Most researchers leverage bottom-up suppression to unlock the underlying mechanisms of unconscious processing. However, a top-down approach – for example via hypnotic suggestion – paves the road to experimental innovation and complementary data that afford new scientific insights concerning attention and the unconscious. Drawing from a reliable taxonomy that differentiates subliminal and preconscious processing, we outline how an experimental trajectory that champions top-down suppression techniques, such as those practiced in hypnosis, is uniquely poised to further contextualize and refine our scientific understanding of unconscious processing. Examining subliminal and preconscious methods, we demonstrate how instrumental hypnosis provides a reliable adjunct that supplements contemporary approaches. Specifically, we provide an integrative synthesis of the advantages and shortcomings that accompany a top-down approach to probe the unconscious mind. Our account provides a larger framework for complementing the results from core studies involving prevailing subliminal and preconscious techniques. The unconscious mind fascinates and challenges human thinking . PervasiRecovering from a volatile history plagued by quackery and charlatanism, hypnosis has become a viable venue of cognitive science . At leasUsing hypnosis in the study of the unconscious mind dates back to early psychodynamic conceptions when analysts leveraged hypnotism to probe unconscious thoughts and feelings of analysands . RevisitWe review contemporary suppression and inattention techniques to assess their relative merits and drawbacks. Thereafter, we contrast the strengths and weaknesses of contemporary approaches – i.e., subliminal and preconscious methods – with those of instrumental hypnosis. Showcasing findings using hypnosis, we sketch out how this top-down approach provides the experimental means to foster new perspectives to study the unconscious mind.Subliminal and preconscious approaches represent active areas of research within the domain of unconscious cognition . Guided Figure 1; The global workspace model entails that unconscious processing of sensory events occurs in two ways: conscious suppression of sensory signals, corresponding to perceptual failures, and preconscious processing of sensory events reflecting attentional failures . In this procedure, both stimuli compete to access consciousness, resulting in the temporary conscious suppression of the ineffective stimulus , which elicits longer and deeper suppression compared to BR (Frontiers in Psychology research topic on conscious suppression). Importantly, interocular suppression techniques yield competition at the sensory level and at the representational level . Bistable representations reflect the inherent ambiguity conveyed by these images as our brain processes resolve these competing interpretations , these failures to detect prominent task-irrelevant stimuli occur when individuals engage in a demanding cognitive task  and CB mainly reflect lapses of attention, wherein unattended signals lack the necessary energy and sustainability to reach conscious perception . Both exUnattended events during IB and CB induce preconscious processing, yielding priming effects e.g., , impliciIn a stream of rapidly presented visual stimuli, attending to a task-related stimulus impairs attentional processing of subsequent stimuli at short latencies . This atFigure 1; Subliminal approaches exploit the limits of perception to suppress awareness of sensory events . These tThe broad range of mechanisms selectively engaged by each of the abovementioned methods challenges our capacity to generalize findings across different tasks. As we explained, these techniques yield important findings about the scope and depth of subliminal and preconscious processing. Notably, bottom-up approaches afford researchers with plentiful experimental control, yet offer limited ecological validity. Conversely, top-down approaches, such as IB and CB, propose an ecological tactic to investigate unconscious processing , but remFigure 3), we follow the criteria put forth in the literature (To assess the aforementioned techniques (see terature . This se(i)Generality: whether the technique applies to a broad range of stimuli or only to a select few.(ii)Stimulus location: whether the stimulus has to be presented at the center or the periphery of the visual field.(iii)Temporal constraint: whether the technique imposes a temporal constraint relative to the duration of the stimulus presentation.(iv)Robustness: whether this technique completely abolishes awareness.(v)Invariant stimulation: whether conscious suppression requires significant modifications of sensory events to make a stimulus invisible – e.g., adding a mask to induce conscious suppression during backward masking.Hypnosis represents an increasingly popular area of research in cognitive science, including notable ventures in the domains of perception, attention, memory, and motor control . For exaTheoretical frameworks for hypnosis largely cluster around the appellations of state and non-state models. State theories posit that hypnosis implies a particular psychological state – e.g., an altered state of consciousness – whereas non-state theories typically argue that hypnosis essentially reduces to sociocognitive factors such as motivation and compliance . In spitTop-down regulatory processes – e.g., attention, cognitive control and monitoring – play a central role in mediating responses to hypnotic suggestions . SpecifiEmphasizing the importance of individual variability, compliant participants frequently report using different cognitive strategies to successfully respond to the very same suggestion . This inFigure 4; Figure 5), a significant experimental benefit to better isolate the NCC. The content of hypnotic suggestions selectively targets specific mental functions and behaviors. Thus, we will demonstrate how hypnosis encompasses a wide variety of experimental possibilities to investigate unconscious processes . Here we discuss several avenues based on such research developments.Hypnotic suggestions divide as a function of type and content .Hypnosis also modulates phenomenological aspects of conscious experience, such as pain perception . Called Posthypnotic amnesia (PHA) represents memory lapses of events that took place under hypnosis, after termination of hypnotic induction . AffordiPast research shows that temporarily irretrievable material influences behavior nonetheless . For exaContrary to PHA, few studies looked at the effects of hypnotic agnosia – i.e., the functional inability to access semantic knowledge . This reHypnosis can decouple volitions and actions . HypnotiIntrusive cognitions and emotions often accompany psychopathology . In ordeIn experimental psychopathology, hypnotic suggestions target specific functions and dramatically influence cognitions and behaviors . For exaThe fields of neuropsychology and behavioral neurology often feature deficits that are amenable to top-down influences  at diffeWhether hypnosis acts through suppressive means or influences attention to impede conscious access, this top-down methodological approach possesses formidable potential to study the unconscious mind. Two general features make hypnosis a unique approach. First, hypnotic suggestions afford researchers with a wide spectrum of experimental possibilities. Second, whereas the prevailing approaches either take advantage of perceptual limitations or interfere with top-down amplification processes, hypnosis harness top-down processes to investigate both subliminal and preconscious phenomena. Indeed, due to the variety of hypnotic suggestions, hypnosis can prompt perceptual and attentional failures. Also, the accuracy of hypnosis  allows rFigure 1). During hypnotically induced subliminal and preconscious processing, hypnotic responses recruit frontal networks implicated in top-down attentional regulation, control and monitoring processes : this approach applies to a broad range of visual and non-visual stimuli; works equally well for stimuli presented centrally or peripherally; hardly necessitates temporal constraint relative to the presentation of the stimulus or variation in sensory events. Finally, various experiments imply the robustness of unconscious hypnotic phenomena, even if the phenomenological dimensions of hypnosis remain roughly defined (Overall, the use of hypnosis to investigate the cognitive unconscious compares favorably to contemporary methodologies (see  defined . This ap defined . In compDespite these benefits, certain obstacles to the use of hypnosis in the context of the suppression of consciousness might arise. Here we address some of these concerns. First, HHSs are often carefully selected in hypnosis experiments to demonstrate the full potential of hypnotic suggestions , despiteA final concern pertains to the objective control of subjects’ awareness, a central issue that transcends research on conscious and unconscious processes . AlongsiHere we herald instrumental hypnosis as a new experimental vehicle to probe the structure and functioning of the cognitive unconscious. Whereas most current techniques investigate the unconscious mind via subliminal approaches that challenge our perceptual limitations and preconscious approaches that rest on inattention, the hypnosis lens facilitates both suppression and inattention via top-down mechanisms. Beyond the empirical potential to explore novel ideas and hypotheses, top-down control provides scientists with increased experimental flexibility by allowing target processing of specific sensory events. Moreover, hypnotic hallucinations provide an efficient means to capture the NCC using a full two-by-two balanced design allowing for a direct comparison of conscious and unconscious conditions. Thus, scholars stand to benefit from the use of hypnosis in their quest to better understand the underpinnings of the unconscious mind . IncorpoThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The cerebellum plays an important role in motor control. The cerebellar key players include Purkinje cells (PCs), mossy fibers, climbing fibers, and parallel fibers. Each PC receives inputs from many parallel fibers and from a single climbing fiber. Cerebellar outputs originate from the deep cerebellar and vestibular nuclei. Cerebellar nuclei (CN) neurons receive inhibitory inputs from PCs and excitatory inputs from mossy fiber and climbing fiber collaterals. In this work, we studied how regular and irregular, as well as synchronous and asynchronous, PC firing frequencies affect the eye movements in mice and CN neuron model behavior. Floccular PCs on one side of the head were optogenetically stimulated . We use


Mental health care services play an important role following disasters  program over a 2-year period following two major Australian bushfire and flood/cyclone disasters. Predictor variables examined in negative binomial regression analysis included consumer  and event characteristics (disaster type).The bushfire disaster resulted in significantly greater service volume, with more than twice the number of referrals and nearly three times the number of sessions. Service delivery for both disasters peaked in the third quarter. Consumers affected by bushfires, diagnosed with depression, anxiety, or both of these disorders utilized sessions at significantly higher rates.The substantial demand for primary mental health services following disaster can vary with disaster type. Disaster type and need-based variables as key drivers of service use intensity indicate an equitable level of service use. Established usage patterns assist with estimating future service capacity requirements. Flexible referral pathways can enhance access to disaster mental health care. Future research should examine the impact of program- and agency-level factors on mental health service use and factors underpinning treatment non-adherence following disaster.


The ideal cancer therapy not only induces the death of all localized tumor cells, but also activates a systemic antitumor immunity. High intensity focused ultrasound (HIFU) has the potential to be such a treatment, as it can non-invasively ablate a targeted tumor below the skin surface, and may subsequently augment host antitumor immunity.This talk is to introduce increasing animal and clinical evidences linking antitumor immune response to HIFU ablation, review the potential mechanisms, and discuss challenges and opportunities involved in HIFU-enhanced host antitumor immunity.It is concluded that HIFU immunotherapy may play an important role in preventing local recurrence and metastasis of cancer after HIFU treatment.


The last decade has witnessed an exponential increase in the researches being carried out to combat aging using drug therapy. Few specific drugs like Metformin, Rapamycin and Resveratrol have displayed promising results in anti-aging research of mice, fruit fly and worm. Basically these drugs interfere genetically with the important aging pathways such as IIS, TOR, and NAD+ dependent pathway, and results in lifespan extension in a number of species ranging from worm to mammals .Drosophila resulting in lifespan extension along with increased stress resistance, reduced fecundity and increased lipid levels. Also rapamycin treatment has shown to further extend the lifespan of some long lived IIS mutants, and dietary restricted flies, indicating additional mechanisms of lifespan extension [Rapamycin which was originally an immuno-suppressive drug used for kidney transplant patients for years, is an inhibitor of protein kinase target of rapamycin (TOR). Rapamycin inhibits the TOR by forming a complex with FKBP12, which goes on to bind with TOR complex1. The mechanism of rapamycin mediated lifespan extension has largely remained conserved in different model species, for example the genetic mutations/deletions of S6K and 4E-BP in mice and its homologues in worms have resulted in extended lifespan. Rapamycin treatment has led to reduced phosphorylation of S6K in Drosophila. In flies the midgut stability is maintained by multipotent intestinal stem cells (ISCs) in hindgut proliferation zone (HPZ) and controlled by locally emanating Wingless  and Hh signals. Under the stress conditions such as aging, pathogen exposure, genotoxins or ROS inducing compounds, the ISC proliferation increases strongly in order to restore the large parts of intestinal epithelium. The epithelial integrity is disrupted by this regenerative event leading to accumulation of mis-differentiated cells and resulting in a dysplastic pheno-type [Gut has been considered as an unique important target organ in mediating the lifespan extension at the organismal level because of its immunity and nutrition intake . Also theno-type . Intereseno-type .Drosophila as a model system to carry out such study [Drosophila intestinal epithelium. We have proposed that, along with inhibiting mTOR, rapamycin can also significantly delay the microbial expansion by upregulating the negative regulators of IMD/Rel pathway in the aging guts , is significantly up regulated in rapamycin treated flies suggesting that rapamycin can improve the intestinal capacity for antioxidants. The autophagy genes atg1, atg5 and atg8b displayed increased mRNA expression level in intestinal tissues, indicating that rapamycin can induce autophagy and increase the lifespan. The anti-microbial peptide (AMP) gene dpt and the dual oxidase gene (duox), which is associated with reactive oxygen species (ROS) levels, were significantly decreased in rapamycin treated aged guts, indicating that rapamycin may reduce the intestinal ROS accumulation in aging flies . Thus raThese findings clearly show that rapamycin treatment maintains the gut stability during aging in Drosophila, leading to healthspan and lifespan extension. It should be noted that due to the high evolutionary conservation of mTOR pathway in different species, the same mechanism underlying rapamycin treatment could apply in other species as well. Thus rapamycin holds great future potential in various gastrointestinal disorders and cancers along with lifespan extension.


Paraneoplastic neurological syndromes (PNS) are neurologic deficits triggered by an underlying remote tumor. PNS can antedate clinical manifestation of ovarian malignancy and enable its diagnosis at an early stage. Interestingly, neoplasms associated with PNS are less advanced and metastasize less commonly than those without PNS. This suggests that PNS may be associated with a naturally occurring antitumor response.N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis. An approach to the diagnostic workup of underlying tumors is discussed.We review the literature on the diagnosis, pathogenesis and management of PNS associated with ovarian tumors: paraneoplastic cerebellar degeneration (PCD) and anti-PCD can precede the manifestation of ovarian carcinoma. Anti-NMDAR encephalitis in young women appears often as a result of ovarian teratoma. Since ovarian tumors and nervous tissue share common antigens , autoimmune etiology is a probable mechanism of these neurologic disorders. The concept of cross-presentation, however, seems insufficient to explain entirely the emergence of PNS. Early resection of ovarian tumors is a significant part of PNS management and improves the outcome.The diagnosis of PNS potentially associated with ovarian tumor indicates a need for a thorough diagnostic procedure in search of the neoplasm. In some patients, explorative laparoscopy/laparotomy can be considered. PNS precede clinical manifestation of ovarian tumors and enable their diagnosis at an early stage.Paraneoplastic cerebellar degeneration (PCD) can coexist with ovarian carcinoma.Anti-NMDAR antibodies detected in patient affected with encephalitis are highly suggestive of ovarian teratoma.Ovarian tumors and nervous tissue share common antigens in PNS —the concept of cross-presentation, however, may not be sufficient to explain an emergence of PNS.Cell-mediated immune response plays a role in the pathogenesis of PNS.Antibody-mediated immune response is a major mechanism of anti-NMDAR encephalitis and other NSAS.In patients with PNS associated potentially with ovarian tumors, transvaginal ultrasound examination and pelvic CT scan are indicated—if negative, PET imaging is required.If imaging studies remain normal, explorative laparoscopy/laparotomy should be considered.An early resection of ovarian tumors is a significant part of PNS management and improves the outcome.Paraneoplastic neurological syndromes (PNS) are defined as the pathologic involvement of the nervous system in the course of malignancy. This entity does not include tumor infiltration, compression or metastasis of the nervous system , balance and gait disturbances, speech disorder (dysarthria) and altered ocular movements   may display pleocytosis (with a high fraction of lymphocytes), elevated protein or oligoclonal bands  in PCD can reveal cerebellar atrophy  strongly indicates the presence of ovarian tumor in patients with neurological deficit. If the tumor is not identified, an obligation for systematic screening exists. Surgery and immunomodulatory treatment are considered as the most important management among such a group of patients.


In this guest editorial, Andrew Beck discusses the importance of open access to big data for translating knowledge of cancer heterogeneity into better outcomes for cancer patients. Cancer is a heterogeneous disease, which is comprised of a collection of diseases traditionally categorized by tissue type of origin. A distinct set of etiologic causes, treatments, and prognoses are associated with different cancers, and even within a given tissue type, cancer shows significant variability in molecular and clinical features across patients. This interpatient heterogeneity is a major rationale for large-scale research efforts  to comprehensively profile the molecular landscape of patient cancer samples across all major cancers ,2. ThesePLOS Medicine show the potential clinical utility of measuring intratumoral genetic heterogeneity in clinical cancer samples.A major challenge in cancer therapy is the development of resistance to molecularly targeted therapies. Although targeted therapies may show initial benefit in the subset of patients carrying a targeted molecular alteration, most patients will nevertheless go on to develop resistance for most advanced solid cancers. Identifying and overcoming drug resistance represents one of the most significant challenges facing cancer researchers today . It is iIn one, James Brenton, Florian Markowetz, and colleagues applied the Minimum Event Distance for Intra-tumour Copy-number Comparisons (MEDICC) algorithm they recently developed for phylogenetic quantification of intratumoral genetic heterogeneity from multiregion DNA copy number profiling data  to prediThe second study comes from James Rocco and colleagues . PreviouThe continuing generation of high-quality, open-access Omics data sets from large populations of cancer patients will be critically important to enable the development of computational methods to translate knowledge of cancer heterogeneity into new diagnostics and improved clinical outcomes for cancer patients. As one step towards this goal, the DREAM  consortium will use open innovation crowd sourcing to identify top-performing computational methods for inferring genetic heterogeneity from next-generation sequencing data provided by a large multi-institutional community of cancer genomics projects, including the ICGC and TCGA . If succIn parallel with these advances in computational methods for inferring intratumoral heterogeneity from genomics data, genomics technologies for measuring intratumoral heterogeneity at increasingly fine levels of granularity continue to improve. For example, recent advances in single-cell sequencing of DNA have provided detailed portraits of intratumoral genetic heterogeneity and clonal evolution in cancer ,21, and Establishing the clinical utility of these new approaches for measuring intratumoral molecular heterogeneity will require applying these methods to large sets of archival tumor samples from randomized trials of cancer therapeutics  and high


High density microelectrode arrays (MEAs) provide extracellular recordings from thousands of closely spaced electrodes and with sub-millisecond resolution. These devices offer thus novel capabilities to investigate the interplay between ongoing and evoked electrophysiological signaling within networks in-vitro. However, to effectively take advantage from the spatiotemporal resolution of these MEAs, adapted analysis tools are needed. Here we report on our recent advancements toward this goal. A novel high density MEA with on-chip stimulating electrodes was used to record from 4096 electrodes and electrical stimulation was delivered alternatively through one of the 16 equally spaced electrodes on hippocampal primary cultures derived from mouse. The evoked activities propagated reliably across the network and were specific to the stimulating electrode ). Here,


In routine cardiac MRI (CMRI) practice, radiological technologists are expected to optimize and utilize EKGs in gating and physiological monitoring. Many cardiac sequences are critically dependent on heart rate and rhythm and EKG gating problems lead to poor or non-diagnostic images. The technologist's syllabus does not routinely include formal EKG recognition or CMRI trouble-shooting techniques.In this educational exhibit, we describe common EKG rhythms and discuss imaging parameter options for overcoming magneto-hemodynamic effects, dealing with high or low heart rates and abnormal rhythms.An image sequence/EKG rhythm quick algorithm is included for reference and will be the basis of the exhibit.Basic EKG rhythm recognition and imaging optimization tips are the building blocks of good cardiac MRI - something every good CMRI technologist should know but are rarely formally taught.None.


The adult liver has unique regenerative capabilities. Adult livers generally regenerate fully functional liver cells when injured, unlike other vital adult organs which typically respond to cell loss by forming scar tissue. The mechanisms underlying these differences are not well understood, particularly since adult livers are perfectly capable of scarring. In fact, transient scar formation normally occurs in situations that lead to efficient and complete recovery of functional liver mass, such as 70% partial hepatectomy (PH). Scarring also occurs to some extent during many types of chronic liver injury, although progressive scarring (dubbed cirrhosis) occurs in only a minority of individuals with chronic liver injury. Even in cirrhotic livers, however, scarring has been shown to regress gradually once factors driving chronic injury are alleviated. The aggregate data suggested to us that the unique regenerative capabilities of adult livers are linked to its ability to control the formation and regression of scar. Our research has focused on delineating the mechanisms that control scarring. The results will help to clarify why injured livers typically regenerate healthy parenchyma, as well as why other organs replace wounded tissue with scar.The wound healing process necessitates some degree of scarring. Scarring is characterized by excessive extracellular matrix deposition, but also involves inflammation, vascular remodeling, and accumulation of cell types that are relatively inconspicuous in healthy tissues, such as progenitors and myofibroblasts (MF). In adult livers, each of these scarring-related responses is regulated by Hedgehog (Hh), a fetal morphogenic signaling pathway that reactivates during adult liver injury . Hh pathRecently, we proved that canonical Hh signaling controls the fate of liver MF . MF accuRecently, we have begun to evaluate a related novel hypothesis, namely, that Hedgehog controls liver regeneration after PH by modulating the differentiation of these multi-potent myofibroblastic progenitor cells. Transgenic mice were generated to permit conditional deletion of either floxed-Smoothened or floxed-YFP alleles in aSMA-expressing cells. By studying the Smoothened-deleted mice, we were able to determine how selectively abrogating Hh signaling in aSMA(+) cells (and their progeny) influenced regenerative responses to PH. By studying the YFP-marked mice, we were able to track the fate of cells that expressed aSMA after PH. The results demonstrate that Hh signaling in aSMA(+) cells orchestrates both scarring and regeneration after PH; prove that these processes are required for the liver to regenerate normally after PH; and show that post-PH regeneration involves differentiation of myofibroblastic progenitors into hepatocytic and ductular cells .Regeneration of adult livers requires Hh-dependent modulation of epithelial-mesenchymal transitions in multipotent progenitors. Data generated by studying models of acute and chronic liver injury reveal that robust epithelial to mesenchymal transitions (EMT) normally occur in injured livers, and show that conditionally abrogating canonical Hedgehog signaling in multi-potent aSMA-expressing cells blocks these EMT, instead triggering a cascade of mesenchymal-to-epithelial transitions (MET). This has global consequences for liver wound healing. Regeneration of different types of liver cells becomes unbalanced, leading to excessive accumulation of quiescent HSC but reduced outgrowth of hepatocytic and ductular progenitors and their progeny, as well as depletion of MF populations. Thus, de-regulating Hh-sensitive EMT/MET responses disrupts both scarring and regeneration of injured livers. These findings, in turn, suggest that the liver is uniquely suited for regeneration because it harbors large populations of multi-potent progenitors and is generally able to constrain signals, such as Hedgehog, that modulate the differentiation of these cells towards less epithelial  phenotypes.


The human genome contains nearly 400,000 sequences related to retroviruses that have accumulated due to ancient infections of the germ line and subsequent fixation during evolution. Most of these endogenous retroviral sequences (ERVs) currently exist as solitary long terminal repeats (LTRs), the product of recombination between LTRs of the integrated proviral form. Since retroviral LTRs naturally contain transcriptional promoters and enhancers, these sequences have great potential to impact regulation of individual genes and gene regulatory networks. Numerous cases of LTRs serving as promoters for human genes have been described by our group and others, and some examples will be presented. While such co-option of LTRs as regulatory gene modules indeed occurs in normal cells, particularly in placenta or in early development, transcriptional activity of most endogenous LTRs is epigenetically suppressed in somatic tissues, likely as a host defense against unregulated transcription. Cancer cells represent an abnormal epigenetic environment where LTRs and other classes of transposable elements (TEs) are often hypomethylated, leading to their transcriptional activation. This activation could result in abnormal, cancer-specific expression of nearby genes. To study this phenomenon, we are analyzing whole transcriptome data of cancers specifically to identify gene deregulation due to transcriptional activity of LTRs or other TEs. Our results suggest that the regulatory potential of these sequences is often used by cancer cells, providing one avenue to up-regulate genes. Thus, while some LTRs/TEs have been co-opted to serve in normal gene expression, the same regulatory qualities can be exploited in carcinogenesis.


Introduction. Chronic pancreatitis (CP) is considered an inflammatory disease that may cause varying degrees of pancreatic dysfunction. Conservative and surgical treatment options are available depending on dysfunction severity. Presentation of Case. A 36-year-old male with history of heavy alcohol consumption and diagnosed CP underwent a duodenal-preserving pancreatic head resection (DPPHR or Beger procedure) after conservative treatment failure. Refractory pain was reported on follow-up three months after surgery and postoperative imaging uncoveredstones within the main pancreatic duct and intestinal dilation. The patient was subsequently subjected to another surgical procedure and intraoperative findings included protein plugs within the main pancreatic duct and pancreaticojejunal anastomosis stricture. A V-shaped enlargement and main pancreatic duct dilation in addition to the reconstruction of the previous pancreaticojejunal anastomosis were performed. The patient recovered with no further postoperative complications in the follow-up at an outpatient clinic. Discussion. Main duct and pancreaticojejunal strictures are an unusual complication of the Beger procedure but were identified intraoperatively as the cause of patient's refractory pain and explained intraductal protein plugs accumulation. Conclusion. Patients that undergo Beger procedures should receive close outpatient clinical follow-up in order to guarantee postoperative conservative treatment success and therefore guarantee an early detection of postoperative complications. Chronic pancreatitis (CP) is a progressive inflammatory disease that may lead to exocrine and endocrine organ dysfunction . An overA 36-year-old male was referred to an outpatient clinic due to constant chronic abdominal pain. The subject had a history of heavy alcohol intake and was diagnosed with CP. Initial conservative treatment included Omeprazole, Pancreatin, nonsteroidal analgesics, and lifestyle modifications that consisted in a fractionated diet and alcohol intake cessation. Despite conservative treatment, symptoms persisted with progressive weight loss and mild steatorrhea was reported. Initial CT scan showed small calcification areas on pancreatic head and sparse calcifications in pancreatic body and tail. Mild enlargement of the pancreatic head and fibrosis without defined focal lesions  was also present. Main pancreatic duct (maximum diameter of 1.0 cm) and common bile duct dilation were evidenced (maximum diameter of 1.4 cm). Following a 3-year conservative treatment failure, the patient underwent Beger procedure in January 2014 with no intraoperative complications and consisted in pancreatic head resection with main pancreatic duct stenotic portion responsible for main pancreatic duct dilation. Also, no further signs of intrinsic obstruction were found. The subject developed a biliodigestive anastomosis fistula as a postoperative complication that was conservatively treated and was discharged from the hospital. Three months after the Beger procedure, subject reported new onset epigastric and bilateral hypochondrial abdominal pain but no fever, vomiting, weight loss, or any signs of obstruction . Subsequent laboratory findings excluded the possibility of biliary tract obstruction. A CT scan revealed diffuse thickening of small intestine and suggested inflammation near the residual pancreatic parenchyma. A subsequent MRI  evidenceThree surgical approaches have been described so far for chronic pancreatitis: decompression, pancreatic resection, and denervation. Some surgical procedures employ a combination of these approaches. Decompression therapies consist of duodenal-preserving pancreatic head resection (DPPHR) and local resection of the pancreatic head with extended longitudinal pancreaticojejunostomy (LR-LPJ), known as Beger and Frey procedures, respectively. Trials comparing Beger and Frey procedures have shown no statistical difference concerning morbidity, mortality, and pancreatic function, as both ensure gastrointestinal continuity. Frey procedure preserves the posterior capsule of the pancreas and requires pancreaticojejunal anastomosis, while DPPHR requires a pancreaticojejunal and a biliodigestive anastomosis. Therefore, surgical experience should be taken into consideration when electing which technique to perform . ExocrinDuring clinical investigations of refractory pain after Beger procedure, imaging may reveal worsened pancreas parenchymal abnormalities and protein plugs due to defective drainage of a narrowed main pancreatic duct or pancreaticojejunal anastomosis stricture. This case demonstrates an uncommon complication of Beger procedure. Therefore, patients that undergo surgical treatment have to be closely monitored in an outpatient clinic in order to guarantee postoperative conservative treatment and early detection of possible complications related to the initial surgical procedure.


Vestibular migraine (VM) has been increasingly recognized as a possible cause of episodic vertigo, but its pathophysiology is still unclear.We used advanced non-invasive neuroimaging to examine the functional response of neural pathways associated with vestibular stimulation in patients with VM.Twelve patients with VM underwent whole-brain blood oxygen level-dependent (BOLD) fMRI during ear irrigation with cold water. The functional response of neural pathways to this stimulation in patients with VM was compared to age- and gender-matched patients with migraine without aura (MwoA) and healthy controls (HC). Secondary analyses explored associations between BOLD signal change and clinical features of migraine in patients.We observed a robust cortical and subcortical pattern of BOLD signal change in response to ear irrigation across all participants. Patients with VM showed significantly increased thalamic activation in comparison with both patients with MwoA and HC. The magnitude of thalamic activation was positively correlated with the frequency of migraine attacks in patients with VM.We provide novel evidence for abnormal thalamic functional response to vestibular stimulation in patients with VM. These functional abnormalities in central vestibular processing may contribute to VM pathophysiology.No conflict of interest.


Periodontitis is an established common chronic disease, yet its burden on health care costs remains largely neglected. The aim of this study was to estimate the cost of periodontal procedures in dental specialist clinics in the Malaysian public sector.Five periodontal specialist clinics in the Ministry of Health were randomly selected. A list of periodontal procedures was identified by an expert group. Procedures were classified as diagnostics, non-surgical periodontics and periodontal surgeries. Costing for each procedure was primarily activity-based to measure cost of dental equipment, consumables and labour cost (average treatment time). Expenditures for administration, utilities and maintenance at clinics used unit cost calculations employed from step-down approach. A total of 165 patients newly diagnosed with periodontitis were followed up for one year to determine the cost of managing these patients during the said period.A total examination package costed USD38, but separate diagnostics procedures such as full-mouth periodontal assessment, electric pulp test, intraoral and panoramic radiographs costed an average of USD23. For nonsurgical procedures, full-mouth supragingival scaling costed USD68 and full-mouth subgingival debridement costed USD135, higher if with systemic/ local delivery antibiotics. Costs for desensitisation, occlusal adjustments (with selective grinding) and splinting were USD41, USD42 and USD50, respectively. Surgical procedures cost an average of USD294 for resective surgeries and USD613 for regenerative surgeries. The total provider costs for managing periodontitis patients for one year was estimated to be USD805. The costs borne for patients requiring surgeries  was about three-fold  compared to those who required only nonsurgical periodontal treatment (USD540).Specialist dental treatment for periodontitis patients in the public sector is costly. Cost estimates obtained from this study are useful for estimating economic burden of specialist periodontitis management at the national level, as well as providing the basis for economic evaluation of the specialist periodontal care programme.


WGS) and Next Generation Sequencing (here: NGS-CA) approaches were witnessed in the past few years, since cataloging or landscaping all possible cancer aberrations appears to be both scientifically relevant and useful for therapeutic strategies. This search has been performed through Medline using NGS with appropriate cancer types/subtypes definitions and paying particular attention to the major overviews from groups on both sides of the Atlantic . The scope here is to overview general pitfalls and perspectives in the whole area of NGS-CA studies and to suggest probable trends and prudent recommendations.Great increase in Whole Genome Sequencing (elstein:  and 2]))WGS) andWGS-NGS studies have been published so far on neuroblastoma or other pediatric tumors  is stCAN-GEN approach ) demo) demoint pursued  .


A 73-year-old lady sustained mutliple injuries including pelvic fractures and extensive soft tissue injuries to her left groin and thigh after being run over by a car and trailer. Closed internal degloving injury of the left thigh was diagnosed and required surgical management.How should this patient be managed initially?What is a Morel-Lavallee lesion?Describe the pathophysiology of this injury?How is this injury managed surgically?The patient was transferred to a major trauma hospital with injuries to her left arm, trunk, groin, and leg for assessment and management. Initial management followed the Advanced Trauma Life Support principles. On arrival to the emergency department, her airway was patent, breathing spontaneously, with a heart rate of 70, blood pressure of 100/60, and Glasgow Coma Scale of 15. Examination revealed multiple soft tissue and skeletal injuries. Initial investigations showed Hb 90, unremarkable chest X-ray with plain trauma films demonstrating comminuted left superior and inferior pubic rami fractures and left wrist fractures. Computed tomographic scan showed the pelvic fractures and subcutaneous emphysema involving the left anterior thigh and anterior abdominal wall due to extensive thigh degloving injury.The lady sustained significant soft tissue injury and pelvic trauma from a low-velocity motor vehicle accident. On examination, she had extensive contusions and abrasions to the left proximal thigh extending to groin and posteriorly to the buttock, as well as a perineal hematoma. Closed internal degloving injury is caused by blunt injury producing significant soft tissue injury that is associated with pelvic trauma. A Morel-Lavallee lesion is a closed internal degloving injury overlying the greater trochanter.1The injury occurs when the subcutaneous tissue is sheared from the underlying fascia with avulsion of the perforating vessels. The cavity is filled with hematoma and liquefied adipose tissue. The force exerted on the superficial soft tissue also disrupts the vascular supply to the skin. This can also cause abrasions or friction burns.The patient underwent exploration and washout in theater with 1.7 L of haemoserous fluid drained initially from the cavity. Thorough debridement of devascularized tissue is the mainstay of surgical management of internal degloving injuries. Often multiple debridement procedures are required to excise nonviable tissue, with vacuum-assisted closure useful for temporary coverage. (3) In some instances, the patient's condition may dictate a delay to complete debridement. Similarly, extensive open avulsion type soft tissue injuries require staged debridement. (2) Expanding hematoma in the zone of injury may further jeopardize the overlying tissue and requires immediate drainage, either percutaneously or open. (4) Delayed closure of skin flaps and/or split-thickness skin graft are used to repair the defect after adequate debridement. Undamaged but avascular skin can be reapplied to the debrided surface as a full-thickness skin graft after excising the subcutaneous fat. (2) The patient was stabilized in intensive care unit, and the left thigh skin was allowed to demarcate and then debridement and application of negative pressure dressing (vacuum-assisted closure) was performed. She required multiple procedures for further washouts and change of dressings. The defect was reconstructed with split-thickness skin graft  and skin flap repair with sutures and autologous platelet enriched/bovine thrombin glue.Closed internal degloving injuries require prompt surgical assessment. Patient factors including severity of skeletal injuries direct the surgical management of the associated soft tissue injury but debridement and delayed repair remains the mainstay of treatment.


Ranitomeya variabilis. This species deposits its tadpoles and egg clutches in phytotelmata and chemically recognizes and avoids sites with both predatory conspecific and non-predatory heterospecific tadpoles . Combining chemical analyses with in-situ bioassays, we identified the molecular formulas of the chemical compounds triggering this behavior. We found that both species produce distinct chemical compound combinations, suggesting two separate communication systems. Bringing these results into an ecological context, we classify the conspecific R. variabilis compounds as chemical cues, advantageous only to the receivers (the adult frogs), not the emitters (the tadpoles). The heterospecific compounds, however, are suggested to be chemical signals , being advantageous to the emitters (the heterospecific tadpoles) and likely also to the receivers (the adult frogs). Due to these assumed receiver benefits, the heterospecific compounds are possibly synomones which are advantageous to both emitter and receiver ‒ a very rare communication system between animal species, especially vertebrates.The evolution of chemical communication and the discrimination between evolved functions  and unintentional releases (cues) are among the most challenging issues in chemical ecology. The accurate classification of inter- or intraspecific chemical communication is often puzzling. Here we report on two different communication systems triggering the same parental care behavior in the poison frog  Communication in the biological sense is defined by Wilson  as the aRanitomeya variabilis )S1 File(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.


One of the most critical shifts must be away from top-down mercury policy toward active engagement with ASGM communities to effectively address the underlying social and economic reasons why mercury is used. Notably, Annex C of the Convention  requiresStrategies should reflect lessons learned in past programs about the mining policies required for mercury reduction solutions to take hold in ASGM communities. The United Nations Industrial Development Organization (UNIDO) conducted mercury abatement programs in ASGM that yielded some positive results , includiTo convey messages about mercury risks and mercury-free alternatives, community-based approaches can be more effective than conventional technical strategies that have dominated mercury-reduction initiatives. In Zimbabwe, UNIDO mercury abatement campaigns had some promising results in promoting cleaner technologies using such alternative approaches . In KadoFinally, public health officials and others should ensure that ambitious mercury reduction targets are not used as a rationale for harshly policing impoverished mining communities. The government of Zimbabwe implemented heavy-handed police crackdowns on ASGM between 2006 and 2009, which had negative environmental and social repercussions, weakening trust between regulators and low-income mining communities . More thThe challenges of reducing mercury use in ASGM have long been documented, as noted previously . We stro


Controversy exists regarding the structural and functional causes of hallux limitus including metatarsus primus elevatus, long first metatarsal, first ray hypermobility, shape of the first metatarsal head and the presence of hallux interphalangeus. Papers have reported on the radiographic evaluation of these measurements in feet affected by hallux limitus, however no study to date has made direct comparisons between the affected and unaffected foot in a group of patients with unilateral hallux limitus. This case-control pilot study aimed to establish if any such differences existed.Dorsoplantar and lateral weightbearing x-rays of both feet in 30 patients with unilateral hallux limitus were assessed for grade of disease, lateral intermetatarsal angle, metatarsal protrusion distance, plantar gapping at the first metatarso-cuneiform joint, metatarsal head shape and hallux abductus interphalangeus angle. Data analysis was performed using SPSS version 22.0.0.0 .Mean radiographic measurements for both affected and unaffected feet demonstrated that metatarsus primus elevatus, a short first metatarsal, first ray hypermobility, a flat metatarsal head shape and hallux interphalangeus were prevalent in both feet. There was no statistically significant difference found between feet for any of the radiographic parameters measured .No significant differences exist in the presence of structural risk factors examined between the affected and unaffected foot in patients with unilateral hallux limitus. The influence of other intrinsic factors including footedness and family history should be investigated further.


Hypertrophic cardiomyopathy is a common cardiovascular genetic disease characterized by sarcomeric gene mutations which lead to findings of cardiac hypertrophy, myocyte disarray, and fibrosis. While late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) detects focal, macroscopic regions of replacement fibrosis non-invasively, novel T1 CMR measurement techniques including extracellular volume fraction (ECV) diffuse interstitial fibrosis throughout the myocardium. Plasma B-type natriuretic peptide levels are often elevated in situations of increased wall tension and volume overload. Given that such states may be associated with myocardial fibrosis, and because BNP levels provide independent prognostic insight in HCM, we sought to determine the association between BNP and ECV measurement by CMR.We recruited 50 consecutive patients referred to the UPMC Hypertrophic Cardiomyopathy Center and UPMC Cardiovascular Magnetic Resonance Center for clinical evaluation to participate in a prospective cohort formed to describe the association between CMR data and outcomes. Contemporaneous echocardiography, treadmill stress echocardiography, and clinical evaluation data were recorded. BNP levels were obtained as part of routine clinical care or drawn the same day as CMR study using research funding. We computed ECV from measures of pre and post contrast T1 of mid-myocardium and blood (short axis prescriptions at the base and mid ventricle) using modified Look-Locker inversion recovery (MOLLI) pulse sequences. BNP levels were natural log transformed given their skewed distribution. Univariable and multivariable regression models tested for associations between markers of cardiac remodeling as well as other predictors of BNP , left ventricular outflow obstruction, body mass index(BMI), findings of late gadolinium enhancement, ECV). Models were constrained to 4 independent variables to avoid overfitting.There was a moderate correlation  between lnBNP and ECV (Figure We found a novel association between lnBNP and ECV by CMR, after adjustment for confounding variables. The relationship persisted even after including LGE in regression models and stratifying by its presence. BNP and ECV are both strong predictors of adverse events. Detection of diffuse interstitial fibrosis by ECV may be a meaningful imaging biomarker to characterize HCM status, progression, and outcomes and warrants further study.American Heart Association, Pittsburgh Foundation.


Saccadic eye movements are made about twice a second to shift our gaze either consciously or unconsciously. Brainstem burst neurons trigger each saccade with a bursting activity closely related to saccadic velocity that must be transformed into persistent firing activity to maintain post-saccadic eye position. A conceptual neural mechanism achieving this velocity to position integration is the oculomotor neural integrator (NI). Neurons in the nucleus of prepositus hypoglossi (NPH) in mammals and equivalently Area I (AI) in goldfish have been demonstrated to exhibit persistent activity relating to eye position. Ipsilateral positive feedback found in NPH and AI , and comThe model consists of an excitatory burst neuron (EBN), an inhibitory burst neuron (IBN), a tonic neuron (TN), and a bilateral NI network in which 15 integrator neurons (INs) are included unilaterally. Each IN receives input from TN, EBN, and IBN, and also has positive recurrent feedback connections from all ipsilateral INs including commissural inhibitory connections from all contralateral INs. The output of EBN, IBN, and each NI are weighted-summed at a motor neuron whose output is sent to an eye plant model to simulate eye movements. These neuron models are described as conductance-based spiking neurons. Synaptic weights in the model were carefully tuned to reproduce saccades and post-saccadic stable eye positions. Following individual modification of either the synaptic weights of ipsilateral feedback connection or those of commissural inhibition we measured post-saccadic eye position drift.Simulation results showed that persistent firing activity of INs is maintained principally by the ipsilateral positive feedback. By contrast, commissural inhibition contributed mainly to null eye position which is the asymptote from which the NI becomes leaky. These findings are the first demonstration by a NI neuronal network model assigning specific and different roles to the ipsilateral positive feedback and the commissural inhibition. In future work, we will use this model to evaluate the elective eye holding properties within the two hemi-field NIs.


Parkinson’s disease (PD) is one of the most common movement disorders in adults, often cannot be adequately controlled with medical treatment, and thereby treated with the neurosurgical procedures. Unilateral pallidotomy, making a lesion in the globus pallidus pars interna (GPi), was the predominant surgical technique until early 1900s. Thereafter, deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become a mainstream surgical technique for managing not only the cardinal dopaminergic features of PD, but also levodopa-induced motor fluctuations and dyskinesia.Recent review studies, however, reported that unilateral pallidotomy also has long-term effect on both cardinal symptoms  and motor complications . Currently, transcranial magnetic resonance guided focused ultrasound (MRgFUS), without necessity of opening the cranium, has been developed as a minimal invasive surgical technique, generating precise and focal thermal lesion in the brain compared to previous radiofrequency thermal lesion.The authors underwent world first MRgFUS pallidotomy to confirm its efficacy as well as potential side effects. We hereby demonstrated the beneficial effects of MRgFUS pallidotomy in PD patient for improving levodopa induced dyskinesia as well as motor symptoms.


Volition is generally considered as a defining human faculty; but the outcome of a voluntary decision can be predicted by brain activity even before subject’s conscious awareness , and simGymnotus sp. revealed a bimodal distribution of electric organ discharge rate (EODR) demonstrating Down- and Up-states of sensory sampling and neural activity; movements only occurred during Up-states and Up-states were initiated before movement-onset. EODR during voluntary swimming initiation exhibited greater trial-to-trial variability than the sound-evoked increases in EODR. The sensory sampling variability increased before, and declined after voluntary movement onset as previously observed for the neural variability associated with decision-making in primates [Cortical activity precedes self-initiated movements by several seconds in mammals; this observation has led into inquiries on the nature of volition . Preparaprimates . In contprimates . SpontanUsing statistical analyses of spontaneous exploratory behaviors and associated preparatory sensory sampling increase, we conclude that electric fish exhibit all the established hallmarks of volition, and that voluntary behaviors in vertebrates may generally be preceded by increased sensory sampling. The dorsal telencephalon is required for spatial learning in teleosts and might initiate movement via its projections to the tectum . Our res


Subarachnoid hemorrhage may be complicated by neurogenic stunned myocardium, a catecholamine-induced transient cardiomyopathy that displays a wide clinical spectrum of cardiac abnormalities, including electrocardiographic changes, arrhythmias, myocardial necrosis, and left ventricular systolic and diastolic dysfunction. However, less is known about the cardiac metabolic consequences of acute subarachnoid hemorrhage. Prunet and coworkers’ recent study provides scintigraphic evidence suggesting that glucose metabolism and sympathetic cardiac innervation are severely and globally depressed during the acute phase of the disease. Metabolic and innervation abnormalities are largely overlapped and are probably not causally related to myocardial ischemia, suggesting that impaired glucose metabolism is probably neurogenic in nature. The scintigraphic defects seem to reverse slowly, within months of the onset of cerebral bleeding. Interestingly, scintigraphic evidence of metabolic myocardial alterations may exist even in the absence of clinical features of cardiac disease, possibly representing a subclinical type of neurogenic stunned myocardium. Critical Care deals with this poorly studied area [Subarachnoid hemorrhage (SAH) may cause transient cardiac dysfunction, possibly attributed to massive release of catecholamines. The influence of catecholamine oversecretion on cardiac metabolism has been extensively studied in Takotsubo cardiomyopathy (TTC), which is also considered catecholamine induced in nature. However, data regarding acute myocardial metabolic alterations in SAH are sparse. The recent article by Prunet and colleagues in ied area .18 F-fluorodesoxyglucose positron emission tomography) and sympathetic innervation (studied by 123I-meta-iodobenzylguanidine scintigraphy) in 83.3% (25/30) and 90% (27/30), respectively, of 30 patients with acute SAH. Despite extensive changes in glucose metabolism and innervation, coronary perfusion was not affected. The topography and extent of metabolic and innervation scintigraphic defects were largely overlapped, supporting the hypothesis that metabolic shifts occurred secondarily to neurocardiogenic injury rather than cardiac ischemia [123I-meta-iodobenzylguanidine scintigraphy 6 months later [In their recent article, Prunet and coworkers assessed myocardial glucose metabolism and sympathetic innervation in SAH by means of scintigraphy, and investigated the possible associations with left ventricular (LV) systolic and diastolic dysfunction, troponin elevation and SAH outcomes . The autSAH-induced neurocardiogenic injury demonstrates comparable scintigraphic features ,5 with TAlthough increased adrenergic tone has been accounted for in both SAH and TTC , there mWhat is remarkable in the study by Prunet and colleagues is not the detection of neurometabolic myocardial alterations in SAH – such changes might probably be expected, since similar findings have been described in TTC. No, what is remarkable is that regional scintigraphic defects may widely exist within myocardium of SAH patients without clinical, echocardiographic or laboratory evidence of neurogenic stunned myocardium (NSM). The term NSM has been introduced to describe myocardial injury and dysfunction occurring after diverse types of acute brain injury (including SAH) as a result of imbalance of the autonomic nervous system . The diaOne should point out that the presence of neurometabolic cardiac abnormalities showed no association with clinical outcomes in Prunet and colleagues’ study . HoweverIn conclusion, the study by Prunet and colleagues underlines two different aspects in SAH. First, alterations in glucose metabolism, possibly neurogenic in origin, may affect widely the myocardium during the acute phase of SAH. Second, and more important, the study emphasizes that prolonged and slowly reversible neurometabolic abnormalities may globally occur in SAH even when conventional cardiac evaluation is negative for NSM. The clinical impact of such neurometabolic shifts may be greatly underestimated, as they are difficult to diagnose in the clinical practice. Additional research, including also hemodynamically unstable patients with depressed LV function, is necessary to clarify further the role of neurometabolic cardiac alterations in acute SAH.


Diagnostic assays that leverage bloodborne neuron-derived  nanoscale extracellular vesicles (nsEVs) as “windows into the brain” can predict incidence of Alzheimer's Disease (AD) many years prior to onset. Beyond diagnostics, bloodborne neuronal nsEVs analysis may have substantial translational impact by revealing mechanisms of AD pathology; such knowledge could enlighten new drug targets and lead to new therapeutic approaches. The potential to establish three-dimensional nsEV analysis methods that characterize highly purified bloodborne nsEV populations in method of enrichment, cell type origin, and protein or RNA abundance dimensions could bring this promise to bear by yielding nsEV “omics” datasets that uncover new AD biomarkers and enable AD therapeutic development. In this review we provide a survey of both the current status of and new developments on the horizon in the field of neuronal nsEV analysis. This survey is supplemented by a discussion of the potential to translate such neuronal nsEV analyses to AD clinical diagnostic applications and drug development. Bloodborne neuron-derived  nanoscale extracellular vesicles (nsEVs) have shown substantial potential as “windows into the brain” that enlighten central nervous system (CNS) disorder-associated changes in brain biochemistry and intercellular communication –7. This There are no universally accepted criteria for classifying nsEVs. This lack of standard taxonomy creates ambiguity in interpreting and communicating the results of nsEV-related experiments. Our simple classification system defines nsEVs as cell-derived vesicles with submicron diameters and groups them into two categories: exosomes and ectosomes.Exosomes are manufactured within multivesicular bodies (MVBs), cytoplasmic vesicles that have diameters in the 250–1,000 nm range , 9, and Others have categorized ectosomes into a number of somewhat ambiguous subclasses: shedding vesicles, microvesicles, exosome-like vesicles, nanoparticles, microparticles, and oncosomes . AlthougnsEVs with diameters between 100 nm and 200 nm can be either exosomes or ectosomes; the vesicle category into which a given nsEV would be classified would be determined by whether the nsEV is formed within a MVB or budded off from the cell plasma membrane. The preceding sentence is framed in a hypothetical sense because, as suggested by the above remarks regarding tetraspanins being common to both exosomes and ectosomes, there are no existing analytical methods that allow one to determine whether a given nsEV isolated from blood was formed inside of a MVB or is instead the product of budding from the plasma membrane.nsEVs encapsulate nucleic acids, primarily microRNAs (miRNAs) and messenger RNAs (mRNAs). nsEVs also feature integral membrane proteins, proteins covalently bound to nsEV membranes, proteins noncovalently associated with nsEV membranes, and proteins that occupy nsEV interior volumes. nsEVs' principal function is transferring signals from sender to recipient cells. nsEVs originating from sender cells can fuse with membranes of and release their contents into the cytoplasm of recipient cells  or have Given the desire to leverage bloodborne nsEV analysis in enlightening AD-associated changes and brain biochemistry and intercellular signaling processes, we note here that neuronal nsEVs have been observed to migrate from the CNS into the bloodstream in animal experiments . The exiThe predictive ability of bloodborne neuronal nsEV analysis illustrated by the biomarker validation studies of Goetzl and coworkers, which accurately forecasted AD onset up to ten years prior to clinical diagnosis –4, has gThe first step in Goetzl's nsEV AD biomarker quantification process was chemical precipitation (CP) to isolate nsEVs from plasma. After nsEV precipitation, neuronal nsEVs were enriched from the bulk nsEV population using streptavidin-coated agarose beads loaded with biotinylated anti-neuronal marker protein (CD171) Abs. Finally, nsEVs were exposed to lysing conditions and biomarker proteins in nsEV lysates were quantified by ELISA. The Cartesian coordinate system of As illustrated in The third nsEV analysis dimension, biomarker abundance, differs from the other two dimensions in that biomarker abundance, and thus position on the biomarker abundance axis, is dictated by nsEV composition. The researcher chooses which biomarker(s) to quantify and thus defines biomarker abundance axis label(s). As discussed in The underexplored opportunity in the area of leveraging bloodborne neuronal nsEV omics profiling in AD biomarker discovery for drug molecule and therapeutic modality development is well framed by discussing existing neuronal nsEV AD biomarker validation and discovery-related literature; the latter is particularly relevant to utilizing neuronal nsEV analysis in identification of novel drug targets and establishment of new treatment paradigms. In this discussion we define nsEV biomarkers as protein or nucleic acid nsEV constituents with abundances that differ in diseased relative to normal subjects. This definition encompasses nsEV-associated molecules with relative abundances that change prior to clinical manifestation of disease symptoms and thus can be predictive of disease onset as well as molecules with abundances that change as functions of disease progression or reversion due to positive treatment responses.β42)  experiments featuring nanogold-conjugated Ab labeling  of respeThere are several technical considerations that are important for generating nsEV omics datasets that would enable 3D nsEV analysis such as depicted in Obtaining neuronal nsEV omics datasets using methods described above will provide omics analyses with even greater translational potential. Next generation analyses could be enabled by advances in two emerging areas: microfluidic devices that sort bloodborne neuronal nsEV subpopulations directly from plasma based on abundances of multiple nsEV surface markers and engineered Abs or aptamers that bind epitopes exclusive to AD neuronal nsEV exteriors.6-fold lower than cell volumes, to flow cytometric sorting of individual nsEVs. First, nsEV flow rate must be rigorously controlled to prevent “swarming,” a phenomenon causing groups of nsEVs to be detected as single fluorescence events and leading to encapsulation of multiple nsEVs within sorted fluid droplets [There are two primary obstacles, which arise from nsEV volumes being 10droplets . Second,droplets . The utiFurther development of existing nonstandard flow cytometers could allow swarming and autofluorescence issues to be overcome. Regarding swarming, Pulse Laser Activated Cell Sorter (PLACS) microfluidics devices  achieve Proteins with posttranslational modifications such as glycation, glycosylation, and nitration –37 can gAntigen-loaded Dynabeads are routinely used for probe library screening . As suchMulticolor nsEV cytometry with various combinations of AD nsEV-specific probes and/or commercial Abs against AD nsEV biomarker surface proteins identified by proteomic profiling can address the important question of whether the overall bloodborne neuronal nsEV population is comprised of distinct subpopulations featuring different combinations of AD-specific surface proteins and/or epitopes. Sorting nsEV subpopulations would facilitate downstream omics and/or individual AD biomarker analyses that may enlighten both cell-to-cell heterogeneity of AD-associated changes in neuronal molecular composition and the existence of neuronal nsEVs that carry distinct groups of signaling molecules. Knowledge of such heterogeneity and distinct modes of intercellular communication could enlighten the interplay among different mechanisms of AD pathology and thus be a valuable facilitator of AD drug target identification and therapeutic development.With respect to forthcoming developments in the area of neuronal nsEV diagnostics hardware for clinical applications, recent progress in miniaturizing complex laboratory operations suggests that the future may prove to hold substantial advances in terms of constructing portable devices for point-of-care quantification of neuronal nsEV biomarkers. Regarding the specifics of this recent progress, protein microarray-based multiplex fluorescent ELISA assays  and accuAdvances in neuronal nsEV isolation and analysis methods that leverage neuronal nsEVs could provide “windows into the brain” using noninvasive diagnostic assays, requiring only microliters of blood obtained during routine doctor's office visits, which quantify Alzheimer's Disease (AD) biomarker proteins in nsEVs. Such assays could enable rapid diagnosis for CNS disorders and facilitate the development of personalized treatment programs. Continued increases in public and private funding for nsEV-focused research should enable realization of this goal in a timely manner and hasten the development of next generation nsEV analyses that provide a more accurate analysis of AD biomarkers in plasma. Although it will take time, as has been the case for the human genome sequence, to translate omics-derived AD biomarker discoveries from bench-to-bedside, it is clear that the ever-increasing convergence of biomedical research will augment the relative rate of translation. As such, it is anticipated that we are only years, rather than decades, away from seeing drugs and/or therapeutic modalities inspired by 3D bloodborne neuronal nsEV analyses have a clinical impact in treating this devastating disease.


ReGeneraTing Agents (RGTAs) are a family of polymers bioengineered to stabilise heparin-binding growth factors by mimicking HeparanSulphate (HS) thereby protecting them and promoting tissue repair and regeneration. In inflammation, destruction of HS exposes the ExtraCellularMatrix – ECM  to the actions of proteases and glycanases which break them down and also act on cytokines and growth factors to prevent adequate repair. In injured tissue, RGTAs would replace destroyed HS by binding to the structural proteins and reconstruct the ECM scaffold. Growth factors will also bind to RGTA and resume position and organization resembling that of non-injured tissue. Hence RGTAs showed they induce a regeneration process by restoring -the proper cellular micro-environment. More recently a RGTA named CACIPLIQ20 was adapted to skin lesions and has shown efficacy in various trials of non-healing leg ulcers.In this pilot prospective study, we applied the same RGTA with meticulous wound care techniques practiced on 10 patients with wounds of varying sizes (average of 13cm²) and depth but with the same underlying theme of poor vascularity and using the recommended sterile application technique twice a week until the wounds healed or over-granulation occurred.All wounds eventually healed, even chronic ones. We found that granulation tissue grew again where there was dead skin  and no visible underlying blood supply which in usual circumstances would have resulted in loss of limb length,dry gangrene or at best healing by severe scarring. Exposed tendons were also covered with granulation tissue, but instead of a scarred non-mobile digit, simultaneous therapy resulted in a fair range of motion. Full thickness palmar and dorsal wounds also granulated and the dorsal wound healed beautifully reproducing a flexible movable dorsal surface not seen in granulating, scarred healing.The revascularisation, development of non-adherent coverage reproducing normal skin features and mobility preserved overlying tendons all suggest that RGTA is a promising alternative treatment.


Only scarce data is available on early infection by human T-lymphotropic virus (HTLV). In particular, the modes of clonal selection during primary infection cannot be analyzed due to the paucity of available samples. Therefore, we addressed this question in a closely related animal model, bovine leukemia virus (BLV). As HTLV, BLV persist indefinitely into its host and is generally asymptomatic but can also lead to lymphoma or leukemia. Both viruses replicate by colonizing new lymphocytes or via clonal proliferation of infected cells. However, the modes of replication occurring soon after infection of new hosts are currently unknown. We used high-throughput sequencing to map and quantify the insertion sites of the provirus in order to monitor the clonality of the BLV-infected B-cell population (i.e. the number of distinct clones and abundance of each clone). We found that BLV propagation shifts from cell neoinfection to clonal proliferation in less than 3 months post-inoculation. Initially, BLV proviral integration significantly favors transcribed regions of the genome. Negative selection then eliminates more than 96% of the clones detected at seroconversion and disfavoring BLV-infected B-cells carrying a provirus located close to a promoter or a gene. This selection is more stringent in animals where proviral load set point is low. Among the surviving proviruses, clone abundance nevertheless positively correlates with proximity to a transcribed unit or a CpG island. We conclude that massive clone selection occurs during primary infection disfavoring proviruses located nearby genes and this selection is stronger in low proviral load animals.


A 49-year-old man with intermittent headaches and right sided parietal lump was found to have an intraosseous right parietal lesion on computed tomography (CT) and magnetic resonance imaging (MRI). A stereotactic craniectomy and excision of the lesion were performed with histopathology confirming features consistent with primary lipomatous meningioma with intraosseous extension. Lipomatous meningiomas are very uncommon subtype of meningiomas, with ongoing discussions as to their true pathogenesis. To our knowledge this case represents the first reported case of a lipomatous meningioma with predominant intraosseous extension. A 49-year-old Caucasian male who works as a joiner presented with intermittent headaches and a progressively increasing right sided parietal lump. He denied any history of trauma or infective process and past medical history was unremarkable. The physical examination was normal apart from a palpable nonfluctuating, nontender mass overlying the right parietal region.Skull X-ray, CT brain, and MRI brain revealed a single solitary lytic lesion within the right parietal bone with immense thinning of the outer table and erosion through the inner table without intracranial extension , althougThe patient underwent a stereotactic craniectomy of the right parietal lesion. A wide craniotomy was performed and upon elevation of the bone flap a small defect in the dura was present with what appeared to be an arachnoid granulation, consistent with the observations on the MRI. A pale white, well-delineated tumour could be seen eroding through the bone. A dural resection was performed around a small attached tan coloured tumour and the brain was inspected with no evidence of tumour involvement. Ensuring clear margins, duraplasty and cranioplasty were performed.Histology of the skull flap revealed cyst-like spaces surrounded by meningioma with foci showing typical meningothelial morphology interspersed with areas composed of cells showing variable vacuolation Figures . Area ofLipomatous meningiomas are rare subtypes of meningiomas. First described by Bailey and Bucy in 1931 . The WHOMetaplastic lipomatous meningiomas can be defined as meningiomas with striking focal or widespread mesenchymal areas, including osseous, cartilaginous, lipomatous, myxoid, or xanthomatous tissue components . LipomatThroughout the English literature 41 cases of lipomatous meningiomas have been described , one ass


This clinical trial is testing whether drugs that inhibit pain processing pathways in the brain can help with pain in the hand caused by osteoarthritis. Other clinical studies include the ‘Pain Perception in Osteoarthritis’, or PAPO study, investigating tissue damage and pain in people undergoing knee replacement surgery for osteoarthritis. Both studies are on the UK NIHR portfolio of network-adopted studies.The Sofat laboratory currently investigates the mechanisms responsible for pain and tissue damage in arthritis. Clinical studies include ‘Pain management in osteoarthritis using centrally acting analgesics’  to decipher regions of damage in affected joints and evaluating which brain regions are activated by arthritis pain. We also use non-invasive quantitative sensory testing (QST) methods to identify pain pathways. QST identifies sensation and pain thresholds by stimulating the skin.Our laboratory research uses a basic science mechanistic approach to investigate the influence of endogenous damage-associated molecular patterns (DAMPs) in driving chronic inflammation in joints. Molecules of interest include interaction of the DAMPs tenascin-C and fibronectin with oral pathogens.


Chest compression during cardiopulmonary resuscitation (CPR) could bring out unintended complications which are mainly composed of chest injuries. The aim of this study was to assess whether there was a significant difference in the complications of CPR between out-of-hospital cardiac arrest (OHCA) and in-hospital cardiac arrest (IHCA) survivors using multidetector computed tomography (MDCT).We performed a retrospective cohort study in the emergency departments of two academic tertiary care centres from January 2009 to May 2014. We enrolled both OHCA and IHCA patients who underwent successful CPR. The enrolled patients had undergone a chest CT within 48 hours after ROSC. We evaluated the MDCT findings of the CPR-related chest injuries and compared complications between OHCA and IHCA patients.[AQ1]A total of 148 patients were finally enrolled in this study, OHCA were 89 (60.1%) and IHCA were 59 (39.8%). The mean CPR time, both in-hospital and total, was longer in OHCA survivors. Rib fractures were detected more in OHCA survivors. Frequency of multiple rib fractures was higher in OHCA survivors. Frequency of sternum fractures was higher in OHCA survivors, showing no significant difference. In lung injuries, lung contusion and pneumothorax account for the large part, and OHCA survivors had higher incidence in both complications but statistically insignificant. Major complications occurred in eight cases in OHCA survivors and three cases in IHCA survivors during the study period. After adjusting for the time factor in multiple logistic regression analysis, rib fractures and multiple rib fractures became statistically significant in OHCA survivors. See Figures Frequency of rib fractures and multiple rib fractures were higher in OHCA survivors. Further investigation is needed into the relation between the location of CPR and the CPR-related injuries, efforts to reduce the complications after CPR.


Boechera stricta (rockcress), a close perennial relative of model plant Arabidopsis. First, using Bayesian kriging, we mapped the topography and environmental gradients and explored the spatial distribution of naturally occurring rockcress plants and two neighbors, Taraxacum officinale (dandelion) and Solidago missouriensis (goldenrod) found in close proximity within a typical diverse meadow community across topographic and environmental gradients. We then evaluated direct and indirect relationships among variables using Mantel path analysis and developed a network displaying abiotic and biotic interactions in this community. We found significant spatial autocorrelation among rockcress individuals, either because of common microhabitats as displayed by high density of individuals at lower elevation and high soil moisture area, or limited dispersal as shown by significant spatial autocorrelation of naturally occurring inbred lines, or a combination of both. Goldenrod and dandelion density around rockcress does not show any direct relationship with rockcress fecundity, possibly due to spatial segregation of resources. However, dandelion density around rockcress shows an indirect negative influence on rockcress fecundity via herbivory, indicating interspecific competition. Overall, we suggest that common microhabitat preference and limited dispersal are the main drivers for spatial distribution. However, intra-specific interactions and insect herbivory are the main drivers of rockcress performance in the meadow community.This study investigates the relative influence of biotic and abiotic factors on community dynamics using an integrated approach and highlights the influence of space on genotypic and phenotypic traits in plant community structure. We examined the relative influence of topography, environment, spatial distance, and intra- and interspecific interactions on spatial distribution and performance of  Boechera stricta (rockcress), an emerging ecological model plant species . Second, we determined the spatial structure of environmental and intra- and interspecific variables (see Methods for detailed description of these variables) using piecewise Mantel correlograms , aspen (Populus tremuloides), birch (Betula spp.), and burr oak (Quercus macrocarpa). Other common plant species that inhabited the meadow were goldenrod (Solidago missouriensis), dandelion , mouse-ear chickweed (Cerastium vulgatum), snowberry , and sedge (Carex spp.). The relief between the highest and the lowest measured point across the study area was 9.55 m.We studied spatial distribution and performance of rockcress  grid. Please refer to Appendix for exact intervals for individual parameters. Flat priors  and reproduction , and line] of rockcress, density of neighboring plants (goldenrod density and dandelion density), and herbivory on rockcress leaves . Data were standardized before calculating Euclidean distances  of the individual bins of lag distance at every 2.5 m in the correlograms. A pairwise correlation between all the variables was determined using simple Mantel test that guided the path analysis.A correlogram in this context is a plot of the spatial autocorrelation with lag distance, and the Mantel test can be used to test the significance of the correlations. A simple Mantel test Mantel,  was perfa priori hypothesis that A effects B and B effects C, the partial Mantel test can be used to test if C effects A in the absence of B, C~ A|B. If A and/or C displayed significant spatial autocorrelation then space was added as an additional partial, C~A|Space + B, in the partial Mantel test  on underlying ecological processes by looking at the relationship between two variables and keeping all other variables constant. For example, given the P = 0.05, Figure P ≤ 0.05) spatial autocorrelation among rockcress individuals  as well as a positive relationship between soil moisture and rockcress   Figure . The rel) Figure . Vapor p) Figure  and no i) Figure  but thisrosette diameter), reproduction , and line were significantly spatially autocorrelated  to 20.8 m (rosette diameter). Genetically similar individuals were found in close proximity of one another  spatial autocorrelation   around rockcress was positively correlated with rosette herbivory  was negatively correlated with fruit production (fruit number)  spatial autocorrelation in neighboring densities of goldenrod (range = 12.6 m) and dandelion (range = 12.6 m)  was the lowest among intra-specific traits that indicates greater intra-specific diversity of rockcress plants within short distances. Inter-specific interactions showed some indirect influence on rockcress distribution mediated through increased herbivory  than did performance or fitness measures (8–20 m) and landscape attributes , indicating that clustering of similar sized plants had both genetic and micro-environmental influences. To date, local adaptation in rockcress for defensive traits has been documented on a broad geographic scale  of rockcress is usually found in other mountain ranges (about 2500 m) . Probably as a consequence of lower and drier habitats in the Black Hills, we find rockcress on N-facing slopes and in shaded areas. Recent genotyping studies indicate that rockcress in the Black Hills probably originated from lower latitudes in the southern Rockies  are much lower than elevations where this species  that flea beetles tend to attract one another. It should be noted that we did not detect a significant correlation between line and herbivory, despite the detection of significant genetic variation from common garden experiments among these lines in resistance and glucosinolate toxin production in previous studies  and dense   enhanced our understanding of the underlying ecological processes of complex spatial interactions and allowed us to dissect direct and indirect effects of biotic and abiotic factors on distribution and performance of a rockcress population. Our attention to spatial distributions and associations expands the possible causations underlying community assembly associations over non-spatial analyses and our results help generate hypotheses for future experimental studies in ecological and evolutionary genomics.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Determining the exact genetic causes for a patient and providing definite molecular diagnoses are core elements of precision medicine. Individualized patient care is often limited by our current knowledge of disease etiologies and commonly used phenotypic-based diagnostic approach. The broad and incompletely understood phenotypic spectrum of a disease and various underlying genetic heterogeneity also present extra challenges to our clinical practice. With the rapid adaptation of new sequence technology in clinical setting for diagnostic purpose, phenotypic expansions of disease spectrum are becoming increasingly common. Understanding the underlying molecular mechanisms will help us to integrate genomic information into the workup of individualized patient care and make better clinical decisions. Medical textbooks usually provide characteristic descriptions of a disease and its progression. In reality, it can be challenging to recognize clinical presentations in an individual patient due to disease variations. Besides a few cases with classical presentations, many patients have atypical or overlapping manifestations. Understanding the similarities and differences between phenotypic abnormalities of human disease remains a major task for clinicians throughout their long medical training and practice. Meanwhile, precise and individualized diagnosis is often limited by current knowledge of disease etiologies. The large number of diseases, broad and incompletely understood phenotypic spectrums, and various genetic heterogeneity are all the contributing factors that hamper the diagnostic yield. A report from a clinical laboratory specializing in diagnostic exome sequencing discovered that about 5% of individuals in their patient cohort had two definitive genetic disorders . Such oc CFTR gene. Unlike this well-studied disorder, patients with defects in other single genes are often found to have broad clinical presentations without well-defined genotype-phenotype correlations. For example, DNA polymerase gamma (POLG) deficiency can lead to multiple categories of diseases, such as progressive external ophthalmoplegia, Alpers' syndrome, Parkinsonism, and juvenile spinocerebellar ataxia-epilepsy syndrome [ POLG related diseases is generally recessive, while autosomal dominant POLG mutations also exist. The clinical heterogeneity often makes diagnosis considerably difficult and contributes to diagnosis dilemmas. The clinical presentations of mitochondrial DNA (mtDNA) related disorders also show a wide spectrum of clinical variations. Despite relatively high prevalence of mitochondrial disorders, it is widely acknowledged that they are complex diseases to make a definite clinical diagnosis if based on clinical presentations exclusively [ SURF1 gene was found segregating with the disease; therefore, the diagnosis was revised to be Leigh syndrome [ VLDLR-associated congenital cerebellar ataxia with intellectual disability syndrome. However, the original clinical diagnosis is pontocerebellar hypoplasia since the clinical features were different from symptoms described for VLDLR-associated disease.Cystic fibrosis is a well-recognized single-gene disorder, and its disease severity can be roughly correlated to mutations observed in thesyndrome . The inhlusively . Presencsyndrome . In anot EBP gene encoding emopamil-binding protein [ EBP gene.Recently, a novel clinical syndrome was described for male patients with digital abnormalities, intellectual disability, and short stature in a multigeneration family . Extensi protein . As defe MAB21L2 gene were recently identified as a new cause of eye malformations. Interestingly, both dominant and recessive inheritance patterns were observed. The patients with the monoallelic mutations showed much more severe eye abnormalities as well as defects in other systems such as skeletal dysplasia, macrocephaly, and learning disability, while others with a biallelic mutation had only a mild eye phenotype and subtle dysmorphic facial features. This evidence indicated that the zygosity of a genetic defect can contribute to different pathogenic mechanisms [The type of genetic abnormalities can contribute to phenotype variations of a disease. A relatively large size of genomic aberration in terms of copy number variations (CNVs) is commonly seen in autosomal dominant or X-linked diseases. Point mutations are often observed in single-gene related autosomal recessive disorders. When types of point mutations range from nonsense, missense to splice site mutation, the corresponding clinical presentation can also differ considerably. Patients with nonsense mutation in alpha-1 type I collagen can have milder skeletal manifestation than these with missense mutation . Missenschanisms .Currently, clinicians need to know a variety of methodologies in order to request testing for a complete molecular profile of a gene. Patients can only afford a limited number of tests due to financial burden and thus do not have the necessary genetic workup. It is now possible to obtain a relatively comprehensive genetic workup within one assay to detect both point mutation and copy number variation for a set of different genes , 10. As  TBX6 gene [ TBX6 haplotype in this disease. After extensive linkage and genotyping analysis, it was revealed that copresence of a TBX6 null allele and a common haplotype containing three common single-nucleotide polymorphisms (SNPs) can lead to congenital scoliosis in patient. Thus, this common TBX6 haplotype acts as a hypomorphic genetic modifier to modulate the penetrance of the disease presentation in carriers of TBX6 null mutations.The penetrance of a disease phenotype can be influenced by combinatory effect of two alleles. Most recently, sequencing a cohort of patients with sporadic congenital scoliosis identified multiple heterozygous null mutations inBX6 gene . The disGenetic heterogeneity is one of the important factors to consider during genetic workup for disorders with overlapping clinical presentations. For disorders with relatively defined clinical phenotypes, such as glycogen storage disorder, both clinical evaluation and routine laboratory testing may provide initial clues leading to a correct clinical diagnosis. Regarding disorders with nearly indistinguishable clinical phenotypes, such as congenital defects of glycosylation, the result from biochemical testing may not be sufficient to narrow down a possible underlying genetic cause. As to disorders with a broad spectrum of clinical presentations, the large number of genes associated with these phenotypes makes it difficult or impossible to pinpoint an exact gene if molecular testing is not requested. Disease-targeted multigene panels and whole-exome sequencing allow precise molecular diagnosis made for patients with previously unrealized genetic defects , 14. MorEpistatic interactions have been recognized to play important roles in pathogenesis and phenotype variability . When moThe rapid progress of high-throughput genomic sequencing and corresponding analysis tools in molecular diagnosis have revolutionized the practice of clinical diagnosis . ComprehEnding the diagnostic odyssey, the FORGE (Finding of Rare Disease Genes) Canada Consortium identified genetic causes for 146 disorders over a 2-year period through a nation-wide collaboration effort among clinicians and scientists . Precisi


July is National Cleft and Craniofacial Awareness and Prevention Month, an observance intended to raise awareness and improve understanding of birth defects of the head and face. Common craniofacial birth defects include orofacial clefts , craniosynostosis (when the skull sutures join together prematurely), and anotia/microtia .This year, CDC highlights research on the association between smoking during early pregnancy and orofacial clefts. Although the causes of most orofacial clefts are unknown, the 2014 Surgeon General’s report confirmed that maternal smoking during early pregnancy can cause orofacial clefts in babies (http://www.nccapm.org/about.html.Orofacial clefts occur very early in pregnancy. Health-care providers should encourage women who are thinking about becoming pregnant to quit smoking before pregnancy or as soon as they find out that they are pregnant. Additional information regarding National Cleft and Craniofacial Awareness and Prevention Month is available at


We present the case of a 63-year-old woman with limited metastatic colorectal cancer to the lungs and liver treated with FOLFIRI-bevacizumab, followed by consolidative hypofractionated radiotherapy to right paratracheal metastatic lymphadenopathy. We treated the right paratracheal site with 60 Gy in 15 fractions . The patient tolerated the treatment well, and six months later started a five-month course of FOLFIRI-bevacizumab for new metastatic disease. She presented to our clinic six months after completing this, complaining of productive cough with scant hemoptysis, and was found to have localized tracheal wall breakdown and diverticulum in the region of prior high-dose radiation therapy, threatening to progress to catastrophic tracheovascular fistula. This was successfully repaired surgically after a lack of response to conservative measures. We urge caution in treating patients with vascular endothelial growth factor (VEGF) inhibitors in the setting of hypofractionated radiotherapy involving the mucosa of tubular organs, even when these treatments are separated by months. Though data is limited as to the impact of sequence, this may be particularly an issue when VEGF inhibitors follow prior radiotherapy. Bevacizumab is a monoclonal antibody that antagonizes the pro-angiogenic vascular endothelial growth factor (VEGF), and can be a highly effective agent for treating metastatic cancer; it inhibits tumor growth by limiting its blood supply. Bevacizumab has also been shown to be effective when given concurrently and adjuvantly with radiotherapy in the treatment of glioblastoma multiforme . HoweverWe report a case of a patient with oligometastatic colorectal cancer who was treated with FOLFIRI-bevacizumab followed two months later by hypofractionated radiotherapy, and six months later treated with FOLFIRI-bevacizumab again. This patient unfortunately experienced a tracheal diverticulum 17 months after radiotherapy and six months after her second course of FOLFIRI-bevacizumab   imaging. Her most recent bronchoscopy, 15 months postsurgery, shows continued resolution of the tracheal diverticulum Figure . In thisCombination bevacizumab and radiotherapy has been shown to be effective for glioblastoma multiforme, but may be associated with significant adverse effects for treatment of other sites. This risk may be highest when treating mucosal sites. Stephens et al. showed increased rates of tracheoesophageal fistula within the radiation field in patients treated with VEGF inhibitors after hypofractionated radiotherapy adjacent to the esophagus . GoodgamIn this case, we administered highly conformal hypofractionated radiation therapy with definitive intent to an ultra-central right paratracheal nodal metastasis with the high dose region including a portion of the tracheal wall contralateral to the esophagus. Rather than tracheoesophageal fistula, we observed localized tracheal wall breakdown and diverticulum into the mediastinal fat after bevacizumab-containing systemic therapy was administered with a substantial time gap after the completion of radiation therapy. Because of concern of progression to potentially catastrophic fistula between the trachea and superior vena cava, a serratus muscle flap repair was performed with good success.The hypofractionated radiation therapy regimen we used, 60 Gy in 15 fractions, was intensive because of definitive intent. By conventional linear-quadratic modeling, the equivalent dose in 2 Gy fractions would be 70 Gy for early/tumor effects  and 84 Gy for late effects . Even so, this falls within the range of what has been used safely in dose escalation studies of conventionally fractionated radiation therapy alone and chemoradiation for locally advanced lung cancer involving mediastinal nodes, and substantially less than stereotactic ablative radiotherapy regimens used safely for central and ultra-central  tumors such as 50 Gy in 4 fractions or 60 Gy in 8 fractions  . We haveIt is unclear, however, when or if there is a safe way to combine bevacizumab with dose-intensive hypofractionated radiotherapy overlapping mucosal sites. Mucosal irradiation may preclude future administration of bevacizumab due to risk of toxicity, as bevacizumab may inhibit wound-healing after radiotherapy by diminishing angiogenesis to radiation-damaged tissue, which increases risk of treatment-related toxicity. We urge caution when considering dose-intensive radiotherapy to mucosal locations in association with VEGF inhibitors, and recommend close communication with medical oncologists to continue holding VEGF inhibitors after radiotherapy has been completed.We present a case of tracheal diverticulum following bevacizumab and paratracheal radiotherapy. We urge caution in treating patients with vascular endothelial growth factor (VEGF) inhibitors in the setting of hypofractionated radiotherapy involving the mucosa of tubular organs, even when these treatments are separated by months. Though data is limited as to the impact of sequence, this may be particularly an issue when VEGF inhibitors follow prior radiotherapy.