Hydrocephalus is a common neurological disorder leading to expansion of the cerebral ventricles and is associated with significant morbidity and mortality. Most neonatal cases are of unknown etiology and are likely to display complex inheritance involving multiple genes and environmental factors. Identifying molecular mechanisms for neonatal hydrocephalus and developing non-invasive treatment modalities are high priorities. Here we employ a hydrocephalic mouse model of the human ciliopathy Bardet-Biedl Syndrome (BBS) and identify a role for neural progenitors in the pathogenesis of neonatal hydrocephalus. We found that hydrocephalus in this mouse model is caused by aberrant PDGFRα signaling, resulting in increased apoptosis and impaired proliferation of NG2+PDGFRα+ neural progenitors. Targeting this pathway with lithium treatment rescued NG2+PDGFRα+ progenitor cell proliferation in BBS mutant mice, reducing ventricular volume. Our findings demonstrate that neural progenitors are critical in the pathogenesis of neonatal hydrocephalus and we identify novel therapeutic targets for this common neurological disorder.

Object The surgical management of infants with sagittal synostosis has traditionally relied on open cranial vault remodeling (CVR) techniques; however, minimally invasive technologies, including endoscope-assisted craniectomy (EAC) repair followed by helmet therapy (HT, EAC+HT), is increasingly used to treat various forms of craniosynostosis during the 1st year of life. In this study the authors determined the costs associated with EAC+HT in comparison with those for CVR. Methods The authors performed a retrospective case-control analysis of 21 children who had undergone CVR and 21 who had undergone EAC+HT. Eligibility criteria included an age less than 1 year and at least 1 year of clinical follow-up data. Financial and clinical records were reviewed for data related to length of hospital stay and transfusion rates as well as costs associated with physician, hospital, and outpatient clinic visits. Results The average age of patients who underwent CVR was 6.8 months compared with 3.1 months for those who underwent EAC+HT. Patients who underwent EAC+HT most often required the use of 2 helmets (76.5%), infrequently required a third helmet (13.3%), and averaged 1.8 clinic visits in the first 90 days after surgery. Endoscope-assisted craniectomy plus HT was associated with shorter hospital stays (mean 1.10 vs 4.67 days for CVR, p < 0.0001), a decreased rate of blood transfusions (9.5% vs 100% for CVR, p < 0.0001), and a decreased operative time (81.1 vs 165.8 minutes for CVR, p < 0.0001). The overall cost of EAC+HT, accounting for hospital charges, professional and helmet fees, and clinic visits, was also lower than that of CVR ($37,255.99 vs $56,990.46, respectively, p < 0.0001). Conclusions Endoscope-assisted craniectomy plus HT is a less costly surgical option for patients than CVR. In addition, EAC+HT was associated with a lower utilization of perioperative resources. Theses findings suggest that EAC+HT for infants with sagittal synostosis may be a cost-effective first-line surgical option.

Introduction: Researchinto the pathogenesis, molecular signaling, and treatment of glioblastoma multiforme (GBM) has traditionally been conducted using cell lines derived from malignant gliomas. We compared protein expression patterns between solid primary GBMs and GBM cell lines to identify proteins whose expression may be altered in cell culture. Methods: We cultured cell lines U87, U118, U251, and A172 and used tissue-selective microdissection of eight primary GBMs to obtain pure populations of tumor cells, which we studied using two-dimensional gel electrophoresis (2DGE) and examined using differential expression software. Select protein targets expressed differentially between GBM tumors and GBM cell lines were sequenced using tandem mass spectrometry. Results: Analysis of the primary GBM tumor samples (n = 8) and the GBM cell lines revealed reproducibly similar proteomic patterns for each group, which distinguished tumors from the cell lines. Gels contained up to 500 proteins that were consistently identified in the pH 4 to 7 range. Comparison of proteins identified in the GBM tumors and in the cell lines showed f160 proteins that were gained and 60 proteins that were lost on culture. Using normalized intensity patterns from the 2DGE images, ANOVA tests were done and statistically significant spots were identified. Seven proteins found in the cell lines were significantly increased when compared with the GBM tumors (P < 0.05), whereas 10 proteins were significantly decreased from cell lines compared with the GBM tumors. Proteins identified included transcription factors, tumor suppressor genes, cytoskeletal proteins, and cellular metabolic proteins. Conclusion: Global protein and proteomic differences were identified between primary GBM tumor samples and GBM cell lines. The proteins identified by 2DGE analysis elucidate some of the selection pressures of in vitro culture, help accentuate the advantages and limitations of cell culture, and may aid comprehension of gliomagenesis and enhance development of new therapeutics.

Neural tube defects (NTDs) are a set of disorders that occur from perturbation of normal neural development. They occur in open or closed forms anywhere along the craniospinal axis and often result from a complex interaction between environmental and genetic factors. One burgeoning area of genetics research is the effect of cilia signaling on the developing neural tube and how the disruption of primary cilia leads to the development of NTDs. Recent progress has implicated the hedgehog (Hh), wingless-type integration site family (Wnt), and planar cell polarity (PCP) pathways in primary cilia as involved in normal neural tube patterning. A set of disorders involving cilia function, known as ciliopathies, offers insight into abnormal neural development. In this article, the authors discuss the common ciliopathies, such as Meckel-Gruber and Joubert syndromes, that are associated with NTDs, and review cilia-related signaling cascades responsible for mammalian neural tube development. Understanding the contribution of cilia in the formation of NTDs may provide greater insight into this common set of pediatric neurological disorders.

Detection of light in the eye underlies image-forming-vision, but also regulates adaptive responses in physiology and behavior. Typically these adaptive responses do not involve image-forming-vision, but depend on a relatively absolute measure of brightness (non-image-forming irradiance detection). The goal of this study was to further understand how image-forming-vision and non-image-forming irradiance detection contribute to the effects of light on behavior. Three light dependent behaviors were assessed in wild-type, Rpe65−/− and rd1 mice. In Rpe65−/− mice, non-image-forming irradiance detection is severely attenuated, but rod based visual acuity is relatively preserved. In rd1 mice visual acuity is non-recordable, but non-image-forming responses are less severely attenuated than Rpe65−/−. Positive masking, a image-forming-vision dependent increase in wheel running, was absent in rd1 and restricted to higher irradiances in Rpe65−/−. Negative masking, a suppression of wheel running sensitivity with non-image-forming irradiance detection input, was increased in rd1, but reduced in Rpe65−/− mice. By contrast, light-aversion, an avoidance of brightly lit areas, was abolished in both Rpe65−/−and rd1. This shows that image-forming-vision is not sufficient for light-aversion, suggesting non-image-forming irradiance detection motivates this behavior. Further, the differing effects of disease suggest that negative masking and light-aversion are distinct responses with specialized non-image-forming irradiance detection pathways.

Object Hydrocephalus remains a major public health problem. Conventional treatment has relied on extracranial shunting of CSF to another systemic site, but this approach is associated with a high rate of complications. Endoscopic third ventriculostomy (ETV) is a novel treatment for select forms of hydrocephalus that can eliminate the need for implantation of a lifelong ventricular shunt system. However, the indications for ETV are contested and its long-term effectiveness is not well established. Methods The authors selected 100 consecutive patients who underwent ETV for hydrocephalus beginning in 1994. Patients were enrolled and treated at a single institution by a single surgeon. The primary outcome was success of ETV, with success defined as no need for subsequent surgery for hydrocephalus. Results Ninety-five patients satisfied the inclusion criteria. The mean follow-up period was 5.1 years (median 4.7 years) with follow-up data available for as long as 17 years. Patients commonly presented with headache (85%), ataxia (34%), emesis (29%), and changes in vision (27%). The success rate for ETV was 75%. Twenty-one patients (22%) in the series had malfunctioning shunts preoperatively and 13 (62%) were successfully treated with ETV. Preoperative inferior bowing of the third ventricle floor on MRI was significantly associated with ETV success (p < 0.05). Conclusions Endoscopic third ventriculostomy is an effective and durable treatment for select patients with hydrocephalus. When successful, the procedure eliminates the lifelong complications associated with implanted ventricular shunts.

Object Vagus nerve stimulation (VNS) has demonstrated benefit in patients with medically intractable partial epilepsy. As in other therapies with mechanical devices, hardware failure occurs, most notably within the VNS lead, requiring replacement. However, the spiral-designed lead electrodes wrapped around the vagus nerve are often encased in dense scar tissue hampering dissection and removal. The objective in this study was to characterize VNS lead failure and lead revision surgery and to examine VNS efficacy after placement of a new electrode on the previously used segment of vagus nerve. Methods The authors reviewed all VNS lead revisions performed between October 2001 and August 2011 at the University of Iowa Hospitals and Clinics. Twenty-four patients underwent 25 lead revisions. In all cases, the helical electrodes were removed, and a new lead was placed on the previously used segment of vagus nerve. All inpatient and outpatient records of the 25 lead revisions were retrospectively reviewed. Results Four cases were second lead revisions, and 21 cases were first lead revisions. The average time to any revision was 5 years (range 1.8–11.1 years), with essentially no difference between a first and second lead revision. The most common reason for a revision was intrinsic lead failure resulting in high impedance (64%), and the most common symptom was increased seizure frequency (72%). The average duration of surgery for the initial implantation in the 15 patients whose VNS system was initially implanted at the authors' institution was much shorter (94 minutes) than the average duration of lead revision surgery (173 minutes). However, there was a significant trend toward shorter surgical times as more revision surgeries were performed. Sixteen of the 25 cases of lead revision were followed up for more than 3 months. In 15 of these 16 cases, the revision was as effective as the previous VNS lead. In most of these cases, both the severity and frequency of seizures were decreased to levels similar to those following the previous implantation procedure. Only 1 complication occurred, and there were no postoperative infections. Conclusions Lead revision surgery involving the placement of a new electrode at the previously used segment of vagus nerve is effective at decreasing the seizure burden to an extent similar to that obtained following the initial VNS implantation. Even with multiple lead revisions, patients can obtain VNS efficacy similar to that following the initial lead implantation. There is a learning curve with revision surgery, and overall the duration of surgery is longer than for the initial implantation. Note, however, that complications and infection are rare.

Pheochromocytoma is a neuroendocrine tumor associated with a variety of genetic disorders, which include von Hippel-Lindau disease (VHL), multiple endocrine neoplasia type 2 (MEN 2), neurofibromatosis type 1, hereditary paraganglioma, and succinate dehydrogenase gene-related tumors. Previous studies of VHL-associated and MEN 2-associated pheochromocytomas suggest morphological, biochemical, and clinical differences exist among the tumors, but the process by which they develop remains unclear. Studies in other VHL-associated tumors suggest that VHL gene deficiency causes coexpression of erythropoietin (Epo) and its receptor (Epo-R), which facilitates tumor growth. The objective of this study was to understand the different process of tumorigenesis for VHL and MEN 2-associated pheochromocytomas. Ten pheochromocytomas (VHL patients n = 5, MEN 2 patients n = 5) were examined for the presence or absence of Epo and Epo-R using Western blot, immunohistochemistry, and RT-PCR analyses. Coexpression of Epo and Epo-R was found in all five VHL-associated pheochromocytomas; in contrast, expression of Epo-R, but not Epo, was documented in all five MEN 2-associated pheochromocytomas. Expression of Epo appears to be a result of VHL gene deficiency, possibly through activation of the hypoxia inducible factor-1 pathway, whereas Epo-R is an embryonal marker whose sustained expression in both VHL- and MEN 2-associated pheochromocytomas reflects an arrest or defect in development. These findings suggest an alternative process of tumorigenesis in VHL- and MEN 2-associated pheochromocytomas and implicate Epo as a clinical biomarker to differentiate these tumors.