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A three-year process involving the redesign of clinical ladders led to a professional recognition program. After one year, a self-initiating credentialing ladder was established. The second year, one job description/performance evaluation was developed for bedside nurses -- a professional ladder with system-wide and unit-specific requirements. Finally, during the third year, a professional recognition program emerged, recognizing expertise and experience. [ABSTRACT FROM AUTHOR]

Abstract: There are limited data assessing the risk scores for primary treatment failure (PTF) in patients with classical Hodgkin lymphoma (cHL; PTF-cHL) undergoing autologous hematopoietic cell transplantation (auto-HCT). ECLIPSE (Evaluation of Classical Hodgkin Lymphoma patients wIth Primary treatment failure and analySis of outcomEs) is a multicenter retrospective cohort of patients with PTF-cHL (aged ≥15 years) diagnosed on or after 1 January 2005, at 15 US medical centers. PTF was defined as 1 of the following patterns of failure: (1) progressive disease by imaging during or within 6 weeks of completion of frontline chemotherapy (primary progression [PP]); (2) partial response (PR) or stable disease (SD) by imaging after completion of frontline treatment (PR/SD); (3) progression of disease by imaging (and confirmed by biopsy) within 12 months of frontline therapy completion after prior documentation of complete response (CR; early relapse [ER]). A total of 478 patients were included in the analysis. Among these, 217 (45%) were PP, 86 (18%) were PR/SD, and 175 (37%) were ER. The 6-month and 1-year cumulative incidence of nonrelapse mortality after auto-HCT were 0.9% and 1.1%, respectively. The median progression-free survival (PFS) and overall survival (OS) after auto-HCT were 4.33 and 10.09 years, respectively. Although those not in CR at the time of auto-HCT were associated with inferior PFS and OS, advanced age and diagnosis before 2011 were associated with inferior OS. This study showcases the safety and long-term efficacy of auto-HCT, even in patients with high-risk disease who are traditionally considered chemotherapy refractory, and will serve as a benchmark for the ongoing transplant vs no transplant trials., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Disclaimer: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time., Purpose: To demonstrate the challenges with current diagnosis and treatment strategies for precipitated opioid withdrawal secondary to naloxone the emergency department (ED) setting and describe the role of the emergency medicine (EM) pharmacist in its management., Summary: There are no standardized criteria to define precipitated opioid withdrawal syndrome, so the diagnosis is typically based on sentinel signs and symptoms and time course. Complicating factors include a positive urine toxicology screen for nonopioid substances, comorbidities and associated medications prior to admission, medications given in the ED, and a fluctuating patient course during the ED stay that likely involves all these issues. Although buprenorphine is frequently recommended as the primary treatment for precipitated withdrawal, its use can be complicated if patients are on methadone maintenance or other long-acting opioids. The EM pharmacist plays a key role in managing patients with precipitated withdrawal., Conclusion: Practice changes related to the diagnosis and treatment of opioid use disorder (OUD) with precipitated withdrawal in the ED are needed. EM pharmacists as part of the interprofessional care team have an important role in the management of patients with OUD, including those patients undergoing possible precipitated withdrawal., (© American Society of Health-System Pharmacists 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The removal of the X-waiver in the Mainstreaming Addiction Treatment (MAT) Act of 2023 has substantial implications for buprenorphine prescribing as one of the options to treat opioid use disorder. The purpose of this commentary is to discuss the unanswered questions regarding buprenorphine in the intensive care unit (ICU) including how the passage of the MAT Act will affect ICU providers, which patients should receive buprenorphine, what is the most appropriate route of administration and dose of buprenorphine, what medications interact with buprenorphine, and how can transitions of care be optimized for these patients., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr DJG is supported by the National Institute of General Medical Sciences COBRE grant (1P20GM139745) and is a Clinical Specialist in Neurosciences for Lexicomp. The remaining authors have no disclosures.

Purpose: The purpose of this review is to discuss important considerations when prescribing buprenorphine for opioid use disorder (OUD) in the intensive care unit (ICU) setting, recognizing the challenges of providing detailed recommendations in the setting of limited available evidence., Summary: Buprenorphine is a partial mu-opioid receptor agonist that is likely to be increasingly prescribed for OUD in the ICU setting due to the relaxation of prescribing regulations. The pharmacology and pharmacokinetics of buprenorphine are complicated by the availability of several formulations that can be given by different administration routes. There is no single optimal dosing strategy for buprenorphine induction, with regimens ranging from very low-dose to high dose regimens. Faster induction with higher doses of buprenorphine has been studied and is frequently utilized in the emergency department. In patients admitted to the ICU who were receiving opioids either medically or illicitly, analgesia will not occur until their baseline opioid requirements are covered when their preadmission opioid is either reversed or interrupted. For patients in the ICU who are not on buprenorphine at the time of admission but have possible OUD, there are no validated tools to diagnose OUD or the severity of opioid withdrawal in critically ill patients unable to provide the subjective components of instruments validated in outpatient settings. When prescribing buprenorphine in the ICU, important issues to consider include dosing, monitoring, pain management, use of adjunctive medications, and considerations to transition to outpatient therapy. Ideally, addiction and pain management specialists would be available when buprenorphine is prescribed for critically ill patients., Conclusion: There are unique challenges when prescribing buprenorphine for OUD in critically ill patients, regardless of whether they were receiving buprenorphine when admitted to the ICU setting for OUD or are under consideration for buprenorphine initiation. There is a critical need for more research in this area., (© American Society of Health-System Pharmacists 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Topic Importance: Critical care clinicians are likely to see an increasing number of patients admitted to the ICU who are receiving US Food and Drug Administration-approved medications for opioid use disorder (MOUDs) given the well-documented benefits of these agents. Oral methadone, multiple formulations of buprenorphine, and extended-release naltrexone are the three types of MOUD most likely to be encountered by ICU clinicians; however, these drugs vary with respect to formulations, pharmacokinetics, and adverse effects., Review Findings: No published clinical practice guidelines or consensus statements are available to guide decision-making in patients admitted to the ICU setting who are receiving MOUDs before admission. Additionally, no randomized trials and limited observational studies have evaluated issues related to MOUD use in the ICU. Therefore, ICU clinicians caring for patients admitted who are taking MOUDs must base their decision-making on data extrapolation from pharmacokinetic, pharmacologic, and clinical studies performed in non-ICU settings., Summary: Despite the challenges in administering MOUDs in critically ill patients, extrapolation of data from other hospital settings suggests that the benefits of continuing MOUD therapy outweigh the risks in patients able to continue therapy. This article provides guidance for critical care clinicians caring for patients admitted to the ICU already receiving methadone, buprenorphine, or extended-release naltrexone. The guidance includes algorithms to aid clinicians in the clinical decision-making process, recognizing the inherent limitations of the existing evidence on which the algorithms are based and the need to account for patient-specific considerations., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Overdose fatalities are increasingly attributed to synthetic opioids, including fentanyl, which may be added to samples of illicit substances unknowingly to the user. As recently as April 2023, the Centers for Disease Control and Prevention has also raised awareness of the risks of xylazine, an animal tranquilizer that has been found in adulterated samples of illicit substance. A growing body of evidence supports the use of drug testing services, including fentanyl and xylazine test strips, to reduce the risks associated with substance use and prevent fatal overdoses. Emergency medical services clinicians serve on the frontline of the opioid epidemic and are uniquely positioned to distribute harm reduction materials. In this article, we advocate for emergency medical services to distribute fentanyl and xylazine test strips. We also critically evaluate legal and other barriers to implementation., Competing Interests: Declaration of Competing Interest All authors report no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Long-term mental health outcomes were characterized in patients who were diagnosed with Hodgkin lymphoma (HL), and risk factors for the development of mental health disorders were identified., Methods: Patients who were diagnosed with HL between 1997 and 2014 were identified in the Utah Cancer Registry. Each patient was matched with up to five individuals from a general population cohort identified within the Utah Population Database, a unique source of linked records that includes patient and demographic data., Results: In total, 795 patients who had HL were matched with 3575 individuals from the general population. Compared with the general population, patients who had HL had a higher risk of any mental health diagnosis (hazard ratio, 1.77; 95% confidence interval, 1.57-2.00). Patients with HL had higher risks of anxiety, depression, substance-related disorders, and suicide and intentional self-inflicted injuries compared with the general population. The main risk factor associated with an increased risk of being diagnosed with mental health disorders was undergoing hematopoietic stem cell transplantation, with a hazard ratio of 2.06 (95% confidence interval, 1.53-2.76). The diagnosis of any mental health disorder among patients with HL was associated with a detrimental impact on overall survival; the 10-year overall survival rate was 70% in patients who had a mental health diagnosis compared with 86% in those patients without a mental health diagnosis (p < .0001)., Conclusions: Patients who had HL had an increased risk of various mental health disorders compared with a matched general population. The current data illustrate the importance of attention to mental health in HL survivorship, particularly for patients who undergo therapy with hematopoietic stem cell transplantation., (© 2022 American Cancer Society.)

Mutations in the disrupted in schizophrenia-1 (DISC1) gene are associated with an increased risk of developing psychological disorders including schizophrenia, bipolar disorder, and depression. Assessing the impact of knocking out genes, like DISC1, in animal models provides valuable insights into the relationship between the gene and behavioral outcomes. Previous research has relied on mouse models to assess these impacts, however these may not yield as reliable or rich a behavioral analysis as can be obtained using rats. Thus, the goal of the present study was to characterize the behavioral effects of a biallelic functional deletion of the DISC1 gene in the Sprague Dawley rat. Female and male wild type and DISC1 knockout rats were assessed beginning just prior to weaning and during the post-weaning periadolescent period. The primary outcomes evaluated were activity, anxiety, responses to novel objects and conspecifics, and prepulse inhibition. These behaviors were selected as analogous indices of psychological dysfunction in humans. The DISC1 knockout had significant effects on behavior, although the kind and magnitude of deficits was different for females and males: in females, effects included hyperactivity, aversion to novelty, and a modest prepulse inhibition deficit; in males, effects in anxiety and neophobia were mild but their prepulse inhibition deficit was large. These data confirm that the DISC1 knockout rat model is an excellent way to reproduce and study symptoms of psychological disorders and provides compelling evidence for differential consequences of its dysfunction for females and males in the progression and emergence of specific behavioral deficits., (© 2021 International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)

The hippocampus (HPC) may compete with other memory systems when establishing a representation, a process termed overshadowing. However, this overshadowing may be mitigated by repeated learning episodes, making a memory resistant to post-training hippocampal damage. In the current study, we examined this overshadowing process for a hippocampal-dependent visual discrimination memory in rats. In Experiment 1, male rats were trained to criterion (80% accuracy on two consecutive days) on a visual discrimination and then given 50 additional trials distributed over 5 days or 10 weeks. Regardless of this additional learning, extensive damage to the HPC caused retrograde amnesia for the visual discrimination, suggesting that the memory remained hippocampal-dependent. In Experiment 2, rats received hippocampal damage before learning and required approximately twice as many trials to acquire the visual discrimination as control rats, suggesting that, when the overshadowing or competition is removed, the non-hippocampal memory systems only slowly acquires the discrimination. In Experiment 3, increasing the additional learning beyond criterion by 230 trials, the amount needed in Experiment 2 to train the non-hippocampal systems in absence of competition, successfully prevented the retrograde amnesic effects of post-training hippocampal damage. Combined, the findings suggest that a visual discrimination memory trace can be strengthened in non-hippocampal systems with overtraining and become independent of the HPC., 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 Lehmann, Stykel and Glenn.)

In the last decade, a better understanding of the molecular pathogenesis of B-cell non-Hodgkin lymphomas has resulted in the development of novel targeted therapies, such as small molecule inhibitors of select kinases in the B-cell receptor pathway, antibody-drug conjugates, and small molecules that target a variety of proteins (eg, CD-19, EZH2, and XPO-1-mediated nuclear export). Anti-CD19 CAR T-cell therapy, first approved for relapsed/refractory (R/R) diffuse large B-cell lymphoma, has also emerged as a novel treatment option for R/R follicular lymphoma and mantle cell lymphoma. These NCCN Guideline Insights highlight the new targeted therapy options included in the NCCN Guidelines for B-Cell Lymphomas for the treatment of R/R disease.

Chronic lymphocytic leukemia (CLL) patients who develop Hodgkin lymphoma (HL) have limited survival. No current therapeutic standard of care exists. We conducted a multi-center retrospective study of patients with Hodgkin Transformation (HT) of CLL. Clinicobiologic characteristics, treatment type, and survival outcomes were analyzed and compared with historic case series. Ninety-four patients were identified. Median age at HT was 67 years (range, 38-85). Median time from CLL diagnosis to HT was 5.5 years (range, 0-20.2). Prior to HT, patients received a median of 2 therapies for CLL (range, 0-12). As initial therapy for HT, 61% (n=62) received ABVD-based regimens (adriamycin, bleomycin, vinblastine, and dacarbazine). Seven (7%) patients received hematopoietic cell transplantation (HCT) while in first complete remission (CR1). The median number of treatments for HT per patient was 1 (range, 0-5) with 59 (61%) patients only receiving one line of therapy. After HT, patients had a median follow-up of 1.6 years (range, 0-15.1). Two-year overall survival (OS) after HT diagnosis was 72% (95%CI 62-83%). The patients who received standard ABVD-based therapy had a median OS of 13.2 years. Although limited by small sample size, the patients who underwent HCT for HT in CR1 had a similar 2-year OS (n=7; 67%) compared to patients who did not undergo HCT for HT in CR1 (n=87; 72%; p=0.46). In this multi-center study, HT patients treated with ABVD-based regimens had prolonged survival supporting the use of these regimens as standard of care for these patients.

Treatment with buprenorphine significantly reduces both all-cause and overdose mortality among individuals with opioid use disorder. Offering buprenorphine treatment to individuals who experience a nonfatal opioid overdose represents an opportunity to reduce opioid overdose fatalities. Although some emergency departments (EDs) initiate buprenorphine treatment, many individuals who experience an overdose either refuse transport to the ED or are transported to an ED that does not offer buprenorphine. Emergency medical services (EMS) professionals can help address this treatment gap. In this Concepts article, we describe the federal legal landscape that governs the ability of EMS professionals to administer buprenorphine treatment, and discuss state and local regulatory considerations relevant to this promising and emerging practice., (Copyright © 2021 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Objective: To determine if COVID-19 was associated with a change in patient refusals after Emergency Medical Services (EMS) administration of naloxone., Methods: This is a retrospective cohort study in which the incidence of refusals after naloxone administration in a single EMS system was evaluated. The number of refusals after naloxone administration was compared across the before-pandemic interval (01/01/20 to 02/15/20) and the during-pandemic interval (03/16/20 to 04/30/20). For comparison the incidence of all other patient refusals before and during COVID-19 as well as the incidences of naloxone administration before and during COVID-19 were also reported., Results: Prior to the widespread knowledge of the COVID-19 pandemic, 24 of 164 (14.6%) patients who received naloxone via EMS refused transport. During the pandemic, 55 of 153 (35.9%) patients who received naloxone via EMS refused transport. Subjects receiving naloxone during the COVID-19 pandemic were at greater risk of refusal of transport than those receiving naloxone prior to the pandemic (RR = 2.45; 95% CI 1.6-3.76). Among those who did not receive naloxone, 2067 of 6956 (29.7%) patients were not transported prior to the COVID-19 pandemic and 2483 of 6016 (41.3%) were not transported during the pandemic. Subjects who did not receive naloxone with EMS were at greater risk of refusal of transport during the COVID-19 pandemic than prior to it (RR = 1.39; 95% CI 1.32-1.46)., Conclusion: In this single EMS system, more than a two-fold increase in the rate of refusal after non-fatal opioid overdose was observed following the COVID-19 outbreak.

Aim: Chronic lymphocytic leukemia (CLL) has been shown to cluster in families. First-degree relatives of individuals with CLL have an ~8 fold increased risk of developing the malignancy. Strong heritability suggests pedigree studies will have good power to localize pathogenic genes. However, CLL is relatively rare and heterogeneous, complicating ascertainment and analyses. Our goal was to identify CLL risk loci using unique resources available in Utah and methods to address intra-familial heterogeneity., Methods: We identified a six-generation high-risk CLL pedigree using the Utah Population Database. This pedigree contains 24 CLL cases connected by a common ancestor. We ascertained and genotyped eight CLL cases using a high-density SNP array, and then performed shared genomic segment (SGS) analysis - a method designed for extended high-risk pedigrees that accounts for heterogeneity., Results: We identified a genome-wide significant region ( P = 1.9 × 10 -7 , LOD-equivalent 5.6) at 2q22.1. The 0.9 Mb region was inherited through 26 meioses and shared by seven of the eight genotyped cases. It sits within a ~6.25 Mb locus identified in a previous linkage study of 206 small CLL families. Our narrow region intersects two genes, including CXCR4 which is highly expressed in CLL cells and implicated in maintenance and progression., Conclusion: SGS analysis of an extended high-risk CLL pedigree identified the most significant evidence to-date for a 0.9 Mb CLL disease locus at 2q22.1, harboring CXCR4. This discovery contributes to a growing literature implicating CXCR4 in inherited risk to CLL. Investigation of the segregating haplotype in the pedigree will be valuable for elucidating risk variant(s).

Diffuse large B-cell lymphomas (DLBCLs) and follicular lymphoma (FL) are the most common subtypes of B-cell non-Hodgkin's lymphomas in adults. Histologic transformation of FL to DLBCL (TFL) occurs in approximately 15% of patients and is generally associated with a poor clinical outcome. Phosphatidylinositol 3-kinase (PI3K) inhibitors have shown promising results in the treatment of relapsed/refractory FL. CAR T-cell therapy (axicabtagene ciloleucel and tisagenlecleucel) has emerged as a novel treatment option for relapsed/refractory DLBCL and TFL. These NCCN Guidelines Insights highlight important updates to the NCCN Guidelines for B-Cell Lymphomas regarding the treatment of TFL and relapsed/refractory FL and DLBCL.

We evaluated outcome of 235 primary treatment failure (PTF) diffuse large B-cell lymphoma (DLBCL) patients based on salvage chemotherapy regimen and putative cell-of-origin (COO). Patients were divided into two groups; group A (n = 38) received high-dose cytarabine containing regimen, either DHAP or ESHAP. Patients in group B (n = 197) received ifosfamide, carboplatin, and etoposide (ICE) +/- rituximab. No difference in overall response rates (CR + PR) was observed based on salvage chemotherapy regimen and COO. After adjustment for the presence of ultra high-risk features, overall survival of germinal center B-cell like (GCB) DLBCL patients in group A was not significantly different from survival in group B (HR 0.86, 95% CI 0.46-1.60, p = .64). Similarly, within non-GCB DLBCL cohort, survival in group A was comparable to group B (HR 0.53, 95% CI 0.20-1.44, p = .21). We did not find an outcome difference between two commonly used salvage chemotherapy regimens in patients with PTF DLBCL based on COO.

Abnormal serum immunoglobulin (Ig) free light chains (FLC) are established biomarkers of early disease in multiple B-cell lymphoid malignancies, including chronic lymphocytic leukemia (CLL). Heavy chains have also been shown to be biomarkers in plasma cell disorders. An unanswered question is whether these Ig biomarkers are heritable, i.e., influenced by germline factors. CLL is heritable but highly heterogeneous. Heritable biomarkers could elucidate steps of disease pathogenesis that are affected by germline factors, and may help partition heterogeneity and identify genetic pleiotropies across malignancies. Relatives in CLL pedigrees present an opportunity to identify heritable biomarkers. We compared FLCs and heavy chains between relatives in 23 high-risk CLL pedigrees and population controls. Elevated IgM (eIgM) and abnormal FLC (aFLC) ratio was significantly increased in relatives, suggesting that these Ig biomarkers are heritable and could offer risk stratification in pedigree relatives. Within high-risk CLL pedigrees, B-cell lymphoid malignancies were five times more prevalent in close relatives of individuals with eIgM, prostate cancer was three times more prevalent in relatives of individuals with aFLC, and monoclonal B-cell lymphocytosis increased surrounding individuals with normal Ig levels. These different clustering patterns suggest Ig biomarkers have the potential to partition genetic heterogeneity in CLL and provide insight into distinct heritable pleiotropies associated with CLL.

Drug-free macromolecular therapeutics (DFMT) is a new paradigm for the treatment of B cell malignancies. Apoptosis is initiated by the biorecognition of complementary oligonucleotide motifs at the cell surface resulting in crosslinking of CD20 receptors. DMFT is composed from two nanoconjugates: 1) bispecific engager, Fab'-MORF1 (anti-CD20 Fab' fragment conjugated with morpholino oligonucleotide), and 2) a crosslinking (effector) component P-(MORF2) X (N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer grafted with multiple copies of complementary morpholino oligonucleotide). We evaluated this concept in 44 samples isolated from patients diagnosed with various subtypes of B cell malignancies. Apoptosis was observed in 65.9% of the samples tested. Pretreatment of cells with gemcitabine (GEM) or polymer-gemcitabine conjugate (2P-GEM) enhanced CD20 expression levels thus increasing apoptosis induced by DFMT. These positive results demonstrated that DFMT has remarkable therapeutic potential in various subtypes of B cell malignancies., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Are 9-1-1 ambulances relatively late to poorer neighborhoods? Studies suggesting so often rely on weak measures of neighborhood (e.g., postal zip code), limit the analysis to particular ambulance encounters (e.g., cardiac arrest responses), and do little to account for variations in dispatch priority or intervention severity., Methods: We merged EMS ambulance contact records in a single California county (n = 87,554) with tract-level data from the American Community Survey (n = 300). After calculating tract-level median ambulance response time (MART), we used ordinary least squares (OLS) regression to estimate a conditional average relationship between neighborhood poverty and MART and quantile regression to condition this relationship on 25th, 50th, and 75th percentiles of MART. We also specified each of these outcomes by five dispatch priorities and by three intervention severities. For each model, we estimated the associated changes in MART per 10 percentage point increase in tract-level poverty while adjusting for emergency department proximity, population density, and population size., Results: Our study produced three major findings. First, most of our tests suggested tract-level poverty was negatively associated with MART. Our baseline OLS model estimates that a 10 percentage point increase in tract-level poverty is associated with almost a 24 s decrease in MART (-23.55 s, 95% confidence interval [CI] -33.13 to -13.98). Results from our quantile regression models provided further evidence for this association. Second, we did not find evidence that ambulances are relatively late to poorer neighborhoods when specifying MART by dispatch priority. Third, we were also unable to identify a positive association between tract-level poverty and MART when we specified our outcomes by three intervention severities. Across each of our 36 models, tract-level poverty was either not significantly associated with MART or was negatively associated with MART by a magnitude smaller than a full minute per estimated 10 percentage point increase in poverty concentration., Conclusion: Our study challenges the commonly held assumption that ambulances are later to poor neighborhoods. We scrutinize our findings before cautiously considering their relevance for ambulance response time research and for ongoing conversations on the relationship between neighborhood poverty and prehospital care.

Relapses in acute myelogenous leukemia (AML) are a result of quiescent leukemic stem cells (LSCs) in marrow stromal niches, where they resist chemotherapy. LSCs employ CXCL12/CXCR4 to home toward protective marrow niches. Heparin disrupts CXCL12-mediated sequestration of cells in the marrow. CX-01 is a low-anticoagulant heparin derivative. In this pilot study, we combined CX-01 with chemotherapy for the treatment of AML. Induction consisted of cytarabine and idarubicin (7 + 3) with CX-01. Twelve patients were enrolled (median age, 56 years; 3 women). Three, 5, and 4 patients had good-, intermediate-, and poor-risk disease, respectively. Day 14 bone marrows were available on 11 patients and were aplastic in all without detectable leukemia. Eleven patients (92%) had morphologic complete remission after 1 induction (CR1). Eight patients were alive at a median follow-up of 24 months (4 patients in CR1). Three patients received an allogeneic stem cell transplant in CR1. Median disease-free survival was 14.8 months. Median overall survival was not attained at the maximum follow-up time of 29.4 months. No CX-01-associated serious adverse events occurred. Median day to an untransfused platelet count of at least 20 × 10 9 /L was 21. CX-01 is well tolerated when combined with intensive therapy for AML and appears associated with enhanced count recovery and treatment efficacy., (© 2018 by The American Society of Hematology.)

Choline is essential to the development and function of the central nervous system and supplemental choline during development is neuroprotective against a variety of insults, including neurotoxins like dizocilpine (MK-801). MK-801 is an NMDA receptor antagonist that is frequently used in rodent models of psychological disorders, particularly schizophrenia. At low doses, it causes cognitive impairments, and at higher doses it induces motor deficits, anhedonia, and neuronal degeneration. The primary goals of the present study were to investigate whether prenatal choline supplementation protects against the cognitive impairments, motor deficits, and neuropathologies that are precipitated by MK-801 administration in adulthood. Adult male Sprague-Dawley rats were fed a standard or supplemented choline diet prenatally. Using the novelty preference test of object recognition, we found that only prenatal standard-fed rats displayed memory consolidation deficits induced by low-dose MK-801 administered immediately following study of sample objects; all other groups, including prenatal choline supplemented rats given MK-801, showed intact memory. Following high-dose MK-801, prenatal choline supplementation significantly alleviated rats' motor response to MK-801, particularly ataxia. Using doublecortin and Ki67 to mark neurogenesis and cell division, respectively, in the hippocampus, we found that prenatal choline supplementation, in the face of MK-801 toxicity, protected against reduced hippocampal plasticity. Taken together, the current findings suggest that prenatal choline supplementation protects against a variety of behavioral and neural pathologies induced by the neurotoxin, MK-801. This research contributes to the growing body of evidence supporting the robust neuroprotective capacity of choline., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Mild traumatic brain injuries (mTBI) are an increasing health concern due to persistent behavioral and neurological effects. To better understand these effects, researchers frequently rely on animal injury models. Existing models, however, may not adequately reproduce the mechanism of injury as it occurs in humans., New Method: Our new model for inducing mTBI in rodents entails acceleration of the animal toward a stationary impact zone to produce rapid rotational movement of the head. The aim of the present experiment was to characterize the effects of this injury in female and male rats on behavior, cognition, and neural plasticity., Results: mTBI produced the most widespread effects in females: they were more active during recovery within minutes of mTBI and more active in the center of the open field 4days after mTBI. Spatial learning deficits in the water maze were mild but persistent and accompanied by reduced numbers of immature neurons in the hippocampus along with reductions in sera levels of the neurotrophin, BDNF. By contrast, male mTBI rats mainly exhibited mild spatial learning deficits, with no other observed effects., Comparison With Existing Methods: Our model induced effects on behavior and biology in rats that aligned with existing models. However, new patterns were observed, particularly when comparing females and males., Conclusions: Taken together, these findings confirm the validity of this model and point to key differences between females and males in symptom severity and type. Additionally, our model adds a novel injury mechanism that complements existing rodent models., (Copyright © 2017 Elsevier B.V. All rights reserved.)

B lymphoblastic leukemia (B-ALL) in adults has a higher risk of relapse and lower long-term survival than pediatric B-ALL, but data regarding genetic prognostic biomarkers are much more limited for adult patients. We identified 70 adult B-ALL patients from three institutions and performed genome-wide analysis via single nucleotide polymorphism (SNP) arrays on DNA isolated from their initial diagnostic sample and, when available, relapse bone marrow specimens to identify recurring copy number alterations (CNA). As B-cell developmental genes play a crucial role in this leukemia, we assessed such for recurrent deletions in diagnostic and relapse samples. We confirmed previous findings that the most prevalent deletions of these genes occur in CDKN2A, IKZF1, and PAX5, with several others at lower frequencies. Of the 16 samples having paired diagnostic and relapse samples, 5 showed new deletions in these recurrent B-cell related genes and 8 showed abolishment. Deletion of EBF1 heralded a significant negative prognostic impact on relapse free survival in univariate and multivariate analyses. The combination of both a CDKN2A/B deletion and an IKZF1 alteration (26% of cases) also showed a trend toward predicting worse overall survival compared to having only one or neither of these deletions. These findings add to the understanding of genomic influences on this comparably understudied disease cohort that upon further validation may help identify patients who would benefit from upfront treatment intensification., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease and managed in much the same way. The advent of novel CD20 monoclonal antibodies led to the development of effective chemoimmunotherapy regimens. More recently, small molecule inhibitors targeting kinases involved in a number of critical signaling pathways and a small molecule inhibitor of the BCL-2 family of proteins have demonstrated activity for the treatment of patients with CLL/SLL. These NCCN Guidelines Insights highlight important updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CLL/SLL for the treatment of patients with newly diagnosed or relapsed/refractory CLL/SLL., (Copyright © 2017 by the National Comprehensive Cancer Network.)

The outcomes of patients with DLBCL and primary treatment failure (PTF) in the rituximab era are unclear. We analyzed 331 patients with PTF, defined as primary progression while on upfront chemoimmunotherapy (PP), residual disease at the end of upfront therapy (RD) or relapse < 6 months from end of therapy (early relapse; ER). Median age was 58 years and response to salvage was 41.7%. Two-year OS was 18.5% in PP, 30.6% in RD and 45.5% in ER. The presence of PP, intermediate-high/high NCCN-IPI at time of PTF or MYC translocation predicted 2-year OS of 13.6% constituting ultra-high risk (UHR) features. Among the 132 patients who underwent autologous hematopoietic cell transplantation, 2-year OS was 74.3%, 59.6% and 10.7% for patients with 0,1 and 2-3 UHR features respectively. Patients with PTF and UHR features should be prioritized for clinical trials with newer agents and innovative cellular therapy., (© 2016 Wiley Periodicals, Inc.)

Background: Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma., Methods: We performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality., Results: We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P < 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry-European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4 Correlated variants in 7p15.3 clustered around an enhancer at the 3' end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 × 10 -7 ) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-κB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7 CONCLUSIONS: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles., Impact: A subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional. Cancer Epidemiol Biomarkers Prev; 25(12); 1609-18. ©2016 AACR., (©2016 American Association for Cancer Research.)

Peripheral T-cell lymphomas (PTCLs) represent a relatively uncommon heterogeneous group of non-Hodgkin's lymphomas (NHLs) with an aggressive clinical course and poor prognosis. Anthracycline-based multiagent chemotherapy with or without radiation therapy followed by first-line consolidation with high-dose therapy followed by autologous stem cell rescue (HDT/ASCR) is the standard approach to most of the patients with newly diagnosed PTCL. Relapsed or refractory disease is managed with second-line systemic therapy followed by HDT/ASCR or allogeneic stem cell transplant, based on the patient's eligibility for transplant. In recent years, several newer agents have shown significant activity in patients with relapsed or refractory disease across all 4 subtypes of PTCL. These NCCN Guideline Insights highlight the important updates to the NCCN Guidelines for NHL, specific to the management of patients with relapsed or refractory PTCL., (Copyright © 2016 by the National Comprehensive Cancer Network.)

Diffuse large B-cell lymphomas (DLBCL) are now considered a heterogeneous group of distinct molecular subtypes (germinal center B-cell DLBCL, activated B-cell DLBCL, and primary mediastinal large B-cell lymphoma (PMBL) with varied natural history and response to therapy. In addition, a subset of patients with DLBCL have concurrent MYC and/or BCL2 gene rearrangements (double-hit lymphomas; DHL) and others have a dual expression of both MYC and BCL2 proteins (double-expressing DLBCL; DEL). The standard of care for the treatment of patients with PMBL, DHL, or DEL has not been established. Adequate immunophenotyping and molecular testing (in selected circumstances) are necessary for the accurate diagnosis of different subtypes of DLBCL. The NCCN Guidelines included in this issue, part of the NCCN Guidelines for non-Hodgkin's lymphomas, address the diagnosis and management of DLBCL and its subtypes., (Copyright © 2016 by the National Comprehensive Cancer Network.)

The present study explored the effects of supplementing male rats with either choline, omega-3 fatty acids, or phytoestrogens, from weaning into early adulthood, on emotionality and hippocampal plasticity. Because of the neuroprotective properties of these nutrients, we hypothesized that they would positively affect both behavior and hippocampal function when compared to non-supplemented control rats. To test this hypothesis, male Sprague Dawley rats were assigned to one of four nutrient conditions after weaning: 1) control (normal rat chow); 2) choline (supplemented in drinking water); 3) omega 3 fatty acids (daily oral supplements); or 4) phytoestrogens (supplemented in chow). After 4weeks on their respective diets, a subset of rats began 3weeks of behavioral testing, while the remaining behaviorally naïve rats were sacrificed after 6weeks on the diets to assess numbers of adult-born hippocampal neurons using the immature neuron marker, doublecortin. The results revealed that choline supplementation affected emotional functioning; compared to rats in other diet conditions, rats in this group were less anxious in an open field and after exposure to predator odor and showed less behavioral despair after forced swimming. Similar behavioral findings were evident following supplementation with omega-3 fatty acids and phytoestrogen supplementation, though not on all tests and not to the same magnitude. Histological findings followed a pattern consistent with the behavioral findings: choline supplementation, followed by omega-3 fatty acid supplementation, but not phytoestrogen supplementation, significantly increased the numbers of new-born hippocampal neurons. Choline and omega-3 fatty acids have similar biological functions-affecting cell membranes, growth factor levels, and epigenetically altering gene transcription. Thus, the present findings suggest that targeting nutrients with these effects may be a viable strategy to combat adult psychopathologies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: Based on previous molecular studies, a small fraction of primary mediastinal (thymic) large B-cell lymphoma (PMBL) demonstrates MYC alterations. However, no studies have evaluated MYC protein expression by immunohistochemistry (IHC) with follow-up fluorescence in situ hybridization (FISH) analysis. We aim to evaluate the clinicopathologic importance of MYC IHC expression in PMBL., Methods: Three pathologists independently evaluated MYC IHC expression in 32 cases of PMBL for percent tumor positivity and nuclear intensity. FISH analysis for MYC rearrangement was performed on cases with high MYC IHC expression. Clinical data including treatment, follow-up, and outcome were also reviewed in a subset of cases., Results: Variable MYC protein expression by IHC was detected in 30 (94%) of 32 cases of PMBL. One-third of the positive cases (10/30) showed high MYC IHC expression of at least 30% nuclear positivity. FISH analyses for MYC rearrangement on these 10 cases were negative. Review of clinical data on a subset of cases with high and low MYC IHC expression showed no differences in clinical outcome., Conclusions: MYC protein expression by IHC is present in most PMBLs. Increased MYC protein expression can be seen in one-third of the cases; however, it does not correlate with genetic abnormalities by FISH. There is also no significant impact of MYC protein expression on clinical outcomes., (Copyright© by the American Society for Clinical Pathology.)

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease, which are managed in the same way. The advent of novel monoclonal antibodies (ofatumumab and obinutuzumab) led to the development of effective chemoimmunotherapy regimens. The recently approved small molecule kinase inhibitors (ibrutinib and idelalisib) are effective treatment options for CLL in elderly patients with decreased tolerance for aggressive regimens and in patients with poor prognostic features who do not benefit from conventional chemoimmunotherapy regimens. This portion of the NCCN Guidelines for Non-Hodgkin's Lymphomas describes the recent specific to the incorporation of recently approved targeted therapies for the management of patients with newly diagnosed and relapsed or refractory CLL/SLL., (Copyright © 2015 by the National Comprehensive Cancer Network.)

Non-Hodgkin's lymphomas (NHL) are a heterogeneous group of lymphoproliferative disorders originating in B lymphocytes, T lymphocytes, or natural killer cells. Mantle cell lymphoma (MCL) accounts for approximately 6% of all newly diagnosed NHL cases. Radiation therapy with or without systemic therapy is a reasonable approach for the few patients who present with early-stage disease. Rituximab-based chemoimmunotherapy followed by high-dose therapy and autologous stem cell rescue (HDT/ASCR) is recommended for patients presenting with advanced-stage disease. Induction therapy followed by rituximab maintenance may provide extended disease control for those who are not candidates for HDT/ASCR. Ibrutinib, a Bruton tyrosine kinase inhibitor, was recently approved for the treatment of relapsed or refractory disease. This manuscript discusses the recommendations outlined in the NCCN Guidelines for NHL regarding the diagnosis and management of patients with MCL., (Copyright © 2014 by the National Comprehensive Cancer Network.)

Non-Hodgkin's lymphomas (NHLs) are a heterogeneous group of lymphoproliferative disorders originating in B lymphocytes, T lymphocytes, or natural killer cells. Follicular lymphoma (FL) is the most common subtype of indolent NHL, accounting for approximately 22% of all newly diagnosed cases of NHL. The incorporation of rituximab to chemotherapy regimens has become a widely accepted standard of care for first-line therapy for patients with FL. Maintenance and consolidation therapy with rituximab and radioimmunotherapy have also been associated with improved progression-free survival in patients experiencing response to first-line therapy. Despite therapeutic advances that have improved outcomes, FL is generally considered a chronic disease characterized by multiple recurrences with current therapies. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with FL., (Copyright © 2014 by the National Comprehensive Cancer Network.)

We examined if the strength of contextual fear learning determines whether remote memories become independent of the hippocampus. Rats received 3 or 10 shocks in a single contextual fear conditioning session and then received sham or complete neurotoxic lesions of the hippocampus 7, 50, or 100 days later. Following recovery from surgery, the rats were returned to the conditioning context for a 5-min retention test. During this test, freezing, complete immobility except for breathing, was used as an index of memory. Regardless of the learning-to-surgery interval, the rats with hippocampal damage from the 3-shock condition showed little and significantly less freezing than their respective control group, suggesting profound flat graded retrograde amnesia. Similarly, each group of hippocampal-damaged rats from the 10-shock condition froze significantly less than their respective control group. However, the rats that received hippocampal damage 50 days after learning froze significantly more than the rats that received the damage 7 days after learning. The latter gradient to the retrograde amnesia did not increase with more time as the freezing was not as high in the most remote memory group (100 days). Combined, these findings suggest that a contextual fear memory acquired in a single session under stronger learning parameters remains dependent on the hippocampus., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Cocaine generates drug-seeking behavior by creating long-lasting changes in the reward pathway. The role of the growth factor, brain-derived neurotrophic factor (BDNF) in facilitating these changes was investigated in the present report with a genetic rat model. Using conditioned place preference, the current study investigated the hypothesis that a partial knockout of the BDNF gene in rats (BDNF(+/-)) would attenuate the rewarding effects of cocaine. Wildtype rats exposed to cocaine exhibited normal cocaine-seeking responses one day after conditioning and cocaine-seeking behavior was reinstated with drug priming following drug abstinence. In contrast, BDNF(+/-) rats did not show cocaine-seeking behavior one day after conditioning, nor did they respond to drug priming. A median split of rats based on BDNF levels in sera collected prior to behavioral procedures revealed that wildtype rats with high BDNF levels showed stronger conditioned place preference and reinstatement to cocaine. Together, the results support the hypothesis that a partial knockout of the BDNF gene attenuates the rewarding properties of cocaine. Additionally, individual differences in BDNF levels may predict future cocaine-seeking behavior. An underlying mechanism of these effects may be a reduction of the amount of synaptic changes made in the reward pathway., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

These NCCN Guidelines Insights summarize several key updates to the NCCN Guidelines for Non-Hodgkin's Lymphomas (NHL) and provide a discussion of the clinical evidence that support the updates. The updates discussed in this article feature recommendations for additional treatment options in patients with chronic lymphocytic leukemia and guidance surrounding the management of hepatitis virus reactivation/infections in high-risk patients with NHL undergoing antitumor therapy.

These NCCN Guidelines Insights summarize several key updates to the 2012 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Hodgkin's Lymphomas (NHL) and describe the clinical evidence supporting the updates. The featured updates include changes to the recommendations for treatment options in patients with chronic lymphocytic leukemia (including in elderly or frail patients and patients with poor-risk cytogenetics), guidance surrounding surveillance imaging for follow-up of patients with NHL, and the addition of first-line consolidation options for patients with mantle cell lymphoma.

In the present study, we investigated whether the essential nutrient choline may protect against schizophrenic-like cognitive deficits in a rat model. Theories regarding the etiology of schizophrenia suggest that early life events render an individual more vulnerable to adult challenges, and the combination may precipitate disease onset. To model this, the adult male offspring of dams who either experienced stress during late gestation or did not were given a 5 mg/kg dose of the NMDA antagonist,MK-801. The presence of both the prenatal challenge of stress and the adult challenge of MK-801 was expected to impair memory in these offspring. Memory was not expected to be impaired in rats that did not experience prenatal stress, but did receive MK-801 as adults. To study whether choline levels altered outcomes in these groups, rats were fed a choline-supplemented, -deficient, or standard diet during the period between the two challenges: beginning at weaning and continuing for 25 days. All rats consumed regular rat chow thereafter. The efficacy of the model was confirmed in the standard fed rats in that only those that were prenatally stressed and received MK-801 as adults displayed impaired memory on a novelty preference test of object recognition. Contrary to this finding and consistent with our hypothesis, choline-supplemented rats that were also both prenatally stressed and given MK-801 as adults showed intact memory. Choline deficiency impaired memory in rats that were just prenatally stressed, just given MK-801 as adults, and subjected to both. Thus, a choline deficient diet may render rats vulnerable to either challenge. Taken together, we offer evidence that developmental choline levels modulate the effects of prenatal stress and/or MK-801 and thereby alter the cognitive outcome in a rat model of schizophrenia.

S0515 was a phase 2 trial to determine whether the addition of bevacizumab to cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) plus rituximab (R-CHOP) would improve progression-free survival (PFS) without adding significant toxicity in patients with newly diagnosed advanced diffuse large B-cell lymphoma. A total of 73 patients were enrolled. For the 64 eligible patients, median age was 68 years, and 60% had International Prognostic Index scores more than or equal to 3. The observed 1- and 2-year PFS estimates were 77% and 69%, respectively. These PFS estimates were not statistically different from the expected PFS for this population if treated with R-CHOP alone. Grade 3 or higher toxicities were observed in 81% of patients, including 2 grade 5 events. The majority of serious toxicities were hematologic but also included 5 patients with gastrointestinal perforations, 4 patients with thrombotic events, and 11 patients who developed grade 2 or 3 left ventricular dysfunction. Higher baseline urine VEGF and plasma VCAM levels correlated with worse PFS and overall survival. In conclusion, the addition of bevacizumab to R-CHOP chemotherapy was not promising in terms of PFS and resulted in increased serious toxicities, especially cardiac and gastrointestinal perforations. This study is registered at www.clinicaltrials.gov as #NCT00121199.

Background: Protein from plant, as opposed to animal, sources may be preferred in chronic kidney disease (CKD) because of the lower bioavailability of phosphate and lower nonvolatile acid load., Study Design: Observational cross-sectional study., Setting and Participants: A total of 2,938 participants with CKD and information on their dietary intake at the baseline visit in the Chronic Renal Insufficiency Cohort Study., Predictors: Percentage of total protein intake from plant sources (percent plant protein) was determined by scoring individual food items using the National Cancer Institute Diet History Questionnaire (DHQ)., Outcomes: Metabolic parameters, including serum phosphate, bicarbonate (HCO₃), potassium, and albumin, plasma fibroblast growth factor 23 (FGF-23), and parathyroid hormone (PTH), and hemoglobin levels., Measurements: We modeled the association between percent plant protein and metabolic parameters using linear regression. Models were adjusted for age, sex, race, diabetes status, body mass index, estimated glomerular filtration rate, income, smoking status, total energy intake, total protein intake, 24-hour urinary sodium concentration, use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and use of diuretics., Results: Higher percent plant protein was associated with lower FGF-23 (P = .05) and higher HCO₃ (P = .01) levels, but not with serum phosphate or parathyroid hormone concentrations (P = .9 and P = .5, respectively). Higher percent plant protein was not associated with higher serum potassium (P = .2), lower serum albumin (P = .2), or lower hemoglobin (P = .3) levels. The associations of percent plant protein with FGF-23 and HCO₃ levels did not differ by diabetes status, sex, race, CKD stage (2/3 vs. 4/5), or total protein intake (≤0.8 g/kg/day vs. >0.8 g/kg/day; P-interaction >.10 for each)., Limitations: This is a cross-sectional study; determination of percent plant protein using the Diet History Questionnaire has not been validated., Conclusions: Consumption of a higher percentage of protein from plant sources may lower FGF-23 and raise HCO₃ levels in patients with CKD., (Copyright © 2012 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Perinatal choline supplementation in rats is neuroprotective against insults such as fetal alcohol exposure, seizures, and advanced age. In the present study we explored whether dietary choline supplementation may also confer protection from psychological challenges, like stress, and act as a natural buffer against stress-linked psychological disorders, like depression. We previously found that choline supplementation increased adult hippocampal neurogenesis, a function compromised by stress, lowered in depression, and boosted by antidepressants; and increased levels of growth factors linked to depression, like brain-derived neurotrophic factor. Together, these were compelling reasons to study the role of choline in depressed mood. To do this, we treated rats with a choline supplemented diet (5 mg/kg choline chloride in AIN76A) prenatally on embryonic days 10-22, on postnatal days (PD) 25-50, or as adults from PD75 onward. Outside of these treatment periods rats were fed a standard diet (1.1 mg/kg choline chloride in AIN76A); control rats consumed only this diet throughout the study. Starting on PD100 rats' anxiety-like responses to an open field, learning in a water maze, and reactivity to forced swimming were assessed. Rats given choline supplementation during pre- or post-natal development, but not adult-treated rats, were less anxious in the open field and less immobile in the forced swim test than control rats. These effects were not mediated by a learning deficit as all groups performed comparably and well in the water maze. Thus, we offer compelling support for the hypothesis that supplemental dietary choline, at least when given during development, may inoculate an individual against stress and major psychological disorders, like depression., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Choline is a vital nutrient needed during early development for both humans and rodents. Severe dietary choline deficiency during pregnancy leads to birth defects, while more limited deficiency during mid- to late pregnancy causes deficits in hippocampal plasticity in adult rodent offspring that are accompanied by cognitive deficits only when task demands are high. Because prenatal choline supplementation confers neuroprotection of the adult hippocampus against a variety of neural insults and aids memory, we hypothesized that prenatal choline deficiency may enhance vulnerability to neural injury. To examine this, adult offspring of rat dams either fed a control diet (CON) or one deficient in choline (DEF) during embryonic days 12-17 were given multiple injections (i.p.) of saline (control) or kainic acid to induce seizures and were euthanized 16 days later. Perhaps somewhat surprisingly, DEF rats were not more susceptible to seizure induction and showed similar levels of seizure-induced hippocampal histopathology, GAD expression loss, upregulated hippocampal GFAP and growth factor expression, and increased dentate cell and neuronal proliferation as that seen in CON rats. Although prenatal choline deficiency compromises adult hippocampal plasticity in the intact brain, it does not appear to exacerbate the neuropathological response to seizures in the adult hippocampus at least shortly after excitotoxic injury., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Status epilepticus (SE) in adulthood dramatically alters the hippocampus and produces spatial learning and memory deficits. Some factors, like environmental enrichment and exercise, may promote functional recovery from SE. Prenatal choline supplementation (SUP) also protects against spatial memory deficits observed shortly after SE in adulthood, and we have previously reported that SUP attenuates the neuropathological response to SE in the adult hippocampus just 16 days after SE. It is unknown whether SUP can ameliorate longer-term cognitive and neuropathological consequences of SE, whether repeatedly engaging the injured hippocampus in a cognitive task might facilitate recovery from SE, and whether our prophylactic prenatal dietary treatment would enable the injured hippocampus to more effectively benefit from cognitive rehabilitation. To address these issues, adult offspring from rat dams that received either a control (CON) or SUP diet on embryonic days 12-17 first received training on a place learning water maze task (WM) and were then administered saline or kainic acid (KA) to induce SE. Rats then either remained in their home cage, or received three additional WM sessions at 3, 6.5, and 10 weeks after SE to test spatial learning and memory retention. Eleven weeks after SE, the brains were analyzed for several hippocampal markers known to be altered by SE. SUP attenuated SE-induced spatial learning deficits and completely rescued spatial memory retention by 10 weeks post-SE. Repeated WM experience prevented SE-induced declines in glutamic acid decarboxylase (GAD) and dentate gyrus neurogenesis, and attenuated increased glial fibrilary acidic protein (GFAP) levels. Remarkably, SUP alone was similarly protective to an even greater extent, and SUP rats that were water maze trained after SE showed reduced hilar migration of newborn neurons. These findings suggest that prophylactic SUP is protective against the long-term cognitive and neuropathological effects of KA-induced SE, and that rehabilitative cognitive enrichment may be partially beneficial., (Copyright © 2010 Wiley-Liss, Inc.)

Evidence from lesion and inactivation studies suggests that the hippocampus (HPC) and dorsal striatum compete for control over navigation behavior, and there is some evidence in males that the structure with greater relative activation controls behavior. Estradiol has been shown to enhance HPC-dependent place learning and impair dorsal striatum-dependent response learning in female rats, possibly by increasing hippocampal activation and/or decreasing striatal activation. We used Fos-immunoreactivity (Fos-IR) to examine the activation of several subregions of the HPC and striatum in ovariectomized female rats with or without estradiol replacement 30 min after place or response learning. In 4-month-old rats, neither task nor estradiol increased Fos-IR above explore control levels in any subregion analyzed, even though estradiol impaired response learning. In 12-month-old rats, estradiol increased Fos-IR in the dentate gyrus, dorsal medial striatum, and dorsal lateral striatum in place task learners, while the absence of estradiol increased Fos-IR in these regions in response task learners. However, learning rate was not affected by estradiol in either task. We also included a group of long-term ovariectomized 12-month-old rats that displayed impaired place learning and altered Fos-IR in CA1 of the HPC. These results suggest that task-specific effects of estradiol on hippocampal and striatal activation emerge across age but that relative hippocampal and striatal activation are not related to learning rate during spatial navigation learning.