Andrew T. Hale

MLKL Requires the Inositol Phosphate Code to Execute Necroptosis

Necroptosis is an important form of lytic cell death triggered by injury and infection, but whether mixed lineage kinase domain-like (MLKL) is sufficient to execute this pathway is unknown. In a genetic selection for human cell mutants defective for MLKL-dependent necroptosis, we identified mutations in IPMK and ITPK1, which encode inositol phosphate (IP) kinases that regulate the IP code of soluble molecules. We show that IP kinases are essential for necroptosis triggered by death receptor activation, herpesvirus infection, or a pro-necrotic MLKL mutant. In IP kinase mutant cells, MLKL failed to oligomerize and localize to membranes despite proper receptor-interacting protein kinase-3 (RIPK3)-dependent phosphorylation. We demonstrate that necroptosis requires IP-specific kinase activity and that a highly phosphorylated product, but not a lowly phosphorylated precursor, potently displaces the MLKL auto-inhibitory brace region. These observations reveal control of MLKL-mediated necroptosis by a metabolite and identify a key molecular mechanism underlying regulated cell death.

Differentiating meningioma grade by imaging features on magnetic resonance imaging

Atypical meningioma has an aggressive clinical course. Distinguishing atypical from benign meningioma preoperatively could affect surgical planning and improve treatment outcomes. In this study, we examined whether pre-operative magnetic resonance imaging (MRI) features could distinguish between benign and atypical meningioma. Imaging factors analyzed included peritumoral edema, the presence of a draining vein, tumor necrosis, tumor location and tumor volume. Using univariate analysis, the most striking predictor of grade was tumor volume (p < .001). When adjusting for the degree of peritumoral edema, volume remained a positive predictor of higher histological grade meningioma (p = .042) and was the strongest single predictor of higher-grade meningioma in this study. Additional imaging features associated with increased risk for atypical pathology in univariate analysis included the presence of tumor necrosis (p = .012), peritumoral edema (p = .022) and location along the falx and convexity (p = .026). Despite statistically significant associations using univariate analysis, in multivariate analysis, we found that only presence of peritumoral edema was predictive of a higher-grade meningioma. Further multivariate analyses suggests that edema, draining vein and necrosis are all positive predictors of tumor volume (p < .0001). Overall, these data suggest that radiographic features including presence of tumor necrosis, and tumor location along the falx or convexity may be predictive of higher-grade meningioma when considered alone. However, most strikingly, our data point to tumor volume as the most robust pre-operative indicator of higher-grade meningioma.

Modulation of intestinal sulfur assimilation metabolism regulates iron homeostasis

Significance Regulation of iron homeostasis is perturbed in numerous pathologic states. Thus, identifications of mechanisms responsible for iron metabolism have broad implications for disease modification. Here, we link the sulfur assimilation pathway to iron-deficiency anemia. Deletion of bisphosphate 3′-nucleotidase (Bpnt1), a key component of the sulfur assimilation pathway, leads to accumulation of phosphoadenosine phosphate (PAP), causing iron deficiency anemia in part due to inhibition of hypoxia-inducible factor 2-α. Reduction of PAP through introduction of a hypomorphic mutation in 3′-phosphoadenosine 5-phosphosulfate synthase 2 gene (Papss2, the enzyme responsible for PAP production) rescues the iron deficiency phenotype. Sulfur assimilation is an evolutionarily conserved pathway that plays an essential role in cellular and metabolic processes, including sulfation, amino acid biosynthesis, and organismal development. We report that loss of a key enzymatic component of the pathway, bisphosphate 3′-nucleotidase (Bpnt1), in mice, both whole animal and intestine-specific, leads to iron-deficiency anemia. Analysis of mutant enterocytes demonstrates that modulation of their substrate 3′-phosphoadenosine 5′-phosphate (PAP) influences levels of key iron homeostasis factors involved in dietary iron reduction, import and transport, that in part mimic those reported for the loss of hypoxic-induced transcription factor, HIF-2α. Our studies define a genetic basis for iron-deficiency anemia, a molecular approach for rescuing loss of nucleotidase function, and an unanticipated link between nucleotide hydrolysis in the sulfur assimilation pathway and iron homeostasis.

A Case of a 4-Year-Old Female with a Primary Spinal Malignancy Presenting with Froin's Syndrome

We report the case of a 4-year-old female with a primary extradural intramedullary atypical teratoid/rhabdoid tumor (AT/RT) leading to a middle cerebral artery (MCA) infarct and Froins syndrome. She presented with a 6-pound weight loss over the previous week, as well as a decreased urinary output and an altered mental status. She underwent a brain MRI that revealed a left MCA infarct, mild ventriculomegaly, and bilateral internal carotid artery, M1, and A1 stenosis. An external ventricular drain (EVD) was placed due to increased intracranial pressure. Cerebrospinal fluid (CSF) was analyzed via lumbar puncture that revealed extremely elevated protein. However, CSF sampled from the EVD was completely normal, a phenomenon called Froins syndrome. The following day, she developed a right MCA infarct. Her grim prognosis was discussed with her family and care was eventually withdrawn. The patient underwent an autopsy which confirmed a spinal AT/RT. To our knowledge, this is the first reported case of stroke and Froins syndrome as the initial manifestations of a primary spinal AT/RT with a late onset of spinal cord compression due to tumor obstruction.

Invasive Insular Sampling in Pediatric Epilepsy: A Single-Institution Experience

BACKGROUND It has been increasingly recognized that the insular cortex plays an important role in frontotemporal-parietal epilepsy in children. The insula, however, cannot be properly interrogated with conventional subdural grids, and its anatomy makes it difficult to implicate the insula with semiology or noninvasive modalities. Frame-based, stereotactic placement of insular depth electrodes for direct extraoperative monitoring is a relatively low-risk maneuver that allows for conclusive interrogation of this region, and, in select cases, can easily be replaced with a laser applicator for minimally invasive treatment via thermoablation. OBJECTIVE To describe the largest reported series of pediatric patients with refractory epilepsy undergoing insular depth electrode placement. METHODS We used current procedural terminology billing records to identify cases of depth electrode insertion performed at our institution. Clinical information from patients undergoing invasive insular sampling was then retrospectively collected. RESULTS Seventy-four insular depth electrodes were placed in 49 patients for extraoperative, inpatient monitoring. The decision to place insular depth electrodes was determined by a multidisciplinary epilepsy team. In 65.3% of cases, direct invasive sampling implicated the insula in seizure onset and prompted either thermoablation or surgical resection of some portion of the insula. There were no serious adverse effects or complications associated with the placement of insular depth electrodes. CONCLUSION Given the low morbidity of insular depth electrode insertion and the high proportion of patients who exhibited insular involvement, it is worth considering whether insular depth electrodes should be part of the standard presurgical evaluation in children with treatment-refractory frontotemporal-parietal epilepsy.

Emerging Insights and New Perspectives on the Nature of Hydrocephalus

(e.g., cyst, tumor) can cause an “obstructive hydrocephalus” in which the reabsorption mechanisms are presumably intact, but bulk flow is blocked and the ventricles dilate proximal to the obstruction. In both variants, ventricular dilation is thought to be the end result of hydrostatic pressure build-up within the ventricles. Though perhaps intuitive, the preceding narrative of CSF physiology and pathophysiology is surprisingly thinly supported by empirical evidence. Furthermore, recent investigations, both in the realm of basic science using animal models and radiological sciences using advanced imaging techniques (e.g., cine phase-contrast MRI), have directly challenged many of the underlying assumptions of the classical dogma. Belgian scientist Georges LeMaitre, the physicist who first proposed the Big Bang theory, recognized that even a single experiment that yielded observations inconsistent with the fundamental claims of the theory risked invalidating the entire hypothesis [4] . At the very least, such an experiment would mandate a modification of the theory to account for the new and discordant observations. Only recently has the neurosurgical community begun to apply the same level of scientific rigor to the study of hydrocephalus. In a 2006 report by Bergsneider et al. [5] , the provocative and important question was posed: “...is there more to hydrocephalus than our long-held and oversimplified concept of it as a plumbing problem of mismatched CSF production and resorption...?” Asking questions and challenging old beliefs is only the first step. But it is the Introduction

Instrumented fusion in a 12-month-old with atlanto-occipital dislocation: case report and literature review of infant occipitocervical fusion

BackgroundThe treatment of atlantoaxial dislocation in very young children is challenging and lacks a consensus management strategy.DiscussionWe review the literature on infantile occipitocervical (OC) fusion is appraised and technical considerations are organized for ease of reference. Surgical decisions such as graft type and instrumentation details are summarized, along with the use of bone morphogenic protein and post-operative orthoses.Illustrative caseWe present the case of a 12-month-old who underwent instrumented occipitocervical (OC) fusion in the setting of traumatic atlanto-occipital dislocation (AOD).ConclusionOccipitocervical (OC) arthrodesis is obtainable in very young infants and children. Surgical approaches are variable and use a combination of autologous grafting and creative screw and/or wire constructs. The heterogeneity of pathologic etiology leading to OC fusion makes it difficult to make definitive recommendations for surgical management.