Claude J. Bajada, Briony Banks, Matthew A. Lambon Ralph, Lauren L. Cloutman. Reconnecting with Joseph and Augusta Dejerine: 100 years on. Brain 2017; 140: 2752-2759. 10.1093/brain/awx225.
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Τετάρτη 11 Οκτωβρίου 2017
Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma.
Abstract
Background
Combined CTLA-4 and PD-1 blockade induces high rates of immune-related adverse events (irAEs). The safety of resuming anti-PD-1 in patients who discontinue combination therapy due to irAEs is not known. Patients and Methods
We assessed patients who experienced clinically significant irAEs from combined CTLA-4 and PD-1 blockade leading to treatment discontinuation at four academic centers. We assessed the safety of resuming anti-PD-1 in terms of recurrent and distinct irAEs. Results
Eighty patients discontinued combination therapy due to irAEs, including colitis (41%), hepatitis (36%), and pneumonitis (4%). Of these, 96% received corticosteroids, and 21% received additional immunosuppression (e.g. infliximab). All were rechallenged with anti-PD-1, and 14 (18%) had recurrent irAEs at a median of 14 days after therapy resumption (6 grade 1-2, 7 grade 3-4, 1 grade 5 Stevens-Johnson Syndrome). Colitis was less likely to recur than other irAEs (6% vs. 28%, p=0.01). Clinically significant but distinct toxicities occurred in an additional 17 (21%) patients (11 grade 1-2, 6 grade 3-4). Duration of steroid taper, severity of initial irAEs, and use of additional immunosuppressants did not predict for toxicity on rechallenge, although patients remaining on steroid therapy at anti-PD-1 resumption had higher rates of toxicities (55% vs. 31%, p=0.03). Conclusions
Patients who discontinued CTLA-4/PD-1 blockade for severe irAEs had relatively high rates of recurrent or distinct toxicities with anti-PD-1 resumption. However, many patients, particularly with combination-induced colitis, tolerated anti-PD-1 rechallenge well, and this approach can be considered in select patients.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2gynDPa
The predictive value of interim FDG-PET in early-stage Hodgkin lymphoma is not well established
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Biomechanical Properties of Airway Stents: Implications for Clinical Practice
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Postnatal reduction of tuberous sclerosis complex 1 expression in astrocytes and neurons causes seizures in an age-dependent manner
Summary
Objective
Epilepsy is one of the most prominent symptoms of tuberous sclerosis complex (TSC), a genetic disorder, and may be related to developmental defects resulting from impaired TSC1 or TSC2 gene function in astrocytes and neurons. Inactivation of the Tsc1 gene driven by a glial-fibrillary acidic protein (GFAP) promoter during embryonic brain development leads to widespread pathologic effects on astrocytes and neurons, culminating in severe, progressive epilepsy in mice (Tsc1GFAP-Cre mice). However, the developmental timing and cellular specificity relevant to epileptogenesis in this model has not been well defined. The present study evaluates the effect of postnatal Tsc1 gene inactivation on pathologic features of astrocytes and neurons and development of epilepsy.
Methods
An inducible Tsc1 knock-out mouse was created utilizing a tamoxifen-driven GFAP-CreER line (Tsc1GFAP-CreER mice) with TSC1 reduction induced postnatally at 2 and 6 weeks of age, and compared to conventional Tsc1GFAP-Cre mice with prenatal TSC1 reduction. Western blotting, immunohistochemistry, histology, and video–electroencephalography (EEG) assessed mechanistic target of rapamycin (mTOR) pathway activation, astrogliosis, neuronal organization, and spontaneous seizures, respectively.
Results
Tsc1 gene inactivation at 2 weeks of age was sufficient to cause astrogliosis and mild epilepsy in Tsc1GFAP-CreER mice, but the phenotype was much less severe than that observed with prenatal Tsc1 gene inactivation in Tsc1GFAP-Cre mice. Both astrocytes and neurons were affected by prenatal and postnatal Tsc1 gene activation to a degree similar to the severity of epilepsy, suggesting that both cellular types may contribute to epileptogenesis.
Significance
These findings support a model in which the developmental timing of TSC1 loss dictates the severity of neuronal and glial abnormalities and resulting epilepsy.
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Auditory sequential accumulation of spectral information
Source:Hearing Research
Author(s): Yi Shen
In many listening situations, information about the spectral content of a target sound may be distributed over time, and estimating the target spectrum requires efficient sequential processing. Listeners' ability to estimate the spectrum of a random-frequency, six-tone complex was investigated and the spectral content of the complex was revealed using a sequence of bursts. Whether each of the six tones was presented within each burst was determined at random according to a presentation probability. In separate conditions, the presentation probabilities (p) ranged from 0.2 to 1, the total number of bursts varied from 1 to 16, and the inter-burst interval was either 0 or 200 ms. To evaluate the information acquired by the listener, the burst sequence was followed, after a 500-ms silent interval, by the six-tone complex acting as an informational masker and the listener was required to detect a pure-tone target presented simultaneously with the masker. Greater performance in this task indicates more accurate estimation of the spectrum of the complex by the listener. Evidence for integration of information across bursts was observed, and the integration process did not significantly depend on inter-burst interval.
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Improved knowledge of and difficulties in palliative care among physicians during 2008 and 2015 in Japan: Association with a nationwide palliative care education program
BACKGROUND
Palliative care education for health care professionals is a key element in improving access to quality palliative care. The Palliative Care Emphasis Program on Symptom Management and Assessment for Continuous Medical Education (PEACE) was designed to provide educational opportunities for all physicians in Japan. As of 2015, 57,764 physicians had completed it. The objective of this study was to estimate the effects of the program.
METHODS
This study was an analysis of 2 nationwide observational studies from 2008 and 2015. We conducted 2 questionnaire surveys for representative samples of physicians. The measurements used were the Palliative Care Knowledge Test (range, 0-100) and the Palliative Care Difficulties Scale (range, 1-4). Comparisons were made with the unpaired Student t test and with a multivariate linear regression model using 2 cohorts and a propensity score–matched sample.
RESULTS
This study analyzed a total of 48,487 physicians in 2008 and a total of 2720 physicians in 2015. Between 2008 and 2015, physicians' knowledge and difficulties significantly improved on the Palliative Care Knowledge Test with total scores of 68 and 78, respectively (P < .001; effect size, 0.40) and on the Palliative Care Difficulties Scale with total scores of 2.65 and 2.49, respectively (P < .001; effect size, 0.29). Propensity-score matching resulted in 619 untrained physicians matched to 619 trained physicians, and physicians who trained with the PEACE program had a higher knowledge score (74 vs 86; P < .001; effect size, 0.64) and a lower difficulties score (2.6 vs 2.3; P < .001; effect size, 0.42).
CONCLUSIONS
Physicians' knowledge of and difficulties with palliative care improved on a national level. The PEACE program may have contributed to these improvements. Cancer 2017. © 2017 American Cancer Society.
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The TERT hypermethylated oncologic region predicts recurrence and survival in pancreatic cancer
Future Oncology, Ahead of Print.
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What role does stereotactic ablative radiotherapy have in advanced castrate-resistant prostate cancer?
Future Oncology, Ahead of Print.
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Prof. Gian Franco Bottazzo MD FRCP FRCPath (1946–2017)
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Luciano Martini (1927–2017): a memoir
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Phrenic motoneurons: output elements of a highly organized intraspinal network
The pontomedullary respiratory network generates the respiratory pattern and relays it to bulbar and spinal respiratory motor outputs. The phrenic motor system controlling diaphragm contraction receives and processes descending commands to produce orderly, synchronous, and cycle-to-cycle-reproducible spatiotemporal firing. Multiple investigators have studied PhMNs in an attempt to shed light on local mechanisms underlying phrenic pattern formation. We recorded PhMNs in unanesthetized, decerebrate rats and related their activity to simultaneous phrenic nerve (PhN) activity by creating a time-frequency representation of PhMN-PhN power and coherence. Based on their temporal firing patterns and relationship to PhN activity, we categorized PhMNs into three classes, each of which emerges as a result of intrinsic biophysical and network properties and organizes the orderly contraction of diaphragm motor fibers. For example, early inspiratory diaphragmatic activation by the early coherent burst generated by high-frequency PhMNs may be necessary in order to prime it to overcome its initial inertia. We have also demonstrated the existence of a prominent role for local intraspinal inhibitory mechanisms in shaping phrenic pattern formation. The objective of this review is to relate and synthesize recent findings with those of previous studies with the aim of demonstrating that the phrenic nucleus is a region of active local processing, rather than a passive relay of descending inputs.
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Norepinephrine enhances song responsiveness and encoding in the auditory forebrain of male zebra finches
Norepinephrine (NE) can dynamically modulate excitability and functional connectivity of neural circuits in response to changes in external and internal states. Regulation by NE has been demonstrated extensively in mammalian sensory cortices, but whether NE-dependent modulation in sensory cortex alters response properties in downstream sensorimotor regions is less clear. Here, we examine this question in male zebra finches, a songbird species with complex vocalizations and a well-defined neural network for auditory processing of those vocalizations. We test the hypothesis that NE modulates auditory processing and encoding using paired extracellular electrophysiology recordings and pattern classifier analyses. We report that a NE infusion into the auditory cortical region NCM (caudomedial nidopallium; analogous to mammalian secondary auditory cortex) enhances the auditory responses, burst firing, and coding properties of single NCM neurons. Furthermore, we report that NE-dependent changes in NCM coding properties, but not auditory response strength, are transmitted downstream to the sensorimotor nucleus HVC. Lastly, NE modulation in the NCM of males is qualitatively similar to that observed in females: in both sexes, NE increases auditory response-strengths. However, we observed a sex difference in the mechanism of enhancement: whereas NE increases response strength in females by decreasing baseline firing rates, NE increases response strength in males by increasing auditory-evoked activity. Therefore, NE signaling exhibits a compensatory sex difference to achieve a similar, state-dependent enhancement in signal-to-noise ratio and coding accuracy in males and females. In summary, our results provide further evidence for adrenergic regulation of sensory processing and modulation of auditory/sensorimotor functional connectivity.
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Saccades and reaches curve away from the other effector's target in simultaneous eye and hand movements.
Simultaneous eye and hand movements are highly coordinated and tightly coupled. This raises the question whether the selection of eye and hand targets relies on a shared attentional mechanism or separate attentional systems. Previous studies have revealed conflicting results by reporting evidence for both a shared as well as separate systems. Movement properties such as movement curvature can provide novel insights into this question as they provide a sensitive measure for attentional allocation during target selection. In the current study, participants performed simultaneous eye and hand movements to the same or different visual target locations. We show that both saccade and reaching movements curve away from the other effector's target location when they are simultaneously performed to spatially distinct locations. We argue that there is a shared attentional mechanism involved in selecting eye and hand targets which may be found on the level of effector independent priority maps.
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Eye-hand coordination during flexible manual interception of an abruptly appearing, moving target
As a vital skill in an evolving world, interception of moving objects relies on accurate prediction of target motion. In natural circumstances, active gaze shifts often accompany hand movements when exploring targets of interest, but how eye and hand movements are coordinated during manual interception and their dependence on visual prediction remain unclear. Here, we trained gaze-unrestrained monkeys to manually intercept targets appearing at random locations and circularly moving with random speeds. We found that well-trained animals were able to intercept the targets with adequate compensation for both sensory transmission and motor delays. Before interception, the animals' gaze followed the targets with adequate compensation for the sensory delay, but not for extra target displacement during the eye movements. Both hand and eye movements were modulated by target kinematics, and their reaction times were correlated. Moreover, retinal errors and reaching errors were correlated across different stages of reach execution. Our results reveal eye-hand coordination during manual interception, yet the eye and hand movements may show different levels of prediction based on the task context.
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A dual-axis rotation rule for updating the head direction cell reference frame during movement in three dimensions
In the mammalian brain, allocentric (Earth-referenced) head direction, called azimuth, is encoded by head direction (HD) cells, which fire according to the facing direction of the animal's head. On a horizontal surface, rotations of the head around the dorso-ventral (D-V) axis, called yaw, correspond to changes in azimuth, and elicit appropriate updating of the HD 'compass' signal to enable large-scale navigation. However, if the animal moves through three-dimensional (3D) space then there is no longer a simple relationship between yaw rotations and azimuth changes, and so processing of three-dimensional rotations is needed. Construction of a global 3D compass would require complex integration of 3D rotations, and also a large neuronal population, most neurons of which would be silent most of the time since animals rarely sample all available 3D orientations. We propose that instead, the HD system treats the 3D space as a set of interrelated 2D surfaces. It could do this by updating activity according to both yaw rotations around the D-V axis and rotations of the D-V axis around the gravity-defined vertical axis. We present preliminary data to suggest that this rule operates when rats move between walls of opposing orientations. This dual-axis rule, which we show is straightforward to implement using the classic one-dimensional 'attractor' architecture, allows consistent representation of azimuth even in volumetric space, and thus may be a general feature of mammalian directional computations even for animals that swim or fly.
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In vivo beta and gamma subthreshold oscillations in rat mitral cells: origin and gating by respiratory dynamics
In mammals, olfactory bulb (OB) dynamics are paced by slow and fast oscillatory rhythms at multiple levels: local field potential, spike discharge, and/or membrane potential oscillations. Interactions between these levels have been well studied for the slow rhythm linked to animal respiration. However, less is known regarding rhythms in the fast beta (10-35Hz) and gamma (35-100Hz) frequency ranges, particularly at the membrane potential level. Using a combination of intracellular and extracellular recordings in the OB of freely breathing rats, we show that beta and gamma subthreshold oscillations (STO) coexist intracellularly and are related to extracellular LFP oscillations in the same frequency range. However, they are differentially affected by changes in cell excitability and by odor stimulation. This leads us to suggest that beta and gamma STOs may rely on distinct mechanisms: gamma STOs would mainly depend on mitral cell intrinsic resonance while beta STOs could be mainly driven by synaptic activity. In a second part, we found that STO occurrence and timing are constrained by the influence of the slow respiratory rhythm on mitral/tufted cells. First, respiratory-driven excitation seems to favor gamma STOs while respiratory-driven inhibition favors beta STOs. Second, the respiratory rhythm is needed at the subthreshold level in order to lock gamma and beta STOs in similar phases as their LFP counterparts and to favor the correlation between STO frequency and spike discharge. Overall, this study helps to understand how the interaction between slow and fast rhythms at all levels of OB dynamics shapes its functional output.
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Glutamine addiction in kidney cancer suppresses oxidative stress and can be exploited for real-time imaging
Many cancers appear to activate intrinsic antioxidant systems as a means to counteract oxidative stress. Some cancers, such as clear cell renal cell carcinoma (ccRCC), require exogenous glutamine for growth and exhibit reprogrammed glutamine metabolism, at least in part due to the glutathione pathway, an efficient cellular buffering system that counteracts reactive oxygen species (ROS) and other oxidants. We show here that ccRCC xenograft tumors under the renal capsule exhibit enhanced oxidative stress compared to adjacent normal tissue and the contralateral kidney. Upon glutaminase inhibition with CB-839 or BPTES, the RCC cell lines SN12PM-6-1 (SN12) and 786-O exhibited decreased survival and pronounced apoptosis associated with a decreased GSH/GSSG ratio, augmented nuclear factor erythroid related factor 2 (NRF2), and increased 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a marker of DNA damage. SN12 tumor xenografts showed decreased growth when treated with CB-839. Furthermore, PET imaging confirmed that ccRCC tumors exhibited increased tumoral uptake of 18F-(2S,4R)4- fluoroglutamine (18F-FGln) compared to the kidney in the orthotopic mouse model. This technique can be utilized to follow changes in ccRCC metabolism in vivo. Further development of these paradigms will lead to new treatment options with glutaminase inhibitors and the utility of PET to identify and manage ccRCC patients who are likely to respond to glutaminase inhibitors in the clinic.-
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DDB2 is a Novel Regulator of Wnt-Signaling in Colon Cancer
Deregulation of the Wnt/β-catenin signaling pathway drives the development of colorectal cancer (CRC) but understanding of this pathway remains incomplete. Here we report that the damage-specific DNA-binding protein DDB2 is critical for β-catenin-mediated activation of RNF43, which restricts Wnt signaling by removing Wnt receptors from the cell surface. Reduced expression of DDB2 and RNF43 was observed in human hyperplastic colonic foci. DDB2 recruited EZH2 and β-catenin at an upstream site in the RNF43 gene, enabling functional interaction with distant TCF4/β-catenin binding sites in the intron of RNF43. This novel activity of DDB2 was required for RNF43 function as a negative feedback regulator of Wnt signaling. Mice genetically deficient in DDB2 exhibited increased susceptibility to colon tumor development in a manner associated with higher abundance of Wnt receptor-expressing cells and greater activation of the downstream Wnt-pathway. Our results identify DDB2 as both a partner and regulator of Wnt signaling with an important role in suppressing colon cancer development.
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Distinct angiogenic changes during carcinogenesis defined by novel label-free dark field imaging in a hamster cheek pouch model
There remain gaps in knowledge concerning how vascular morphology evolves during carcinogenesis. In this study, we imaged neovascularization by label-free dark field microscopy of a DMBA-induced hamster cheek pouch model of oral squamous cell carcinoma (SCC). Wavelength-dependent imaging revealed distinct vascular features at different imaging depths and vessel sizes. Vascular tortuosity increased significantly in high-risk lesions, while diameter decreased significantly in hyperplastic and SCC lesions. Large vessels preserved the same trends seen in the original images, whereas small vessels displayed different trends, with length and diameter increasing during carcinogenesis. Based on these data we developed and validated a classification algorithm incorporating vascular features from different vessel masks. Receiver operator curves generated from the classification results demonstrated high accuracies in discriminating normal and hyperplasia from high-grade lesions (area under the curve>0.95). Overall, these results provided automated imaging of vasculature in the earliest stages of carcinogenesis from which one can extract robust endpoints. The optical toolbox described here is simple, low-cost and portable and can be used in a variety of health care and research settings for cancer prevention and pharmacology research.
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Histone acetyltransferase KAT6A upregulates PI3K/Akt signaling through TRIM24 binding
Lysine acetyltransferase KAT6A is a chromatin regulator that contributes to histone modification and cancer, but the basis of its actions are not well understood. Here we identify a KAT6A signaling pathway that facilitates glioblastoma (GBM) where it is upregulated. KAT6A expression was associated with GBM patient survival. KAT6A silencing suppressed cell proliferation, cell migration, colony formation and tumor development in an orthotopic mouse xenograft model system. Mechanistic investigations demonstrated that KAT6A acetylates lysine 23 of histone H3 (H3K23), which recruits the nuclear receptor binding protein TRIM24 to activate PIK3CA transcription, thereby enhancing PI3K/AKT signaling and tumorigenesis. Overexpressing activated AKT or PIK3CA rescued the growth inhibition due to KAT6A silencing. Conversely, the pan-PI3K inhibitor LY294002 abrogated the growth-promoting effect of KAT6A. Overexpression of KAT6A or TRIM24, but not KAT6A acetyltransferase activity- deficient mutants or TRIM24 mutants lacking H3K23ac binding sites promoted PIK3CA expression, AKT phosphorylation and cell proliferation. Taken together, our results define an essential role of KAT6A in glioma formation, rationalizing its candidacy as a therapeutic target for GBM treatment.
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Metabolite profiling reveals the glutathione biosynthetic pathway as a therapeutic target in triple negative breast cancer
Cancer cells can exhibit altered dependency on specific metabolic pathways and targeting these dependencies is a promising therapeutic strategy. Triple negative breast cancer (TNBC) is an aggressive and genomically heterogeneous subset of breast cancer that is resistant to existing targeted therapies. To identify metabolic pathway dependencies in TNBC, we first conducted mass spectrometry-based metabolomics of TNBC and control cells. Relative levels of intracellular metabolites distinguished TNBC from non-transformed breast epithelia and revealed two metabolic subtypes within TNBC that correlate with markers of basal-like versus non-basal-like status. Among the distinguishing metabolites, levels of the cellular redox buffer glutathione were lower in TNBC cell lines compared to controls and markedly lower in non-basal-like TNBC. Significantly, these cell lines showed enhanced sensitivity to pharmacological inhibition of glutathione biosynthesis that was rescued by N-acetylcysteine, demonstrating a dependence on glutathione production to suppress ROS and support tumor cell survival. Consistent with this, patients whose tumors express elevated levels of –glutamylcysteine ligase, the rate-limiting enzyme in glutathione biosynthesis, had significantly poorer survival. We find, further, that agents that limit the availability of glutathione precursors enhance both glutathione depletion and TNBC cell killing by –glutamylcysteine ligase inhibitors in vitro. Importantly, we demonstrate the ability to this approach to suppress glutathione levels and TNBC xenograft growth in vivo. Overall, these findings support the potential of targeting the glutathione biosynthetic pathway as a therapeutic strategy in TNBC and identify the non-basal-like subset as most likely to respond.
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Experimental Evidence From Newborn Chicks Enriches Our Knowledge on Human Spatial–Numerical Associations
Abstract
Núñez and Fias raised concerns on whether our results demonstrate a linear number-space mapping. Patro and Nuerk urge caution on the use of animal models to understand the origin (cultural vs. biological) of the orientation of spatial–numerical association. Here, we discuss why both objections are unfounded.
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Synchronous HPV-Related Cancer of Bilateral Tonsils Detected Using Transoral Endoscopic Examination with Narrow-Band Imaging
Background. The incidence of human papillomavirus- (HPV-) related oropharyngeal squamous cell carcinoma (OPSCC) has been rapidly increasing worldwide. HPV is reported in approximately 50% cases of OPSCC in Japan. However, there are few reports of synchronous bilateral HPV-positive tonsillar carcinoma, and, in almost all those cases, carcinoma was detected using positron emission tomography/computed tomography and/or bilateral tonsillectomy. Methods and Results. We report the case of a 63-year-old male with bilateral tonsillar carcinoma detected using transoral endoscopic examination with narrow-band imaging (NBI). A biopsy of the bilateral tonsils revealed squamous cell carcinoma, which was demonstrated to be HPV-related using in situ hybridization and p16 immunohistochemistry. The patient was diagnosed as synchronous bilateral tonsillar carcinoma: T1 (2) N2b M0. He was treated with induction chemotherapy, bilateral radical tonsillectomy with neck dissection, and radiotherapy. Conclusion. To our knowledge, this is the first report of a synchronous bilateral tonsillar carcinoma detected using transoral NBI in the outpatient setting. Early diagnosis without the inspection under general anesthesia is beneficial for the patients with lymph node metastasis from unknown primary lesion.
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Down-regulation of KLF5 in cancer-associated fibroblasts inhibit gastric cancer cells progression by CCL5/CCR5 axis
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Atrial fibrillation and central nervous complications in liver transplanted hereditary transthyretin amyloidosis patients.
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Management of Patients who Receive an Organ Transplant Abroad and Return Home for Follow-up Care: Recommendations From the Declaration of Istanbul Custodian Group.
Eradicating transplant tourism depends upon complex solutions that include efforts to progress towards self-sufficiency in transplantation. Meanwhile, professionals and authorities are faced with medical, legal, and ethical problems raised by patients who return home after receiving an organ transplant abroad, particularly when the organ has been obtained through illegitimate means. In 2016, the Declaration of Istanbul Custodian Group convened an international, multidisciplinary workshop in Madrid, Spain, to address these challenges and provide recommendations for the management of these patients, which are presented in this paper. The core recommendations are grounded in the belief that principles of transparency, traceability and continuity of care applied to patients who receive an organ domestically should also apply to patients who receive an organ abroad. Governments and professionals are urged to ensure that, upon return, patients are promptly referred to a transplant center for evaluation and care; not cover the costs of transplants resulting from organ or human trafficking; register standardized information at official registries on patients who travel for transplantation; promote international exchange of data for traceability; and develop a framework for the notification of identified or suspected cases of transnational transplant-related crimes by health professionals to law enforcement agencies. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.
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Rhesus Alloimunization Occurs After Rh Incompatible Liver Transplantation in Children.
Venous Thromboembolism After Adult Lung Transplantation: A Frequent Event Associated with Lower Survival.
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Contemporary Policies Regarding Alcohol and Marijuana use Among Liver Transplant Programs in the United States.
BACKGROUND: Alcoholic liver disease is a common indication for liver transplantation (OLT). Although OLT has been shown to confer survival benefit to patients with acute alcoholic hepatitis (AAH), historically most programs require a 6-month abstinence period prior to OLT which excludes patients with AAH. Marijuana has become legal in more than half the states in the United States. This survey of liver transplant programs was conducted to evaluate current policies regarding alcohol, marijuana and methadone use. METHODS: A questionnaire was distributed to 100 UNOS-approved liver transplant programs in North America that have performed at least 30 liver transplants/year in the last 5 years. RESULTS: Forty-nine programs responded. Only 43% of programs required a specific period of abstinence prior to transplant for alcoholic liver disease and only 26% enforced 6-month abstinence policy. For patients with AAH, 71% programs waived the 6-month abstinence requirement and considered psychosocial factors such as family support, patient's motivation or commitment to rehabilitate. Few programs used validated instruments to assess risk of relapse in AAH patients. Fourteen percent of programs transplant patients actively using marijuana and an additional 28% of programs listed patients using marijuana provided they discontinue by the time of OLT. Active methadone users were accepted in 45% of programs. CONCLUSIONS: Policies regarding alcohol use have become more flexible particularly toward patients with AAH. Marijuana use is also more accepted. Although policies regarding alcohol and marijuana have changed significantly in the last decade, they remain highly variable among programs. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.
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The Optimization of the Prevascularization Procedures for Improving Subcutaneous Islet Engraftment.
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Prognostic significance of standardized uptake value on F18-FDG PET/CT in patients with extranodal nasal type NK/T cell lymphoma: A multicenter, retrospective analysis
The purpose of this study was to evaluate the value of parameters assessed with F18-flurodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in predicting relapse free survival and overall survival in patients with extranodal nasal type NK/T cell lymphoma.
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NEURONOPATHY AND NEUROPATHY IN AUTOSOMAL DOMINANT SPINO-CEREBELLAR ATAXIA (SCA): A PRELIMINARY PERIPHERAL NERVE ULTRASOUND STUDY
Somatosensory or sensorimotor impairment is not uncommon in autosomal dominant spino-cerebellar ataxia (SCA) (Linnemann et al., 2015; Schöls et al., 2004), but it is unclear to what extent this is a primary peripheral nerve pathology, as typically seen in length-dependent neuropathy, or neuronopathy from neuron degeneration in dorsal root ganglia and/or anterior horn cells (van de Warrenburg et al., 2004). It is also unclear if neuropathy and neuronopathy are differently represented in the SCA subtypes.
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Enhancement of multiple cranial and spinal nerves in vanishing white matter: expanding the differential diagnosis
Abstract
Abnormal cranial or spinal nerve contrast enhancement on MRI in cases of suspected pediatric leukodystrophy is recognized as an important clue to the diagnosis of either metachromatic leukodystrophy or globoid cell leukodystrophy (Krabbe disease). We report a case of genetically confirmed childhood vanishing white matter with enhancement of multiple cranial and spinal nerves in addition to the more typical intracranial findings. This case expands the limited differential diagnosis of cranial nerve or spinal nerve enhancement in cases of suspected leukodystrophy and may aid in more efficient work-up and earlier diagnosis of vanishing white matter.
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The sex-specific interaction between food responsiveness and sleep duration explaining body mass index among children
The inverse relationship between sleep duration and body mass index (BMI) has been well established and appears to be stronger among boys than girls. However, less is known about the mechanisms responsible for this sex-specific link. The main aim of the current study was to examine the sex-specific interaction between food responsiveness and sleep duration in explaining BMI among children. This sex-specific moderation will give more insight into a possible underlying food intake mechanism.
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Continuous positive airway pressure treatment with nasal pillows in obstructive sleep apnea: long-term effectiveness and adherence
s: Mask-related side effects can negatively influence adherence to continuous positive airway pressure (CPAP). Nasal pillows (P) can be an alternative to the standard nasal masks (N), although there are no data about their long-term efficacy. This study aimed to assess long-term effectiveness and adherence to CPAP therapy delivered with nasal pillows in obstructive sleep apnea syndrome (OSAS) patients.
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Assessment of intervention-related changes in non-rapid-eye-movement sleep depth: importance of sleep depth changes within stage 2
Depth of sleep within non-rapid-eye-movement (non-REM) stage-2 (N2-depth) varies from being nearly similar to stage-1 to nearly similar to stage-3. Differences in N2-depth are not captured by conventional indices of sleep depth (N1–N3 times, arousal/awakening index) when comparing sleep depth under different conditions. Magnitude of changes in N2-depth in the same individual under different experimental conditions, and the importance of measuring these changes are unknown.
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Prevalence of sleep-disordered breathing in Japanese medical students based on type-3 out-of-center sleep test
Sleep-disordered breathing (SDB), especially obstructive sleep apnea disorder (OSA), is thought to mainly affect men over the age of 40. Following findings that Asian people are more likely to experience severe OSA, regardless of obesity, we investigated the prevalence of SDB and OSA in a larger sample and in more younger age groups than those described in previous reports.
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Longitudinal associations between sleep and anxiety during pregnancy, and the moderating effect of resilience, using parallel process latent growth curve models
For many women, pregnancy-related sleep disturbances and pregnancy-related anxiety change as pregnancy progresses are both associated with lower maternal quality of life and less favorable birth outcomes. Thus, the interplay between these two problems across pregnancy is of interest. In addition, psychological resilience may explain individual differences in this association, as it may promote coping with both sleep disturbances and anxiety, and thereby reduce their mutual effects. Therefore, the aim of the current study was to examine whether sleep quality and sleep duration, and changes in sleep are associated with the level of and changes in anxiety during pregnancy.
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Long-term treatment with dopamine D3 receptor agonists induces a behavioral switch that can be rescued by blocking the dopamine D1 receptor
Restless legs syndrome (RLS) is commonly treated with the dopamine agonists, pramipexole and rotigotine, which target the inhibitory dopamine receptor subtype, D3R. While initially highly effective, these compounds lose their efficacy in treating RLS over time, and long-term therapy regularly leads to a worsening of the symptoms (augmentation). This dopamine agonist-induced augmentation has become a prime concern in the treatment of RLS, and while alternate therapies are being proposed, the mechanisms leading to augmentation remain opaque.
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Gender differences in sleep symptoms after repeat concussions
There are notable gender differences in concussion as well as sleep. Sleep disturbance is a major symptom of post-concussive syndrome. The interplay between sleep disturbance, concussion, and gender has yet to be examined. The objective of this study was to determine whether sleep disturbance plays a role in the known gender differences associated with concussion.
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The role of α1- and α2-adrenoceptor subtypes in the vasopressor responses induced by dihydroergotamine in ritanserin-pretreated pithed rats
Dihydroergotamine (DHE) is an acute antimigraine agent that displays affinity for dopamine D2-like receptors, serotonin 5-HT1/2 receptors and α1/α2-adrenoceptors. Since activation of vascular α1/α2-adrenoceptors ...
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High LC3/Beclin Expression Correlates with Poor Survival in Glioma: a Definitive Role for Autophagy as Evidenced by In Vitro Autophagic Flux
Abstract
Recent studies suggest the role of autophagy, an evolutionarily conserved catabolic process, in determining the response of gliomas to treatment either positively or negatively. The study attempts to characterize autophagy in low and high-grade glioma by investigating the autophagic flux and clinical significance of autophagy proteins (LC3 and beclin 1) in a group of glioma patients. We evaluated the expression of autophagic markers in resected specimens of low-grade glioma (LGG) and high-grade glioma (HGG) tissues, by immunohistochemistry and Western blotting. Our results show that expression of autophagy proteins were more prominent in HGG than in LGG. Increased level of autophagic proteins in HGG can be due to an increased rate of autophagy or can be because of blockage in the final degradation step of autophagy (defective autophagy). To distinguish these possibilities, the autophagic flux assay which helps to determine the rate of degradation/synthesis of autophagic proteins (LC3-II and p62) over a period of time by blocking the final degradation step of autophagy using bafilomycin A1 was used . The assessment of autophagic flux in ex vivo culture of primary glioma cells revealed for the first time increased turnover of autophagy in high grade compared to low grade-glioma. Though autophagic markers were reduced in LGG, functionally autophagy was non defective in both grades of glioma. We then investigated whether autophagy in gliomas is regulated by nutrient sensing pathways including mTOR and promote cell survival by providing an alternate energy source in response to metabolic stress. The results depicted that the role of autophagy during stress varies with tissue and has a negative correlation with mTOR substrate phosphorylation. We also evaluated the expression of LC3 and beclin 1 with progression free survival (PFS) using Kaplan-Meier survival analysis and have found that patients with low LC3/beclin 1 expression had better PFS than those with high expression of LC3/beclin 1 in their tumors. Together, we provide evidence that autophagy is non-defective in glioma and also show that high LC3/beclin 1 expression correlates with poor PFS in both LGG and HGG.
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EMCrit Wee – Dissemination and Information Transfer (Questions not Answers)
I need help...
EMCrit by Scott Weingart.
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The addition of PRP to facial lipofilling: a double-blind placebo-controlled randomized trial.
Background: Lipofilling is a treatment modality to restore tissue volume, but may also rejuvenate the aging skin. Platelet-rich plasma has been reported to augment the efficacy of lipofilling, both on graft take and rejuvenation by altering the ADSC. Authors hypothesized that PRP addition would increase the rejuvenating effect while shortening recovery time. Methods: The study conducted was a single-centre, double blinded, placebo-controlled randomized trial (2012-2015). In total, a well-defined cohort of 32 healthy females enrolled in the study, with 25 completing the follow-up. All patients underwent aesthetic facial lipofilling with either saline or PRP added. Outcome was determined by changes in skin elasticity, volumetric changes of the nasolabial fold, recovery time and patient satisfaction during follow-up (1 year). Results: PRP did not improve the outcome of facial lipofilling when looking at skin elasticity improvement, graft volume maintenance in the nasolabial fold or patient satisfaction. Patient recovery after surgery however, dropped significantly. Furthermore, no skin rejuvenation effects from lipofilling could be observed. Conclusion: This study clearly demonstrates that the addition of PRP to the lipograft significantly reduces patient's reported recovery time, but does not significantly improve skin elasticity, volume retention nor overall patient satisfaction as compared to lipofilling alone. Moreover, reported effects of 'normal' (not SVF/ADSC enriched) lipofilling on skin rejuvenation, as has been reported and suggested to be seen in clinical studies when used in combination with facelift surgery, could also not be addressed. (C)2017American Society of Plastic Surgeons
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Bony/Cartilaginous Mismatch: A radiologic investigation into the etiology of tension nose deformity.
Background: Tension nose deformity is believed to be due to an "oversized" septal quadrangular cartilage. Prior studies have shown that quadrangular cartilage size is relatively consistent in size in populations. We hypothesize that the tension nose deformity is actually due to an external extrusion of a normal sized septal cartilage from an undersized bony septal encasement. Methods: A retrospective case-control study of sagittal CT scans was conducted, measuring the perimeter and surface area of the quadrangular cartilage and bony septal aperture in tension nose cases and controls. Statistical analysis was performed. Results: Of 23 patients enrolled in the study, 12 patients were sorted into the tension nose group, while 11 patients were considered controls. Both groups had similar perimeter and surface area of their quadrangular cartilage, without statistical difference between the two groups. However, the tension nose group had a statistically significant reduction in bony septal aperture perimeter when compared to controls (p
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Outcomes After Phalloplasty: Do Transgender Patients and Multiple Urethral Procedures Carry a Higher Rate of Complication?.
Introduction: Phalloplasty is associated with improved quality-of-life in those with penile defects, and in female-to-male transgender (transmale) patients seeking gender-confirming surgery. However, aggregate complication and outcome data is sparse. This study compares phalloplasty outcomes between transmale and cismale patients and between those with primary versus staged urethroplasty. Methods: A comprehensive literature search of PubMed, MEDLINE, and Google Scholar databases was conducted for studies relating to phalloplasty. Data on techniques, complications, outcomes, and patient demographics were collected. Analysis using the random-effects model with subgroup analyses was performed. Results: A total of 50 studies (1,351 patients) were included; 19 studies (869 patients) for transmale patients and 31 studies (482 patients) for cismale patients. The urethral complication rate in the transmale group was 39.4% (95% CI: 30.6-48.9, p=0.028) compared to 24.8% (95% CI: 16.5-35.4, p
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Split-Overlapping Genioplasty: Surgical Technique, Morphological and Radiological Long-Term Outcomes.
Background: The overlapping bone flap genioplasty, described by Tessier, was developed to treat major retrognathia or long and retruded chins. For 15 years, we have used a modified version of this technique to avoid its drawbacks. The aim of this article is to describe our modification and evaluate the long-term morphologic and radiologic outcomes. Patients and Method: The authors included every split-overlapping genioplasty performed in our department between 2004 and 2014. Demographics, surgical data, and complications were recorded. Radiologic bone resorption was evaluated comparing preoperative, day-1 postoperative, and year-1 postoperative cephalometric x-rays. Morphologic outcomes were evaluated on standardized pre- and postoperative views using an analogic Likert scale. Surgical Technique: The main modification of the procedure consists in separating the posterior cortex of the transplant using a reciprocating saw. After overlapping the reduced transplant onto the mandible, the posterior cortex is used as an apposition graft to soften the labiomental crease. Results: Forty-seven patients were analyzed during this period. In 44 patients, the procedure was combined with mandibular and/or maxillary osteotomy. The average reduction of symphysis height was 5 mm, and the average pogonion advancement was 4.3 mm. After 1 year, we recorded 7% average bone resorption. No major complications (nerve injury, hematoma, among others) were reported. Morphologic outcomes were deemed satisfactory or very satisfactory in the vast majority of cases. Conclusion: Split-overlapping genioplasty is a safe and reliable procedure with stable, long-lasting outcomes. This versatile technique is particularly useful for the correction of a massive symphysis or high and retruded chins. (C) 2017 by Mutaz B. Habal, MD.
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A Research of Pyogenic Granuloma Genesis Factor With Immunohistochemical Analysis.
Pyogenic granuloma (PG) is a type of vascular tumor for which the growth mechanism is poorly understood. Estrogen and progesterone may influence vascular malformations by increasing neovascularization in the lesions. Pregnancy tumor is a term for PG that occurs on the gingival mucosa of pregnant women in response to local irritation or injury. The etiology and pathogenesis of this phenomenon are not fully understood. Hormonal imbalance has been hypothesized to be responsible for the development of gingival hyper-reactive inflammatory responses. Moreover, it has been shown in vitro that the female sex hormone is a potential regulator of the production of several growth factors, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor, and nerve growth factor, in various cell types. Epidermal growth factor receptor (EGFR) is also involved in a signaling cascade that influences proliferation and other tumor-promoting activities, as well as the responsiveness to chemotherapy. The aim of this study was to examine the relationship between PG pathogenesis and hormone imbalance in 21 patients. All specimens were analyzed by immunohistochemical staining with hematoxylin and eosin for the following hormones: estrogen receptor, progesterone receptor, VEGF, and EGFR. The analysis of the specimens showed that estrogen receptor and EGFR were not associated with PG, while VEGF was statistically related to PG. In addition, there was no significantly difference between sex, tumor location, or pregnancy. There are few studies about correlation between the pathogenesis of PG and sex hormones or growth factors demonstrated via immunohistochemical analysis. The results of this study indicate that estrogen and progesterone do not influence the pathogenesis of PG; however, VEGF may be associated with the pathogenesis of PG. (C) 2017 by Mutaz B. Habal, MD.
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Ex Situ Hepatectomy and Liver Autotransplantation for Cholangiocarcinoma
Abstract
Background
Hepatic resection of tumors invading the retrohepatic vena cava and hepatic veins are a challenge for surgeons, who consider them unresectable most of the time.1 ,2 Ex situ hepatectomy and liver autotransplantation has developed to improve resectability of these malignancies.3,4
Methods
The patient was a 51-year-old man who had jaundice secondary to a intrahepatic cholangiocarcinoma 7 cm in diameter in the right lobe of the liver and the caudate lobe. A volumetric scan showed a future liver remnant (segments 2 and 3) not sufficient according to the body weight. The patient was considered to be unresectable by conventional resection due to the critical invasion to the retrohepatic vena cava together with the three hepatic veins. Therefore, an ex vivo extended right hepatectomy and autotransplantation were indicated.
Results
The patient underwent biliary decompression through a percutaneous transhepatic catheter and right portal vein embolization for left lobe hypertrophy. During the surgery, the liver was removed with the retrohepatic vena cava, which was replaced by a prosthetic graft without a veno-venous bypass. Ex vivo extended right hepatectomy was performed, and a prosthetic graft was used to replace the vena cava where the remaining left hepatic vein was anastomosed. The surgery duration was 9 h, and the anhepatic time was 4.5 h. The postoperative hospital stay was 19 days, and at this writing, 3 years later, the patient is disease-free.
Conclusion
Ex vivo hepatectomy without veno-venous bypass should be considered a valid therapeutic option for selected patients with cholangiocarcinoma invading the retrohepatic vena cava.
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Ex Situ Hepatectomy and Liver Autotransplantation for Cholangiocarcinoma
Abstract
Background
Hepatic resection of tumors invading the retrohepatic vena cava and hepatic veins are a challenge for surgeons, who consider them unresectable most of the time.1 ,2 Ex situ hepatectomy and liver autotransplantation has developed to improve resectability of these malignancies.3,4
Methods
The patient was a 51-year-old man who had jaundice secondary to a intrahepatic cholangiocarcinoma 7 cm in diameter in the right lobe of the liver and the caudate lobe. A volumetric scan showed a future liver remnant (segments 2 and 3) not sufficient according to the body weight. The patient was considered to be unresectable by conventional resection due to the critical invasion to the retrohepatic vena cava together with the three hepatic veins. Therefore, an ex vivo extended right hepatectomy and autotransplantation were indicated.
Results
The patient underwent biliary decompression through a percutaneous transhepatic catheter and right portal vein embolization for left lobe hypertrophy. During the surgery, the liver was removed with the retrohepatic vena cava, which was replaced by a prosthetic graft without a veno-venous bypass. Ex vivo extended right hepatectomy was performed, and a prosthetic graft was used to replace the vena cava where the remaining left hepatic vein was anastomosed. The surgery duration was 9 h, and the anhepatic time was 4.5 h. The postoperative hospital stay was 19 days, and at this writing, 3 years later, the patient is disease-free.
Conclusion
Ex vivo hepatectomy without veno-venous bypass should be considered a valid therapeutic option for selected patients with cholangiocarcinoma invading the retrohepatic vena cava.
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Lolium perenne peptides for treatment of grass pollen allergy: A randomized, double-blind, placebo-controlled clinical trial
Source:Journal of Allergy and Clinical Immunology
Author(s): Mohamed H. Shamji, Jan Ceuppens, Claus Bachert, Peter Hellings, Gaël Placier, Gaëtan Thirion, Nicolas Bovy, Stephen R. Durham, Jean Duchateau, Thierry Legon, Sabine Pirotton
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Genome-wide association study and meta-analysis in multiple populations identifies new loci for peanut allergy and establishes c11orf30/EMSY as a genetic risk factor for food allergy
Publication date: Available online 10 October 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Yuka Asai, Aida Eslami, C. Dorien van Ginkel, Loubna Akhabir, Ming Wan, George Ellis, Moshe Ben-Shoshan, David Martino, Manuel A. Ferreira, Katrina Allen, Bruce Mazer, Hans de Groot, Nicolette W. de Jong, Roy N. Gerth van Wijk, Anthony E.J. Dubois, Rick Chin, Steven Cheuk, Joshua Hoffman, Eric Jorgensen, John S. Witte, Ronald B. Melles, Xiumei Hong, Xiaobin Wang, Jennie Hui, Arthur W. (Bill) Musk, Michael Hunter, Alan L. James, Gerard H. Koppelman, Andrew J. Sandford, Ann E. Clarke, Denise Daley
BackgroundPeanut allergy (PA) is a complex disease with both environmental and genetic risk factors. Previously PA loci were identified in FLG and HLA in candidate gene studies, and loci in HLA in a genome-wide association study and meta-analysis.ObjectiveTo investigate genetic susceptibility to PA.MethodsEight hundred and fifty cases and 926 hyper-controls and >7.8 million genotyped and imputed single nucleotide polymorphisms (SNPs) were analyzed in a genome-wide association study to identify susceptibility variants for PA in the Canadian population. Meta-analysis of two phenotypes (PA and food allergy) was conducted using 7 studies from the Canadian, American (2), Australian, German and Dutch (2) populations.ResultsA SNP near ITGA6 reached genome-wide significance with PA (p=1.80×10-8), while SNPs associated with SKAP1, MMP12/MMP13, CTNNA3, ARHGAP24, ANGPT4, c11orf30 (EMSY), and EXOC4 reached a threshold suggestive of association (p≤1.49×10-6). In the meta-analysis of PA, loci in or near ITGA6, ANGPT4, MMP12/MMP13, c11orf30 and EXOC4 were significant (p≤1.49×10-6). When a phenotype of any food allergy was used for meta-analysis, the c11orf30 locus reached genome-wide significance (p=7.50×10-11), while SNPs associated with ITGA6, ANGPT4, MMP12/MMP13, EXOC4 and additional c11orf30 SNPs were suggestive (p≤1.49×10-6). Functional annotation indicated SKAP1 regulates expression of CBX1, which co-localizes with the EMSY protein coded by c11orf30.ConclusionThis study identifies multiple novel loci as risk factors for PA and food allergy and establishes c11orf30 as a risk locus for both peanut and food allergy. Multiple genes (c11orf30/EMSY, SKAP1 and CTNNA3) identified by this study are involved in epigenetic regulation of gene expression.
Teaser
C11orf30 (EMSY) is a risk locus for food allergy, reaching genome-wide significance in meta-analysis (p=7.50×10-11). Meta-analyses showed five loci suggestive of significance with peanut allergy. These 6 novel loci suggest epigenetic mechanisms.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2z0aNAa
Esophagectomy for End-Stage Achalasia: Systematic Review and Meta-analysis
Abstract
Background
Indications for surgery and clinical outcomes of esophagectomy in the management of end-stage achalasia are not clearly defined. The aim of this systematic review and meta-analysis was to provide evidence-based information to help in the decision-making and in the choice of surgical technique.
Methods
An extensive literature search was conducted to identify all reports on esophagectomy for end-stage achalasia patients over the past three decades. MEDLINE, Embase and Cochrane databases were thoroughly consulted matching the terms "achalasia," "end-stage achalasia," "esophagectomy" and "esophageal resection" with "AND" and "OR." Short- and long-term outcome data were extracted. Pooled prevalence of pneumonia, anastomotic leakage and mortality were calculated using Freeman–Tukey double arcsine transformation and DerSimonian–Laird estimator in random effect meta-analysis. Heterogeneity among studies was evaluated using I 2-index and Cochrane Q test. Meta-regression was used to address the effect of potential confounders.
Results
Eight papers published between 1989 and 2014 matched the inclusion criteria. In total, 1307 patients were included. Esophagectomy was performed through a transthoracic (78.7%) or a transhiatal (21.3%) approach. The stomach was used as an esophageal substitute in 95% of patients. Pooled prevalence of pneumonia, anastomotic leakage and mortality were 10% (95% CI 4–18%), 7% (95% CI 4–10%) and 2% (95% CI 1–3%), respectively.
Conclusions
Esophagectomy for end-stage achalasia is safe and effective. Based on the results of this study, esophagectomy should be performed without hesitation in patients who are fit for major surgery and present with disabling symptoms, poor quality of life and dolichomegaesophagus recalcitrant to multiple endoscopic dilatations and/or surgical myotomies.
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From nose to memory: the involuntary nature of odor-evoked autobiographical memories in Alzheimer’s disease
Abstract
Research suggests that odors may serve as a potent cue for autobiographical retrieval. We tested this hypothesis in Alzheimer's disease (AD) and investigated whether odor-evoked autobiographical memory is an involuntary process that shares similarities with music-evoked autobiographical memory. Participants with mild AD and controls were asked to retrieve two personal memories after odor exposure, after music exposure, and in an odor-and-music-free condition. AD participants showed better specificity, emotional experience, mental time travel, and retrieval time after odor and music exposure than in the control condition. Similar beneficial effects of odor and music exposure were observed for autobiographical characteristics (i.e., specificity, emotional experience, and mental time travel), except for retrieval time which was more improved after odor than after music exposure. Interestingly, regression analyses suggested executive involvement in memories evoked in the control condition but not in those evoked after music or odor exposure. These findings suggest the involuntary nature of odor-evoked autobiographical memory in AD. They also suggest that olfactory cuing could serve as a useful and ecologically valid tool to stimulate autobiographical memory, at least in the mild stage of the disease.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2kHM15A
Role of endocannabinoids on sweet taste perception, food preference and obesity-related disorders
Abstract
The prevalence of obesity and obesity-related disorders such as type 2 diabetes and metabolic syndrome has increased significantly in the past decades, reaching epidemic levels and therefore becoming a major health issue worldwide. Chronic overeating of highly palatable foods is one of the main responsible aspects behind overweight. Food choice is driven by food preference, which is influenced by environmental and internal factors, from availability to rewarding properties of food. Consequently, the acquisition of a dietary habit that may lead to metabolic alterations is the result of a learning process in which many variables take place. From genetics to socioeconomic status, the response to food and how this food affects energy metabolism is heavily influenced, even before birth. In this work, we review how food preference is acquired and established, particularly as regards sweet taste; towards which flavors and tastes we are positively predisposed by our genetic background, our early experience, further lifestyle, and our surroundings; and, especially, the role that the endocannabinoid system plays in all of this. Ultimately, we try to summarize why this system is relevant for health purposes and how this is linked to important aspects of eating behavior, as its function as a modulator of energy homeostasis affects, and is affected by, physiological responses directly associated with obesity.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2xzcB75
Initial evaluation of the Celesteion large-bore PET/CT scanner in accordance with the NEMA NU2-2012 standard and the Japanese guideline for oncology FDG PET/CT data acquisition protocol version 2.0
Abstract
Background
The goal of this study was to evaluate the performance of the Celesteion positron emission tomography/computed tomography (PET/CT) scanner, which is characterized by a large-bore and time-of-flight (TOF) function, in accordance with the NEMA NU-2 2012 standard and version 2.0 of the Japanese guideline for oncology fluorodeoxyglucose PET/CT data acquisition protocol. Spatial resolution, sensitivity, count rate characteristic, scatter fraction, energy resolution, TOF timing resolution, and image quality were evaluated according to the NEMA NU-2 2012 standard. Phantom experiments were performed using 18F-solution and an IEC body phantom of the type described in the NEMA NU-2 2012 standard. The minimum scanning time required for the detection of a 10-mm hot sphere with a 4:1 target-to-background ratio, the phantom noise equivalent count (NECphantom), % background variability (N 10mm), % contrast (Q H,10mm), and recovery coefficient (RC) were calculated according to the Japanese guideline.
Results
The measured spatial resolution ranged from 4.5- to 5-mm full width at half maximum (FWHM). The sensitivity and scatter fraction were 3.8 cps/kBq and 37.3%, respectively. The peak noise-equivalent count rate was 70 kcps in the presence of 29.6 kBq mL−1 in the phantom. The system energy resolution was 12.4% and the TOF timing resolution was 411 ps at FWHM. Minimum scanning times of 2, 7, 6, and 2 min per bed position, respectively, are recommended for visual score, noise-equivalent count (NEC)phantom, N 10mm, and the Q H,10mm to N 10mm ratio (QNR) by the Japanese guideline. The RC of a 10-mm-diameter sphere was 0.49, which exceeded the minimum recommended value.
Conclusions
The Celesteion large-bore PET/CT system had low sensitivity and NEC, but good spatial and time resolution when compared to other PET/CT scanners. The QNR met the recommended values of the Japanese guideline even at 2 min. The Celesteion is therefore thought to provide acceptable image quality with 2 min/bed position acquisition, which is the most common scan protocol in Japan.
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Older Patients With Breast Cancer Still Overtreated With RT -- Why?
Surgeons and radiation oncologists frequently overestimate the benefits of radiotherapy (RT) after lumpectomy and thus continue to recommend its use, despite a lack of evidence for a survival benefit or protection against local recurrence.
Medscape Medical News
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The prognostic value of C-X-C motif chemokine receptor 4 in patients with sporadic malignant peripheral nerve sheath tumors
Recent studies indicate that C-X-C motif chemokine receptor 4 (CXCR4) and its ligand, C-X-C motif chemokine ligand 12 (CXCL12), stimulate expression of the cell cycle regulatory protein Cyclin D1 in neurofibro...
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Minimally Invasive Adrenalectomy for Adrenocortical Carcinoma: Five-Year Trends and Predictors of Conversion
Abstract
Background
Adrenocortical carcinoma (ACC) is rare but often fatal. Surgery offers the only chance of cure. As minimally invasive (MI) procedures for cancer become common, their role for ACC is still debated. We reviewed usage of MI approaches for ACC over time and risk factors for conversion using a large national database.
Methods
ACC patients with localized disease were identified in the National Cancer Data Base from 2010 to 2014. A retrospective review examined trends in the surgical approach over time. Patient demographics, surgical approach, and tumor characteristics between MI, open, and converted procedures were compared.
Results
588 patients underwent adrenalectomy for ACC, of which 200 were minimally invasive. From 2010 to 2014, MI operations increased from 26 to 44% with robotic procedures increasing from 5 to 16%. The use of MI operations compared to open was not different based on facility type (p = 0.40) or location (p = 0.63). MI tumors were more likely to be confined to the adrenal (p < 0.001) but final margin status was not different (p = 0.56). Conversion was performed in 38/200 (19%). Average tumor size was 10.2 cm in the converted group compared to 8.6 cm in the MI group (p = 0.09). There was no difference in extent of disease (p = 0.33), margin status (p = 0.12), or lymphovascular invasion (p = 0.59) between MI and converted procedures. Tumor size > 5 cm was the only significant predictor of conversion (p = 0.04). No patients with pathologic stage I disease required conversion (0/19).
Conclusions
The frequency of MI approaches for ACC is increasing. In the final year of the study, 44% of adrenalectomies were MI. Size > 5 cm was the only significant predictor of conversion.
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Derivation and Validation of a Novel Physiological Emergency Surgery Acuity Score
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Thromboprophylaxis in autologous breast reconstruction
Publication date: Available online 10 October 2017
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): Sarita Vamadeva, Francis Henry, Judith Hunter, Simon Wood, Navid Jallali
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Isolated Limb Perfusion and Infusion for Extremity Soft Tissue Sarcoma: A Contemporary Systematic Review and Meta-Analysis
Abstract
Background
Isolated limb perfusion (ILP) and isolated limb infusion (ILI) have been variably used in recent years for the treatment of locally advanced or marginally resectable extremity soft tissue sarcomas (STSs). We performed a systematic review and meta-analysis of contemporary studies to further characterize treatment patterns and outcomes.
Methods
PubMed was queried for articles published in or after the year 2000, in the English language, with > 10 patients, and with adequate outcome data following ILP/ILI. Descriptive aggregate statistics were performed.
Results
Nineteen studies that met the inclusion criteria were identified, with a total of 1288 patients. Weighted mean patient age was 55.9 years and 52% were male. The majority underwent ILP (88%) versus 12% for ILI, and chemotherapeutic regimens used were as follows: (1) melphalan with tumor necrosis factor (TNF)-α (78%), (2) melphalan ± actinomycin (10%), and (3) other regimens (12%). Most common histologies treated were malignant fibrous histiocytoma (21%), liposarcoma (16%), synovial (11%) and leiomyosarcoma (7%). Aggregate overall response rate (ORR) post-procedure was 73.3%, with 25.8% demonstrating a complete response (CR). Similar unadjusted ORRs were noted in the melphalan treatment groups with and without TNFα (72.0 and 67.0%, respectively; p = 0.27). Grade III toxicity was observed in 15.4% of patients, and grade IV/V toxicity was observed in 6.0% of patients. Overall limb salvage rate was 73.8% and median time to local (in-field) progression ranged from 4 to 28 months (weighted median 22.1 months).
Conclusion
ILP and ILI for extremity STS can be safely performed with appreciable response rates and significant limb salvage rates. Further study is needed to identify optimal treatment regimens by histology.
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High Expression of the Mitophagy-Related Protein Pink1 is Associated with a Poor Response to Chemotherapy and a Poor Prognosis for Patients Treated with Neoadjuvant Chemotherapy for Esophageal Squamous Cell Carcinoma
Abstract
Background
Autophagy plays a major role in cellular homeostasis and is implicated in cancer progression. Damaged mitochondria are scavenged and eliminated by mitochondrial autophagy, referred to as mitophagy, which can promote cancer cell survival. This study investigated the expression and effects of the autophagy-related protein LC3 and the mitophagy-related protein Pink1 in human esophageal squamous cell carcinoma (ESCC).
Methods
Both LC3 and Pink1 were analyzed by immunohistochemistry in tissues from 217 ESCC patients, including 159 patients undergoing neoadjuvant chemotherapy. The relationships between LC3 and Pink1 expression and various clinicopathologic factors were determined. In vitro assays were performed to assess the role of LC3 and Pink1 in ESCC chemoresistance.
Results
High LC3 expression was observed in 47.9% and high Pink1 expression in 48.4% of the ESCC patients. Pink1 expression was significantly higher in patients who underwent chemotherapy than in patients who did not (p = 0.032). High LC3 and Pink1 expression was significantly correlated with poor response to chemotherapy (p = 0.004 and p < 0.001, respectively), and high expression of Pink1, but not LC3, was significantly correlated with a poor prognosis for patients treated with preoperative chemotherapy (p = 0.007). Multivariate analysis identified Pink1 expression as an independent prognostic factor (p = 0.042). In vitro assays demonstrated that LC3-II and Pink1 expression increased after chemotherapeutic treatment in the ESCC cell line, and inhibition of autophagy and mitophagy using chloroquine and siPink1, respectively, restored chemosensitivity.
Conclusions
High expression of Pink1 is associated with chemoresistance and a poor prognosis for ESCC patients undergoing neoadjuvant chemotherapy.
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Application of EGFR inhibitor reduces circulating tumor cells during transcatheter arterial embolization
Abstract
Purpose
Transcatheter arterial embolization (TAE) has been widely used in treating non-curative hepatocellular carcinoma (HCC). However, it is noticed that TAE may cause invasion of some cancer cells into circulation, resulting in distal metastasis and poor therapeutic outcome. Here, we aimed to reduce the side effects of TAE using the inhibitors for epidermal growth factor receptor (EGFR).
Methods
Transient hepatic artery ligation (HAL) was used as a mouse model for TAE. EGFR inhibitors were applied. Tumor size, presence of tumor cells in circulation, distal tumor formation, and activation of genes associated with tumor cell invasion and metastasis were analyzed.
Results
Inhibitors for EGFR significantly reduced the size of primary tumor, presence of tumor cells in circulation, and distal tumor formation after HAL. Further studies showed that EGFR inhibition suppressed several genes associated with tumor cell invasion and metastasis, such as vascular endothelial growth factor-A, stromal cell-derived factor 1, and Slug.
Conclusion
EGFR inhibitor application may reduce circulating cancer cells during TAE and thus improve the therapy for advanced HCC.
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EZH2 regulates dental pulp inflammation by direct effect on inflammatory factors
Source:Archives of Oral Biology, Volume 85
Author(s): Tianqian Hui, Peng A., Yuan Zhao, Jing Yang, Ling Ye, Chenglin Wang
ObjectivePulpitis is a multi-factorial disease that could be caused by complex interactions between genetics, epigenetics and environmental factors. We aimed to evaluate the role of Enhancer of Zeste Homolog 2 (EZH2) in the inflammatory response of human dental pulp cells (HDPCs) and dental pulp tissues.MethodsThe expressions of inflammatory cytokines in HDPCs treated by EZH2 complex or EZH2 siRNA with or without rhTNF-α were examined by quantitative real-time polymerase chain reaction (q-PCR). The levels of secreted inflammatory cytokines including IL-6, IL-8, IL-15, CCL2 and CXCL12 in culture supernatants were measured by Luminex assay. In rat pulpitis model, the effects of EZH2 on dental pulp tissues were verified by histology. We invested the mechanisms of the effect of EZH2 on the inflammatory factors by ChIP assay.ResultsEZH2 down-regulation inhibited the expression of inflammatory factors, including IL-6, IL-8, IL-15, CCL2 and CXCL12 in HDPCs. EZH2 complex promoted the expression and secretion of these inflammatory factors in HDPCs, while EZH2 silencing could attenuate the promotion of inflammatory factors that were induced by rhTNF-α. In pulpitis models of rats, EZH2 down-regulation inhibited the inflammatory process of dental pulp while EZH2 complex showed no significant facilitation of pulpal inflammation. In addition, EZH2 could bind on the promoters of IL-6, IL-8 and CCL2, but not IL-15 and CXCL12, to affect the transcription of these proinflammatory cytokines.ConclusionsIn HDPCs, EZH2 could induce inflammation, while EZH2 down-regulation could attenuate the inflammatory responses. EZH2 plays an important role in this inflammatory process of dental pulp.
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Role of PDGF-BB in proliferation, differentiation and maintaining stem cell properties of PDL cells in vitro
Source:Archives of Oral Biology, Volume 85
Author(s): Zornitsa Mihaylova, Rozaliya Tsikandelova, Pavel Sanimirov, Natalia Gateva, Vanyo Mitev, Nikolay Ishkitiev
ObjectivePlatelet-derived growth factor-BB (PDGF-BB) is one of the most abundant growth factors in platelet derived products and has been shown to stimulate regeneration after tissue injury. There is a population of mesenchymal stem cells (MSC) in human periodontal ligament (PDL) which can contribute to tissue regeneration under appropriate conditions.DesignPDL cells were isolated and characterized using stem cell and differentiation markers via immunofluorescence and flow cytometry and then cultured in vitro and treated with different concentrations of PDGF-BB. The effect of PDGF-BB on cell proliferation, stem cell and differentiation markers expression, soluble collagen production, lysyl oxidase (LOX) activity, alkaline phosphatase (ALP) activity and calcium nodules formation was assessed.ResultsPDGF-BB stimulated the proliferation of cells with the maximum effect at 50ng/mL. The growth factor increased the expression of stem cell markers and SPARC; Col1a2 expression was decreased, whereas the expression of Col3a1 remain unchanged. Soluble collagen production, ALP activity and calcium nodules formation were also significantly decreased by PDGF-BB; LOX activity was significantly increased.ConclusionsPDGF-BB is a powerful promoter of cell proliferation and increases the expression of stem cell markers; inhibites collagen production and mineraliration but accelerates the maturation of collagen chains through increased LOX activity and SPARC expression.
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Isolated Limb Perfusion and Infusion for Extremity Soft Tissue Sarcoma: A Contemporary Systematic Review and Meta-Analysis
Abstract
Background
Isolated limb perfusion (ILP) and isolated limb infusion (ILI) have been variably used in recent years for the treatment of locally advanced or marginally resectable extremity soft tissue sarcomas (STSs). We performed a systematic review and meta-analysis of contemporary studies to further characterize treatment patterns and outcomes.
Methods
PubMed was queried for articles published in or after the year 2000, in the English language, with > 10 patients, and with adequate outcome data following ILP/ILI. Descriptive aggregate statistics were performed.
Results
Nineteen studies that met the inclusion criteria were identified, with a total of 1288 patients. Weighted mean patient age was 55.9 years and 52% were male. The majority underwent ILP (88%) versus 12% for ILI, and chemotherapeutic regimens used were as follows: (1) melphalan with tumor necrosis factor (TNF)-α (78%), (2) melphalan ± actinomycin (10%), and (3) other regimens (12%). Most common histologies treated were malignant fibrous histiocytoma (21%), liposarcoma (16%), synovial (11%) and leiomyosarcoma (7%). Aggregate overall response rate (ORR) post-procedure was 73.3%, with 25.8% demonstrating a complete response (CR). Similar unadjusted ORRs were noted in the melphalan treatment groups with and without TNFα (72.0 and 67.0%, respectively; p = 0.27). Grade III toxicity was observed in 15.4% of patients, and grade IV/V toxicity was observed in 6.0% of patients. Overall limb salvage rate was 73.8% and median time to local (in-field) progression ranged from 4 to 28 months (weighted median 22.1 months).
Conclusion
ILP and ILI for extremity STS can be safely performed with appreciable response rates and significant limb salvage rates. Further study is needed to identify optimal treatment regimens by histology.
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High Expression of the Mitophagy-Related Protein Pink1 is Associated with a Poor Response to Chemotherapy and a Poor Prognosis for Patients Treated with Neoadjuvant Chemotherapy for Esophageal Squamous Cell Carcinoma
Abstract
Background
Autophagy plays a major role in cellular homeostasis and is implicated in cancer progression. Damaged mitochondria are scavenged and eliminated by mitochondrial autophagy, referred to as mitophagy, which can promote cancer cell survival. This study investigated the expression and effects of the autophagy-related protein LC3 and the mitophagy-related protein Pink1 in human esophageal squamous cell carcinoma (ESCC).
Methods
Both LC3 and Pink1 were analyzed by immunohistochemistry in tissues from 217 ESCC patients, including 159 patients undergoing neoadjuvant chemotherapy. The relationships between LC3 and Pink1 expression and various clinicopathologic factors were determined. In vitro assays were performed to assess the role of LC3 and Pink1 in ESCC chemoresistance.
Results
High LC3 expression was observed in 47.9% and high Pink1 expression in 48.4% of the ESCC patients. Pink1 expression was significantly higher in patients who underwent chemotherapy than in patients who did not (p = 0.032). High LC3 and Pink1 expression was significantly correlated with poor response to chemotherapy (p = 0.004 and p < 0.001, respectively), and high expression of Pink1, but not LC3, was significantly correlated with a poor prognosis for patients treated with preoperative chemotherapy (p = 0.007). Multivariate analysis identified Pink1 expression as an independent prognostic factor (p = 0.042). In vitro assays demonstrated that LC3-II and Pink1 expression increased after chemotherapeutic treatment in the ESCC cell line, and inhibition of autophagy and mitophagy using chloroquine and siPink1, respectively, restored chemosensitivity.
Conclusions
High expression of Pink1 is associated with chemoresistance and a poor prognosis for ESCC patients undergoing neoadjuvant chemotherapy.
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Fluid Resuscitation in Patients with Severe Burns: A Meta-Analysis of Randomized Controlled Trials
Abstract
Objectives
Fluid resuscitation is the mainstay treatment to reconstitute intravascular volume and maintain end-organ perfusion in patients with severe burns. The use of a hyper-osmotic or iso-osmotic solution in fluid resuscitation to manage myocardial depression and increased capillary permeability during burn shock has been debated. We conducted a systematic review and meta-analysis to compare the efficacies of hyper-osmotic and iso-osmotic solutions in restoring hemodynamic stability after burn injuries.
Methods
PubMed, Embase, Cochrane Library, Scopus, and ClinicalTrials. gov registry were searched. Randomized control trials evaluating the efficacy and safety of hyper-osmotic and iso-osmotic fluid resuscitation in patients with burn injuries were selected. Eligible trials were abstracted and assessed for the risk of bias by 2 reviewers and results of hemodynamic indicators in the included trials were analyzed.
Results
Ten trials including 502 participants were published between 1983 and 2013. Compared with iso-osmotic group, the hyper-osmotic group exhibited a significant decrease in the fluid load (vol/%TBSA/weight) at 24 h postinjury, with a mean difference of −0.54 (95% confidence interval = −0.92 to −0.17). No differences were observed in the urine output, creatinine level, and mortality at 24 h postinjury between groups.
Conclusions
Hyper-osmotic fluid resuscitation appears to be an attractive choice for severe burns in terms of total body surface area or burn depth. Further investigation is recommended before conclusive recommendation.
This article is protected by copyright. All rights reserved.
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Prevalence and clonality of synchronous primary carcinomas in the bladder and prostate
Abstract
Incidental prostate adenocarcinoma (IPCa) has been frequently discovered during postoperative histopathological evaluation of radical cystoprostatectomy specimens in patients with bladder cancer (BCa). However, there is currently no conclusive study addressing the clinical significance of IPCa and the clonal relatedness of IPCa and BCa. Here, we performed a retrospective single-center review of 919 BCa cases and an additional meta-analysis including a total of 19,868 individuals who underwent radical cystectomy for bladder cancer. IPCa, mostly clinically insignificant, was detected in 67 of 919 BCa patients (7.3%), and was significantly associated with greater age. In the meta-analysis, a lower prevalence was observed in asian than non-asian countries (19% vs. 32%), presumably due to their different rates of prostate cancer occurrence. Whole exome sequencing on matched BCa and IPCa samples unambiguously revealed independent clonal origins of the synchronous tumors. BCa and IPCa lesions from each patient displayed distinctive genomic abnormalities and largely unrelated mutational signatures of single nucleotide variations, indicating disparate mutational processes underlying bladder and prostate oncogenesis. These findings provide important insights into the incidental nature of prostate adenocarcinoma in patients with bladder cancer, and suggest that the two concurrent diseases can be managed separately.
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MRI assessment of treatment delivery for interstitial photodynamic therapy of high-grade glioma in a preclinical model
Background
High-grade gliomas are primary brain tumors that have shown increasing incidence and unfavorable outcomes. Local control is crucial to the management of this pathology. Photodynamic therapy (PDT), based on the light-induced activation of a photosensitizer (PS), achieves local treatment by inducing selective lesions in tumor tissue.
Objectives
Previous studies have reported the outcomes of PDT for glioblastoma via immunohistological data. Our study aimed to evaluate MRI findings, including diffusion, and perfusion sequences, compared with immunohistological data from the same population to address the efficiency of light fractionation.
Materials and Methods
Twenty-six "nude" rats grafted with human U87 cells into the right putamen underwent PDT. After PS precursor (5-ALA) intake, an optical fiber was introduced into the tumor. The rats were randomized into the following groups: those without illumination and those that received two or five fractions of light. Treatment effects were assessed with early high-field MRI to measure the volume of necrosis and edema using diffusion and perfusion sequences; the MRI results were compared with immunohistology results, including necrosis and apoptosis markers.
Results
Elevated diffusion values were observed on MRI in the centers of the tumors of the treated animals, especially in the 5-fraction group (P < 0.01). Perfusion was decreased around the treatment site, especially in the 5-fraction group (P = 0.024). The MRI findings were consistent with previously published histological data. The median volume of necrosis was significantly different between the sham group and treated groups, 0 mm3 versus 2.67 mm3, P < 0.001. The same trend was previously observed in histology data when grading the absence or presence of necrosis and when the presence of necrosis was significantly more predominant for the treated group than for the untreated group (P < 001). Additionally, cell death represented by apoptosis marker data (TUNEL method) was significantly higher in the 5-fraction group than in the 2-fraction group (P = 0.01).
Conclusion
Diffusion and perfusion MRI revealed histological lesions. Interstitial PDT (iPDT) induced specific lesions in the tumor tissue, which were observed with MRI and confirmed by histopathological analysis. Thus, MRI may provide a non-invasive and reliable tool to assess treatment outcomes after PDT. Lasers Surg. Med. © 2017 Wiley Periodicals, Inc.
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T-Cell Mediation of Pregnancy Analgesia Affecting Chronic Pain in Mice
It has been reported consistently that many female chronic pain sufferers have an attenuation of symptoms during pregnancy. Rats display increased pain tolerance during pregnancy due to an increase in opioid receptors in the spinal cord. Past studies did not consider the role of non-neuronal cells, which are now known to play an important role in chronic pain processing. Using an inflammatory (complete Freund's adjuvant) or neuropathic (spared nerve injury) model of persistent pain, we observed that young adult female mice in early pregnancy switch from a microglia-independent to a microglia-dependent pain hypersensitivity mechanism. During late pregnancy, female mice show no evidence of chronic pain whatsoever. This pregnancy-related analgesia is reversible by intrathecal administration of naloxone, suggesting an opioid-mediated mechanism; pharmacological and genetic data suggest the importance of -opioid receptors. We also observe that T-cell-deficient (nude and Rag1-null mutant) pregnant mice do not exhibit pregnancy analgesia, which can be rescued with the adoptive transfer of CD4+ or CD8+ T cells from late-pregnant wild-type mice. These results suggest that T cells are a mediator of the opioid analgesia exhibited during pregnancy.
SIGNIFICANCE STATEMENT Chronic pain symptoms often subside during pregnancy. This pregnancy-related analgesia has been demonstrated for acute pain in rats. Here, we show that pregnancy analgesia can produce a complete cessation of chronic pain behaviors in mice. We show that the phenomenon is dependent on pregnancy hormones (estrogen and progesterone), -opioid receptors, and T cells of the adaptive immune system. These findings add to the recent but growing evidence of sex-specific T-cell involvement in chronic pain processing.
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Domain-General Brain Regions Do Not Track Linguistic Input as Closely as Language-Selective Regions
Language comprehension engages a cortical network of left frontal and temporal regions. Activity in this network is language-selective, showing virtually no modulation by nonlinguistic tasks. In addition, language comprehension engages a second network consisting of bilateral frontal, parietal, cingulate, and insular regions. Activity in this "multiple demand" (MD) network scales with comprehension difficulty, but also with cognitive effort across a wide range of nonlinguistic tasks in a domain-general fashion. Given the functional dissociation between the language and MD networks, their respective contributions to comprehension are likely distinct, yet such differences remain elusive. Prior neuroimaging studies have suggested that activity in each network covaries with some linguistic features that, behaviorally, influence on-line processing and comprehension. This sensitivity of the language and MD networks to local input characteristics has often been interpreted, implicitly or explicitly, as evidence that both networks track linguistic input closely, and in a manner consistent across individuals. Here, we used fMRI to directly test this assumption by comparing the BOLD signal time courses in each network across different people (n = 45, men and women) listening to the same story. Language network activity showed fewer individual differences, indicative of closer input tracking, whereas MD network activity was more idiosyncratic and, moreover, showed lower reliability within an individual across repetitions of a story. These findings constrain cognitive models of language comprehension by suggesting a novel distinction between the processes implemented in the language and MD networks.
SIGNIFICANCE STATEMENT Language comprehension recruits both language-specific mechanisms and domain-general mechanisms that are engaged in many cognitive processes. In the human cortex, language-selective mechanisms are implemented in the left-lateralized "core language network", whereas domain-general mechanisms are implemented in the bilateral "multiple demand" (MD) network. Here, we report the first direct comparison of the respective contributions of these networks to naturalistic story comprehension. Using a novel combination of neuroimaging approaches we find that MD regions track stories less closely than language regions. This finding constrains the possible contributions of the MD network to comprehension, contrasts with accounts positing that this network has continuous access to linguistic input, and suggests a new typology of comprehension processes based on their extent of input tracking.
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Fragile X Mental Retardation Protein Restricts Small Dye Iontophoresis Entry into Central Neurons
Fragile X mental retardation protein (FMRP) loss causes Fragile X syndrome (FXS), a major disorder characterized by autism, intellectual disability, hyperactivity, and seizures. FMRP is both an RNA- and channel-binding regulator, with critical roles in neural circuit formation and function. However, it remains unclear how these FMRP activities relate to each other and how dysfunction in their absence underlies FXS neurological symptoms. In testing circuit level defects in the Drosophila FXS model, we discovered a completely unexpected and highly robust neuronal dye iontophoresis phenotype in the well mapped giant fiber (GF) circuit. Controlled dye injection into the GF interneuron results in a dramatic increase in dye uptake in neurons lacking FMRP. Transgenic wild-type FMRP reintroduction rescues the mutant defect, demonstrating a specific FMRP requirement. This phenotype affects only small dyes, but is independent of dye charge polarity. Surprisingly, the elevated dye iontophoresis persists in shaking B mutants that eliminate gap junctions and dye coupling among GF circuit neurons. We therefore used a wide range of manipulations to investigate the dye uptake defect, including timed injection series, pharmacology and ion replacement, and optogenetic activity studies. The results show that FMRP strongly limits the rate of dye entry via a cytosolic mechanism. This study reveals an unexpected new phenotype in a physical property of central neurons lacking FMRP that could underlie aspects of FXS disruption of neural function.
SIGNIFICANCE STATEMENT FXS is a leading heritable cause of intellectual disability and autism spectrum disorders. Although researchers established the causal link with FMRP loss >;25 years ago, studies continue to reveal diverse FMRP functions. The Drosophila FXS model is key to discovering new FMRP roles, because of its genetic malleability and individually identified neuron maps. Taking advantage of a well characterized Drosophila neural circuit, we discovered that neurons lacking FMRP take up dramatically more current-injected small dye. After examining many neuronal properties, we determined that this dye defect is cytoplasmic and occurs due to a highly elevated dye iontophoresis rate. We also report several new factors affecting neuron dye uptake. Understanding how FMRP regulates iontophoresis should reveal new molecular factors underpinning FXS dysfunction.
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GD1a Overcomes Inhibition of Myelination by Fibronectin via Activation of Protein Kinase A: Implications for Multiple Sclerosis
Remyelination failure by oligodendrocytes contributes to the functional impairment that characterizes the demyelinating disease multiple sclerosis (MS). Since incomplete remyelination will irreversibly damage axonal connections, treatments effectively promoting remyelination are pivotal in halting disease progression. Our previous findings suggest that fibronectin aggregates, as an environmental factor, contribute to remyelination failure by perturbing oligodendrocyte progenitor cell (OPC) maturation. Here, we aim at elucidating whether exogenously added gangliosides (i.e., cell surface lipids with a potential to modulate signaling pathways) could counteract fibronectin-mediated inhibition of OPC maturation. Exclusive exposure of rat oligodendrocytes to GD1a, but not other gangliosides, overcomes aggregated fibronectin-induced inhibition of myelin membrane formation, in vitro, and OPC differentiation in fibronectin aggregate containing cuprizone-induced demyelinated lesions in male mice. GD1a exerts its effect on OPCs by inducing their proliferation and, at a late stage, by modulating OPC maturation. Kinase activity profiling revealed that GD1a activated a protein kinase A (PKA)-dependent signaling pathway and increased phosphorylation of the transcription factor cAMP response element-binding protein. Consistently, the effect of GD1a in restoring myelin membrane formation in the presence of fibronectin aggregates was abolished by the PKA inhibitor H89, whereas the effect of GD1a was mimicked by the PKA activator dibutyryl-cAMP. Together, GD1a overcomes the inhibiting effect of aggregated fibronectin on OPC maturation by activating a PKA-dependent signaling pathway. Given the persistent presence of fibronectin aggregates in MS lesions, ganglioside GD1a might act as a potential novel therapeutic tool to selectively modulate the detrimental signaling environment that precludes remyelination.
SIGNIFICANCE STATEMENT As an environmental factor, aggregates of the extracellular matrix protein fibronectin perturb the maturation of oligodendrocyte progenitor cells (OPCs), thereby impeding remyelination, in the demyelinating disease multiple sclerosis (MS). Here we demonstrate that exogenous addition of ganglioside GD1a overcomes the inhibiting effect of aggregated fibronectin on OPC maturation, both in vitro and in vivo, by activating a PKA-dependent signaling pathway. We propose that targeted delivery of GD1a to MS lesions may act as a potential novel molecular tool to boost maturation of resident OPCs to overcome remyelination failure and halt disease progression.
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