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Recent documents in eScholarship@UMMS
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Charting a New Path: The Evolution of the Journal of eScience Librarianship

Fri, 12/16/2016 - 12:21pm

The Journal of eScience Librarianship (JeSLIB) has been successful in providing quality and timely scholarship in the area of data science and library services. However, it is a wise strategy to gather feedback and suggestions from readership when planning future changes and initiatives.

Librarian as Researcher

Wed, 12/14/2016 - 11:00am

In this webinar, four Institute for Research Design in Librarianship (IRDL) scholars shared how their research projects have developed over time, the IRDL application process, and how participants can also embrace the Librarian as Researcher role. This session reviewed the IRDL 2017 call for applications, and discussed how librarians with a passion for research and a desire to improve their research skills may utilize IRDL.

Macrophages Are Regulators of Whole Body Metabolism: A Dissertation

Mon, 12/12/2016 - 9:54am

Obesity is the top risk factor for the development of type 2 diabetes mellitus in humans. Obese adipose tissue, particularly visceral depots, exhibits an increase in macrophage accumulation and is described as being in a state of chronic low-grade inflammation. It is characterized by the increased expression and secretion of inflammatory cytokines produced by both macrophages and adipocytes, and is associated with the development of insulin resistance. Based on these observations, we investigated the potential role of macrophage infiltration on whole body metabolism, using genetic and diet-induced mouse models of obesity.

Using flow cytometry and immunofluorescence imaging we found that a significant percentage of macrophages proliferate locally in adipose tissue of obese mice. Importantly, we identified monocyte chemoattractant protein 1 (MCP-1) as the stimulating factor. We also found that ATMs can be targeted for specific gene silencing using glucan encapsulated siRNA particles (GeRPs). Knockdown of the cytokine osteopontin improved regulation of systemic glucose levels as well as insulin signaling in adipocytes. Conversely, targeting lipoprotein lipase (LPL) abrogated the buffering of lipid spillover from adipose tissue, resulting in increased hepatic glucose output. Finally, silencing of the master regulator of inflammation NF-κB in resident liver macrophages called Kupffer cells significantly improved hepatic insulin signaling. Thus this work demonstrates that macrophages can regulate whole body metabolism.

Identification of Essential Metabolic and Genetic Adaptations to the Quiescent State in Mycobacterium Tuberculosis: A Dissertation

Mon, 12/12/2016 - 9:54am

Mycobacterium tuberculosis stably adapts to respiratory limited environments by entering into a nongrowing but metabolically active state termed quiescence. This state is inherently tolerant to antibiotics due to a reduction in growth and activity of associated biosynthetic pathways. Understanding the physiology of the quiescent state, therefore, may be useful in developing new strategies to improve drug efficiency. Here, we used an established in vitro model of respiratory stress, hypoxia, to induce quiescence. We utilized metabolomic and genetic approaches to identify essential and active pathways associated with nongrowth. Our metabolomic profile of hypoxic M. tuberculosis revealed an increase in several free fatty acids, metabolite intermediates in the oxidative pathway of the tricarboxylic acid (TCA) cycle, as well as, the important chemical messenger, cAMP. In tandem, a high-throughput transposon mutant library screen (TnSeq) revealed that a cAMP-regulated protein acetyltransferase, MtPat, was conditionally essential for survival in the hypoxic state. Via 13C-carbon flux tracing we show an MtPat mutant is deficient in re-routing hypoxic metabolism away from the oxidative TCA cycle and that MtPat is involved in inhibiting fatty-acid catabolism in hypoxia. Additionally, we show that reductive TCA metabolism is required for survival of hypoxia by depletion of an essential TCA enzyme, malate dehydrogenase (Mdh) both in in vitro hypoxia and in vivo mouse infection. Inhibition of Mdh with a novel compound resulted in a significantly greater killing efficiency than the first-line anti-M. tuberculosis drug isoniazid (INH). In conclusion, we show that understanding the physiology of the quiescent state can lead to new drug targets for M. tuberculosis.

Imaging in the Lion City: Singapore Radiology Country Report

Fri, 12/09/2016 - 1:50pm

Singapore is a small tropical island city-state with limited natural resources that has achieved remarkable healthcare outcomes through effective long-term planning and judicious investment in human resources and technology. A full-range of medical imaging services is available in the country, with integrated care delivered to patients through a network of both government and private hospitals. Training in diagnostic radiology, interventional radiology, nuclear medicine and diagnostic radiography continue to evolve in Singapore, with an aim to further increase the range of subspecialty medical imaging services available and address projected challenges for the healthcare system in the future, such as an aging population. Continued government investment in technology and biomedical imaging is expected to further expand the scope and depth of medical imaging services in the future.

Creating a campus-wide research data services committee: The good, The bad, and The…... Part 2: Launching your collaboration

Thu, 12/08/2016 - 2:58pm

A panel of presenters in this two-part webinar series shared their experiences about how academic libraries are taking the lead in developing cross-campus collaborations in establishing research data committees to spearhead institutional efforts related to data stewardship and digital projects. This interactive session lead participants through the various steps needed in order to initiate a similar effort within their institutional context.

Part 2: Launching your collaboration

Learning Objectives:

  • Identify best practices and lessons learned for working with established committees who are working on broad-scale projects and programs
  • Evaluate different institutional models to compare and customize for different academic environments
  • Analyze best practices strategies for successful project management, collaboration, and program development for established committees

Creating a campus-wide research data services committee: The good, The bad, and The...... Part 1: Building bridges and planting seeds

Thu, 12/08/2016 - 2:58pm

A panel of presenters in this two-part webinar series shared their experiences about how academic libraries are taking the lead in developing cross-campus collaborations in establishing research data committees to spearhead institutional efforts related to data stewardship and digital projects. This interactive session lead participants through the various steps needed in order to initiate a similar effort within their institutional context.

Part 1: Building bridges and planting seeds

Learning Objectives:

  • Focus on early-stage efforts to build partnerships and bring key stakeholders to the table
  • Acquire practical tips for addressing the institutional challenges involved in developing a campus-wide data committee
  • Identify key individuals who could be instrumental in establishing a campus-wide data committee

Central IRBs: Enhanced Protections for Research Participants

Thu, 12/08/2016 - 9:14am

Institutional Review Boards (IRBs) play a critical role in research, and assure safety and fairness to participants enrolled in research studies. Multisite studies are often reviewed by multiple IRBs (an IRB review at each site participating in the study), which can slow down study approval, result in duplication of effort, and occasionally produce contradictory decisions by different IRBs. To address these problems, the federal government has promoted the use of single IRBs (referred to as Central IRBs or CIRBs), where a single IRB is responsible for the review of all sites where the research study is conducted. The National Institutes of Health (NIH) has recently announced that beginning in 2017 all research conducted at multiple sites must be reviewed by a CIRB. This CIRB process is new and requires careful study to understand its pitfalls and benefits. As such, UMass Medical School and Columbia University received a (NIH) grant to study how different institutions conduct reviews of research involving multiple sites.

Insulin Receptor Substrate Adaptor Proteins Mediate Prognostic Gene Expression Profiles in Breast Cancer

Wed, 12/07/2016 - 3:43pm

Therapies targeting the type I insulin-like growth factor receptor (IGF-1R) have not been developed with predictive biomarkers to identify tumors with receptor activation. We have previously shown that the insulin receptor substrate (IRS) adaptor proteins are necessary for linking IGF1R to downstream signaling pathways and the malignant phenotype in breast cancer cells. The purpose of this study was to identify gene expression profiles downstream of IGF1R and its two adaptor proteins. IRS-null breast cancer cells (T47D-YA) were engineered to express IRS-1 or IRS-2 alone and their ability to mediate IGF ligand-induced proliferation, motility, and gene expression determined. Global gene expression signatures reflecting IRS adaptor specific and primary vs. secondary ligand response were derived (Early IRS-1, Late IRS-1, Early IRS-2 and Late IRS-2) and functional pathway analysis examined. IRS isoforms mediated distinct gene expression profiles, functional pathways, and breast cancer subtype association. For example, IRS-1/2-induced TGFb2 expression and blockade of TGFb2 abrogated IGF-induced cell migration. In addition, the prognostic value of IRS proteins was significant in the luminal B breast tumor subtype. Univariate and multivariate analyses confirmed that IRS adaptor signatures correlated with poor outcome as measured by recurrence-free and overall survival. Thus, IRS adaptor protein expression is required for IGF ligand responses in breast cancer cells. IRS-specific gene signatures represent accurate surrogates of IGF activity and could predict response to anti-IGF therapy in breast cancer.

Accurate Prediction of Transposon-Derived piRNAs by Integrating Various Sequential and Physicochemical Features

Wed, 12/07/2016 - 3:42pm

BACKGROUND: Piwi-interacting RNA (piRNA) is the largest class of small non-coding RNA molecules. The transposon-derived piRNA prediction can enrich the research contents of small ncRNAs as well as help to further understand generation mechanism of gamete.

METHODS: In this paper, we attempt to differentiate transposon-derived piRNAs from non-piRNAs based on their sequential and physicochemical features by using machine learning methods. We explore six sequence-derived features, i.e. spectrum profile, mismatch profile, subsequence profile, position-specific scoring matrix, pseudo dinucleotide composition and local structure-sequence triplet elements, and systematically evaluate their performances for transposon-derived piRNA prediction. Finally, we consider two approaches: direct combination and ensemble learning to integrate useful features and achieve high-accuracy prediction models.

RESULTS: We construct three datasets, covering three species: Human, Mouse and Drosophila, and evaluate the performances of prediction models by 10-fold cross validation. In the computational experiments, direct combination models achieve AUC of 0.917, 0.922 and 0.992 on Human, Mouse and Drosophila, respectively; ensemble learning models achieve AUC of 0.922, 0.926 and 0.994 on the three datasets.

CONCLUSIONS: Compared with other state-of-the-art methods, our methods can lead to better performances. In conclusion, the proposed methods are promising for the transposon-derived piRNA prediction. The source codes and datasets are available in S1 File.

Glucose Metabolism Disorder Is Associated with Pulmonary Tuberculosis in Individuals with Respiratory Symptoms from Brazil

Wed, 12/07/2016 - 3:42pm

BACKGROUND: Diabetes mellitus (DM) has been associated with increased risk for pulmonary tuberculosis (PTB) in endemic settings but it is unknown whether PTB risk is also increased by pre-DM. Here, we prospectively examined the association between glucose metabolism disorder (GMD) and PTB in patients with respiratory symptoms at a tuberculosis primary care reference center in Brazil.

METHODS: Oral glucose tolerance test was performed and levels of fasting plasma glucose and glycohemoglobin (HbA1c) were measured in a cohort of 892 individuals presenting with respiratory symptoms of more than two weeks duration. Patients were also tested for PTB with sputum cultures. Prevalence of pre-DM and DM (based on HbA1c) was estimated and tested for association with incident PTB. Other TB risk factors including smoking history were analyzed.

RESULTS: The majority of the study population (63.1%) exhibited GMD based on HbA1c > /=5.7%. Patients with GMD had higher prevalence of PTB compared to normoglycemic patients. Individuals with DM exhibited increased frequency of TB-related symptoms and detection of acid-fast bacilli in sputum smears. Among patients with previous DM diagnosis, sustained hyperglycemia (HbA1c > /=7.0%) was associated with increased TB prevalence. Smoking history alone was not significantly associated with TB in our study population but the combination of smoking and HbA1c > /=7.0% was associated with 6 times higher odds for PTB.

CONCLUSIONS: Sustained hyperglycemia and pre-DM are independently associated with active PTB. This evidence raises the question whether improving glycemic control in diabetic TB patients would reduce the risk of TB transmission and simultaneously reduce the clinical burden of disease. A better understanding of mechanisms underlying these associations, especially those suggesting that pre-DM may be a factor driving susceptibility to TB is warranted.

Early Combination Antiretroviral Therapy Limits Exposure to HIV-1 Replication and Cell-Associated HIV-1 DNA Levels in Infants

Wed, 12/07/2016 - 3:42pm

The primary aim of this study was to measure HIV-1 persistence following combination antiretroviral therapy (cART) in infants and children. Peripheral blood mononuclear cell (PBMC) HIV-1 DNA was quantified prior to and after 1 year of cART in 30 children, stratified by time of initiation (early, age < 3 months, ET; late, age > 3 months-2 years, LT). Pre-therapy PBMC HIV-1 DNA levels correlated with pre-therapy plasma HIV-1 levels (r = 0.59, p < 0.001), remaining statistically significant (p = 0.002) after adjustment for prior perinatal antiretroviral exposure and age at cART initiation. PBMC HIV-1 DNA declined significantly after 1 year of cART (Overall: -0.91+/-0.08 log10 copies per million PBMC, p < 0.001; ET: -1.04+/-0.11 log10 DNA copies per million PBMC, p < 0.001; LT: -0.74 +/-0.13 log10 DNA copies per million PBMC, p < 0.001) but rates of decline did not differ significantly between ET and LT. HIV-1 replication exposure over the first 12 months of cART, estimated as area-under-the-curve (AUC) of circulating plasma HIV-1 RNA levels, was significantly associated with PBMC HIV-1 DNA at one year (r = 0.51, p = 0.004). In 21 children with sustained virologic suppression after 1 year of cART, PBMC HIV-1 DNA levels continued to decline between years 1 and 4 (slope -0.21 log10 DNA copies per million PBMC per year); decline slopes did not differ significantly between ET and LT. PBMC HIV-1 DNA levels at 1 year and 4 years of cART correlated with age at cART initiation (1 year: p = 0.04; 4 years: p = 0.03) and age at virologic control (1 and 4 years, p = 0.02). Altogether, these data indicate that reducing exposure to HIV-1 replication and younger age at cART initiation are associated with lower HIV-1 DNA levels at and after one year of age, supporting the concept that HIV-1 diagnosis and cART initiation in infants should occur as early as possible.

Association between Responsible Pet Ownership and Glycemic Control in Youths with Type 1 Diabetes

Wed, 12/07/2016 - 3:41pm

Type 1 diabetes mellitus (T1DM) a chronic characterized by an absolute insulin deficiency requires conscientious patient self-management to maintain glucose control within a normal range. Family cohesion and adaptability, positive coping strategies, social support and adequate self-regulatory behavior are found to favorably influence glycemic control. Our hypothesis was that the responsible care of a companion animal is associated with these positive attributes and correlated with the successful management of a chronic illness such as type 1 diabetes. We recruited 223 youths between 9 and 19 years of age from the Pediatric Diabetes clinic at the University of Massachusetts Medical School, reviewed the status of their glycemic control (using three consecutive A1c values) and asked them questions about the presence of a pet at home, and their level of involvement with its care. Multivariate analyses show that children who care actively for one or more pets at home are 2.5 times more likely to have control over their glycemic levels than children who do not care for a pet, adjusting for duration of disease, socio-economic status, age and self-management [1.1 to 5.8], pWald = 0.032. A separate model involving the care of a pet dog only yielded comparable results (ORa = 2.6 [1.1 to 5.9], pWald = 0.023).

Discordant Expression of Circulating microRNA from Cellular and Extracellular Sources

Wed, 12/07/2016 - 3:41pm

MicroRNA (miRNA) expression has rapidly grown into one of the largest fields for disease characterization and development of clinical biomarkers. Consensus is lacking in regards to the optimal sample source or if different circulating sources are concordant. Here, using miRNA measurements from contemporaneously obtained whole blood- and plasma-derived RNA from 2391 individuals, we demonstrate that plasma and blood miRNA levels are divergent and may reflect different biological processes and disease associations.

Utilizing a TLR5-Adjuvanted Cytomegalovirus as a Lentiviral Vaccine in the Nonhuman Primate Model for AIDS

Wed, 12/07/2016 - 3:41pm

Despite tremendous progress in our understanding of human immunodeficiency virus (HIV) natural history and advances in HIV treatment, there is neither an approved vaccine nor a cure for infection. Here, we describe the development and characterization of a novel replicating vaccine vector utilizing Cytomegalovirus (CMV) and a TLR5 adjuvant. After partial truncation of the central, immunodominant hypervariable domain, flagellin (fliC) from Salmonella was cloned downstream of a codon optimized gag gene from simian immunodeficiency virus (SIV) and transiently expressed in telomerized rhesus fibroblast (TeloRF) cells in culture. Lysates generated from these transfected cells induced the tumor necrosis factor alpha (TNF-alpha), in a mouse macrophage cell line, in a TLR5-dependent manner. The Gag/FliC expression construct was cloned into a bacterial artificial chromosome encoding the rhesus CMV (RhCMV) genome, and infectious RhCMV was generated following transfection of TeloRF cells. This virus stably expressed an SIV Gag/FliC fusion protein through four serial passages. Lysates generated from infected cells induced TNF-alpha in a TLR5-dependent manner. Western blot analysis of infected cell lysates verified expression of a Gag/FliC fusion protein using a SIV p27 capsid monoclonal antibody. Lastly, rhesus macaques inoculated with this novel RhCMV virus demonstrated increased inflammatory responses at the site of inoculation seven days post-infection when compared to the parental RhCMV. These results demonstrate that an artificially constructed replicating RhCMV expressing an SIV Gag/FliC fusion protein is capable of activating TLR5 in a macrophage cell line in vitro and induction of an altered inflammatory response in vivo. Ongoing animals studies are aimed at determining vaccine efficacy, including subsequent challenge with pathogenic SIV.

Prevalence, Predictors, and Same Day Treatment of Positive VIA Enhanced by Digital Cervicography and Histopathology Results in a Cervical Cancer Prevention Program in Cameroon

Wed, 12/07/2016 - 3:40pm

BACKGROUND: In 2007, the Cameroon Baptist Convention Health Services (CBCHS) implemented a screen-and-treat cervical cancer prevention program using visual inspection with acetic acid enhanced by digital cervicography (VIA-DC).

METHODS: We retrospectively analyzed 46,048 medical records of women who received care through the CBCHS Women's Health Program from 2007 through 2014 to determine the prevalence and predictors of positive VIA-DC, rates of same day treatment, and cohort prevalence of invasive cervical cancer (ICC).

RESULTS: Of the 44,979 women who were screened for cervical cancer, 9.0% were VIA-DC-positive, 66.8% were VIA-DC-negative, 22.0% were VIA-DC-inadequate (normal ectocervix, but portions of the transformation zone were obscured), and 2.2% were VIA-DC-uncertain (cervical abnormalities confounding VIA-DC interpretation). Risk factors significantly associated with VIA-DC-positive screen were HIV-positivity, young age at sexual debut, higher lifetime number of sexual partners, low education status and higher gravidity. In 2014, 31.1% of women eligible for cryotherapy underwent same day treatment. Among the 32,788 women screened from 2007 through 2013, 201 cases of ICC were identified corresponding to a cohort prevalence of 613 per 100,000.

CONCLUSIONS: High rate of VIA-DC-positive screens suggests a significant burden of potential cervical cancer cases and highlights the need for expansion of cervical cancer screening and prevention throughout the 10 regions of Cameroon. VIA-DC-inadequate rates were also high, especially in older women, and additional screening methods are needed to confirm whether these results are truly negative. In comparison to similar screening programs in sub-Saharan Africa there was low utilization of same day cryotherapy treatment. Further studies are required to characterize possible program specific barriers to treatment, for example cultural demands, health system challenges and cost of procedure. The prevalence of ICC among women who presented for screening was high and requires further investigation.

Recombinant AAV Vectors for Enhanced Expression of Authentic IgG

Wed, 12/07/2016 - 3:40pm

Adeno-associated virus (AAV) has become a vector of choice for the treatment of a variety of genetic diseases that require safe and long-term delivery of a missing protein. Muscle-directed gene transfer for delivery of protective antibodies against AIDS viruses and other pathogens has been used experimentally in mice and monkeys. Here we examined a number of variations to AAV vector design for the ability to produce authentic immunoglobulin G (IgG) molecules. Expression of rhesus IgG from a single single-stranded AAV (ssAAV) vector (one vector approach) was compared to expression from two self-complementary AAV (scAAV) vectors, one for heavy chain and one for light chain (two vector approach). Both the one vector and the two vector approaches yielded considerable levels of expressed full-length IgG. A number of modifications to the ssAAV expression system were then examined for their ability to increase the efficiency of IgG expression. Inclusion of a furin cleavage sequence with a linker peptide just upstream of the 2A self-cleaving sequence from foot-and-mouth disease virus (F2A) increased IgG expression approximately 2 fold. Inclusion of these sequences also helped to ensure a proper sequence at the C-terminal end of the heavy chain. Inclusion of the post-transcriptional regulatory element from woodchuck hepatitis virus (WPRE) further increased IgG expression 1.5-2.0 fold. IgG1 versions of the two rhesus IgGs that were examined consistently expressed better than the IgG2 forms. In contrast to what has been reported for AAV2-mediated expression of other proteins, introduction of capsid mutations Y445F and Y731F did not increase ssAAV1-mediated expression of IgG as determined by transduction experiments in cell culture. Our findings provide a rational basis for AAV vector design for expression of authentic IgG.

Newer Oral Anticoagulants: Stroke Prevention and Pitfalls

Wed, 12/07/2016 - 3:39pm

Warfarin is very effective in preventing stroke in patients with atrial fibrillation. However, its use is limited due to fear of hemorrhagic complications, unpredictable anticoagulant effects related to multiple drug interactions and dietary restrictions, a narrow therapeutic window, frequent difficulty maintaining the anticoagulant effect within a narrow therapeutic window, and the need for inconvenient monitoring. Several newer oral anticoagulants have been approved for primary and secondary prevention of stroke in patients with non-valvular atrial fibrillation. These agents have several advantages relative to warfarin therapy. As a group, these direct oral anticoagulants (DOAC), which include the direct thrombin inhibitor, dabigatran, and the factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban), are more effective than dose adjusted warfarin for prevention of all-cause stroke (including both ischemic and hemorrhagic stroke), and have an overall more favorable safety profile. Nevertheless, an increased risk of gastrointestinal bleeding (with the exception of apixaban), increased risk for thrombotic complication with sudden discontinuation, and inability to accurately assess and reverse anticoagulant effect require consideration prior to therapy initiation, and pose a challenge for decision making in acute stroke therapy.

Impact of a family medicine resident wellness curriculum: a feasibility study

Wed, 12/07/2016 - 3:39pm

BACKGROUND: Up to 60% of practicing physicians report symptoms of burnout, which often peak during residency. Residency is also a relevant time for habits of self-care and resiliency to be emphasized. A growing literature underscores the importance of this; however, evidence about effective burnout prevention curriculum during residency remains limited.

OBJECTIVES: The purpose of this project is to evaluate the impact of a new, 1-month wellness curriculum for 12 second-year family medicine residents on burnout, empathy, stress, and self-compassion.

METHODS: The pilot program, introduced during a new rotation emphasizing competencies around leadership, focused on teaching skills to cultivate mindfulness and self-compassion in order to enhance empathy and reduce stress. Pre-assessments and 3-month follow-up assessments on measures of burnout, empathy, self-compassion, and perceived stress were collected to evaluate the impact of the curriculum. It was hypothesized that this curriculum would enhance empathy and self-compassion as well as reduce stress and burnout among family medicine residents.

RESULTS: Descriptive statistics revealed positive trends on the mean scores of all the measures, particularly the Mindfulness Scale of the Self-Compassion Inventory and the Jefferson Empathy Scale. However, the small sample size and lack of sufficient power to detect meaningful differences limited the use of inferential statistics.

CONCLUSIONS: This feasibility study demonstrates how a residency wellness curriculum can be developed, implemented, and evaluated with promising results, including high participant satisfaction.

The Effect of Parathion on Red Blood Cell Acetylcholinesterase in the Wistar Rat

Wed, 12/07/2016 - 3:38pm

Organophosphorus (OP) pesticide poisoning is a significant problem worldwide. Research into new antidotes for these acetylcholinesterase inhibitors, and even optimal doses for current therapies, is hindered by a lack of standardized animal models. In this study, we sought to characterize the effects of the OP pesticide parathion on acetylcholinesterase in a Wistar rat model that included comprehensive medical care. Methods. Male Wistar rats were intubated and mechanically ventilated and then poisoned with between 20 mg/kg and 60 mg/kg of intravenous parathion. Upon developing signs of poisoning, the rats were treated with standard critical care, including atropine, pralidoxime chloride, and midazolam, for up to 48 hours. Acetylcholinesterase activity was determined serially for up to 8 days after poisoning. Results. At all doses of parathion, maximal depression of acetylcholinesterase occurred at 3 hours after poisoning. Acetylcholinesterase recovered to nearly 50% of baseline activity by day 4 in the 20 mg/kg cohort and by day 5 in the 40 and 60 mg/kg cohorts. At day 8, most rats' acetylcholinesterase had recovered to roughly 70% of baseline. These data should be useful in developing rodent models of acute OP pesticide poisoning.