampal disconnection were modeled, and theoretical MRgFUS surgical plans were devised. Distances between the targets and optic radiations were measured, helmet angulations were prescribed, and the numbers of available MRgFUS array elements were calculated., Results: Tractograms of fornix-fimbria and optic radiations were generated in all ET and MTS patients successfully. Of the 10 patients with both the CT and MRI data necessary for the analysis, 8 patients had adequate elements available to target the ablation site. A margin (mean 8.5 mm, range 6.5-9.8 mm) of separation was maintained between the target lesion and optic radiations., Conclusions: MRgFUS offers a noninvasive option for seizure tract disruption. DTI identifies fornix-fimbria and optic radiations to localize optimal ablation targets and critical surrounding structures, minimizing risk of postoperative visual field deficits. This theoretical modeling study provides the necessary groundwork for future clinical trials to apply this novel neurosurgical technique to patients with refractory MTLE and surgical contraindications, multiple prior surgeries, or other factors favoring noninvasive treatment.

Background: The association between mid-facial clefts and Chiari malformation in the medical literature has been restricted to patients with syndromic craniofacial abnormalities. A common shared developmental pathway including causative factors for facial clefts and "complex" Chiari malformations, both midline skull base pathologies, seems logical but has not been reported. The coincident presentation of these findings in a single patient, and our subsequent discovery of other patients harboring these mutual findings prompted further investigation., Case Illustration: We describe the case of a patient born with a cleft palate which was repaired during his first year of life, subsequently presenting as a teenager to our hospital with a severe and symptomatic complex Chiari malformation. We discuss his treatment strategy, suboccipital decompression with occipitocervical fusion and endoscopic anterior decompression surgeries, as well as his favorable radiological and clinical outcome, demonstrated at long-interval follow-up. Furthermore, we review his two pathologies, cleft palate and Chiari malformation, and posit a common embryological linkage., Conclusions: The embryologic interaction between the paraxial mesoderm and ectoderm may explain the co-occurrence of cleft palate and complex Chiari malformation in a single patient. Complete radiological, clinical, and genetic evaluation and counseling is advised in this situation and raises the question of whether the presence of a cleft palate independently increases the risk for other skull base developmental abnormalities.

Background: Although ventriculoperitoneal shunt (VPS) surgery is the most frequent surgical treatment for patients with hydrocephalus, modern rates of complications in adults are uncertain., Methods: We performed a retrospective cohort study of adult patients hospitalized at the time of their first recorded procedure code for VPS surgery between 2005 and 2012 at nonfederal acute care hospitals in California, Florida, and New York. We excluded patients who during the index hospitalization for VPS surgery had concomitant codes for VPS revision, central nervous system (CNS) infection, or died during the index hospitalization. Patients were followed for the primary outcome of a VPS complication, defined as the composite of CNS infection or VPS revision. Survival statistics were used to calculate the cumulative rate and incidence rate of VPS complications., Results: A total of 17,035 patients underwent VPS surgery. During a mean follow-up of 3.9 (± 1.8) years, at least 1 VPS complication occurred in 23.8% (95% confidence interval [CI], 22.9%-24.7%) of patients. The cumulative rate of CNS infection was 6.1% (95% CI, 5.7%-6.5%) and of VPS revision 22.0% (95% CI, 21.1%-22.9%). Most complications occurred within the first year of hospitalization for VPS surgery. Complication rates were 21.3 (95% CI, 20.6-22.1) complications per 100 patients per year in the first year after VPS surgery, 5.7 (95% CI, 5.3-6.1) in the second year after VPS surgery, and 2.5 (95% CI, 2.1-3.0) in the fifth year after VPS surgery., Conclusions: Complications are not infrequent after VPS surgery; however, most complications appear to be clustered in the first year after VPS insertion., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Little is known about the natural history of non-surgically managed subdural hematoma (SDH). The purpose of this study is to determine rates of adverse events after non-surgical management of SDH and whether these outcomes differ depending on traumatic versus nontraumatic etiology. A retrospective cohort study was conducted using administrative claims data on all emergency department visits and acute care hospitalizations at nonfederal facilities in California from 2005 to 2011, Florida from 2005 to 2012, and New York from 2006 to 2011. We included patients who were discharged home after hospitalization with a first-recorded diagnosis of SDH and no record of surgical hematoma evacuation., Methods: Patients were followed for readmission with SDH, readmission for surgical SDH evacuation, and fatal readmission with SDH. Survival statistics and the log-rank test were used to compare rates of these adverse events after traumatic versus nontraumatic SDH. Multivariable Cox regression analysis was used to compare hazards for traumatic versus nontraumatic etiology while adjusting for age, sex, race, insurance status, presence of dementia, alcohol use, acquired abnormalities in coagulation, acquired abnormalities in platelet function, hypertension, atrial fibrillation, venous thromboembolism, ischemic stroke, coronary heart disease, and valvular disease., Results: We identified 27,502 conservatively treated patients with SDH, of which 70.9% were traumatic and 29.1% nontraumatic. Compared to patients with traumatic SDH, patients with nontraumatic SDH had significantly higher rates of subsequent hospitalization with SDH (cumulative 90-day rates: 15.3 % [95% CI 14.5-16.1%] vs. 10.3% [95% CI 9.9-10.8%]), surgical SDH evacuation (7.8% [95% CI 7.3-8.5%] vs. 5.5% [95% CI 5.2-5.8%]), and SDH-related in-hospital death (1.0% [95% CI 0.8-1.2%] vs. 0.4% [95 % CI 0.3-0.5%]). In multivariable Cox regression analysis, nontraumatic etiology was associated with a higher hazard of readmission with SDH (HR 1.4; 95% CI 1.3-1.5), surgery (HR 1.3; 95% CI 1.2-1.4), and in-hospital mortality (HR 1.9; 95% CI 1.4-2.5). Our findings were unchanged in sensitivity analyses that also adjusted for Elixhauser comorbidities., Conclusions: Approximately one in eight patients with a conservatively managed SDH was readmitted with SDH within 90 days. A substantial proportion of these readmissions involved surgical hematoma evacuation. These outcomes occurred significantly more often after nontraumatic as compared to traumatic SDH.

Tuberous sclerosis complex (TSC) is characterized by developmental malformations of the cerebral cortex known as tubers, comprised of cells that exhibit enhanced mammalian target of rapamycin (mTOR) signaling. To date, there are no reports of mTORC1 and mTORC2 activation in fetal tubers or in neural progenitor cells lacking Tsc2. We demonstrate mTORC1 activation by immunohistochemical detection of substrates phospho-p70S6K1 (T389) and phospho-S6 (S235/236), and mTORC2 activation by substrates phospho-PKCα (S657), phospho-Akt (Ser473), and phospho-SGK1 (S422) in fetal tubers. Then, we show that Tsc2 shRNA knockdown (KD) in mouse neural progenitor cells (mNPCs) in vitro results in enhanced mTORC1 (phospho-S6, phospho-4E-BP1) and mTORC2 (phospho-Akt and phospho-NDRG1) signaling, as well as a doubling of cell size that is rescued by rapamycin, an mTORC1 inhibitor. Tsc2 KD in vivo in the fetal mouse brain by in utero electroporation causes disorganized cortical lamination and increased cell volume that is prevented with rapamycin. We demonstrate for the first time that mTORC1 and mTORC2 signaling is activated in fetal tubers and in mNPCs following Tsc2 KD. These results suggest that inhibition of mTOR pathway signaling during embryogenesis could prevent abnormal brain development in TSC.

A rare neurodevelopmental disorder in the Old Order Mennonite population called PMSE (polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome; also called Pretzel syndrome) is characterized by infantile-onset epilepsy, neurocognitive delay, craniofacial dysmorphism, and histopathological evidence of heterotopic neurons in subcortical white matter and subependymal regions. PMSE is caused by a homozygous deletion of exons 9 to 13 of the LYK5/STRADA gene, which encodes the pseudokinase STRADA, an upstream inhibitor of mammalian target of rapamycin complex 1 (mTORC1). We show that disrupted pathfinding in migrating mouse neural progenitor cells in vitro caused by STRADA depletion is prevented by mTORC1 inhibition with rapamycin or inhibition of its downstream effector p70 S6 kinase (p70S6K) with the drug PF-4708671 (p70S6Ki). We demonstrate that rapamycin can rescue aberrant cortical lamination and heterotopia associated with STRADA depletion in the mouse cerebral cortex. Constitutive mTORC1 signaling and a migration defect observed in fibroblasts from patients with PMSE were also prevented by mTORC1 inhibition. On the basis of these preclinical findings, we treated five PMSE patients with sirolimus (rapamycin) without complication and observed a reduction in seizure frequency and an improvement in receptive language. Our findings demonstrate a mechanistic link between STRADA loss and mTORC1 hyperactivity in PMSE, and suggest that mTORC1 inhibition may be a potential treatment for PMSE as well as other mTOR-associated neurodevelopmental disorders.

Objective: Focal cortical dysplasia type IIB (FCDIIB) is a sporadic developmental malformation of the cerebral cortex highly associated with pediatric epilepsy. Balloon cells (BCs) in FCDIIB exhibit constitutive activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. Recently, the high-risk human papillomavirus type 16 oncoprotein E6 was identified as a potent activator of mTORC1 signaling. Here, we test the hypothesis that HPV16 E6 is present in human FCDIIB specimens., Methods: HPV16 E6 protein expression was assayed by immunohistochemistry in FCDIIB specimens (n = 50) and control brain specimens (n = 36). HPV16 E6 DNA was assayed by polymerase chain reaction (PCR) and in situ hybridization; HPV16 E6 mRNA was assayed by reverse transcriptase PCR. HPV16 E6 was transfected into fetal mouse brains by in utero electroporation to test the effects of E6 on cortical development., Results: HPV16 E6 protein was robustly expressed in all FCDIIB specimens in BCs, but not in regions without BCs or in control tissue specimens including normal brain, lymphoblasts, and fibroblasts, cortical tubers, and U87 glioma cells. E6 expression in FCDIIB colocalized with phosphoactivated S6 protein, a known mTORC1 substrate. HPV16 E6 DNA and mRNA were detected in representative specimens of FCDIIB but not control cortex, and were confirmed by sequencing. Transfection of E6 into fetal mouse brains caused a focal cortical malformation in association with enhanced mTORC1 signaling., Interpretation: Our results indicate a new association between HPV16 E6 and FCDIIB and demonstrate for the first time HPV16 E6 in the human brain. We propose a novel etiology for FCDIIB based on HPV16 E6 expression during fetal brain development., (Copyright © 2012 American Neurological Association.)

Object: The incidence of, and risk factors for, perioperative seizures and the need for perioperative antiepileptic drugs (AEDs) in previously seizure-free children with brain tumors remains unclear. The authors have undertaken a review of previously seizure-free pediatric patients with brain tumors undergoing resection to identify the incidence of seizures in the perioperative period, and to characterize risk factors for perioperative seizures in this population., Methods: A retrospective review was conducted of all patients between 0 and 19 years of age without prior seizures who underwent intracranial tumor resection at the authors' institution between January 2005 and December 2009., Results: Of the 223 patients undergoing 229 operations, 7.4% experienced at least 1 clinical seizure during the surgical admission. Over half of all tumors were supratentorial. Only 4.4% of patients received prophylactic AEDs. Independent factors associated with perioperative seizures included supratentorial tumor, age < 2 years, and hyponatremia due to syndrome of inappropriate antidiuretic hormone or cerebral salt wasting. Tumor type, lobe affected, operative blood loss, and length of surgery were not independently associated with seizure incidence., Conclusions: Perioperative seizures in previously seizure-free children undergoing resection of brain tumors are associated with supratentorial tumor location, age < 2 years, and postoperative hyponatremia. Perioperative seizures are not associated with tumor pathology, tumor size, or frontotemporal location. Due to the low incidence of seizures in this series in patients more than 2 years old with normal serum sodium, the authors recommend that pediatric patients with brain tumors not routinely receive perioperative prophylactic AEDs. However, the role for prophylaxis in patients younger than 2 years of age deserves further study.

Epidermal growth factor (EGF), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF) regulate angiogenesis and cell growth in the developing brain. EGF, HGF, and VEGF modulate the activity of the mammalian target of rapamycin (mTOR) cascade, a pathway regulating cell growth that is aberrantly activated in tuberous sclerosis complex (TSC). We hypothesized that expression of EGF, HGF, VEGF, and their receptors EGFR, c-Met, and Flt-1, respectively, would be altered in TSC. We show by cDNA array and immunohistochemical analysis that EGF, EGFR, HGF, c-Met, and VEGF, but not Flt-1, mRNA, and protein expression was up-regulated in Tsc1 conditional knockout (Tsc1(GFAP)CKO) mouse cortex. Importantly, these alterations closely predicted enhanced expression of these proteins in tuber and subependymal giant cell astrocytoma (SEGA) specimens in TSC. Expression of EGF, EGFR, HGF, c-Met, and VEGF protein, as well as hypoxia inducible factor-1α, a transcription factor that regulates VEGF levels and is also modulated by mTOR cascade activity, was enhanced in SEGAs (n = 6) and tubers (n = 10) from 15 TSC patients. Enhanced expression of these growth factors and growth factor receptors in human SEGAs and tubers and in the Tsc1(GFAP)CKO mouse may account for enhanced cellular growth and proliferation in tubers and SEGAs and provides potential target molecules for therapeutic development in TSC., (Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE) is a rare human autosomal-recessive disorder characterized by abnormal brain development, cognitive disability, and intractable epilepsy. It is caused by homozygous deletions of STE20-related kinase adaptor alpha (STRADA). The underlying pathogenic mechanisms of PMSE and the role of STRADA in cortical development remain unknown. Here, we found that a human PMSE brain exhibits cytomegaly, neuronal heterotopia, and aberrant activation of mammalian target of rapamycin complex 1 (mTORC1) signaling. STRADalpha normally binds and exports the protein kinase LKB1 out of the nucleus, leading to suppression of the mTORC1 pathway. We found that neurons in human PMSE cortex exhibited abnormal nuclear localization of LKB1. To investigate this further, we modeled PMSE in mouse neural progenitor cells (mNPCs) in vitro and in developing mouse cortex in vivo by knocking down STRADalpha expression. STRADalpha-deficient mNPCs were cytomegalic and showed aberrant rapamycin-dependent activation of mTORC1 in association with abnormal nuclear localization of LKB1. Consistent with the observations in human PMSE brain, knockdown of STRADalpha in vivo resulted in cortical malformation, enhanced mTORC1 activation, and abnormal nuclear localization of LKB1. Thus, we suggest that the aberrant nuclear accumulation of LKB1 caused by STRADalpha deficiency contributes to hyperactivation of mTORC1 signaling and disruption of neuronal lamination during corticogenesis, and thereby the neurological features associated with PMSE.

Repetition suppression (RS) is a reduction of neural response that is often observed when stimuli are presented more than once. Many functional magnetic resonance imaging (fMRI) studies have exploited RS to probe the sensitivity of cortical regions to variations in different stimulus dimensions; however, the neural mechanisms underlying fMRI-RS are not fully understood. Here we test the hypothesis that long-interval (between-trial) and short-interval (within-trial) RS effects are caused by distinct and independent neural mechanisms. Subjects were scanned while viewing visual scenes that were repeated over both long and short intervals. Within the parahippocampal place area (PPA) and other brain regions, suppression effects relating to both long- and short-interval repetition were observed. Critically, two sources of evidence indicated that these effects were engendered by different underlying mechanisms. First, long- and short-interval RS effects were entirely noninteractive even although they were measured within the same set of trials during which subjects performed a constant behavioral task, thus fulfilling the formal requirements for a process dissociation. Second, long- and short-interval RS were differentially sensitive to viewpoint: short-interval RS was only significant when scenes were repeated from the same viewpoint while long-interval RS less viewpoint-dependent. Taken together, these results indicate that long- and short-interval fMRI-RS are mediated by different neural mechanisms that independently modulate the overall fMRI signal. These findings have important implications for understanding the results of studies that use fMRI-RS to explore representational spaces.

A key component of spatial navigation is the ability to use visual information to ascertain where one is located and how one is oriented in the world. We used functional magnetic resonance imaging to examine the neural correlates of this phenomenon in humans. Subjects were scanned while retrieving different kinds of topographical and nontopographical information in response to visual scenes. In the three critical conditions, they viewed images of a familiar college campus, and reported either the location of the place depicted in the image (location task), the compass direction that the camera was facing when the image was taken (orientation task), or whether the location was on campus or not (familiarity task). Our analyses focused on the retrosplenial cortex (RSC)/parietal-occipital sulcus region and the parahippocampal place area (PPA), which previous studies indicate play a critical role in place recognition. RSC activity depended on the type of information retrieved, with the strongest response in the location task. In contrast, PPA activity did not depend on the retrieval task. Additional analyses revealed a strong effect of familiarity in RSC but not in the PPA, with the former region responding much more strongly to images of the familiar campus than to images of an unfamiliar campus. These results suggest that the PPA and RSC play distinct but complementary roles in place recognition. In particular, the PPA may primarily support perception of the immediate scene, whereas RSC may support memory retrieval mechanisms that allow the scene to be localized within the broader spatial environment.

Experiments were done on commercial potato crops in the UK to investigate the effect of different insecticide sequences on the control and insecticide resistance status of Myzus persicae (Sulzer). The work was done to provide field validation of similar laboratory studies done in 'field simulators'. To ensure adequate aphid populations and to influence the initial resistance status of the aphid population, cultured M. persicae from a clone of known resistance status (esterase R1, kdr heterozygote, non-MACE (modified acetylcholinesterase)) were inoculated into both experiments. Two-spray programmes starting with lambda-cyhalothrin (a pyrethroid insecticide) gave poor control in comparison with programmes starting with pirimicarb (a carbamate insecticide) or pirimicarb-containing mixtures. This concurred closely with the results obtained from single applications in field simulator studies. Treatment sequences containing pymetrozine (a pyridine azomethine insecticide) were also effective, though slower-acting. This again concurs with field simulator studies. The proportions of aphids carrying different resistance mechanisms were largely unaffected by treatment in these experiments. The implications of these results for field control strategies are discussed., (Copyright (c) 2006 Society of Chemical Industry.)

Populations of many phloem-feeding aphid species in temperate regions increase exponentially in early summer and then 'disappear', usually over a time-scale of a few days, in July. To understand these dynamics, empirical investigation of the causes and modelling of the processes underlying population change are required. Numbers of the aphids Myzus persicae(Sulzer) and Macrosiphum euphorbiae (Thomas), monitored over three years in commercial potato fields in the UK, increased to a maximum of 2-2.5 per leaflet on 16 July in 1999 and 2001, and then declined to < 0.25 per leaflet by 26 July. In 2000, aphid numbers remained very low (< 0.25 per leaflet) throughout the season. The onset of the crash in aphid numbers (16-19 July in 1999 and 2001) was consistently associated with changes in the phloem amino acid composition of potato leaflets. Natural enemies, including syrphids, parasitoids, coccinellids, chrysopids and entomopathogenic fungi, increased in abundance throughout the sampling period. The incidence of winged emigrant aphids prior to the crash was low (< 10%). Experimental manipulation during 2001 demonstrated that, during the crash period, the fecundity of aphids (caged on leaves to exclude natural enemies) was depressed by 25-45% relative to earlier in the season, and that presence of natural enemies reduced aphid numbers by up to 68%. Using these data, an excitable medium model was constructed, which provided a robust description of aphid population dynamics in terms of plant development-induced changes in aphid fecundity and temporal change in natural enemy pressure.

To define plant 'nutritional quality' for aphids, the causal basis of the variation in aphid performance between host plants of different developmental ages was explored using the aphids Myzus persicae and Macrosiphum euphorbiae on potato plants (Solanum tuberosum). Both aphid species performed better on developmentally young ('pre-tuber-filling') plants than on mature ('tuber-filling') plants. Aphid performance did not vary with leaf phloem sucrose:amino acid ratio but could be related to changes in the amino acid composition of the phloem, which included a developmental shift from high glutamine levels in pre-tuber-filling plants to low glutamine levels in tuber-filling plants. Aphid performance on chemically defined 'young' and 'old' diets, with amino acid composition corresponding to that of phloem amino acid composition in pre-tuber-filling and tuber-filling plants, respectively, confirmed that phloem amino acid composition contributed to low aphid performance on tuber-filling plants. The relatively poor performance on 'old' diets could be accounted for, at least in part, by depressed feeding rates. These data suggest that amino acid composition of the phloem is one factor shaping the nutritional quality of plants for aphids.