Treatment of Medically Refractory Cancer Pain with a Combination of Intrathecal Neuromodulation and Neurosurgical Ablation: Case Series and Literature Review

Objective Up to 90% of patients with advanced cancer experience intractable pain. For these patients, oral analgesics are the mainstay of therapy, often augmented with intrathecal drug delivery. Neurosurgical ablative procedures have become less commonly used, though their efficacy has been well‐established. Unfortunately, little is known about the safety of ablation in the context of previous neuromodulation. Therefore, the aim of this study is to present the results from a case series in which patients were treated successfully with a combination of intrathecal neuromodulation and neurosurgical ablation. Design Retrospective case series and literature review. Setting Three institutions with active cancer pain management programs in the U nited S tates. Methods All patients who underwent both neuroablative and neuromodulatory procedures for cancer pain were surveyed using the visual analog scale prior to the first procedure, before and after a second procedure, and at long‐term follow‐up. Based on initial and subsequent presentation, patients underwent intrathecal morphine pump placement, cordotomy, or midline myelotomy. Results Five patients (2 male, 3 female) with medically intractable pain (initial VAS  = 10) were included in the series. Four subjects were initially treated with intrathecal analgesic neuromodulation, and 1 with midline myelotomy. Each patient experienced recurrence of pain ( VAS  ≥ 9) following the initial procedure, and was therefore treated with another modality (intrathecal, N = 1; midline myelotomy, N = 1; percutaneous radiofrequency cordotomy, N = 3), with significant long‐term benefit ( VAS 1–7). Conclusion In cancer patients with medically intractable pain, intrathecal neuromodulation and neurosurgical ablation together may allow for more effective control of cancer pain.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108610/1/pme12481.pd

Effects of Forest Fragment Area on Interactions Between Plants and Their Natural Enemies: Consequences for Plant Diversity at Multiple Spatial Scales

Density-dependent interactions between plants and their natural enemies, including fungal pathogens and insect herbivores, help maintain plant species coexistence and diversity at local scales (α-diversity). However, turnover in plant species composition across space also contributes to biodiversity at larger spatial scales (β-diversity). Despite mounting evidence that enemies can maintain α-diversity, we know little about their contributions to β-diversity. Additionally, in the light of widespread habitat fragmentation and potentially modified insect and pathogen communities in forest fragments, the effects of fragment area on their diversity-maintaining roles are largely unknown. We carried out a field experiment to investigate how natural enemies in impact tree α and β-diversity in a fragmented rainforest landscape in the Western Ghats, India. In 21 rainforest fragments, we suppressed insects and fungi/oomycetes with pesticides, and examined changes in the diversity of tree seedlings. We found that fungicide had no effect on α-diversity, but significantly decreased β-diversity (species turnover among plots). The facilitative effects of fungi and oomycetes on β-diversity, however, weakened as fragments decreased in area, indicating that certain specialized plant-pathogen interactions may be lost when fragments become smaller. Insecticide, in contrast, increased α-diversity but tended to decrease β-diversity between distant plots. In summary, we found that interactions between plants and their natural enemies help maintain β-diversity in large forest fragments but not in small fragments. Small fragments are often viewed as future reservoirs of biodiversity in human-dominated landscapes, but our findings suggest that modified interactions with natural enemies may result in the erosion of this diversity over time

“Orthotopic” ossiculum terminale persistens and atlantoaxial instability in a child less than 12 years of age: a case report and review of the literature

We report ossiculum terminale persistens associated with atlantoaxial instability in a child less than 12 years of age. Static and dynamic X-rays, thin-cut computed tomography with sagittal and coronal reconstructions, and magnetic resonance imaging of the cervical spine showed atlantoaxial instability and an “orthotopic” ossiculum terminale persistens. This pathologic state was differentiated from the primary ossification center at the tip of the odontoid, which normally is not expected to fuse with the body of the odontoid until the age of 12 years. The patient was taken to the operating room for a posterior instrumented fusion of C1 and C2. The patient has done well in short- and long-term follow-up

Comparative secretome analysis of Colletotrichum falcatum identifies a cerato-platanin protein (EPL1) as a potential pathogen-associated molecular pattern (PAMP) inducing systemic resistance in sugarcane

Colletotrichum falcatum, an intriguing hemibiotrophic fungal pathogen causes the devastating red rot disease of sugarcane. Repeated in vitro subculturing of C. falcatum under dark condition alters morphology and reduces virulence of the culture. Hitherto, no information is available on this phenomenon at molecular level. In this study, the in vitro secretome of C. falcatum cultured under light and dark conditions was analyzed using 2-DE coupled with MALDI TOF/TOF MS. Comparative analysis identified nine differentially abundant proteins. Among them, seven proteins were less abundant in the dark-cultured C. falcatum, wherein only two protein species of a cerato-platanin protein called EPL1 (eliciting plant response-like protein) were found to be highly abundant. Transcriptional expression of candidate high abundant proteins were profiled during host-pathogen interaction using qRT-PCR. Comprehensively, this comparative secretome analysis identified five putative effectors, two pathogenicity-related proteins and one pathogen-associated molecular pattern (PAMP) of C. falcatum. Functional characterization of three distinct domains of the PAMP (EPL1) showed that the major cerato-platanin domain (EPL1 Δ N1–92) is exclusively essential for inducing defense and hypersensitive response (HR) in sugarcane and tobacco, respectively. Further, priming with EPL1 Δ N1–92 protein induced systemic resistance and significantly suppressed the red rot disease severity in sugarcane. Biological significance Being the first secretomic investigation of C. falcatum, this study has identified five potential effectors, two pathogenicity-related proteins and a PAMP. Although many reports have highlighted the influence of light on pathogenicity, this study has established a direct link between light and expression of effectors, for the first time. This study has presented the influence of a novel N-terminal domain of EPL1 in physical and biological properties and established the functional role of major cerato-platanin domain of EPL1 as a potential elicitor inducing systemic resistance in sugarcane. Comprehensively, the study has identified proteins that putatively contribute to virulence of C. falcatum and for the first time, demonstrated the potential role of EPL1 in inducing PAMP-triggered immunity (PTI) in sugarcane

Deep Brain Stimulation for Obsessive Compulsive Disorder: Evolution of Surgical Stimulation Target Parallels Changing Model of Dysfunctional Brain Circuits

Obsessive compulsive disorder (OCD) is a common, disabling psychiatric disease characterized by persistent, intrusive thoughts and ritualistic, repetitive behaviors. Deep brain stimulation (DBS) is thought to alleviate OCD symptoms by modulating underlying disturbances in normal cortico-striato-thalamo-cortical (CSTC) circuitry. Stimulation of the ventral portion of the anterior limb of the internal capsule (ALIC) and underlying ventral striatum (“ventral capsule/ventral striatum” or “VC/VS” target) received U.S. FDA approval in 2009 for patients with severe, treatment-refractory OCD. Over the decades, DBS surgical outcome studies have led to an evolution in the electrical stimulation target. In parallel, advancements in neuroimaging techniques have allowed investigators to better visualize and define CSTC circuits underlying the pathophysiology of OCD. A critical analysis of these new data suggests that the therapeutic mechanism of DBS for OCD likely involves neuromodulation of a widespread cortical/subcortical network, accessible by targeting fiber bundles in the ventral ALIC that connect broad network regions. Future studies will include advances in structural and functional imaging, analysis of physiological recordings, and utilization of next-generation DBS devices. These tools will enable patient-specific optimization of DBS therapy, which will hopefully further improve outcomes

State of the world's birds

We present an overview of the global spatiotemporal distribution of avian biodiversity, changes in our knowledge of that biodiversity, and the extent to which it is imperilled. Birds are probably the most completely inventoried large taxonomic class of organisms, permitting a uniquely detailed understanding of how the Anthropocene has shaped their distributions and conservation status in space and time. We summarize the threats driving changes in bird species richness and abundance, highlighting the increasingly synergistic interactions between threats such as habitat loss, climate change, and overexploitation. Many metrics of avian biodiversity are exhibiting globally consistent negative trends, with the International Union for Conservation of Nature's Red List Index showing a steady deterioration in the conservation status of the global avifauna over the past three decades. We identify key measures to counter this loss of avian biodiversity and associated ecosystem services, which will necessitate increased consideration of the social context of bird conservation interventions in order to deliver positive transformative change for nature

Order in Spontaneous Behavior

Brains are usually described as input/output systems: they transform sensory input into motor output. However, the motor output of brains (behavior) is notoriously variable, even under identical sensory conditions. The question of whether this behavioral variability merely reflects residual deviations due to extrinsic random noise in such otherwise deterministic systems or an intrinsic, adaptive indeterminacy trait is central for the basic understanding of brain function. Instead of random noise, we find a fractal order (resembling Lévy flights) in the temporal structure of spontaneous flight maneuvers in tethered Drosophila fruit flies. Lévy-like probabilistic behavior patterns are evolutionarily conserved, suggesting a general neural mechanism underlying spontaneous behavior. Drosophila can produce these patterns endogenously, without any external cues. The fly's behavior is controlled by brain circuits which operate as a nonlinear system with unstable dynamics far from equilibrium. These findings suggest that both general models of brain function and autonomous agents ought to include biologically relevant nonlinear, endogenous behavior-initiating mechanisms if they strive to realistically simulate biological brains or out-compete other agents

The Case for Adaptive Neuromodulation to Treat Severe Intractable Mental Disorders

Mental disorders are a leading cause of disability worldwide, and available treatments have limited efficacy for severe cases unresponsive to conventional therapies. Neurosurgical interventions, such as lesioning procedures, have shown success in treating refractory cases of mental illness, but may have irreversible side effects. Neuromodulation therapies, specifically Deep Brain Stimulation (DBS), may offer similar therapeutic benefits using a reversible (explantable) and adjustable platform. Early DBS trials have been promising, however, pivotal clinical trials have failed to date. These failures may be attributed to targeting, patient selection, or the “open-loop” nature of DBS, where stimulation parameters are chosen ad hoc during infrequent visits to the clinician’s office that take place weeks to months apart. Further, the tonic continuous stimulation fails to address the dynamic nature of mental illness; symptoms often fluctuate over minutes to days. Additionally, stimulation-based interventions can cause undesirable effects if applied when not needed. A responsive, adaptive DBS (aDBS) system may improve efficacy by titrating stimulation parameters in response to neural signatures (i.e., biomarkers) related to symptoms and side effects. Here, we present rationale for the development of a responsive DBS system for treatment of refractory mental illness, detail a strategic approach for identification of electrophysiological and behavioral biomarkers of mental illness, and discuss opportunities for future technological developments that may harness aDBS to deliver improved therapy

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data