Cranioectodermal dysplasia (CED) is a disorder characterized by craniofacial, skeletal, and ectodermal abnormalities. Most cases reported to date are sporadic, but a few familial cases support an autosomal-recessive inheritance pattern. Aiming at the elucidation of the genetic basis of CED, we collected 13 patients with CED symptoms from 12 independent families. In one family with consanguineous parents two siblings were affected, permitting linkage analysis and homozygosity mapping. This revealed a single region of homozygosity with a significant LOD score (3.57) on chromosome 3q21-3q24. By sequencing candidate genes from this interval we found a homozygous missense mutation in the IFT122 (WDR10) gene that cosegregated with the disease. Examination of IFT122 in our patient cohort revealed one additional homozygous missense change in the patient from a second consanguineous family. In addition, we found compound heterozygosity for a donor splice-site change and a missense change in one sporadic patient. All mutations were absent in 340 control chromosomes. Because IFT122 plays an important role in the assembly and maintenance of eukaryotic cilia, we investigated patient fibroblasts and found significantly reduced frequency and length of primary cilia as compared to controls. Furthermore, we transiently knocked down ift122 in zebrafish embryos and observed the typical phenotype found in other models of ciliopathies. Because not all of our patients harbored mutations in IFT122, CED seems to be genetically heterogeneous. Still, by identifying CED as a ciliary disorder, our study suggests that the causative mutations in the unresolved cases most likely affect primary cilia function too.

The Hedgehog (Hh) signaling pathway plays a key role in cell fate specification, proliferation, and survival during mammalian development. Cells require a small organelle, the primary cilium, to respond properly to Hh signals and the key regulators of Hh signal transduction exhibit dynamic localization to this organelle when the pathway is activated. Here, we investigate the role of Cell Cycle Related kinase (CCRK) in regulation of cilium-dependent Hh signaling in the mouse. Mice mutant for Ccrk exhibit a variety of developmental defects indicative of inappropriate regulation of this pathway. Cell biological, biochemical and genetic analyses indicate that CCRK is required to control the Hedgehog pathway at the level or downstream of Smoothened and upstream of the Gli transcription factors, Gli2 and Gli3. In vitro experiments indicate that Ccrk mutant cells show a greater deficit in response to signaling over long time periods than over short ones. Similar to Chlamydomonas mutants lacking the CCRK homolog, LF2, mouse Ccrk mutant cells show defective regulation of ciliary length and morphology. Ccrk mutant cells exhibit defects in intraflagellar transport (the transport mechanism used to assemble cilia), as well as slowed kinetics of ciliary enrichment of key Hh pathway regulators. Collectively, the data suggest that CCRK positively regulates the kinetics by which ciliary proteins such as Smoothened and Gli2 are imported into the cilium, and that the efficiency of ciliary recruitment allows for potent responses to Hedgehog signaling over long time periods.

Epidural electrical stimulation (EES) of the spinal cord has been shown to restore function after spinal cord injury (SCI). Characterization of EES-evoked motor responses has provided a basic understanding of spinal sensorimotor network activity related to EES-enabled motor activity of the lower extremities. However, the use of EES-evoked motor responses to guide EES system implantation over the spinal cord and their relation to post-operative EES-enabled function in humans with chronic paralysis attributed to SCI has yet to be described. Herein, we describe the surgical and intraoperative electrophysiological approach used, followed by initial EES-enabled results observed in 2 human subjects with motor complete paralysis who were enrolled in a clinical trial investigating the use of EES to enable motor functions after SCI. The 16-contact electrode array was initially positioned under fluoroscopic guidance. Then, EES-evoked motor responses were recorded from select leg muscles and displayed in real time to determine electrode array proximity to spinal cord regions associated with motor activity of the lower extremities. Acceptable array positioning was determined based on achievement of selective proximal or distal leg muscle activity, as well as bilateral muscle activation. Motor response latencies were not significantly different between intraoperative recordings and post-operative recordings, indicating that array positioning remained stable. Additionally, EES enabled intentional control of step-like activity in both subjects within the first 5 days of testing. These results suggest that the use of EES-evoked motor responses may guide intraoperative positioning of epidural electrodes to target spinal cord circuitry to enable motor functions after SCI.

Glioblastoma (GBM) is the most common primary brain tumor in adults an carries and carries a terrible prognosis. The current regiment of surgical resection, radiation, and chemotherapy has remained largely unchanged in recent years as new therapeutic approaches have struggled to demonstrate benefit. One of the most challenging hurdles to overcome in developing novel treatments is the profound immune suppression found in many GBM patients. This limits the utility of all manner of immunotherapeutic agents, which have revolutionized the treatment of a number of cancers in recent years, but have failed to show similar benefit in GBM therapy. Understanding the mechanisms of tumor-mediated immune suppression in GBM is critical to the development of effective novel therapies, and reversal of this effect may prove key to effective immunotherapy for GBM. In this review, we discuss the current understanding of tumor-mediated immune suppression in GBM in both the local tumor microenvironment and systemically. We also discuss the effects of current GBM therapy on the immune system. We specifically explore some of the downstream effectors of tumor-driven immune suppression, particularly myeloid-derived suppressor cells (MDSCs) and other immunosuppressive monocytes, and the manner by which GBM induces their formation, with particular attention to the role of GBM-derived extracellular vesicles (EVs). Lastly, we briefly review the current state of immunotherapy for GBM and discuss additional hurdles to overcome identification and implementation of effective therapeutic strategies.

OBJECT Anterior nuclear (AN) stimulation has been reported to reduce the frequency of seizures, in some cases dramatically; however, it has not been approved by the US Food and Drug Administration. The anterior nucleus is difficult to target because of its sequestered location, partially surrounded by the ventricle. It has traditionally been targeted by using transventricular or lateral transcortical routes. Here, the authors report a novel approach to targeting the anterior nucleus and neurophysiologically confirming effective stimulation of the target, namely evoked potentials in the hippocampus. METHODS Bilateral AN 3389 electrodes were placed in a novel trajectory followed by bilateral hippocampal 3391 electrodes from a posterior trajectory. Each patient was implanted bilaterally with a Medtronic Activa PC+S device under an investigational device exemption approval. Placement was confirmed with CT. AN stimulation-induced hippocampal evoked potentials were measured to functionally confirm placement in the anterior nucleus. RESULTS Two patients had implantations by way of a novel AN trajectory with concomitant hippocampal electrodes. There were no lead misplacements. Postoperative stimulation of the anterior nucleus with a PC+S device elicited evoked potentials in the hippocampus. Thus far, both patients have reported a > 50% improvement in seizure frequency. CONCLUSIONS Placing AN electrodes posteriorly may provide a safer trajectory than that used for traditionally placed AN electrodes. In addition, with a novel battery that is capable of electroencephalographic recording, evoked potentials can be used to functionally assess the Papez circuit. This treatment paradigm may offer increased AN stimulation efficacy for medically intractable epilepsy by assessing functional placement more effectively and thus far has proven safe.

Field and greenhouse studies were conducted to evaluate herbicides in pumpkin. Field experiments at three Illinois locations determined weed control and crop injury from clomazone, dimethenamid, ethalfluralin, sulfentrazone, imazamox, RPA 201772, flumiclorac, and halosulfuron applied preemergence. Clomazone plus sulfentrazone controlled redroot pigweed 78 to 99%, ivyleaf morningglory 80 to 97%, common lambsquarters 97%, common purslane 84 to 99%, and velvetleaf 55 to 99%. Imazamox plus clomazone commonly provided more consistent broadleaf weed control than did ethalfluralin plus clomazone. RPA 201772 when used on sandy soils killed the pumpkin. Sulfentrazone initially caused chlorosis and necrosis on pumpkin seedlings when soil organic matter was low (< 1%) or when soil moisture was high. However, plants recovered rapidly, and yields were not affected. In a greenhouse study pumpkin was more tolerant to clomazone plus sulfentrazone than to sulfentrazone.

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OBJECTIVEThe authors sought to investigate the incidence and predictors of venous thromboembolic events (VTEs) after craniotomy for tumor resection, which are not well established, and the efficacy of and risks associated with VTE chemoprophylaxis, which remains controversial.METHODSThe authors investigated the incidence of VTEs in a consecutive series of patients presenting to the authors’ institution for resection of an intracranial lesion between 2012 and 2017. Information on patient and tumor characteristics was collected and independent predictors of VTEs were determined using stepwise multivariate logistic regression analysis. Review of the literature was performed by searching MEDLINE using the keywords “venous thromboembolism,” “deep venous thrombosis,” “pulmonary embolism,” “craniotomy,” and “brain neoplasms.”RESULTSThere were 1622 patients included for analysis. A small majority of patients were female (52.6%) and the mean age of the cohort was 52.9 years (SD 15.8 years). A majority of intracranial lesions were intraaxial (59.3%). The incidence of VTEs was 3.0% and the rates of deep venous thromboses and pulmonary emboli were 2.3% and 0.9%, respectively. On multivariate analysis, increasing patient age (unit OR 1.02, 95% CI 1.00–1.05; p = 0.018), history of VTE (OR 7.26, 95% CI 3.24–16.27; p < 0.001), presence of motor deficit (OR 2.64, 95% CI 1.43–4.88; p = 0.002), postoperative intracranial hemorrhage (OR 4.35, 95% CI 1.51–12.55; p < 0.001), and prolonged intubation or reintubation (OR 3.27, 95% CI 1.28–8.32; p < 0.001) were independently associated with increased odds of a VTE. There were 192 patients who received VTE chemoprophylaxis (11.8%); the mean postoperative day of chemoprophylaxis initiation was 4.6 (SD 3.8). The incidence of VTEs was higher in patients receiving chemoprophylaxis than in patients not receiving chemoprophylaxis (8.3% vs 2.2%; p < 0.001). There were 30 instances of clinically significant postoperative hemorrhage (1.9%), with only 1 hemorrhage occurring after initiation of VTE chemoprophylaxis (0.1%).CONCLUSIONSThe study results show the incidence and predictors of VTEs after craniotomy for tumor resection in this patient population. The incidence of VTE within this cohort appears low and comparable to that observed in other institutional series, despite the lack of routine prophylactic anticoagulation in the postoperative setting.