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Amy Lawson Moore,1 Terissa M Miller,1 Jeffrey J Moore,1 Christina Ledbetter1,2 1Department of Psychology, Gibson Institute of Cognitive Research, Colorado Springs, CO, USA; 2Department of Neurosurgery, Louisiana State University Health, Shreveport, LA, USACorrespondence: Amy Lawson Moore, Gibson Institute of Cognitive Research, 5085 List Drive, Suite 200-A, Colorado Springs, CO, 80919, USA, Tel +1 719-219-0940, Email amoore@gibsonresearch.orgBackground: The state of reading proficiency among children in the United States continues to be a subject of concern among psychologists, teachers, parents, policy makers, and the education community at large. Despite the widespread use of curricular methods that teach basic reading skills, there remains a large percentage of children that struggle to read. Therefore, novel approaches to reading remediation should be explored.Purpose: The aims of this study were to examine 1) the effect of a multicomponent cognitive and reading intervention on cognitive and reading skills; 2) the role of ADHD, age, sex, IQ score, and individual cognitive skills on the effectiveness of the ReadRx intervention; and 3) parent-reported behavioral outcomes following the ReadRx intervention.Methods: The current study analyzed a large real-world dataset to examine cognitive, reading, and behavioral outcomes for struggling readers (n = 3527) who had completed 24 weeks (120 hours) of intense cognitive training integrated with a structured literacy intervention using ReadRx in a one-on-one clinic setting.Results: Analyses of pretest and post-test scores showed statistically significant changes on all cognitive and reading measures including attention, visual processing, processing speed, long-term memory, working memory, reasoning, phonological awareness, Work Attack, phonetic coding, spelling, comprehension, and overall IQ score with medium to very large effect sizes. The results included an average 4.1-year gain in reading skills including a 6-year gain in phonological awareness. No differences were found based on age, sex, or ADHD status, and minimal differences were found based on pre-intervention IQ score and cognitive test scores. The study also included a qualitative thematic analysis of parent-reported behavioral outcomes revealing themes of improved cognition, academic performance, and psychosocial skills including confidence and perseverance.Conclusion: Our findings were consistent with previous controlled studies on this intervention and offer an encouraging alternative instructional approach to reading remediation that aligns with the Science of Reading and includes intensive remediation of underlying cognitive skills.Keywords: cognitive training, brain training, LearningRx, reading, dyslexia, phonemic awareness, literacy, reading disorder

© 2015 Nature America, Inc. All rights reserved. During real-world (RW) exploration, rodent hippocampal activity shows robust spatial selectivity, which is hypothesized to be governed largely by distal visual cues, although other sensory-motor cues also contribute. Indeed, hippocampal spatial selectivity is weak in primate and human studies that use only visual cues. To determine the contribution of distal visual cues only, we measured hippocampal activity from body-fixed rodents exploring a two-dimensional virtual reality (VR). Compared to that in RW, spatial selectivity was markedly reduced during random foraging and goal-directed tasks in VR. Instead we found small but significant selectivity to distance traveled. Despite impaired spatial selectivity in VR, most spikes occurred within ∼2-s-long hippocampal motifs in both RW and VR that had similar structure, including phase precession within motif fields. Selectivity to space and distance traveled were greatly enhanced in VR tasks with stereotypical trajectories. Thus, distal visual cues alone are insufficient to generate a robust hippocampal rate code for space but are sufficient for a temporal code.

In the quest to model neuronal function amid gaps in physiological data, a promising strategy is to develop a normative theory that interprets neuronal physiology as optimizing a computational objective. This study extends current normative models, which primarily optimize prediction, by conceptualizing neurons as optimal feedback controllers. We posit that neurons, especially those beyond early sensory areas, steer their environment toward a specific desired state through their output. This environment comprises both synaptically interlinked neurons and external motor sensory feedback loops, enabling neurons to evaluate the effectiveness of their control via synaptic feedback. To model neurons as biologically feasible controllers which implicitly identify loop dynamics, infer latent states, and optimize control we utilize the contemporary direct data-driven control (DD-DC) framework. Our DD-DC neuron model explains various neurophysiological phenomena: the shift from potentiation to depression in spike-timing-dependent plasticity with its asymmetry, the duration and adaptive nature of feedforward and feedback neuronal filters, the imprecision in spike generation under constant stimulation, and the characteristic operational variability and noise in the brain. Our model presents a significant departure from the traditional, feedforward, instant-response McCulloch-Pitts-Rosenblatt neuron, offering a modern, biologically informed fundamental unit for constructing neural networks., Competing Interests: Competing interests statement:The authors declare no competing interest.

Objective: A quality improvement initiative (QII) was conducted with five community-based health systems' oncology care centers (sites A-E). The QII aimed to increase referrals, genetic counseling (GC), and germline genetic testing (GT) for patients with ovarian cancer (OC) and triple-negative breast cancer (TNBC)., Methods: QII activities occurred at sites over several years, all concluding by December 2020. Medical records of patients with OC and TNBC were reviewed, and rates of referral, GC, and GT of patients diagnosed during the 2 years before the QII were compared to those diagnosed during the QII. Outcomes were analyzed using descriptive statistics, two-sample t-test, chi-squared/Fisher's exact test, and logistic regression., Results: For patients with OC, improvement was observed in the rate of referral (from 70% to 79%), GC (from 44% to 61%), GT (from 54% to 62%) and decreased time from diagnosis to GC and GT. For patients with TNBC, increased rates of referral (from 90% to 92%), GC (from 68% to 72%) and GT (81% to 86%) were observed. Effective interventions streamlined GC scheduling and standardized referral processes., Conclusion: A multi-year QII increased patient referral and uptake of recommended genetics services across five unique community-based oncology care settings., Competing Interests: Declaration of Competing Interest The following authors report no conflict of interest: Erica M. Bednar, Minxing Chen, Michael T. Walsh, Jr., Amanda L. Eppolito, Molly H. Klein, Kelly Teed, Brittany Hodge, Jordan Hunter, Dillon Davis, Wilshauna Serchion, Cara Yobbi, Sandra B. Jenkinson, Jennifer J. Moore, Cassandra Garcia, Christina Johnson, Fatimaeliza Gonzalez, Towanna Murray, Linda D. Nielsen, Brenda Ho, Megan Haas, Sarah B. Greenzweig, Abby Anderson, Nichole A. Morman, Elizabeth Bowdish, Emaline Wise, Julia N. Cooper, Pauline Kefalas Russ, Katelyn Tondo-Steele, Buonarotti F. de Gracia, Brooke Levin, Kristin Mattie, Molly Kalasinski, Kathryn Zarnawski, Jennifer Stone, Caitlin O'Brien, Alexa Bream, Aidan M. Kennedy, Rachel A. Paul, Michelle Bilbao, Maureen Romero, Anna K. Vercruyssen, Kaycee Leon, Banu K. Arun, Andrew V. Grainger, David P. Warshal, Erin Bowman, Timothy A. Goedde, Deepa Halaharvi, Kellie Rath, Generosa Grana, Lida Mina, Karen H. Lu. The following authors disclose potential conflicts of interest: Han Gill Chao is an employee at Fulgent Genetics and received restricted stock units as part of compensation, and Rebecca L. Carr is a full-time salaried employee of Ambry Genetics however, Han Gill Chao and Rebecca L. Carr were not employed by these organizations during their participation in the study. Rebekah Krukenberg received payment from Ambry Genetics for educational speaking opportunities and reimbursement of travel to educational speaking events. Jennifer Siettmann holds an unpaid, elected leadership position with Arizona Genetics Alliance., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Decades of work propose that hippocampal activity supports internal representation of learned experiences and contexts, allowing individuals to form long-term memories and quickly adapt behavior to changing environments. However, recent studies insinuate hippocampal representations can drift over time, raising the question: how could the hippocampus hold stable memories when activity of its neuronal maps fluctuates? We hypothesized that task-dependent hippocampal maps set by learning rules and structured attention stabilize as a function of behavioral performance. To test this, we imaged hippocampal CA1 pyramidal neurons during learning and memory recall phases of a new task where mice use odor cues to navigate between two reward zones. Across learning, both orthogonal and overlapping task-dependent place maps form rapidly, discriminating trial context with strong correlation to behavioral performance. Once formed, task-selective place maps show increased long-term stability during memory recall phases. We conclude that memory demand and attention stabilize hippocampal activity to maintain contextually rich spatial representations., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

For patients with newly diagnosed multiple myeloma, survival outcomes continue to improve significantly: however, nearly all patients will relapse following induction treatment. Optimisation of induction therapy is essential to provide longer term disease control and the current standard of care for most patients incorporates an immunomodulatory agent and proteasome inhibitor, most commonly lenalidomide and bortezomib in combination with dexamethasone (RVD), with maintenance until progression. Historically there has been limited access to RVD as an induction strategy outside of the United States; fortunately, there is now increasing access worldwide. This review discusses the rationale for use of RVD as induction therapy and aims to provide guidance in prescribing this regimen in order to optimise efficacy while minimising the toxicities of treatment. We also highlight the increasing evidence for the utility of addition of a monoclonal antibody to the RVD backbone to deepen responses and potentially provide longer disease control., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Dendrites are elaborate neural processes which integrate inputs from various sources in space and time. While decades of work have suggested an independent role for dendrites in driving nonlinear computations for the cell, only recently have technological advances enabled us to capture the variety of activity in dendrites and their coupling dynamics with the soma. Under certain circumstances, activity generated in a given dendritic branch remains isolated, such that the soma or even sister dendrites are not privy to these localized signals. Such branch-specific activity could radically increase the capacity and flexibility of coding for the cell as a whole. Here, we discuss these forms of localized and branch-specific activity, their functional relevance in plasticity and behavior, and their supporting biophysical and circuit-level mechanisms. We conclude by showcasing electrical and optical approaches in hippocampal area CA3, using original experimental data to discuss experimental and analytical methodology and key considerations to take when investigating the functional relevance of independent dendritic activity., (Copyright © 2022 IBRO. Published by Elsevier Ltd. All rights reserved.)

Objective: Autologous haematopoietic stem cell transplantation (AHSCT) has the potential to induce sustained periods of disease remission in multiple sclerosis (MS), which is an inflammatory disease of the central nervous system (CNS) characterised by demyelination and axonal degeneration. However, the mechanisms associated with durable treatment responses in MS require further elucidation., Methods: To characterise the longer term immune reconstitution effects of AHSCT at 24 and 36 months (M) post-transplant, high-dimensional immunophenotyping of peripheral blood mononuclear cells from 22 MS patients was performed using two custom-designed 18-colour flow cytometry panels., Results: The higher baseline frequencies of specific pro-inflammatory immune cells (T-helper-17 (Th17) cells, mucosal-associated invariant T-cells and CNS-homing T-conventional (T-conv) cells observed in MS patients were decreased post-AHSCT by 36M. This was accompanied by a post-AHSCT increase in frequencies and absolute counts of immunoregulatory CD56 hi natural killer cells at 24M and terminally differentiated CD8 + CD28 - CD57 + cells until 36M. A sustained increase in the proportion of naïve B-cells, with persistent depletion of memory B-cells and plasmablasts was observed until 36M. Reconstitution of the B-cell repertoire was accompanied by a reduction in the frequency of circulating T-follicular helper cells (cTfh) expressing programmed cell death-1 (PD1 + ) at 36M. Associations between frequency dynamics and clinical outcomes indicated only responder patients to exhibit a decrease in Th17, CNS-homing T-conv and PD1 + cTfh pro-inflammatory subsets at 36M, and an increase in CD39 + T-regulatory cells at 24M., Interpretation: AHSCT induces substantial recalibration of pro-inflammatory and immunoregulatory components of the immune system of MS patients for up to 36M post-transplant., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Autologous haematopoietic stem cell transplantation (AHSCT) is a therapeutic option for haematological malignancies, such as non-Hodgkin's lymphoma (NHL), and more recently, for autoimmune diseases, such as treatment-refractory multiple sclerosis (MS). The immunological mechanisms underlying remission in MS patients following AHSCT likely involve an anti-inflammatory shift in the milieu of circulating cytokines. We hypothesised that immunological tolerance in MS patients post-AHSCT is reflected by an increase in anti-inflammatory cytokines and a suppression of proinflammatory cytokines in the patient blood. We investigated this hypothesis using a multiplex-ELISA assay to compare the concentrations of secreted cytokine in the peripheral blood of MS patients and NHL patients undergoing AHSCT. In MS patients, we detected significant reductions in proinflammatory T helper (Th)17 cytokines interleukin (IL)-17, IL-23, IL-1β, and IL-21, and Th1 cytokines interferon (IFN)γ and IL-12p70 in MS patients from day 8 to 24 months post-AHSCT. These changes were not observed in the NHL patients despite similar pre-conditioning treatment for AHSCT. Some proinflammatory cytokines show similar trends in both cohorts, such as IL-8 and tumour necrosis factor (TNF)-α, indicating a probable treatment-related AHSCT response. Anti-inflammatory cytokines (IL-10, IL-4, and IL-2) were only transiently reduced post-AHSCT, with only IL-10 exhibiting a significant surge at day 14 post-AHSCT. MS patients that relapsed post-AHSCT exhibited significantly elevated levels of IL-17 at 12 months post-AHSCT, unlike non-relapse patients which displayed sustained suppression of Th17 cytokines at all post-AHSCT timepoints up to 24 months. These findings suggest that suppression of Th17 cytokines is essential for the induction of long-term remission in MS patients following AHSCT., Competing Interests: DM has received a research grant from Phebra Pty Ltd outside of submitted work. JCM reports personal fees from Biogen, Merck, Sanofi Genzyme and Teva, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hendrawan, Khoo, Visweswaran, Massey, Withers, Sutton, Ma and Moore.)

Background: Given the increasing numbers of multiple sclerosis (MS) patients undergoing autologous haematopoietic stem cell transplant (AHSCT) worldwide, and with women of childbearing age overrepresented in the target population, it is increasingly important to review fertility and pregnancy outcomes following AHSCT., Objective: To evaluate the rate of pregnancy and complications post-AHSCT for MS., Method: Retrospective evaluation of the rate of pregnancy and associated complications in a cohort of patients post-AHSCT with BEAM conditioning for MS since 2010 in a tertiary referral centre., Results: In our ongoing Phase 2 trial of AHSCT for MS, 55 patients have undergone AHSCT with 30 females being of childbearing age at time of transplantation. Four pregnancies occurred following AHSCT. Two pregnancies were carried to term. No maternal or neonatal complications were reported in either case. Two pregnancies were not carried to term due to elective terminations. Both of these patients became pregnant unexpectedly 2 years following AHSCT. Of the 21 male patients, one patient has fathered three children since his AHSCT. There were no newborn complications., Conclusions: This is the first report to our knowledge on fertility outcomes in both sexes post-AHSCT for MS. Patients of both sexes should be counselled prior to treatment on infertility and contraceptive use.

Three major pillars of hippocampal function are spatial navigation 1 , Hebbian synaptic plasticity 2 and spatial selectivity 3 . The hippocampus is also implicated in episodic memory 4 , but the precise link between these four functions is missing. Here we report the multiplexed selectivity of dorsal CA1 neurons while rats performed a virtual navigation task using only distal visual cues 5 , similar to the standard water maze test of spatial memory 1 . Neural responses primarily encoded path distance from the start point and the head angle of rats, with a weak allocentric spatial component similar to that in primates but substantially weaker than in rodents in the real world. Often, the same cells multiplexed and encoded path distance, angle and allocentric position in a sequence, thus encoding a journey-specific episode. The strength of neural activity and tuning strongly correlated with performance, with a temporal relationship indicating neural responses influencing behaviour and vice versa. Consistent with computational models of associative and causal Hebbian learning 6,7 , neural responses showed increasing clustering 8 and became better predictors of behaviourally relevant variables, with the average neurometric curves exceeding and converging to psychometric curves. Thus, hippocampal neurons multiplex and exhibit highly plastic, task- and experience-dependent tuning to path-centric and allocentric variables to form episodic sequences supporting navigation., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Multiple-target tracking algorithms generally operate in the local frame of the sensor and have difficulty with track reallocation when targets move in and out of the sensor field-of-view. This poses a problem when an unmanned aerial vehicle (UAV) is tracking multiple ground targets on a road network larger than its field-of-view. To address this problem, we propose a Rao-Blackwellized Particle Filter (RBPF) to maintain individual target tracks and to perform probabilistic data association when the targets are constrained to a road network. This is particularly useful when a target leaves and then re-enters the UAV's field-of-view. The RBPF is structured as a particle filter of particle filters. The top level filter handles data association and each of its particles maintains a bank of particle filters to handle target tracking. The tracking particle filters incorporate both positive and negative information when a measurement is received. We implement two path planning controllers, receding horizon and deep reinforcement learning, and compare their ability to improve the certainty for multiple target location estimates. The controllers prioritize paths that reduce each target's entropy. In addition, we develop an algorithm that computes the upper bound on the filter's performance, thus facilitating an estimate of the number of UAVs needed to achieve a desired performance threshold., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Moore, Bidstrup, Peterson and Beard.)

Using a novel in vitro model system combining biochemical/histologic with bioengineering approaches has provided significant insights into the physiology of fetal membrane weakening and rupture along with potential mechanistic reasons for lack of efficacy of currently clinically used agents to prevent preterm premature rupture of the membranes (pPROM) and preterm births. Likewise, the model has also facilitated screening of agents with potential for preventing pPROM and preterm birth., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: We use an in-vitro human fetal membrane (FM) explant-based model to study inflammation-induced FM weakening, a prerequisite for PPROM. In this system, GMCSF is a critical intermediate, both necessary and sufficient for TNFα and thrombin induced FM weakening. α-Lipoic-acid (LA) blocks TNFα and thrombin, as well as GMCSF-induced weakening. Recently, we reported LA concomitantly blocks GMCSF-induction of MMPs 2, 9 and 10 and inhibition of TIMPs 1-3. The aim of this study was to show that LA blocks GMCSF-induced increases in additional proteases and reductions in additional protease inhibitors., Methods: FM fragments were cultured±LA and then±GMCSF. In other experiments, weak versus strong, fresh FM were cultured without additions. Fragments were strength tested and media analyzed by multiplex protein ELISA for proteases and protease inhibitors., Results: GMCSF induced FM weakening and concomitantly increased several Proteases (Cathepsin-S, Proteinase-3, Elastase-2) and decreased several protease inhibitors (NGAL, Cystatin-C, HE4 and Thrombospondin1). LA inhibited GMCSF-induced FM weakening and all enzymatic changes. Untreated weaker versus stronger regions of fresh FM showed comparable differences in proteases and protease inhibitor patterns to GMCSF-stimulated versus controls., Conclusion: LA blocks GMCSF-induced human FM weakening and associated protease increases and inhibitor decreases. The GMCSF-induced spectrum of protease/protease-inhibitor changes is similar to that in the natural weak FM fragments. In concert with previously reported GMCSF-induced changes in MMPs & TIMPs, these other protease and protease-inhibitor changes presumably facilitate FM weakening and rupture. LA blocks these GMCSF effects and therefore may be a useful agent to prevent PPROM., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Nearly half of all mild brain injury sufferers experience long-term cognitive impairment, so an important goal in rehabilitation is to address their multiple cognitive deficits to help them return to prior levels of functioning. Cognitive training, or the use of repeated mental exercises to enhance cognition, is one remediation method for brain injury. The primary purpose of this hypothesis-generating pilot study was to explore the statistical and clinical significance of cognitive changes and transfer of training to real-life functioning following 60 h of Brain Booster, a clinician-delivered cognitive training program, for six patients with mild traumatic brain injury (TBI) or non-traumatic acquired brain injury (ABI). The secondary purpose was to explore changes in functional connectivity and neural correlates of cognitive test gains following the training. We used a multiple case study design to document significant changes in cognitive test scores, overall IQ score, and symptom ratings; and we used magnetic resonance imaging (MRI) to explore trends in functional network connectivity and neural correlates of cognitive change. All cognitive test scores showed improvement with statistically significant changes on five of the seven measures (long-term memory, processing speed, reasoning, auditory processing, and overall IQ score). The mean change in IQ score was 20 points, from a mean of 108 to a mean of 128. Five themes emerged from the qualitative data analysis including improvements in cognition, mood, social identity, performance, and Instrumental Activities of Daily Living (IADLs). With MRI, we documented significant region-to-region changes in connectivity following cognitive training including those involving the cerebellum and cerebellar networks. We also found significant correlations between changes in IQ score and change in white matter integrity of bilateral corticospinal tracts (CST) and the left uncinate fasciculus. This study adds to the growing body of literature examining the effects of cognitive training for mild TBI and ABI, and to the collection of research on the benefits of cognitive training in general. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02918994., (Copyright © 2020 Moore, Carpenter, James, Miller, Moore, Disbrow and Ledbetter.)

Autologous haematopoietic stem cell transplantation shows increasing promise as a therapeutic option for patients with treatment-refractory autoimmune disease, particularly systemic sclerosis and multiple sclerosis. However, this intensive chemotherapy-based procedure is not always possible due to potential treatment toxicities and comorbidities. The biological mechanisms of how this procedure induces long-term remission in autoimmune disease are increasingly understood. The focus of this review is on recent research findings on the role of CD4+ T regulatory cells (Tregs) in resetting the immune system leading to the eradication of the autoimmune disease after transplantation. Discovery of the precise mechanisms of this process will allow development of novel Treg-based therapies and thus avoid the need for intensive chemotherapy-based treatment for these autoimmune diseases in the future.

Changes in rocky shore community composition as responses to climatic fluctuations and anthropogenic warming can be shown by changes in average species thermal affinities. In this study, we derived thermal affinities for European Atlantic rocky intertidal species by matching their known distributions to patterns in average annual sea surface temperature. Average thermal affinities (the Community Temperature Index, CTI) tracked patterns in sea surface temperature from Portugal to Norway, but CTI for communities of macroalgae and plant species changed less than those composed of animal species. This reduced response was in line with the expectation that communities with a smaller range of thermal affinities among species would change less in composition along thermal gradients and over time. Local-scale patterns in CTI over wave exposure gradients suggested that canopy macroalgae allow species with ranges centred in cooler than local temperatures ('cold-affinity') to persist in otherwise too-warm conditions. In annual surveys of rocky shores, communities of animal species in Shetland showed a shift in dominance towards warm-affinity species ('thermophilization') with local warming from 1980 to 2018 but the community of plant and macroalgal species did not. From 2002 to 2018, communities in southwest Britain showed the reverse trend in CTI: declining average thermal affinities over a period of modest temperature decline. Despite the cooling, trends in species abundance were in line with the general mechanism of direction and magnitude of long-term trends depending on the difference between species thermal affinities and local temperatures. Cold-affinity species increased during cooling and warm-affinity ones decreased. The consistency of responses across different communities and with general expectations based on species thermal characteristics suggests strong predictive accuracy of responses of community composition to anthropogenic warming., (© 2019 John Wiley & Sons Ltd.)

Fetal membranes (FMs) play a role in pregnancy maintenance and promoting parturition at term. The FMs are not just part of the placenta, structurally or functionally. Although attached to the placenta, the amnion has a separate embryologic origin, and the chorion deviates from the placenta by the first month of pregnancy. Other than immune protection, these FM functions are not those of the placenta. FM dysfunction is associated with and may cause adverse pregnancy outcomes. Ongoing research may identify biomarkers for pending preterm premature rupture of the FMs as well as therapeutic agents, to prevent it and resulting preterm birth., Competing Interests: Disclosure R. Menon is supported by grants from (NIH/NICHD1R03HD098469-01), NIH/1R21AI140249-01A1. J.J. Moore is supported by Burroughs Wellcome Fund Prematurity Research Grant #1015024., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Preterm premature rupture of membranes (PPROM) and thrombin generation by decidual cell-expressed tissue factor often accompany abruptions. Underlying mechanisms remain unclear. We hypothesized that thrombin-induced colony-stimulating factor-2 (CSF-2) in decidual cells triggers paracrine signaling via its receptor (CSF2R) in trophoblasts, promoting fetal membrane weakening and abruption-associated PPROM. Decidua basalis sections from term (n = 10), idiopathic preterm birth (PTB; n = 8), and abruption-complicated pregnancies (n = 8) were immunostained for CSF-2. Real-time quantitative PCR measured CSF2 and CSF2R mRNA levels. Term decidual cell (TDC) monolayers were treated with 10 -8 mol/L estradiol ± 10 -7 mol/L medroxyprogesterone acetate (MPA) ± 1 IU/mL thrombin pretreatment for 4 hours, washed, and then incubated in control medium with estradiol ± MPA. TDC-derived conditioned media supernatant effects on fetal membrane weakening were analyzed. Immunostaining localized CSF-2 primarily to decidual cell cytoplasm and cytotrophoblast cell membranes. CSF-2 immunoreactivity was higher in abruption-complicated or idiopathic PTB specimens versus normal term specimens (P < 0.001). CSF2 mRNA was higher in TDCs versus cytotrophoblasts (P < 0.05), whereas CSF2R mRNA was 1.3 × 10 4 -fold higher in cytotrophoblasts versus TDCs (P < 0.001). Thrombin enhanced CSF-2 secretion in TDC cultures fourfold (P < 0.05); MPA reduced this effect. Thrombin-pretreated TDC-derived conditioned media supernatant weakened fetal membranes (P < 0.05), which MPA inhibited. TDC-derived CSF-2, acting via trophoblast-expressed CSFR2, contributes to thrombin-induced fetal membrane weakening, eliciting abruption-related PPROM and PTB., (Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Introduction: We have previously demonstrated two associations of PPROM, (1) inflammation/infection (modeled by tumor necrosis factor (TNF)) and (2) decidual bleeding (modeled by thrombin), both decrease fetal membrane (FM) rupture strength in-vitro. Furthermore, Granulocyte-Macrophage-Colony-Stimulating-Factor (GM-CSF) induced by both TNF and thrombin is a critical intermediate, necessary and sufficient for weakening by either agent. The amnion is the strength component of FM and must weaken for FM to rupture. It is unclear whether GM-CSF weakens amnion (AM) directly, or initially targets choriodecidua (CD) which secondarily releases agents to act on amnion., Methods: Full thickness FM fragments were treated with/without GM-CSF. Some were preincubated with alpha-lipoic acid (LA), a known inhibitor of FM weakening. The FM fragments were then strength-tested. Separately, FM fragments were initially separated to AM and CD. AM fragments were cultured with Medium ± GM-CSF and then strength-tested. In other experiments, CD fragments were cultured with Medium, GM-CSF, LA, or LA + GM-CSF. Conditioned medium from each group was then incubated with AM. AM was then strength-tested. Matrix Metalloproteinases (MMPs) and Tissue Inhibitors of Matrix Metalloproteinases (TIMPs) were analyzed by Mutiplex Elisa., Results: GM-CSF weakened intact FM which was blocked by LA. GM-CSF did not weaken isolated AM. However, GM-CSF conditioned CD media weakened AM and this weakening was inhibited by LA. GM-CSF treatment of CD increased MMPs 2, 9, and 10, and decreased TIMPs 1-3. LA reversed these effects., Conclusions: GM-CSF does not weaken amnion directly; GM-CSF acts on CD to increase proteases and decrease anti-proteases which secondarily weaken the amnion., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Respiratory syncytial virus (RSV) is capable of transient viremia and extrapulmonary dissemination. Recently, this virus has been identified in fetal cord blood, suggesting the possibility of in utero acquisition in humans. Here, we assess permissivity and kinetics of RSV replication in primary human placental cells, examine their potential to transfer this infection to neighboring cells, and measure the inflammatory response evoked by the virus., Methods and Findings: Human placental villus tissue was collected immediately upon delivery and processed for isolation of placental cytotrophoblast, fibroblast, and macrophage (Hofbauer) cells. Isolated cells were infected with a recombinant RSV-A2 strain (rrRSV) expressing red fluorescent protein (RFP) and analyzed by fluorescence microscopy, Western blot, and quantitative PCR (qPCR). Based on RFP expression, rrRSV exhibited differential tropism for the three major placental cell types. Placental fibroblasts and Hofbauer cells were permissive and supported productive rrRSV replication. While infected cytotrophoblast cells expressed viral glycoprotein (G protein), only limited RSV replication was detected. Importantly, qPCR and fluorescence-focused unit assay revealed that the viral progeny remains trapped within infected Hofbauer cells for up to 30 days, with no release into surrounding media. Yet, Hofbauer cells passed the infection onto overlaid naïve 16HBE cells, suggesting contact-dependent trans-infection. Lastly, a significant increase in proinflammatory cytokines, particularly IL-6, TNF-alpha, and IFN-gamma was measured in the supernatant of infected Hofbauer cells by multiplex cytokine assay and conventional ELISA., Conclusions: This study demonstrates that RSV can replicate in human placenta, exhibits differential tropism for distinct placental cell types, can be stored and transferred to neighboring cells by Hofbauer cells, and elicits an inflammatory response. It also supports the hypothesis that this respiratory virus can be vertically transferred to the fetus and potentially affect its development and the outcome of pregnancies., Competing Interests: The authors have declared that no competing interests exist.

Purpose of Review: In this review, we summarize the recently published literature that demonstrates the efficacy and safety of autologous haematopoietic stem cell therapy (AHSCT) in multiple sclerosis (MS) and highlight the importance of supportive care required for the safe and well-tolerated delivery of AHSCT., Recent Findings: MS is an autoimmune inflammatory and degenerative disorder of the central nervous system (CNS). In the majority of patients, the illness runs a relapsing remitting course (RRMS), culminating in a secondary progressive phase with gradual accumulation of fixed disabilities. Currently available disease-modifying therapies suppress CNS inflammation but have a limited effect on preventing disease progression for which there remains no effective therapy. Over the last two decades, there has been increasing evidence that AHSCT is a highly effective therapeutic strategy for treatment-resistant inflammatory types of MS, especially RRMS. Concerns about the safety of AHSCT in MS, usually a nonlife-threatening disease, have previously limited its use. However, AHSCT can now be delivered safely with major long-term benefits because of increasing transplant centre experience, judicious patient selection and good supportive care., Summary: MS is currently the fastest growing indication for AHSCT in Europe. Supportive care before, during and after the transplant period is key to the successful delivery of AHSCT.

Background: Autologous haematopoietic stem cell transplantation (AHSCT) has been explored as a therapeutic intervention in multiple sclerosis (MS) over the last two decades; however, prospective clinical trials of the most common myeloablative conditioning regimen, BEAM, are limited. Furthermore, patient selection, optimal chemotherapeutic regimen and immunological changes associated with disease response require ongoing exploration. We present the outcomes, safety and immune reconstitution (IR) of patients with active, treatment refractory MS., Methods: This study was a single-centre, phase II clinical trial of AHSCT for patients with active relapsing remitting (RRMS) and secondary progressive MS (SPMS). Patients underwent AHSCT using BEAM (carmustine, etoposide, cytarabine, melphalan)+antithymocyte globulin chemotherapeutic regimen., Outcomes: The primary outcome was event-free survival (EFS); defined as no clinical or radiological relapses and no disability progression. Multiparameter flow cytometry was performed for evaluation of post-transplant IR in both MS and lymphoma patients receiving the same chemotherapy regimen., Results: Thirty-five patients (20 RRMS, 15 SPMS) completed AHSCT, with a median follow-up of 36 months (range 12-66). The median Expanded Disability Status Scores (EDSS) was 6 (2-7) and patients had failed a median of 4 (2-7) disease modifying therapies. 66% failed treatment with natalizumab. EFS at 3 years was 60%, (70% RRMS). Sustained improvement in EDSS was seen in 15 (44%) of patients. There was no treatment-related mortality. A sustained rise in CD39 + T regulatory cells, immunosuppressive CD56 hi natural killer cells and ablation of proinflammatory mucosal-associated invariant T cells was seen for 12 months following AHSCT in patients with MS. These changes did not occur in patients with lymphoma receiving the same chemotherapy for AHSCT., Conclusions: The EFS in our MS cohort is significantly greater than other high-efficacy immunosuppressive therapies and similar to other AHSCT studies despite a more heavily pretreated cohort., Trial Registration Number: ACTRN12613000339752., Competing Interests: Competing interests: IJS reports personal fees from Biogen, Merck, Sanofi Genzyme and Teva, outside the submitted work. JCM reports personal fees from Biogen, Merck, Sanofi Genzyme and Teva, outside the submitted work. YB reports grants and other from Genzyme-Sanofi, grants and other from Novartis, grants from Biogen, other from Teva, grants and other from Merck outside the submitted work and YB is a cofounder of Medical Safety Systems, which provides automated pathology monitoring for patients prescribed immunotherapies (including alemtuzumab) in Australia and (under the trading name RxMx) the USA. RZ has received speaker honoraria and consultant fees from Genzyme-Sanofi, Novartis, Claret Medical, Celgene and EMD Serono. He has received research support from EMD Serono, Genzyme-Sanofi, Claret Medical, Protembis, QuintilesIMS and Novartis. outside the submitted work. DDFM has received a research grant from Phebra outside the submitted work., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Preterm birth is a significant cause of infant morbidity and mortality, which are primarily the result of respiratory and neurodevelopmental complications. However, no objective biomarker is currently available to predict at birth the risk and severity of such complications. Thus, we sought to determine whether serum neurotrophins concentrations measured at birth correlate with risk for later development of bronchopulmonary dysplasia (BPD) and long-term neurodevelopmental outcomes., Methods: This study prospectively included 223 newborns admitted to neonatal intensive care units (NICU) and divided into three groups: (i) preterm infants who developed BPD; (ii) preterm infants who did not develop BPD; (iii) term infants. An exploratory cohort was enrolled in West Virginia, followed by a validation cohort recruited in four NICUs in Ohio. Specimens for serum and tracheal neurotrophins concentrations were collected within 48 h of admission. Infants requiring a fraction of inspired oxygen >0.21 for at least 28 days were diagnosed with BPD. Neurodevelopmental outcomes were extrapolated from Bayley Scales of Infant Development-Third Edition (BSID-III) administered at the 24-month follow-up visit., Results: Serum brain-derived neurotrophic factor (BDNF) concentration at birth had significant negative correlation with later diagnosis of BPD (P = 0.011) and with duration of invasive ventilation and oxygen supplementation (P = 0.009 and 0.015, respectively). Serum nerve growth factor (NGF) concentration at birth had significant positive correlation with BSID-III cognitive and language composite scores at 24 months (P < 0.001 and 0.010, respectively)., Conclusions: These data suggest that serum neurotrophins concentrations measured at birth provide prognostic information on subsequent respiratory and neurodevelopmental outcomes., (© 2018 Wiley Periodicals, Inc.)

Introduction: Immunophenotyping by flow cytometry is routinely employed in distinguishing between chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Inclusion of CD200 has been reported to contribute to more reliable differentiation between CLL and MCL. We investigated the value of CD200 in assessment of atypical CLL cases., Methods: CD200 expression on mature B cell neoplasms was studied by eight-color flow cytometry in combination with a conventional panel of flow cytometry markers. The study included 70 control samples, 63 samples with CLL or atypical CLL phenotype, 6 MCL samples, and 40 samples of other mature B cell neoplasms., Results: All CLL samples were positive for CD200, whereas MCL samples were dim or negative for CD200. Of the CLL samples, 7 were atypical by conventional flow cytometry, with Matutes scores ≤3. These cases were tested for evidence of a t(11;14) translocation, characteristic of MCL, and all were negative, consistent with their classification as atypical CLL. All these atypical CLL samples were strongly positive for CD200., Conclusion: CD200 proved to be a useful marker for differentiation between CLL and MCL by flow cytometry. In particular, CD200 was useful in distinguishing CLL samples with atypical immunophenotypes from MCL., (© 2018 John Wiley & Sons Ltd.)

Introduction: We established an in-vitro model for the study of human fetal membrane (FM) weakening leading to pPROM. In this model, granulocyte-macrophage colony-stimulating factor (GM-CSF) is a critical intermediate for both tumor necrosis factor-α (TNF; modeling infection/inflammation) and thrombin (modeling decidual bleeding/abruption)-induced weakening. Thus, inhibitors of FM weakening can be categorized as targeting GM-CSF production, GM-CSF downstream action, or both. Most progestogens inhibit both, except 17-α hydroxyprogesterone caproate which inhibits FM weakening at only one point, GM-CSF production. α-lipoic acid (LA), an over-the-counter dietary supplement, has also been previously shown to inhibit TNF and thrombin induced FM weakening., Objective: To determine the point of action of LA inhibition of FM weakening., Methods: FM fragments were mounted in Transwell inserts and preincubated with/without LA/24 h, then with/without addition of TNF, thrombin or GM-CSF. After 48 h, medium was assayed for GM-CSF, and FM fragments were rupture-strength tested., Results: TNF and thrombin both weakened FM and increased GM-CSF levels. GM-CSF also weakened FM. LA inhibited both TNF and thrombin induced FM weakening and concomitantly inhibited the increase in GM-CSF in a concentration-dependent manner. In addition, LA inhibited GM-CSF induced FM weakening in a concentration dependent manner., Conclusions: LA blocks TNF and thrombin induced FM weakening at two points, inhibiting both GM-CSF production and downstream action. Thus, we speculate that LA may be a potential standalone therapeutic agent, or supplement to current therapy for prevention of pPROM related spontaneous preterm birth, if preclinical studies to examine feasibility and safety during pregnancy are successfully accomplished., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Multiple sclerosis (MS) is an inflammatory disorder of the central nervous system where evidence implicates an aberrant adaptive immune response in the accrual of neurological disability. The inflammatory phase of the disease responds to immunomodulation to varying degrees of efficacy; however, no therapy has been proven to arrest progression of disability. Recently, more intensive therapies, including immunoablation with autologous hematopoietic stem cell transplantation (AHSCT), have been offered as a treatment option to retard inflammatory disease, prior to patients becoming irreversibly disabled. Empirical clinical observations support the notion that the immune reconstitution (IR) that occurs following AHSCT is associated with a sustained therapeutic benefit; however, neither the pathogenesis of MS nor the mechanism by which AHSCT results in a therapeutic benefit has been clearly delineated. Although the antigenic target of the aberrant immune response in MS is not defined, accumulated data suggest that IR following AHSCT results in an immunotolerant state through deletion of pathogenic clones by a combination of direct ablation and induction of a lymphopenic state driving replicative senescence and clonal attrition. Restoration of immunoregulation is evidenced by changes in regulatory T cell populations following AHSCT and normalization of genetic signatures of immune homeostasis. Furthermore, some evidence exists that AHSCT may induce a rebooting of thymic function and regeneration of a diversified naïve T cell repertoire equipped to appropriately modulate the immune system in response to future antigenic challenge. In this review, we discuss the immunological mechanisms of IR therapies, focusing on AHSCT, as a means of recalibrating the dysfunctional immune response observed in MS.

Background: The progestogen 17-α hydroxyprogesterone caproate (17-OHPC) is 1 of only 2 agents recommended for clinical use in the prevention of spontaneous preterm delivery, and studies of its efficacy have been conflicting. We have developed an in-vitro model to study the fetal membrane weakening process that leads to rupture in preterm premature rupture of the fetal membranes (pPROM). Inflammation/infection associated with tumor necrosis factor-α (TNF-α) induction and decidual bleeding/abruption associated thrombin release are leading causes of preterm premature rupture of the fetal membranes. Both agents (TNF-α and thrombin) cause fetal membrane weakening in the model system. Furthermore, granulocyte-macrophage colony-stimulating factor (GM-CSF) is a critical intermediate for both TNF-α and thrombin-induced fetal membrane weakening. In a previous report, we demonstrated that 3 progestogens, progesterone, 17-alpha hydroxyprogesterone (17-OHP), and medroxyprogesterone acetate (MPA), each inhibit both TNF-α- and thrombin-induced fetal membrane weakening at 2 distinct points of the fetal membrane weakening pathway. Each block both the production of and the downstream action of the critical intermediate granulocyte-macrophage colony-stimulating factor., Objective: The objective of the study was to characterize the inhibitory effects of 17-OHPC on TNF-α- and thrombin-induced fetal membrane weakening in vitro., Study Design: Full-thickness human fetal membrane fragments from uncomplicated term repeat cesarean deliveries were mounted in 2.5 cm Transwell inserts and cultured with/without 17-alpha hydroxyprogesterone caproate (10 -9 to 10 -7 M). After 24 hours, medium (supernatant) was removed and replaced with/without the addition of tumor necrosis factor-alpha (20 ng/mL) or thrombin (10 U/mL) or granulocyte-macrophage colony-stimulating factor (200 ng/mL). After 48 hours of culture, medium from the maternal side compartment of the model was assayed for granulocyte-macrophage colony-stimulating factor and the fetal membrane fragments were rupture strength tested., Results: Tumor necrosis factor-alpha and thrombin both weakened fetal membranes (43% and 62%, respectively) and increased granulocyte-macrophage colony-stimulating factor levels (3.7- and 5.9-fold, respectively). Pretreatment with 17-alpha hydroxyprogesterone caproate inhibited both tumor necrosis factor-alpha- and thrombin-induced fetal membrane weakening and concomitantly inhibited the induced increase in granulocyte-macrophage colony-stimulating factor in a concentration-dependent manner. However, contrary to our prior reports regarding progesterone and other progestogens, 17-alpha hydroxyprogesterone caproate did not also inhibit granulocyte-macrophage colony-stimulating factor-induced fetal membrane weakening., Conclusion: 17-Alpha hydroxyprogesterone caproate blocks tumor necrosis factor-alpha- and thrombin-induced fetal membrane weakening by inhibiting the production of granulocyte-macrophage colony-stimulating factor. However, 17-alpha hydroxyprogesterone caproate did not also inhibit granulocyte-macrophage colony-stimulating factor-induced weakening. We speculate that progestogens other than 17-alpha hydroxyprogesterone caproate may be more efficacious in preventing preterm premature rupture of the fetal membranes-related spontaneous preterm birth., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Neural activity in vivo is primarily measured using extracellular somatic spikes, which provide limited information about neural computation. Hence, it is necessary to record from neuronal dendrites, which can generate dendritic action potentials (DAPs) in vitro, which can profoundly influence neural computation and plasticity. We measured neocortical sub- and suprathreshold dendritic membrane potential (DMP) from putative distal-most dendrites using tetrodes in freely behaving rats over multiple days with a high degree of stability and submillisecond temporal resolution. DAP firing rates were several-fold larger than somatic rates. DAP rates were also modulated by subthreshold DMP fluctuations, which were far larger than DAP amplitude, indicating hybrid, analog-digital coding in the dendrites. Parietal DAP and DMP exhibited egocentric spatial maps comparable to pyramidal neurons. These results have important implications for neural coding and plasticity., (Copyright © 2017, American Association for the Advancement of Science.)

Diet influences the stable isotope ratios of carbon and nitrogen (δ(13) C and δ(15) N values) in animal tissue; but here we explore the influences of particular aspects of the local environment on those values in chimpanzees (Pan troglodytes). In this article we present new δ(13) C and δ(15) N values in Gombe chimpanzees using hairs collected from night nests in 1989. Then, we explore the influence of environmental factors by comparing our Gombe data to those from eight additional Pan study sites with previously published stable isotope data. We compare chimpanzee δ(13) Chair and δ(15) Nhar values to specific characteristics of local site ecology (biome and ecoregion) and to local Mean Annual Precipitation (MAP) to test hypotheses based on known effects of these variables on the δ(13) C and δ(15) N values in plant tissues. The comparison shows that hair from chimpanzees living in savanna sites with lower MAP have higher δ(13) Chair values than do chimpanzees living in woodland and forested sites with higher MAP. These results demonstrate the potential of using δ(13) C values in primate tissue to indicate aspects of their local ecology in cases where the ecology is uncertain, such as samples collected early in the last century and in fossil hominins. In contrast to expectations, however, chimpanzee δ(15) Nhair values from some savanna sites with lower MAP are lower, not higher, than those living in more forested areas with higher MAP. It is likely that diet selectivity by chimpanzees affects δ(15) Nhair values to a greater extent than does the influence of precipitation on plants. Am. J. Primatol. 78:1055-1069, 2016. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Rupture of the fetal membranes (FM) is precipitated by stretch forces acting upon biochemically mediated, pre-weakened tissue. Term FM develop a para-cervical weak zone, characterized by collagen remodeling and apoptosis, within which FM rupture is thought to initiate. Preterm FM also have a weak region but are stronger overall than term FM. Inflammation/infection and decidual bleeding/abruption are strongly associated with preterm premature FM rupture (pPROM), but the specific mechanisms causing FM weakening-rupture in pPROM are unknown. There are no animal models for study of FM weakening and rupture. Over a decade ago we developed equipment and methodology to test human FM strength and incorporated it into a FM explant system to create an in-vitro human FM weakening model system. Within this model TNF (modeling inflammation) and Thrombin (modeling bleeding) both weaken human FM with concomitant up regulation of MMP9 and cellular apoptosis, mimicking the characteristics of the spontaneous FM rupture site. The model has been enhanced so that test agents can be applied directionally to the choriodecidual side of the FM explant consistent with the in-vivo situation. With this enhanced system we have demonstrated that the pathways involving inflammation/TNF and bleeding/Thrombin induced FM weakening overlap. Furthermore GM-CSF production was demonstrated to be a critical common intermediate step in both the TNF and the Thrombin induced FM weakening pathways. This model system has also been used to test potential inhibitors of FM weakening and therefore pPROM. The dietary supplement α-lipoic acid and progestogens (P4, MPA and 17α-hydroxyprogesterone) have been shown to inhibit both TNF and Thrombin induced FM weakening. The progestogens act at multiple points by inhibiting both GM-CSF production and GM-CSF action. The use of a combined biomechanical/biochemical in-vitro human FM weakening model system has allowed the pathways of fetal membrane weakening to be delineated, and agents that may be of clinical use in inhibiting these pathways to be tested., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Fetal membranes (FM) usually fail prior to delivery during term labor, but occasionally fail at preterm gestation, precipitating preterm birth. To understand the FM biomechanical properties underlying these events, study of the baseline in-vivo stretch experienced by the FM is required. This study's objective was to utilize high resolution MRI imaging to determine in-vivo FM stretch., Methods: Eight pregnant women (38.4 ± 0.4wks) underwent abdominal-pelvic MRI prior to (2.88 ± 0.83d) caesarean delivery. Software was utilized to determine the total FM in-vivo surface area (SA) and that of its components: placental disc and reflected FM. At delivery, the SA of the disc and FM in the relaxed state were measured. In-vivo (stretched) to delivered SA ratios were calculated. FM fragments were then biaxially stretched to determine the force required to re-stretch the FM back to in-vivo SA., Results: Total FM SA, in-vivo vs delivered, was 2135.51 ± 108.47 cm(2) vs 842.59 ± 35.86 cm(2); reflected FM was 1778.42 ± 107.39 cm(2) vs 545.41 ± 22.90 cm(2), and disc was 357.10 ± 28.08 cm(2) vs 297.18 ± 22.14 cm(2). The ratio (in-vivo to in-vitro SA) of reflected FM was 3.26 ± 0.11 and disc was 1.22 ± 0.10. Reflected FM re-stretched to in-vivo SA generated a tension of 72.26 N/m, corresponding to approximate pressure of 15.4 mmHg. FM rupture occurred at 295.08 ± 31.73 N/m corresponding to approximate pressure of 34 mmHg. Physiological SA was 70% of that at rupture., Discussion: FM are significantly distended in-vivo. FM collagen fibers were rapidly recruited once loaded and functioned near the failure state during in-vitro testing, suggesting that, in-vivo, minimal additional (beyond physiological) stretch may facilitate rapid, catastrophic failure., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Hippocampal neurons show selectivity with respect to visual cues in primates, including humans, but this has never been found in rodents. To address this long-standing discrepancy, we measured hippocampal activity from rodents during real-world random foraging. Surprisingly, ∼ 25% of neurons exhibited significant directional modulation with respect to visual cues. To dissociate the contributions of visual and vestibular cues, we made similar measurements in virtual reality, in which only visual cues were informative. Here, we found significant directional modulation despite the severe loss of vestibular information, challenging prevailing theories of directionality. Changes in the amount of angular information in visual cues induced corresponding changes in head-directional modulation at the neuronal and population levels. Thus, visual cues are sufficient for-and play a predictable, causal role in-generating directionally selective hippocampal responses. These results dissociate hippocampal directional and spatial selectivity and bridge the gap between primate and rodent studies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Heart and lung transplant recipients have among of the highest incidence rates of post-transplant lymphoproliferative disease (PTLD). Despite this, there is a paucity of data specific to this group. We collated data on heart, lung and heart-lung transplant recipients with PTLD to identify disease features and prognostic factors unique to this group of patients., Methods: Seventy cases of PTLD were identified from a single institution (41 heart, 22 lung, 6 heart-lung and 1 heart-kidney transplant) from 1984 to 2013. Demographics, immunosuppression, treatment, response, complications and survival data were analyzed. Uni- and multivariate Cox regression analyses were performed to identify prognostic factors., Results: The incidence of PTLD was 7.59% in heart-lung, 5.37% in heart and 3.1% in lung transplant recipients. Extranodal disease (82%) with diffuse large B-cell lymphoma (72%) was the most common presentation. Bone marrow involvement (13%) and central nervous system disease (3%) were uncommon. Heart transplant recipients had later onset of PTLD (>1 year post-transplant), with less allograft involvement, compared with lung and heart-lung recipients. Poor prognostic markers were bone marrow involvement (HR 6.75, p < 0.001) and serum albumin <30 g/liter (HR 3.18, p = 0.006). Improved survival was seen with a complete response within 3 months of treatment (HR 0.08, p < 0.001). Five-year overall survival was 29%., Conclusion: This analysis is the largest to date on PTLD in heart and lung transplant recipients. It provides a detailed analysis of the disease in this group of patients and identifies unique prognostic features to aid risk stratification and guide treatment allocation., (Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Objective: Inflammation/infection and abruption are leading causes of preterm premature rupture of the membranes. Recently, we identified granulocyte-macrophage colony-stimulating factor (GM-CSF) as a critical mediator of both tumor necrosis factor-α- (TNF; modeling inflammation) and thrombin-induced (modeling abruption) weakening of the fetal membranes. We found that (1) TNF and thrombin both induced GM-CSF in the choriodecidua, (2) blockade of GM-CSF action with neutralizing antibodies inhibited both TNF- and thrombin-induced fetal membrane weakening, and (3) GM-CSF alone induced fetal membrane weakening. GM-CSF is thus part of an overlap of the inflammation and abruption-induced fetal membrane weakening pathways. The effects of progesterone analogs on the pathways by which fetal membranes are weakened have not been investigated. We examined the effects of progesterone, medroxyprogesterone acetate (MPA) and 17α-hydroxyprogesterone (HP) on TNF- and thrombin-induced fetal membrane weakening., Study Design: Full-thickness fetal membranes from uncomplicated term repeat cesarean deliveries were mounted in Transwell inserts in Minimum Essential Medium alpha and incubated at 37°C in 5% CO2. The choriodecidua side of the fetal membrane fragments were preincubated with progesterone, MPA, HP, or vehicle for 24 hours. Fetal membranes were then exposed to TNF, thrombin, or GM-CSF on the choriodecidua side for an additional 48 hours. The fetal membrane tissues were then strength tested, and medium from the choriodecidua and amnion compartments was assayed for GM-CSF content., Results: TNF and thrombin both weakened fetal membranes and elevated media GM-CSF levels on the choriodecidua side of the fetal membrane. Pretreatment with progesterone, MPA, or HP inhibited both TNF- and thrombin-induced fetal membrane weakening and also inhibited the induced increase in GM-CSF. GM-CSF decreased fetal membrane rupture strength by 68%, which was inhibited by progestogen pretreatment with a potency order: progesterone

Introduction: Inflammation/infection and decidual bleeding/abruption are highly associated with pPROM. As no animal model for pPROM exists, we have developed an in-vitro model system for the study of human fetal membrane (FM) weakening/rupture. Using it we have demonstrated that both TNF/IL-1 (modeling inflammation) and thrombin (modeling bleeding) weaken full thickness FM in a dose dependent manner concomitant with inducing biochemical changes similar to those seen in the FM physiological weak zone., Methods: As the physiological site of infection and bleeding is the choriodecidua (CD), we modified our model system with full thickness FM tissue mounted on modified Transwell culture inserts to permit directional TNF/thrombin exposure on the decidua only (rather than both sides of the FM). After incubation, medium was sampled separately from the CD facing (maternal side) or from the amnion facing (fetal side) compartments and probed for cytokine release and confirmed with western blots. The FM was strength tested within the insert., Results: Full-thickness FM fragments exposed to TNF or thrombin on CD side only showed dose dependent weakening and biochemical changes consistent with previous reports. Concomitantly, GM-CSF increased markedly on the CD but not the amnion side. Numerous proteases including MMP1 and MMP3 also increased on the CD side. Pre-incubation with GM-CSF antibody blocked both thrombin and TNF induced weakening. Finally, GM-CSF weakened FM in a dose dependent manner., Discussion: GM-CSF is a critical common intermediate in the thrombin and TNF FM weakening pathways., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Puncture testing has been applied in several studies for the mechanical characterization of human fetal membrane (FM) tissue, and significant knowledge has been gained from these investigations. When comparing results of mechanical testing (puncture, inflation, and uniaxial tension), we have observed discrepancies in the rupture sequence of FM tissue and significant differences in the deformation behavior. This study was undertaken to clarify these discrepancies. Puncture experiments on FM samples were performed to reproduce previous findings, and numerical simulations were carried out to rationalize particular aspects of membrane failure. The results demonstrate that both rupture sequence and resistance to deformation depend on the samples' fixation. Soft fixation leads to slippage in the clamping, which reduces mechanical loading of the amnion layer and results in chorion rupturing first. Conversely, the stiffer, stronger, and less extensible amnion layer fails first if tight fixation is used. The results provide a novel insight into the interpretation of ex vivo testing as well as in vivo membrane rupture.