Strength of spatial correlation between gray matter connectivity and patterns of proto-oncogene and neural network construction gene expression is associated with diffuse glioma survival.

Introduction: Like other forms of neuropathology, gliomas appear to spread along neural pathways. Accordingly, our group and others have previously shown that brain network connectivity is highly predictive of glioma survival. In this study, we aimed to examine the molecular mechanisms of this relationship via imaging transcriptomics. Methods: We retrospectively obtained presurgical, T1-weighted MRI datasets from 669 adult patients, newly diagnosed with diffuse glioma. We measured brain connectivity using gray matter networks and coregistered these data with a transcriptomic brain atlas to determine the spatial co-localization between brain connectivity and expression patterns for 14 proto-oncogenes and 3 neural network construction genes. Results: We found that all 17 genes were significantly co-localized with brain connectivity (p < 0.03, corrected). The strength of co-localization was highly predictive of overall survival in a cross-validated Cox Proportional Hazards model (mean area under the curve, AUC = 0.68 +/- 0.01) and significantly (p < 0.001) more so for a random forest survival model (mean AUC = 0.97 +/- 0.06). Bayesian network analysis demonstrated direct and indirect causal relationships among gene-brain co-localizations and survival. Gene ontology analysis showed that metabolic processes were overexpressed when spatial co-localization between brain connectivity and gene transcription was highest (p < 0.001). Drug-gene interaction analysis identified 84 potential candidate therapies based on our findings. Discussion: Our findings provide novel insights regarding how gene-brain connectivity interactions may affect glioma survival.

Strength of spatial correlation between structural brain network connectivity and brain-wide patterns of proto-oncogene and neural network construction gene expression is associated with diffuse glioma survival.

Like other forms of neuropathology, gliomas appear to spread along neural pathways. Accordingly, our group and others have previously shown that brain network connectivity is highly predictive of glioma survival. In this study, we aimed to examine the molecular mechanisms of this relationship via imaging transcriptomics. We retrospectively obtained presurgical, T1-weighted MRI datasets from 669 adult patients, newly diagnosed with diffuse glioma. We measured brain connectivity using gray matter networks and coregistered these data with a transcriptomic brain atlas to determine the spatial co-localization between brain connectivity and expression patterns for 14 proto-oncogenes and 3 neural network construction genes. We found that all 17 genes were significantly co-localized with brain connectivity (p < 0.03, corrected). The strength of co-localization was highly predictive of overall survival in a cross-validated Cox Proportional Hazards model (mean area under the curve, AUC = 0.68 +/- 0.01) and significantly (p < 0.001) more so for a random forest survival model (mean AUC = 0.97 +/- 0.06). Bayesian network analysis demonstrated direct and indirect causal relationships among gene-brain co-localizations and survival. Gene ontology analysis showed that metabolic processes were overexpressed when spatial co-localization between brain connectivity and gene transcription was highest (p < 0.001). Drug-gene interaction analysis identified 84 potential candidate therapies based on our findings. Our findings provide novel insights regarding how gene-brain connectivity interactions may affect glioma survival.

General Anesthesia Blocks Pain-Induced Hemorrhage and Locomotor Deficits After Spinal Cord Injury in Rats.

Research has shown that engaging pain (nociceptive) pathways after spinal cord injury (SCI) aggravates secondary injury and undermines locomotor recovery. This is significant because SCI is commonly accompanied by additional tissue damage (polytrauma) that drives nociceptive activity. Cutting communication with the brain by means of a surgical transection, or pharmacologically transecting the cord by slowly infusing a sodium channel blocker (lidocaine) rostral to a thoracic contusion, blocks pain-induced hemorrhage. These observations suggest that the adverse effect of pain after SCI depends on supraspinal (brain) systems. We hypothesize that inhibiting brain activity using a general anesthetic (e.g., pentobarbital, isoflurane) should have a protective effect. The present study shows that placing rats in an anesthetic state with pentobarbital or isoflurane 24 h after a lower thoracic contusion injury blocks pain-induced intraspinal inflammation and hemorrhage when administered before pain. Pentobarbital also extends protective effects against locomotor deficits produced by noxious stimulation. Inducing anesthesia after noxious stimulation, however, has no effect. Similarly, subanesthetic dosages of pentobarbital were also ineffective at blocking pain-induced hemorrhage. Also examined were the hemodynamic impacts of both pain and anesthetic delivery after SCI. Peripheral pain-input induced an acute increase in systolic blood pressure; isoflurane and pentobarbital prevent this increase, which may contribute to the protective effect of anesthesia. The results suggest that placing patients with SCI in a state akin to a medically induced coma can have a protective effect that blocks the adverse effects of pain.

X-Linked Agammaglobulinemia Leading to Chronic Obstructive Lung Disease.

X-linked agammaglobulinemia (XLA) is a rare primary immunodeficiency disorder. It occurs in around one in 200,000 live births and is caused by mutations in the Bruton Tyrosine Kinase (BTK) gene leading to B lymphocyte deficiency and increased susceptibility to infection. Infection is the most common initial clinical presentation, followed by family history and neutropenia. Even in patients with a positive family history, only 34% of patients were diagnosed before clinical symptoms arose. Over half of patients are diagnosed by two years of age. Treatment is aimed at replacing immunoglobulin using intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG) and prophylactic antibiotics to prevent infections. Despite these therapies, patients still suffer from repetitive infections. Another significant source of morbidity in patients with XLA is a chronic lung disease. By the time of diagnosis, 62% of patients had at least one case of pneumonia. We describe the case of a patient who has developed an accelerated course of chronic obstructive pulmonary disease (COPD) secondary to pre-existing X-linked agammaglobulinemia and recurrent respiratory infections.

Learning to promote recovery after spinal cord injury.

The present review explores the concept of learning within the context of neurorehabilitation after spinal cord injury (SCI). The aim of physical therapy and neurorehabilitation is to bring about a lasting change in function-to encourage learning. Traditionally, it was assumed that the adult spinal cord is hardwired-immutable and incapable of learning. Research has shown that neurons within the lower (lumbosacral) spinal cord can support learning after communication with the brain has been disrupted by means of a thoracic transection. Noxious stimulation can sensitize nociceptive circuits within the spinal cord, engaging signal pathways analogous to those implicated in brain-dependent learning and memory. After a spinal contusion injury, pain input can fuel hemorrhage, increase the area of tissue loss (secondary injury), and undermine long-term recovery. Neurons within the spinal cord are sensitive to environmental relations. This learning has a metaplastic effect that counters neural over-excitation and promotes adaptive learning through an up-regulation of brain-derived neurotrophic factor (BDNF). Exposure to rhythmic stimulation, treadmill training, and cycling also enhances the expression of BDNF and counters the development of nociceptive sensitization. SCI appears to enable plastic potential within the spinal cord by down-regulating the Cl- co-transporter KCC2, which reduces GABAergic inhibition. This enables learning, but also fuels over-excitation and nociceptive sensitization. Pairing epidural stimulation with activation of motor pathways also promotes recovery after SCI. Stimulating motoneurons in response to activity within the motor cortex, or a targeted muscle, has a similar effect. It is suggested that a neurofunctionalist approach can foster the discovery of processes that impact spinal function and how they may be harnessed to foster recovery after SCI.