Publications by authors named "Karen Regan"

30 Publications

  • Page 1 of 1

Medical Students and Patients Benefit from Virtual Non-Medical Interactions Due to COVID-19.

J Med Educ Curric Dev 2021 Jan-Dec;8:23821205211028343. Epub 2021 Jul 21.

Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.

Background: Patient care restrictions created by the COVID-19 pandemic constrained medical students' ability to interact directly with patients. Additionally, organ transplant recipients faced increasing isolation due to the rise of telemedicine, the importance of social distancing and their immunosuppressed state. We created a pilot program to pair students with transplant patients for structured, virtual encounters and studied its impact on medical students and patients.

Methods: In May 2020, medical students conducted virtual visits with patients via telephone or video conferencing. Patients and students were surveyed regarding their experiences and independent focus groups were conducted. The survey responses and focus group discussions were deidentified, transcribed, and analyzed for themes.

Results: Ten participating students were in their first, second, or final year of medical school. The 14 patients were liver or kidney transplant recipients or kidney donors. All interactions lasted longer than 30 minutes, with 56% greater than 1 hour. Three themes emerged related to the student experience: improvement of their clinical communication skills, development of knowledge and attitudes related to organ transplantation and donation, and independent management of a patient encounter. Three themes related to the patient experience: appreciation of the opportunity to share their personal patient experience to help educate future physicians, a cathartic and personally illuminating experience and an opportunity to share the message of donation.

Conclusions: This pilot program provided a novel opportunity for virtual student-patient interactions that was feasible, well-received, and mutually beneficial. The use of virtual non-medical patient experiences allowed for experiential learning during which students learned about both clinical medicine and enhanced their communication skills directly from patients. Additionally, patients were able to engage with medical students in a new way, as teachers of clinical interactions, and reported a high level of satisfaction in addition to deriving personal benefit.
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http://dx.doi.org/10.1177/23821205211028343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299878PMC
July 2021

Scientific and Regulatory Policy Committee Best Practices: Documentation of Sexual Maturity by Microscopic Evaluation in Nonclinical Safety Studies.

Toxicol Pathol 2021 07 4;49(5):977-989. Epub 2021 Mar 4.

510456Idorsia Pharmaceuticals Limited, Allschwil, Switzerland.

The sexual maturity status of animals in nonclinical safety studies can have a significant impact on the microscopic assessment of the reproductive system, the interpretation of potential test article-related findings, and ultimately the assessment of potential risk to humans. However, the assessment and documentation of sexual maturity for animals in nonclinical safety studies is not conducted in a consistent manner across the pharmaceutical and chemical industries. The Scientific and Regulatory Policy Committee of the Society of Toxicologic Pathology convened an international working group of pathologists and nonclinical safety scientists with expertise in the reproductive system, pathology nomenclature, and Standard for Exchange of Nonclinical Data requirements. This article describes the best practices for documentation of the light microscopic assessment of sexual maturity in males and females for both rodent and nonrodent nonclinical safety studies. In addition, a review of the microscopic features of the immature, peripubertal, and mature male and female reproductive system and general considerations for study types and reporting are provided to aid the study pathologist tasked with documentation of sexual maturity.
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http://dx.doi.org/10.1177/0192623321990631DOI Listing
July 2021

Opinion on Current Use of Non-Blinded Versus Blinded Histopathologic Evaluation in Animal Toxicity Studies.

Toxicol Pathol 2020 06 29;48(4):549-559. Epub 2020 Apr 29.

Takeda Pharmaceuticals International Co., Cambridge, MA, USA.

The Society of Toxicologic Pathology (STP) explored current institutional practices for selecting between non-blinded versus blinded histopathologic evaluation during Good Laboratory Practice (GLP)-compliant, regulatory-type animal toxicity studies using a multi-question survey and STP-wide discussion (held at the 2019 STP annual meeting). Survey responses were received from 107 individuals representing 83 institutions that collectively employ 589 toxicologic pathologists. Most responses came from industry (N = 46, mainly biopharmaceutical or contract research organizations) and consultants (N = 24). For GLP-compliant animal toxicity studies, histopathologic evaluation usually involves initial (primary) non-blinded analysis, with post hoc informal blinded re-examination at the study pathologist's discretion to confirm subtle findings or establish thresholds. Initial blinded histopathologic evaluation sometimes is chosen by study pathologists to test formal hypotheses and/or by sponsors to address non-pathologist expectations about histopathology data objectivity. Current practice is that a blinded histopathologic evaluation is documented only if formal blinding (ie, using slides with coded labels) is employed, using simple statements without detailed methodology in the study protocol (or an amendment) and/or pathology report. Blinding is not an appropriate strategy for the initial histopathologic evaluation performed during pathology peer reviews of GLP-compliant animal toxicity studies. [Box: see text].
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http://dx.doi.org/10.1177/0192623320920590DOI Listing
June 2020

Diet and Physical Activity Prevention Research Supported by the U.S. NIH From 2012-2017.

Am J Prev Med 2019 12;57(6):818-825

Office of Disease Prevention, NIH, Rockville, Maryland.

Introduction: Poor diet and inadequate physical activity are common contributors to preventable death in the U.S. This paper provides a summary of the NIH-sponsored research on disease prevention that underlies public health and clinical recommendations to improve diet and physical activity.

Methods: A representative sample (n=11,082) of research grants and cooperative agreements (research projects) representing the NIH prevention research portfolio between 2012 and 2017 were hand coded by trained analysts in 2017-2018. This manuscript describes the rationale(s), exposure(s), outcome(s), population(s), and study design(s) in prevention research focused on diet and physical activity and compares this research to identified research gaps in the field.

Results: A relatively stable 7.8% (95% CI=7.0%, 8.8%) and 5.0% (95% CI=4.4%, 5.7%) of the NIH prevention research projects were focused on diet and physical activity, respectively, during 2012-2017. These projects often explored diet and physical activity together in the context of obesity, included observational studies, and focused on a general adult population. Few of these projects focused on development of improved assessment methods. Approximately 50% of these studies were related to research gaps identified by the 2015 Dietary or 2018 Physical Activity Guidelines Advisory Committee Scientific Reports.

Conclusions: Opportunities exist for more engagement by NIH and scientific investigators in diet- and physical activity-focused prevention research, particularly around assessment and known research gaps.
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http://dx.doi.org/10.1016/j.amepre.2019.07.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894494PMC
December 2019

Ovarian Toxicity Assessment in Histopathological Images Using Deep Learning.

Toxicol Pathol 2020 02 8;48(2):350-361. Epub 2019 Oct 8.

Department of Safety Assessment, Genentech, South San Francisco, CA, USA.

As ovarian toxicity is often a safety concern for cancer therapeutics, identification of ovarian pathology is important in early stages of preclinical drug development, particularly when the intended patient population include women of child-bearing potential. Microscopic evaluation by pathologists of hematoxylin and eosin (H&E)-stained tissues is the current gold standard for the assessment of organs in toxicity studies. However, digital pathology and advanced image analysis are being explored with greater frequency and broader applicability to tissue evaluations in toxicologic pathology. Our objective in this work was to develop an automated method that rapidly enumerates rat ovarian corpora lutea on standard H&E-stained slides with comparable accuracy to the gold standard assessment by a pathologist. Herein, we describe an algorithm generated by a deep learning network and tested on 5 rat toxicity studies, which included studies that both had and had not previously been diagnosed with effects on number of ovarian corpora lutea. Our algorithm could not only enumerate corpora lutea accurately in all studies but also revealed distinct trends for studies with and without reproductive toxicity. Our method could be a widely applied tool to aid analysis in general toxicity studies.
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http://dx.doi.org/10.1177/0192623319877871DOI Listing
February 2020

A report of activities related to the Dietary Reference Intakes from the Joint Canada-US Dietary Reference Intakes Working Group.

Am J Clin Nutr 2019 02;109(2):251-259

Office of Nutrition and Food Labeling, Center for Food Safety and Applied Nutrition, US Food and Drug Administration, College Park, MD.

The governments of the United States and Canada have jointly undertaken the development of the Dietary Reference Intakes (DRIs) since the mid-1990s. The Federal DRI committees from each country work collaboratively to identify DRI needs, prioritize nutrient reviews, advance work to resolve methodological issues that is necessary for new reviews, and sponsor DRI-related committees through the National Academies of Sciences, Engineering and Medicine. In recent years, the Joint Canada-US DRI Working Group, consisting of members from both Federal DRI committees, developed an open and transparent nomination process for prioritizing nutrients for DRI review, by which sodium, the omega-3 (n-3) fatty acids, vitamin E, and magnesium were identified. In addition, discussions during the nutrient nomination process prompted the Federal DRI committees to address previously identified issues related to the use of chronic disease endpoints when setting DRIs. The development of guiding principles for setting DRIs based on chronic disease risk reduction will be applied for the first time during the DRI review of sodium and potassium. In summary, the US and Canadian governments have worked collaboratively to adapt our approach to prioritizing nutrients for DRI review and to broaden the scope of the DRIs to better incorporate the concept of chronic disease risk reduction in order to improve public health.
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http://dx.doi.org/10.1093/ajcn/nqy293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500900PMC
February 2019

A small molecule inhibitor of mutant IDH2 rescues cardiomyopathy in a D-2-hydroxyglutaric aciduria type II mouse model.

J Inherit Metab Dis 2016 11 28;39(6):807-820. Epub 2016 Jul 28.

Agios Pharmaceuticals Inc., 88 Sidney Street, Cambridge, MA, 02139-4169, USA.

D-2-hydroxyglutaric aciduria (D2HGA) type II is a rare neurometabolic disorder caused by germline gain-of-function mutations in isocitrate dehydrogenase 2 (IDH2), resulting in accumulation of D-2-hydroxyglutarate (D2HG). Patients exhibit a wide spectrum of symptoms including cardiomyopathy, epilepsy, developmental delay and limited life span. Currently, there are no effective therapeutic interventions. We generated a D2HGA type II mouse model by introducing the Idh2R140Q mutation at the native chromosomal locus. Idh2R140Q mice displayed significantly elevated 2HG levels and recapitulated multiple defects seen in patients. AGI-026, a potent, selective inhibitor of the human IDH2R140Q-mutant enzyme, suppressed 2HG production, rescued cardiomyopathy, and provided a survival benefit in Idh2R140Q mice; treatment withdrawal resulted in deterioration of cardiac function. We observed differential expression of multiple genes and metabolites that are associated with cardiomyopathy, which were largely reversed by AGI-026. These findings demonstrate the potential therapeutic benefit of an IDH2R140Q inhibitor in patients with D2HGA type II.
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http://dx.doi.org/10.1007/s10545-016-9960-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5065612PMC
November 2016

Scientific and Regulatory Policy Committee Points to Consider Review: Inclusion of Reproductive and Pathology End Points for Assessment of Reproductive and Developmental Toxicity in Pharmaceutical Drug Development.

Toxicol Pathol 2016 08 27;44(6):789-809. Epub 2016 May 27.

Pfizer, Cambridge, Massachusetts, USA.

Standard components of nonclinical toxicity testing for novel pharmaceuticals include clinical and anatomic pathology, as well as separate evaluation of effects on reproduction and development to inform clinical development and labeling. General study designs in regulatory guidances do not specifically mandate use of pathology or reproductive end points across all study types; thus, inclusion and use of these end points are variable. The Scientific and Regulatory Policy Committee of the Society of Toxicologic Pathology (STP) formed a Working Group to assess the current guidelines and practices on the use of reproductive, anatomic pathology, and clinical pathology end points in general, reproductive, and developmental toxicology studies. The Working Group constructed a survey sent to pathologists and reproductive toxicologists, and responses from participating organizations were collected through the STP for evaluation by the Working Group. The regulatory context, relevant survey results, and collective experience of the Working Group are discussed and provide the basis of each assessment by study type. Overall, the current practice of including specific end points on a case-by-case basis is considered appropriate. Points to consider are summarized for inclusion of reproductive end points in general toxicity studies and for the informed use of pathology end points in reproductive and developmental toxicity studies.
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http://dx.doi.org/10.1177/0192623316650052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979743PMC
August 2016

The eXtraordinarY Kids Clinic: an interdisciplinary model of care for children and adolescents with sex chromosome aneuploidy.

J Multidiscip Healthc 2015 17;8:323-34. Epub 2015 Jul 17.

Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA ; Child Development Unit, Children's Hospital Colorado, Aurora, CO, USA.

Purpose: Individuals with sex chromosome aneuploidies (SCAs) are born with an atypical number of X and/or Y chromosomes, and present with a range of medical, developmental, educational, behavioral, and psychological concerns. Rates of SCA diagnoses in infants and children are increasing, and there is a need for specialized interdisciplinary care to address associated risks. The eXtraordinarY Kids Clinic was established to provide comprehensive and experienced care for children and adolescents with SCA, with an interdisciplinary team composed of developmental-behavioral pediatrics, endocrinology, genetic counseling, child psychology, pediatric neuropsychology, speech-language pathology, occupational therapy, nursing, and social work. The clinic model includes an interdisciplinary approach to care, where assessment results by each discipline are integrated to develop unified diagnostic impressions and treatment plans individualized for each patient. Additional objectives of the eXtraordinarY Kids Clinic program include prenatal genetic counseling, research, education, family support, and advocacy.

Methods: Satisfaction surveys were distributed to 496 patients, and responses were received from 168 unique patients.

Results: Satisfaction with the overall clinic visit was ranked as "very satisfied" in 85%, and as "satisfied" in another 9.8%. Results further demonstrate specific benefits from the clinic experience, the importance of a knowledgeable clinic coordinator, and support the need for similar clinics across the country. Three case examples of the interdisciplinary approach to assessment and treatment are included.
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http://dx.doi.org/10.2147/JMDH.S80242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4514383PMC
August 2015

Scientific and Regulatory Policy Committee (SRPC) Points to Consider: Histopathology Evaluation of the Pubertal Development and Thyroid Function Assay (OPPTS 890.1450, OPPTS 890.1500) in Rats to Screen for Endocrine Disruptors.

Toxicol Pathol 2015 Dec 6;43(8):1047-63. Epub 2015 May 6.

The Dow Chemical Company, Midland, Michigan, USA Department of Comparative Medicine, University of Washington, Seattle, Washington, USA.

The U.S. Environmental Protection Agency Endocrine Disruptor Screening Program (EDSP) is a multitiered approach to determine the potential for environmental chemicals to alter the endocrine system. The Pubertal Development and Thyroid Function in Intact Juvenile/Peripubertal Female and Male Rats (OPPTS 890.1450, 890.1500) are 2 of the 9 EDSP tier 1 test Guidelines, which assess upstream mechanistic pathways along with downstream morphological end points including histological evaluation of the kidneys, thyroid, and select male/female reproductive tissues (ovaries, uterus, testes, and epididymides). These assays are part of a battery of in vivo and in vitro screens used for initial detection of test article endocrine activity. In this Points to Consider article, we describe tissue processing, evaluation, and nomenclature to aid in standardization of assay results across laboratories. Pubertal assay end points addressed include organ weights, estrous cyclicity, clinical pathology, hormonal assays, and histological evaluation. Potential treatment-related findings that may indicate endocrine disruption are reviewed. Additional tissues that may be useful in assessment of endocrine disruption (vagina, mammary glands, and liver) are discussed. This Points to Consider article is intended to provide information for evaluating peripubertal tissues within the context of individual assay end points, the overall pubertal assay, and tier I assays of the EDSP program.
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http://dx.doi.org/10.1177/0192623315579943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636471PMC
December 2015

Nonproliferative and proliferative lesions of the rat and mouse female reproductive system.

J Toxicol Pathol 2014 ;27(3-4 Suppl):1S-107S

National Institute of Health Sciences, Tokyo, Japan.

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) Project (www.toxpath.org/inhand.asp) is a joint initiative of the Societies of Toxicological Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in the female reproductive tract of laboratory rats and mice, with color photomicrographs illustrating examples of some lesions. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous and aging lesions as well as lesions induced by exposure to test materials. There is also a section on normal cyclical changes observed in the ovary, uterus, cervix and vagina to compare normal physiological changes with pathological lesions. A widely accepted and utilized international harmonization of nomenclature for female reproductive tract lesions in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists.
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http://dx.doi.org/10.1293/tox.27.1SDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253081PMC
December 2014

Dietary supplement research portfolio at the NIH, 2009-2011.

J Nutr 2014 Apr 12;144(4):414-8. Epub 2014 Feb 12.

Office of Dietary Supplements and.

The U.S. dietary supplement market increased by 7.5% in 2012 compared with 2011, reaching $32.5 billion in sales. Therefore, federally supported research on dietary supplements is important to determine their health effects, safety, and efficacy. A portfolio analysis was performed across the NIH and the Office of Dietary Supplements (ODS) for fiscal years (FYs) 2009-2011 by using the databases Human Nutrition Research Information Management (HNRIM) and Computer Access to Research on Dietary Supplements (CARDS). The results indicated that total NIH dietary supplement-related funding for FYs 2009-2011 was $855 million ($295 million in 2009, $311 million in 2010, and $249 million in 2011). The institutes and centers with the highest investment in dietary supplement research were as follows: the National Heart, Lung, and Blood Institute ($135 million); the National Cancer Institute ($188 million); the National Center for Complementary and Alternative Medicine ($99 million); the National Institute of Diabetes and Digestive and Kidney Diseases ($68 million); the National Institute of Environmental Health Sciences ($58 million); and the ODS ($32 million). The dietary supplement ingredients receiving the most funding were botanicals (22%), vitamins (20%), lipids (14%), and minerals and trace elements (10%). The top 3 outcome research areas were cancer (61% of total dietary supplement investment), cardiovascular disease (47%), and women's reproductive health (38%). In FYs 2009, 2010, and 2011, the ODS provided 3.5%, 3.6%, and 4.1%, respectively, of the NIH investment in dietary supplement research. ODS funding focused on cellular, enzymatic, or molecular mechanisms (64% of total ODS funding). This portfolio analysis demonstrates that the NIH has committed substantial funding to dietary supplement research in an effort to expand the scientific knowledge base on the efficacy and safety of dietary supplements.
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http://dx.doi.org/10.3945/jn.113.189803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3952619PMC
April 2014

Expanding research to provide an evidence base for nutritional interventions for the management of inborn errors of metabolism.

Mol Genet Metab 2013 Aug 23;109(4):319-28. Epub 2013 May 23.

Office of Dietary Supplements, National Institutes of Health, Bethesda, MD 20892, USA.

A trans-National Institutes of Health initiative, Nutrition and Dietary Supplement Interventions for Inborn Errors of Metabolism (NDSI-IEM), was launched in 2010 to identify gaps in knowledge regarding the safety and utility of nutritional interventions for the management of inborn errors of metabolism (IEM) that need to be filled with evidence-based research. IEM include inherited biochemical disorders in which specific enzyme defects interfere with the normal metabolism of exogenous (dietary) or endogenous protein, carbohydrate, or fat. For some of these IEM, effective management depends primarily on nutritional interventions. Further research is needed to demonstrate the impact of nutritional interventions on individual health outcomes and on the psychosocial issues identified by patients and their families. A series of meetings and discussions were convened to explore the current United States' funding and regulatory infrastructure and the challenges to the conduct of research for nutritional interventions for the management of IEM. Although the research and regulatory infrastructure are well-established, a collaborative pathway that includes the professional and advocacy rare disease community and federal regulatory and research agencies will be needed to overcome current barriers.
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http://dx.doi.org/10.1016/j.ymgme.2013.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4131198PMC
August 2013

Proliferative and nonproliferative lesions of the rat and mouse male reproductive system.

Toxicol Pathol 2012 Aug;40(6 Suppl):40S-121S

Huntingdon Life Sciences, East Millstone, New Jersey 08875, USA.

The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature and differential diagnosis for classifying microscopic lesions observed in the male reproductive system of laboratory rats and mice, with color microphotographs illustrating examples of some lesions. The standardized nomenclature presented in this document is also available for society members electronically on the Internet (http://goreni.org). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous and aging lesions as well as lesions induced by exposure to test materials. A widely accepted and utilized international harmonization of nomenclature for lesions of the male reproductive system in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists.
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http://dx.doi.org/10.1177/0192623312454337DOI Listing
August 2012

Renal histopathology in toxicity and carcinogenicity studies with tert-butyl alcohol administered in drinking water to F344 rats: a pathology working group review and re-evaluation.

Regul Toxicol Pharmacol 2011 Apr 5;59(3):430-6. Epub 2011 Feb 5.

An independent Pathology Working Group (PWG) re-evaluated the kidney changes in National Toxicology Program (NTP) toxicology/carcinogenicity studies of tert-butyl alcohol (TBA) in F344/N rats to determine possible mode(s) of action underlying renal tubule tumors in male rats at 2-years. In the 13-week study, the PWG confirmed that the normal pattern of round hyaline droplets in proximal convoluted tubules was replaced by angular droplet accumulation, and identified precursors of granular casts in the outer medulla, changes typical of alpha(2u)-globulin (α(2u)-g) nephropathy. In the 2-year study, the PWG confirmed the NTP observation of increased renal tubule tumors in treated male groups. Linear papillary mineralization, another hallmark of the α(2u)-g pathway was present only in treated male rats. Chronic progressive nephropathy (CPN) was exacerbated in high-dose males and females, with a relationship between advanced grades of CPN and renal tumor occurrence. Hyperplasia of the papilla lining was a component of CPN in both sexes, but there was no pelvic urothelial hyperplasia. High-dose females showed no TBA-related nephrotoxicity. The PWG concluded that both α(2u)-g nephropathy and exacerbated CPN modes of action were operative in TBA renal tumorigenicity in male rats, neither of which has relevance for human cancer risk.
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http://dx.doi.org/10.1016/j.yrtph.2011.01.007DOI Listing
April 2011

NIH and USDA funding of dietary supplement research, 1999-2007.

J Nutr 2011 Jan 24;141(1):1-3. Epub 2010 Nov 24.

Division of Nutrition Research Coordination, National Institutes of Health, Bethesda, MD 20892, USA.

Over one-half of U.S. adults use dietary supplements, so federally supported research into the safety and effectiveness of these compounds is important for the health of many Americans. Data collected in the Computer Access to Research on Dietary Supplements database, which compiles federally sponsored dietary supplement-related research, are useful to scientists in determining the type of dietary supplement research that federal agencies are currently funding and where research gaps exist. This article describes the dietary supplement-related research funded by the NIH and the USDA. Between fiscal years 1999 and 2007, the number of research projects and funding for dietary supplement research more than doubled. During that period, NIH funded 6748 dietary supplement-related projects at a cost of $1.9 billion and the USDA funded 2258 projects at a cost of $347 million. The top funded dietary supplement ingredient categories were vitamins and minerals, botanicals, phytochemicals, and fatty acids. Cancer was by far the most frequent health outcome in dietary supplement research funding, nearly double the next closest health outcome category. Other health outcomes with the greatest funding were cellular and molecular mechanisms, cardiovascular health, women's reproductive health, and immune function. The greatest number of dietary supplement research projects are funded by the NIH National Cancer Institute, the NIH National Center for Complementary and Alternative Medicine, the NIH Office of Dietary Supplements, and the USDA Agricultural Research Service.
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http://dx.doi.org/10.3945/jn.110.134106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001234PMC
January 2011

Histopathologic changes in the kidneys of male F344 rats from a 2-year inhalation carcinogenicity study of tetrahydrofuran: a pathology working group review and re-evaluation.

Regul Toxicol Pharmacol 2010 Oct 4;58(1):100-5. Epub 2010 May 4.

Biotechnics Inc, 401 Augusta Rd, Clemson, SC 29631, USA.

Risk evaluation and hazard classification for tetrahydrofuran (THF) is based partly on the incidences of renal tumors in male F344/N rats reported in a 2-year carcinogenicity study by the National Toxicology Program (NTP). A Pathology Working Group (PWG) was commissioned to conduct an independent review of the kidney slides from this bioassay (along with two subchronic studies) to assess renal changes in light of recent scientific work on pathogenesis of pre-neoplastic and neoplastic lesions in rat kidney. PWG pathologists confirmed the NTP assessment that adenomas were non-statistically increased in animals exposed to the highest level of THF. However, when pre-neoplastic and neoplastic lesions were combined, there was no difference between control and THF-exposed groups. Also, the majority of these proliferative lesions were in rats with severe chronic progressive nephropathy (CPN). Accordingly, the PWG concluded that renal lesions in the control and THF-exposed groups resulted primarily from regenerative processes associated with advanced CPN. Based on an alpha(2u)-globulin/hyaline droplet response observed in a 4-week study with THF, the PWG could not exclude the possibility of both advanced CPN and low-grade alpha2u-g nephropathy contributing to the renal proliferative lesions developing chronically in high-dose males. Neither condition has a pathologic counterpart in humans.
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http://dx.doi.org/10.1016/j.yrtph.2010.04.009DOI Listing
October 2010

Depression treatment with selective serotonin reuptake inhibitors for the postacute coronary syndrome population: a literature review.

Authors:
Karen L Regan

J Cardiovasc Nurs 2008 Nov-Dec;23(6):489-96

University of Pennsylvania School of Nursing, Philadelphia, USA.

Objective: After acute coronary syndrome (ACS), patients have a significantly higher incidence of depression compared to the average healthy adult. Depression is independently associated with poorer outcomes and heightens the morbidity and mortality risk in this susceptible population. Selective serotonin reuptake inhibitors (SSRIs) are a newer class of antidepressants recently investigated for use in this population. This article reviews the current research on the safety, efficacy, possible benefits, and limitations of this class of antidepressants for patients with post-ACS.

Data Sources: Information was obtained through a literature search of the electronic databases CINAHL, EMBASE, Ovid Medline (R), and PubMed Plus during the months of January and February of 2007. Keywords searched included acute coronary syndrome, myocardial infarction, selective serotonin reuptake inhibitors, sertraline, paroxetine, fluoxetine, depressive disorder, major depression, and depression. Results were then limited to the English language, adult population, publication years 2002-2007, and primary research articles. The search was broadened to include years 2000-2002.

Study Selection: Abstracts were reviewed for applicability. All studies meeting the criteria for research articles of SSRI use in depressed patients with post-ACS were included. This amounted to 6 articles.

Data Extraction: Independent extraction was conducted by a single observer.

Conclusions: Recent research shows positive outcomes associated with the use of SSRIs for depressed patients with post-ACS. The greatest benefit from these medications appears to be in the recurrently and severely depressed subpopulations. Although the use of SSRIs in patients with post-ACS appears to be associated with a decrease in morbidity and mortality rates, large, randomized control trials are still needed to support this finding.
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http://dx.doi.org/10.1097/01.JCN.0000338929.89210.afDOI Listing
December 2008

28-Day oral (gavage) toxicity studies of green tea catechins prepared for beverages in rats.

Food Chem Toxicol 2008 Mar 30;46(3):978-89. Epub 2007 Oct 30.

WIL Research Laboratories LLC, Ashland, OH 44805-9281, USA.

The beneficial health effects associated with drinking green tea are widely considered to be due primarily to tea catechins. Heat treatment of marketed green tea beverages for sterilization causes epimerization and/or polymerization of tea catechins. Safety studies on heat-treated tea catechins are limited. The objective of the present study was to evaluate potential adverse effects, if any, of two standardized green tea catechin (GTC) preparations: one that underwent heat sterilization (GTC-H) and one that was not heat-sterilized (GTC-UH). A decaffeinated preparation of the GTC-H (GTC-HDC) was also evaluated to ascertain if any effects were due to caffeine. The GTC preparations were administered to rats once daily at levels up to 2000 mg/kg/day for 28 days. There were no deaths attributable to the GTC preparations. The clinical condition of the animals, functional observational battery, motor activity, clinical pathology evaluations, organ weights, and gross necropsy findings were unaffected by any of the GTC preparations. GTC-HDC or GTC-UH dosing had no effects on body weights or microscopic findings, whereas lower body weights and food consumption were observed in the 1000 and 2000 mg/kg/day GTC-H group males. The no observed-adverse-effect level (NOAEL) for localized gastric effects for GTC-H was 1000 mg/kg/day. No other target organs were identified. Thus, the NOAEL for systemic toxicity following oral administration was 2000 mg/kg/day for GTC-H, GTC HDC, and GTC-UH under the conditions of this study.
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http://dx.doi.org/10.1016/j.fct.2007.10.027DOI Listing
March 2008

Inhalation developmental neurotoxicity study of ethylbenzene in Crl-CD rats.

Birth Defects Res B Dev Reprod Toxicol 2007 Feb;80(1):34-48

WFTC, LLC, Victor, New York 15464, USA.

Background: This study was conducted to evaluate the potential adverse effects of whole-body inhalation exposure of F0 and F1 parental animals from a 2-generation reproduction study of ethylbenzene on nervous system functional and/or morphologic end points in the F2 offspring from four groups of male and female Crl:CD (SD)IGS BR rats.

Methods: Thirty rats/sex/group for F0 and 25/sex/group for F1 were exposed to 0, 25, 100, and 500 ppm ethylbenzene for six hours daily for at least 70 consecutive days prior to mating for the F0 and F1 generations. Inhalation exposure for the F0 and F1 females continued throughout mating and gestation through Gestation Day (GD) 20. On lactation days (LD) 1-4, the F0 and F1 females received no inhalation exposure, but instead were administered ethylbenzene in corn oil via oral gavage at dosages estimated to result in similar internal maternal exposure based upon PBPK modeling estimates (0, 26, 90, and 342 mg/kg/day, respectively, divided into three equal doses, approximately two hours apart). Inhalation exposure of the F0 and F1 females was reinitiated on LD 5 and continued through weaning on postnatal day (PND) 21. Survival, body weights, and physical landmarks were assessed in selected F2 offspring. Neurobehavioral development of one F2-generation treatment derived offspring/sex/litter was assessed in a functional observational battery (FOB; PND 4, 11, 22, 45, and 60), motor activity sessions (PND 13, 17, 21, and 61), acoustic startle testing (PND 20 and 60), a Biel water maze learning and memory task (initiated on PND 26 or 62), and in evaluations of whole-brain measurements and brain morphometric and histologic assessments (PND 21 and 72).

Results: There were no adverse effects on reproductive performance in either the F0 or F1 parental generations exposed to up to 500 ppm ethylbenzene [Faber et al. Birth Defects Res Part B 77:10-21, 2006]. In the current developmental neurotoxicity component, parental ethylbenzene exposure did not adversely affect offspring survival, clinical condition, body weight parameters, or acquisition of developmental landmarks of the F2-generation treatment derived offspring. There were no alterations in FOB parameters, motor activity counts, acoustic startle endpoints, or Biel water maze performance in offspring attributed to parental ethylbenzene exposure. A few isolated instances of statistically significant differences obtained in the treatment-derived groups occurred sporadically, and were attributed to unusual patterns of development and/or behavior in the concurrent control group. There were no exposure-related differences in any neuropathology parameters in the F2-generation treatment derived offspring.

Conclusions: The no observed adverse effect level (NOAEL) for maternal reproductive toxicity, developmental toxicity, and developmental neurotoxicity in this study was considered to be 500 ppm/342 mg/kg/day ethylbenzene, the highest exposure level tested in the study.
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http://dx.doi.org/10.1002/bdrb.20101DOI Listing
February 2007

Lactation decreases pancreatic lipase mRNA level in the rat.

Br J Nutr 2005 Dec;94(6):885-9

Department of Nutrition and Food Science, University of Maryland, College Park, MD 20742, USA.

Lactation alters maternal metabolism and increases food intake in rats to support milk production. Pancreatic lipase (PL) is primarily responsible for fat digestion in adults and is regulated by dietary fat. The present research determined the regulation of PL by lactation and dietary fat. In Expt 1, eighteen Sprague-Dawley dams and twelve age-matched virgins (controls) were fed a low-fat diet (LF; 11 % energy as safflower oil) for 7-63 d. At postpartum (day 0), peak lactation (day 15) and post-lactation (day 56) and after 7 d in virgins, the pancreas was removed for mRNA and enzyme analyses. In Expt 2, thirty-six Sprague-Dawley dams were fed LF until day 9 postpartum when dams were divided into three groups of twelve; one continued to be fed LF, one was fed a moderate-fat diet (MF; 40 % energy as safflower oil); and one was fed a high-fat diet (HF; 67 % energy as safflower oil) diet. At peak lactation (day 15) and post-lactation (day 56), the pancreas was removed for mRNA and enzyme analyses. Expt 1 revealed that lactation and post-lactation significantly (P<0.001) decreased PL mRNA (67 % and 76 %, respectively), but only post-lactation decreased PL activity. Increased dietary fat in Expt 2 significantly increased PL mRNA (LF
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http://dx.doi.org/10.1079/bjn20051566DOI Listing
December 2005

Computer access to research on dietary supplements: a database of federally funded dietary supplement research.

J Nutr 2005 Jul;135(7):1796-9

Office of Dietary Supplements, National Institutes of Health, Bethesda, MD 20892-7517, USA.

Dietary supplement use is prevalent in the United States, but support for supplement research has been relatively modest and only recently emphasized at the NIH. The Dietary Supplement Health and Education Act of 1994 led to the creation of the Office of Dietary Supplements (ODS) at the NIH to promote research on dietary supplements. In order to track federally funded dietary supplement research, the ODS developed a database known as Computer Access to Research on Dietary Supplements (CARDS). This article provides an overview of the development and potential uses of the CARDS database. In addition, we report that NIH-funded dietary supplement research steadily increased from fiscal year (FY) 1999 through 2002. The majority of NIH institutes or centers (ICs) funded research relevant to dietary supplements during this time, led by the National Cancer Institute and one of the newest NIH ICs, the National Center for Complementary and Alternative Medicine. CARDS data indicate that NIH-funded dietary supplement research from FY 1999 through 2002 involved primarily vitamins, minerals, botanicals and phytochemicals. Cancer and cardiovascular disease, two of the leading causes of morbidity and mortality in the United States, collectively accounted for almost 45% of the research related to dietary supplements. A variety of types of research studies were funded, with the majority consisting of human intervention studies. This information is useful to evaluate trends in federally funded dietary supplement research, identify research gaps, and help research scientists identify potential sources of NIH funding.
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http://dx.doi.org/10.1093/jn/135.7.1796DOI Listing
July 2005

Treating sudden cardiac arrest in a school setting.

School Nurse News 2004 Sep;21(4):32-6

New Bedford Public School System, New Bedford, Massachusetts, USA.

Sudden cardiac arrest occurs when the heart's electrical system fires very rapidly and in an uncoordinated manner, rendering the heart incapable of pumping blood through the circulatory system. The heart begins to tremble uncontrollably, like a quivering bowl of jelly. The victim becomes unconscious, stops breathing, and typically has no pulse or signs of circulation. Unless this condition is reversed, death follows in a matter of minutes. Defibrillation ("shocking a patient") is the only effective means of re-setting the heart's normal electrical impulses.
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September 2004

Pancreatic lipase and its related protein 2 are regulated by dietary polyunsaturated fat during the postnatal development of rats.

Pediatr Res 2004 Aug 4;56(2):256-62. Epub 2004 Jun 4.

The Institute for Applied Biosciences, Department of Biotechnology Engineering., Ben-Gurion University. P.O. Box 653, Beer-Sheva 84105, Israel.

The developmental gene expression of pancreatic lipase (PL) and its related proteins (PLRP1 and PLRP2) is anticoordinate. It is unknown whether dietary fat regulates the expression of these proteins in the preweanling stage. For determining the regulation of development and diet on PL, PLRP1, and PLRP2 as early as the suckling period, pregnant (Sprague-Dawley) rats consumed from day 15 (d15) of pregnancy through d9 of lactation a purified low (11% of energy) safflower oil diet [low-fat (LF)]. From d9 of lactation, dams and their respective pups were fed LF, medium-fat (MF; 40% of energy), or high-fat (HF; 67% of energy) safflower oil diets to d56. Milk fatty acid content had 15- to 100-fold less C:10 and 2.6- to 3.3-fold more C18:2 in MF and HF groups. Diet (LF < MF = HF; P < 0.002), postnatal development (d15 < d21 < d28 = d56; P < 0.001), and interaction of diet x development significantly affected PL activity starting as early as d15. PL mRNA levels showed a parallel effect of diet (LF < HF = MF; P < 0.013) and development (P < 0.001). Both PLRP1 and PLRP2 mRNA levels were significantly affected by development (P < 0.001) and had an anticoordinate pattern compared with PL expression (d15 > d21 > d28). Reported for the first time is the significant down-regulation of PLRP2 mRNA levels by high polyunsaturated fat in suckling (d15) rats. In conclusion, PL and PLRP2 gene expression is regulated anticoordinately by the amount of dietary polyunsaturated fat starting as early as the preweanling phase of development.
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http://dx.doi.org/10.1203/01.PDR.0000132754.42306.B9DOI Listing
August 2004

Circulating leptin levels in newborn rats: a significant post- natal developmental effect, independent of dietary polyunsaturated fat levels.

Life Sci 2003 Oct;73(21):2761-7

Department of Biotechnology Engineering, The Institute of Applied Biosciences, Ben-Gurion University. P.O. Box 653, Beer-Sheva 84105, Israel.

Leptin expression exhibits developmental and dietary regulation, but it is unknown whether there is an interaction of the regulation by dietary fat and postnatal development. The purpose of this study was to test the effect of different levels of dietary polyunsaturated fat on circulating leptin levels at different post-natal developmental stages. Pregnant (Sprague-Dawley) rats consumed from day 15 of pregnancy through day 9 of lactation a low fat, (11% of energy; LF) polyunsaturated safflower oil diet. From day 9 of lactation, dams and their respective pups were fed low, moderate (40% of energy; MF) or high (67% of energy; HF) polyunsaturated safflower oil diets to full maturation (56 days). Diets were iso-energetic and iso-nitrogenous. Milk fatty acid content reflected the mothers and pups diet, with 15 to 100 fold less C10:0 and 2.6 to 3.3 fold more C18:2 in MF and HF groups compared to LF diet. In newborn rats through post-natal day 56, levels of polyunsaturated fat in mothers' milk and mothers/pups diet had no effect on the levels of circulating leptin. The post-natal development period significantly affected circulating leptin levels (p < 0.001, 15 days = 56 days > 21 days > 28 days). In summary, the developmental postnatal stage regulates leptin levels, independently of the polyunsaturated fat levels in the diet.
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http://dx.doi.org/10.1016/s0024-3205(03)00672-6DOI Listing
October 2003

Recommended tissue list for histopathologic examination in repeat-dose toxicity and carcinogenicity studies: a proposal of the Society of Toxicologic Pathology (STP).

Toxicol Pathol 2003 Mar-Apr;31(2):252-3

Bristol-Myers Squibb Company, Syracuse, New York, USA.

The Executive Committee of the Society of Toxicologic Pathology (STP) appointed an ad hoc task force to devise and recommend a standard list of tissues to be evaluated histopathologically in repeat-dose toxicity and carcinogenicity studies that are used to support the registration of new pharmaceutical products. The recommended tissue list is intended to be a minimum core list that can be used for all types of repeat-dose toxicity and carcinogenicity studies, regardless of route of administration, species or strain of mammalian laboratory animal, duration, or class of drug to be tested. The resulting recommendations of the task force, presented here, were subsequently reviewed by the STP membership and endorsed by the STP Executive Committee.
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http://dx.doi.org/10.1080/01926230390183751DOI Listing
October 2003
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