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The current study assessed neurotrophin protein levels in male and female rat brain tissues at four different ages ranging from postpuberty to senescence. In both sexes nerve growth factor (NGF) increased, and brain-derived neurotrophic factor (BDNF) decreased, from 4 to 24 months of age. Using a slightly older age for the young group, or a slightly younger age for the aged group, had profound effects on whether age effects were realized. There were no sex differences in the pattern of change in neurotrophin levels across age, and neurotrophin levels did not correlate with estrogen levels in females or estrogen or testosterone levels in males. The current findings suggest that profound changes in neurotrophin protein levels can occur within only a few months time, and that these changes influence whether age-related neurotrophin alterations are realized. [ABSTRACT FROM AUTHOR]

How the human brain organizes semantic information has been the subject of debate over the past 20 years. Numerous cases of modality-specific and category-specific semantic deficits have fueled this controversy. Based on this literature, we have proposed a matrix theory of semantic organization (Crosson, Cato, Sadek, & Lu, 2000) that includes three dimensions: modality, category, and attribute. More recently, functional neuroimaging has been used to interrogate the neural substrates of modality- and category-specific processing. However, the contribution of imaging to this endeavor is relatively young. Consequently, findings across imaging studies have led to disparate conclusions. This article reviews competing theories of semantic organization in the brain and provides supporting and refuting evidence for each, incorporating examples from the imaging literature. This literature does provide some support for distinct neural substrates that process specific semantic attributes. Theory-driven research is needed to dissociate modalities, categories, and attributes. Copyright © 2001 by Aspen Publishers, Inc. [ABSTRACT FROM AUTHOR]

Tamoxifen therapy is well known for its success in adjuvant therapy for breast carcinoma; however, despite its benefits, the agents' estrogenic influence on the uterus, and subsequent endometrial cell proliferation may result in development of invasive uterine tumors. It has been estimated that tamoxifen may increase the risk of endometrial-based cancer two- to threefold, but uterine sarcomas remain relatively rare, accounting for 2 to 5 per cent of all uterine malignancies. We report the case of a 72-year-old woman having received tamoxifen for a breast carcinoma and having a hysterectomy nearly 30 years prior who presented with an intra-abdominal, omentum-based mass that on excision was identified as an endometrial stromal sarcoma. [ABSTRACT FROM AUTHOR]

For many intellectual tasks, the people with the least skill overestimate themselves the most, a pattern popularly known as the Dunning-Kruger effect (DKE). The dominant account of this effect depends on the idea that assessing the quality of one's performance (metacognition) requires the same mental resources as task performance itself (cognition). Unskilled people are said to suffer a dual burden : they lack the cognitive resources to perform well, and this deprives them of metacognitive insight into their failings. In this Registered Report , we applied recently developed methods for the measurement of metacognition to a matrix reasoning task, to test the dual-burden account. Metacognitive sensitivity (information exploited by metacognition) tracked performance closely, so less information was exploited by the metacognitive judgements of poor performers; but metacognitive efficiency (quality of metacognitive processing itself) was unrelated to performance. Metacognitive bias (overall tendency towards high or low confidence) was positively associated with performance, so poor performers were appropriately less confident-not more confident-than good performers. Crucially, these metacognitive factors did not cause the DKE pattern, which was driven overwhelmingly by performance scores. These results refute the dual-burden account and suggest that the classic DKE is a statistical regression artefact that tells us nothing much about metacognition., (© 2022 The Authors.)

Modelling a complex system of autonomous individuals moving through space and time essentially entails understanding the (heterogeneous) spatiotemporal context, interactions with other individuals, their internal states and making any underlying causal interrelationships explicit, a task for which agents (including vector-agents) are specifically well-suited. Building on a conceptual model of agent space-time and reasoning behaviour, a design guideline for an implemented vector-agent model is presented. The movement of football players was chosen as it is appropriately constrained in space, time and individual actions. Sensitivity-variability analysis was applied to measure the performance of different configurations of system components on the emergent movement patterns. The model output varied more when the condition of the contextual actors (players' role-areas) was manipulated. The current study shows how agent-based modelling can contribute to our understanding of movement and how causally relevant evidence can be produced, illustrated through a spatiotemporally constrained football case-study., (© 2022. The Author(s).)

Emergency medicine (EM) investigators lag in research funding from the National Institutes of Health (NIH) when compared to other specialties. NIH funding determinations are made in part by a process of NIH study section peer review. Low participation by EM investigators in NIH peer review could be one explanation for low levels of NIH funding by EM investigators. The objective of this study was to establish a current-state metric of EM faculty researchers serving on standing NIH study sections from 2019 to 2020. Publicly available lists of NIH study section membership rosters within the Center for Scientific Review and within individual NIH institutions were reviewed for standing members. Committee members listed as being members of a department of emergency medicine were identified as emergency care researchers. Special emphasis panels and ad hoc members were excluded. Members degrees were categorized as PhD, MD (with or without non-PhD degree), MD/PhD, and other. Similar analysis was performed of AHRQ study sections. A total of 6,113 members on NIH study sections were identified. Degrees held by committee members included PhDs 74% (4,547), MDs 14%(883), MD/PhDs 10% (584), and other (99). Twenty (0.3%) NIH study section members were identified as members of an emergency department (ED). A total of 20% (four) held PhDs, 75% (15) held MDs, and 5%(one) held MD/PhD degrees. A total of 25% (five) of EM faculty were pediatric and 75% (15) were adult. Clustering of study sections within similar institutions was noted with 40% (two) of the pediatric faculty at the same institution while 27% (four) of the adult faculty were at the same institution. AHRQ study section review identified 3% (four/127) as members of an ED. Our data show that 20 EM faculty comprised 0.3% of NIH standing study section members and four EM faculty comprised 3% of AHRQ standing study section members from 2019 to 2020 and that these members were clustered at a few institutions., (© 2021 by the Society for Academic Emergency Medicine.)

Physicians have the potential to decrease opioid misuse through appropriate prescribing practices. We examined the frequency of potentially inappropriate intravenous (IV) opioid use (where oral use would have been more appropriate) in patients hospitalized at a tertiary medical center. We excluded patients with cancer, patients receiving comfort care, and patients with gastrointestinal dysfunction. On the basis of recent guidance from the Society of Hospital Medicine, we defined IV doses as potentially inappropriate if administered more than 24 hours after an initial IV dose in patients who did not have nil per os status. Of the 200 patients studied, 31% were administered potentially inappropriate IV opioids at least once during their hospitalization, and 33% of all IV doses administered were potentially inappropriate. Given the numerous advantages of oral over IV opioids, this study suggests significant potential for improving prescribing practices to decrease risk of addiction, costs, and complications, ultimately improving the value of care provided.

Background: Swimming is known worldwide as one of the healthiest, low-impact forms of exercise that promotes a strong body, heart, and mind. However, several studies have suggested that swimming pool chlorination is responsible for dental erosion, calculus formation, and stain in competitive and recreational swimmers, a phenomenon known as swimmer's mouth. The purpose of this observational study was to assess chlorine stain on the dentition of competitive female swimmers and divers from a university team and to determine if dental preventive practices affected chlorine stains., Methods: Swimmers were recruited from the University of New Mexico Swimming and Diving Team for this IRB-approved study (#17-481). Participants completed a questionnaire regarding individual oral habits and frequency of preventive visits. Following the questionnaire, an oral screening was completed to evaluate for stain. Fisher exact tests, nonparametric Wilcoxon tests, and descriptive statistics were used to analyse the data. Additionally, a cross-sectional analysis was used to compare the chlorine stain between divers and swimmers., Results: Twenty-one females, with a mean age of 20.5 years, participated in the study. One hundred percent of these subjects had staining of the teeth, despite the fact that 85% of them reported brushing their teeth 2 to 3 times per day, and 81% reported receiving regular dental prophylaxis. All participants swam 5 or more times every week, with practice length ranging from 1 to 2 hours. There were no differences in stain between collegiate swimmers and divers., Conclusion: Within this study sample, extrinsic staining of the teeth was identified on all swimmers and divers and the presence of stain was not prevented by the frequency of tooth brushing or professional stain removal. Additional oral hygiene regimens should be explored to facilitate the prevention or complete removal of swimmer stain., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2019, CDHA | ACHD.)

The role of ERα36 in regulating BPA's effects and its potential as a risk factor for human uterine fibroids were evaluated. BPA at low concentrations (10 -6  μM - 10 μM) increased proliferation by facilitating progression of hormonally regulated, immortalized human uterine leiomyoma (ht-UtLM; fibroid) cells from G 0 -G 1 into S phase of the cell cycle; whereas, higher concentrations (100 μM-200 μM) decreased growth. BPA upregulated ERα36 gene and protein expression, and induced increased SOS1 and Grb2 protein expression, both of which are mediators of the MAPK p44/42 /ERK1/2 pathway. EGFR (pEGFR), Ras, and MAPK p44/42 were phosphorylated with concurrent Src activation in ht-UtLM cells within 10 min of BPA exposure. BPA enhanced colocalization of phosphorylated Src (pSrc) to ERα36 and coimmunoprecipitation of pSrc with pEGFR. Silencing ERα36 with siERα36 abolished the above effects. BPA induced proliferation in ht-UtLM cells through membrane-associated ERα36 with activation of Src, EGFR, Ras, and MAPK nongenomic signaling pathways., (Copyright © 2019. Published by Elsevier B.V.)

Purpose of Review: Uterine fibroids are common benign tumors of women in the USA and worldwide, yet the biological nature and pathogenesis of these tumors remain largely unknown. This review presents our view of the stages in the life cycle of a subset of uterine fibroid myocytes, introduces hypothetical concepts and morphological data to explain these changes, and relates these changes in individual myocytes to the phases of fibroid tumor development., Recent Findings: The observations gained from light and electron microscopic, immunohistochemical, and morphometric studies in our laboratory have led to the hypothesis that fibroid changes over time may relate to the excessive production of collagen by phenotypically transformed myocytes. This accumulation of collagen results in decreased microvessel density, followed by myocyte injury and atrophy, with eventual senescence and involution through ischemic cellular degeneration and inanition., Summary: Uterine leiomyomas, or fibroids, are characterized by two histologic features-proliferation of myocytes and production of an extracellular collagenous matrix. In the larger tumors, the collagenous matrix is often abundant. Within those regions in which the accumulating collagen is excessive, the myocytes are progressively separated from their blood supply, resulting in myocyte atrophy and eventually cell death. It is within these hypocellular, hyalinized areas that the complete lifecycle of the fibroid myocyte is realized. It begins with the phenotypic transformation of a contractile cell to one characterized by proliferation and collagen synthesis, progresses through an intermediate stage of atrophy related to interstitial ischemia, and eventuates in cell death due to inanition. Lastly, resorption of inanotic cells appears to occur by a non-phagocytic, presumably enzymatic process of degradation and recycling that we refer to as reclamation., Competing Interests: Conflict of Interest Gordon P. Flake, Alicia B. Moore, Deloris Sutton, Norris Flagler, Natasha Clayton, Grace E. Kissling, Benita Wicker Hall, John Horton, David Walmer, Stanley J. Robboy, and Darlene Dixon declare no conflict of interest.

Bioluminescence is a useful tool for imaging of cancer in in vivo animal models that endogenously express luciferase, an enzyme that requires a substrate for visual readout. Current bioluminescence imaging, using commonly available luciferin substrates, only lasts a short time (15-20 min). To avoid repeated administration of luciferase substrate during cancer detection and surgery, a long lasting bioluminescence imaging substrate or system is needed. A novel water-soluble biotinylated luciferase probe, B-YL (1), was synthesized. A receptor-targeted complex of B-YL with streptavidin (SA) together with a biotinylated epidermal growth factor short peptide (B-EGF) (SA/B-YL/B-EGF = 1:3:1, molar ratio) was then prepared to demonstrate selective targeting. The complex was incubated with brain cancer cell lines overexpressing the EGF receptor (EGFR) and transfected with the luciferase gene. Results show that the complex specifically detects cancer cells by bioluminescence. The complex was further used to image xenograft brain tumors transfected with a luciferase gene in mice. The complex detects the tumor immediately, and bioluminescence lasts for 5 days. Thus, the complex generates a long lasting bioluminescence for cancer detection in mice. The complex with selective targeting may be used in noninvasive cancer diagnosis and accurate surgery in cancer treatment in clinics in the future.

Purpose: Within 30 days of hospital discharge to a skilled nursing facility, older adults are at high risk for death, re-hospitalization, and high-cost health care. The purpose of this study was to examine whether a novel videoconference program called Extension for Community Health Outcomes-Care Transitions (ECHO-CT) that connects an interdisciplinary hospital-based team with clinicians at skilled nursing facilities reduces patient mortality, hospital readmission, skilled nursing facility length of stay, and 30-day health care costs., Methods: We undertook a prospective cohort study comparing cost and health care utilization outcomes between ECHO-CT facilities and matched comparisons from January 2014-December 2014., Results: Thirty-day readmission rates were significantly lower in the intervention group (odds ratio 0.57; 95% CI, 0.34-0.96; P-value .04), as were the 30-day total health care cost ($2602.19 lower; 95% CI, -$4133.90 to -$1070.48; P-value <.001) and the average length of stay at the skilled nursing facility (-5.52 days; 95% CI, -9.61 to -1.43; P = .001). The 30-day mortality rate was not significantly lower in the intervention group (odds ratio 0.38; 95% CI, 0.11-1.24; P = .11)., Conclusion: Patients discharged to skilled nursing facilities participating in the ECHO-CT program had shorter lengths of stay, lower 30-day rehospitalization rates, and lower 30-day health care costs compared with those in matched skilled nursing facilities delivering usual care. ECHO-CT may improve patient transitions to postacute care at lower overall cost., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Technical advancements in research techniques in science are made in slow increments. Even so, large advances from insight and hard work of an individual with a single technique can have astonishing ramifications. Here, we examine the impact of Dr. Maurice B. Burg and the isolated perfused renal tubule technique and celebrate the 50th anniversary of the publication by Dr. Burg and his colleagues of their landmark paper in the American Journal of Physiology in 1966. In this study, we have taken a scientific visualization approach to study the scientific contributions of Dr. Burg and the isolated perfused tubule preparation as determining research impact by the number of research students, postdoctoral fellows, visiting scientists, and national and international collaborators. Additionally, we have examined the research collaborations (first and second generation scientists), established the migrational visualization of the first generation scientists who worked directly with Dr. Burg, quantified the metrics indices, identified and quantified the network of coauthorship of the first generation scientists with their second generation links, and determined the citations analyses of outputs of Dr. Burg and/or his first generation collaborators as coauthors. We also review the major advances in kidney physiology that have been made with the isolated perfused tubule technique. Finally, we are all waiting for the discoveries that the isolated perfused preparation technique will bring during the next 50 years., (Copyright © 2016 the American Physiological Society.)

We present the WormPharm, an automated microfluidic platform that utilizes an axenic medium to culture C. elegans . The WormPharm is capable of sustaining C. elegans for extended periods, while recording worm development and growth with high temporal resolution ranging from seconds to minutes over several days to months. We demonstrate the utility of the device to monitor C. elegans growth in the presence of varying doses of nicotine and alcohol. Furthermore, we show that C. elegans cultured in the WormPharm are amendable for high-throughput genomic assays, i.e. chromatin-immunoprecipitation followed by next generation sequencing, and confirm that nematodes grown in monoxenic and axenic cultures exhibit genetic modifications that correlate with observed phenotypes. The WormPharm is a powerful tool for analyzing the effects of chemical, nutritional and environmental variations on organism level responses in conjunction with genome-wide changes in C. elegans ., Competing Interests: The authors have declared that no competing interests exist.

The present study provides information on length distribution, reproductive biology and diet of Mustelus mosis based on individuals caught in waters off the eastern Arabian Peninsula. Although ageing of vertebral centra was attempted, band pairs were of low clarity and counts could not be confidently assigned., (© 2016 The Fisheries Society of the British Isles.)

Histone phosphorylation has a profound impact on epigenetic regulation of gene expression, chromosome condensation and segregation, and maintenance of genome integrity. Histone H3 Serine 10 is evolutionally conserved and heavily phosphorylated during mitosis. To examine Histone H3 Serine 10 phosphorylation (H3S10ph) dynamics in mitosis, we applied immunogold labeling and confocal microscopy to visualize H3S10ph expression in MCF-7 cells. Confocal observations showed that MCF-7 cells had abundant H3S10ph expression in prophase and metaphase. In anaphase, the H3S10ph expression was significantly decreased and displayed only sparsely localized staining that mainly associated with the chromatid tips. We showed that immunogold bead density distribution followed the H3S10ph expression patterns observed in confocal analysis. At a higher magnification in metaphase, the immunogold beads were readily visible and the bead distribution along the condensed chromosomes was distinctive, indicating the specificity and reliability of the immunogold staining procedure. In anaphase, the beads were found to distribute focally in specific regions of chromatids, reinforcing the confocal observations of differential H3 phosphorylation. To our knowledge, this is the first report to show the specific H3S10ph expression with an immunogold technique and transmission electron microscopy. Additionally, with confocal microscopy, we analyzed H3S10ph expression in an immortalized cell line derived from benign uterine smooth muscle tumor cells. H3S10ph epitope was expressed more abundantly during anaphase in the benign tumor cells, and there was no dramatic differential expression within the condensed chromatid clusters as observed in MCF-7 cells. The differences in H3S10ph expression pattern and dynamics may contribute to the differential proliferative potential between benign tumor cells and MCF-7 cells., (Published 2016. This article is a U.S. Government work and is in the public domain in the USA.)

Uterine leiomyomas in miniature pet pigs occur similarly to those in women with regard to frequency, age, parity, and cycling. Clinical signs, gross, and histologic features of the porcine tumors closely resemble uterine leiomyomas (fibroids) in women. Although fibroids are hormonally responsive in women, the roles of estrogen and progesterone have not been fully elucidated. In this study, immunohistochemistry was used to assess the expression of the steroid hormone receptors, estrogen receptor alpha (ER-α), estrogen receptor beta (ER-β) and progesterone receptor (PR), and cell proliferation markers, proliferating cell nuclear antigen (PCNA) and Ki-67 in tumor and matched myometrial tissues sampled from miniature pigs. A "quickscore" method was used to determine receptor expression and labeling indices were calculated for the markers. ER-α/β and PR were localized to the nuclei of smooth muscle cells in both tissues. PR expression was intense and diffuse throughout all tissues, with correlation between tumors and matched myometria. Conversely, ER-α expression was variable between the myometrial and tumor tissues, as well as between animals. ER-β expression was low. PCNA and Ki-67 were localized to the nucleus and expression varied among tumors; however, normal tissues were overall negative. These findings support further investigation into the use of the miniature pig as a model of fibroids in women., (© The Author(s) 2015.)

Purpose/objectives: To understand the benefits of making art and listening to music and whether those activities may be beneficial for reducing symptoms associated with blood and marrow transplantation. 
., Design: A randomized, three-group, pre-/post-pilot design.
., Setting: Outpatient Blood and Marrow Transplant Clinic at the University of Kansas Cancer Center in Kansas City.
., Sample: 39 adults aged from 22-74 years receiving blood and marrow transplantations.
., Methods: Participants were randomly assigned to one of three groups., Main Research Variables: Therapy-related symptoms, state anxiety, and physiologic distress.
., Findings: Of the 39 participants, 14 were randomized to the control group, 14 to the art group, and 11 to the diversional music group. No significant differences in age, gender, ethnicity, or diagnosis existed between groups. No statistical differences were found between groups on all measures following the intervention. 
., Conclusions: Although the results of the current study did not indicate significant differences, healthcare professionals may still consider creative therapies as a viable option for patients within hospital or outpatient clinics because they do not require specialty training or costly resources, and they may be an enjoyable activity to occupy time for patients and caregivers.
., Implications for Nursing: Art making and music listening are safe and desirable for patients undergoing blood and marrow transplantation in an outpatient clinic. Nurses might consider partnering with therapists to offer these creative therapies as diversion during treatment.

Genistein, an estrogenic, soy-derived isoflavone, may play a protective role against hormone-related cancers. We have reported that a high concentration of genistein inhibits cell proliferation and induces apoptosis in human uterine smooth muscle cells, but not in leiomyoma (fibroid) cells. To better understand the differential cell death responses of normal and tumor cells to a high concentration of genistein, we treated uterine smooth muscle cells and uterine leiomyoma cells with 50 μg/ml of genistein for 72 h and 168 h, and assessed for mediators of apoptosis, cytotoxicity and autophagy. We found that leiomyoma cells had increased protection from apoptosis by expressing an increased ratio of Bcl-2: bak at 72 h and 168 h; however, in smooth muscle cells, the Bcl-2: bak ratio was decreased at 72 h, but significantly rebounded by 168 h. The apoptosis extrinsic factors, Fas ligand and Fas receptor, were highly expressed in uterine smooth muscle cells following genistein treatment at both time points as evidenced by confocal microscopy. This was not seen in the uterine leiomyoma cells; however, cytotoxicity as indicated by elevated lactate dehydrogenase levels was significantly enhanced at 168 h. Increased immunoexpression of an autophagy/autophagosome marker was also observed in the leiomyoma cells, although minimally present in smooth muscle cells at 72 h. Ultrastructurally, there was evidence of autophagic vacuoles in the leiomyoma cells; whereas, the normal smooth muscle cells showed nuclear fragmentation indicative of apoptosis. In summary, our data show differential cell death pathways induced by genistein in tumor and normal uterine smooth muscle cells, and suggest novel cell death pathways that can be targeted for preventive and intervention strategies for inhibiting fibroid tumor cell growth in vivo .

Kuwait's waters are one of only two locations where the smoothtooth blacktip shark Carcharhinus leiodon is known to occur. Concentrations of 11 trace elements were analysed in five juvenile and two adult specimens of this coastal predator. Concentrations of lead in muscle increased with length, whilst manganese concentration decreased. Arsenic concentrations in muscle were among the highest reported in elasmobranchs, and the concentration in the liver increased significantly in relation to length. In comparison to published literature, concentrations of manganese (liver), lead (muscle) and iron (muscle and liver) were high. Mercury concentrations in the muscle exceeded European Food Safety Authority limits and were among the highest reported in any elasmobranch. Concentrations of selenium, which may inhibit mercury toxicity, were also high. These results and previous studies indicate that potentially hazardous levels of mercury and other contaminants may occur in sharks in this region, adding further stressors to these vulnerable populations., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

A total of 10 abnormal free-swimming (i.e., post-birth) elasmobranchs are reported from The (Persian-Arabian) Gulf, encompassing five species and including deformed heads, snouts, caudal fins and claspers. The complete absence of pelvic fins in a milk shark Rhizoprionodon acutus may be the first record in any elasmobranch. Possible causes, including the extreme environmental conditions and the high level of anthropogenic pollution particular to The Gulf, are briefly discussed., (© 2015 The Fisheries Society of the British Isles.)

The northwestern Indian Ocean harbors a number of larger marine vertebrate taxa that warrant the investigation of genetic population structure given remarkable spatial heterogeneity in biological characteristics such as distribution, behavior, and morphology. Here, we investigate the genetic population structure of four commercially exploited shark species with different biological characteristics (Carcharhinus limbatus, Carcharhinus sorrah, Rhizoprionodon acutus, and Sphyrna lewini) between the Red Sea and all other water bodies surrounding the Arabian Peninsula. To assess intraspecific patterns of connectivity, we constructed statistical parsimony networks among haplotypes and estimated (1) population structure; and (2) time of most recent population expansion, based on mitochondrial control region DNA and a total of 20 microsatellites. Our analysis indicates that, even in smaller, less vagile shark species, there are no contemporary barriers to gene flow across the study region, while historical events, for example, Pleistocene glacial cycles, may have affected connectivity in C. sorrah and R. acutus. A parsimony network analysis provided evidence that Arabian S. lewini may represent a population segment that is distinct from other known stocks in the Indian Ocean, raising a new layer of conservation concern. Our results call for urgent regional cooperation to ensure the sustainable exploitation of sharks in the Arabian region.

Background: It has been proposed that cadmium (Cd) is an environmental "metalloestrogen" and that its action is mediated via the estrogen receptor (ER). Cd mimics the effects of estrogen in the rat uterus, and blood Cd concentrations positively correlate with ER levels in uteri of women with fibroids., Objectives: In the present study we explored whether Cd could stimulate proliferation of estrogen-responsive human uterine leiomyoma (ht-UtLM) cells and uterine smooth muscle cells (ht-UtSMCs) through classical interactions with ERα and ERβ, or by nongenomic mechanisms., Methods: We used estrogen response element (ERE) reporters, phosphorylated receptor tyrosine kinase arrays, Western blot analysis, estrogen binding, and cell proliferation assays to evaluate the effects of Cd on ht-UtLM cells and ht-UtSMCs., Results: Cd stimulated growth of both cell types at lower concentrations and inhibited growth at higher concentrations (≥ 50 μM). Cd did not significantly bind to ERα or ERβ, nor did it show transactivation in both cell types transiently transfected with ERE reporter genes. However, in both cells types, Cd (0.1 μM and 10 μM) activated p44/42 MAPK (ERK1/2), and a MAPK inhibitor (PD98059) abrogated Cd-induced cell proliferation. Cd in ht-UtLM cells, but not in ht-UtSMCs, activated the growth factor receptors EGFR, HGFR, and VEGF-R1 upstream of MAPK. Additional studies in ht-UtLM cells showed that AG1478, an EGFR inhibitor, abolished Cd-induced phosphorylation of EGFR and MAPK., Conclusions: Our results show that low concentrations of Cd stimulated cell proliferation in estrogen-responsive uterine cells by nongenomic activation of MAPK, but not through classical ER-mediated pathways.

Background: Studies have documented the short-term vascular benefits of combination lipid therapy., Objective: Our objective was to evaluate the long-term effects of combination lipid therapy on carotid intima-media thickness (CIMT) in patients with coronary artery disease., Methods: We performed a case-control study in patients who had finished the Familial Atherosclerosis Treatment Study (FATS) and returned to usual care with statin therapy alone or had elected to participate in the 20-year FATS-Observational Study (FATS-OS) and received combination therapy with lovastatin (40 mg/day), niacin (2-3 g/day), and colestipol (20 gm/day) for 11 years, then continued with simvastatin (10-80 mg/day) or lovastatin (40-80 mg/day) plus niacin (2-4 g/day). After 17.8 ± 0.8 years with combination therapy and 19.0 ± 0.8 years with usual care, cholesterol levels and CIMT were collected in 43 FATS-OS patients and 26 usual care patients., Results: Combination therapy group had a greater decrease in total cholesterol (-42 ± 14% vs -31 ± 17%, P = .008) and low-density lipoprotein cholesterol (LDL-C) (-57 ± 13% vs -38 ± 25%, P < .001) and greater increase in high-density lipoprotein cholesterol (HDL-C) (38 ± 43% vs 15 ± 23%, P = .02) as compared with usual care. CIMT (0.902 ± 0.164 vs 1.056 ± 0.169 mm, P < .001) on intensive therapy was significantly less compared with usual care. Multivariate regression analysis (coefficient, 95% CI) showed that combination therapy (-0.13; -0.21 to -0.04, P = .003) and on-therapy LDL-C (0.15; 0.02 to 0.28, P = .03) were significant independent predictors of CIMT., Conclusions: Prolonged combination lipid therapy is associated with greater improvements in LDL-C and HDL-C levels and less atherosclerotic burden as compared with statin therapy alone., (Copyright © 2014 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

The aromatase inhibitor (AI)-associated musculoskeletal (MSK) pain symptoms are often debilitating and limit compliance with this important hormonal breast cancer therapy. The etiology of this syndrome is unknown. Hypovitaminosis D has been suggested as a possible risk factor for the development of MSK symptoms in women starting AIs. The objective of this substudy was to define the prevalence of low 25(OH)D in this population, to assess risk of low levels on developing pain and to define a target therapeutic goal for 25(OH)D in this population. This analysis was part of a 6-month prospective cohort study examining the MSK side effects of adjuvant AI therapy in postmenopausal women. Patients were evaluated by a rheumatologist with a joint examination, had 25(OH)D levels measured and completed quality of life questionnaires at baseline, 3 and 6 months. Symptomatic patients were defined as those that self-reported new or worsening MSK symptoms. Of 52 patients, 28 (54%) were symptomatic, and two (3.8%) stopped AIs due to MSK ailments. Thirteen patients had objective evidence of tendonitis on rheumatologic examination. Thirty-three percent of all subjects had baseline 25(OH)D levels <40 ng/mL, 19.2% had levels <30 ng/mL and 5.8% had levels <20 ng/mL. Symptomatic patients were more likely to have had baseline levels below 40 ng/mL, compared with asymptomatic patients (46.4% versus 16.7%, p = 0.037). In multivariate regression analyses, levels <40 ng/mL were associated with developing objective tenosynovitis (p = 0.033) but not with developing nonspecific myalgias. Our findings suggest hypovitaminosis D may be contributing to the AI-associated MSK pain syndrome and in particular to the development of tendonitis. Repletion to 25(OH)D levels >40 ng/mL is advisable. Further research should be carried out on identifying additional modifiable risk factors for this syndrome., (© 2014 Wiley Periodicals, Inc.)

Study Objectives: Variation in computed tomography (CT) use between emergency medicine (EM) physicians may delineate appropriate or inappropriate use. We hypothesize that variation in all types of CT use exists between providers and their use in patients with common chief concerns. We determine EM physicians' variability in CT use of all types and whether high use in one area predicts use of other CT types., Methods: This was a retrospective study of EM physicians practicing at an 800-bed tertiary level 1 trauma center over a 3.5-year period. Computed tomography rates by type and by patient chief concern were modeled for providers as a function of patient acuity, disposition, age, and time of day using logistic regression., Results: Of 195 801 eligible visits, 44 724 visits resulted in at least 1 CT scan. The adjusted rate of CT ordering by providers was 23.8% of patient visits, ranging from 11.5% to 32.7% The upper quartile of providers was responsible for 78% of the CT scans ordered above the mean. There was a large variation in use of all types of CT and by chief concern. There was an 8-fold variation in use of CT abdomen in discharged patients. High head CT use by providers predicts high use in all other CT types., Conclusion: We demonstrate a dramatic variation in CT use among EM physicians in all types of CT and common chief concerns. Greater variation was present in patients who were discharged. Large deviation from the mean by a group of providers may suggest inappropriate use., (© 2013.)

Although the cortical substrates of verbal working memory are reasonably well understood, less is known about the relative contribution of subcortical structures to verbal working memory. Therefore, in addition to elaboration of a model of verbal working memory by including a specific focus on basal ganglia, the purpose of this study also was to examine potential differences in neural function across the complete process of verbal working memory, from encoding through retrieval. Functional magnetic resonance imaging was used to observe regions of brain activation in neurologically normal participants during a task of verbal working memory. The expected frontal-parietal network was found to be active over the course of the verbal working memory task. The encoding portion of the task engaged left inferior frontal regions and bilateral caudate and thalamus. Bilateral medial thalamus and posterior cingulate regions were engaged during the maintenance phase of the task. Retrieval activated the left inferior frontal sulcus and posterior parietal/occipital regions. Findings are considered in light of current models of verbal working memory and subcortical structures., (Published by Elsevier Inc.)

Foragers can show adaptive responses to changes within their environment through morphological and behavioural plasticity. We investigated the plasticity in body size, at sea movements and diving behaviour of juvenile female New Zealand (NZ) sea lions (Phocarctos hookeri) in two contrasting environments. The NZ sea lion is one of the rarest pinnipeds in the world. Most of the species is based at the subantarctic Auckland Islands (AI; considered to be marginal foraging habitat), with a recolonizing population on the Otago Peninsula, NZ mainland (considered to be more optimal habitat). We investigated how juvenile NZ sea lions adjust their foraging behaviour in contrasting environments by deploying satellite-linked platform transmitting terminals (PTTs) and time-depth recorders (TDRs) on 2-3 year-old females at AI (2007-2010) and Otago (2009-2010). Juvenile female NZ sea lions exhibited plasticity in body size and behaviour. Otago juveniles were significantly heavier than AI juveniles. Linear mixed effects models showed that study site had the most important effect on foraging behaviour, while mass and age had little influence. AI juveniles spent more time at sea, foraged over larger areas, and dove deeper and longer than Otago juveniles. It is difficult to attribute a specific cause to the observed contrasts in foraging behaviour because these differences may be driven by disparities in habitat/prey characteristics, conspecific density levels or interseasonal variation. Nevertheless, the smaller size and increased foraging effort of AI juveniles, combined with the lower productivity in this region, support the hypothesis that AI are less optimal habitat than Otago. It is more difficult for juveniles to forage in suboptimal habitats given their restricted foraging ability and lower tolerance for food limitation compared to adults. Thus, effective management measures should consider the impacts of low resource environments, along with changes that can alter food availability such as potential resource competition with fisheries.

We propose, and offer evidence to support, the concept that many uterine leiomyomas pursue a self-limited life cycle. This cycle can be arbitrarily divided on the basis of morphologic assessment of the collagen content into 4 phases: (1) proliferation, (2) proliferation and synthesis of collagen, (3) proliferation, synthesis of collagen, and early senescence, and (4) involution. Involution occurs as a result of both vascular and interstitial ischemia. Interstitial ischemia is the consequence of the excessive elaboration of collagen, resulting in reduced microvascular density, increased distance between myocytes and capillaries, nutritional deprivation, and myocyte atrophy. The end stage of this process is an involuted tumor with a predominance of collagen, little to no proliferative activity, myocyte atrophy, and myocyte cell death. Since many of the dying cells exhibit light microscopic and ultrastructural features that appear distinct from either necrosis or apoptosis, we refer to this process as inanosis, because it appears that nutritional deprivation, or inanition, is the underlying cause of cell death. The disposal of myocytes dying by inanosis also differs in that there is no phagocytic reaction, but rather an apparent dissolution of the cell, which might be viewed as a process of reclamation as the molecular contents are reclaimed and recycled.

Based upon our morphologic observations, we hypothesize and also provide morphometric evidence for the occurrence of progressive developmental changes in many uterine fibroids, which can be arbitrarily divided into 4 phases. These developmental phases are related to the ongoing production of extracellular collagenous matrix, which eventually exceeds the degree of angiogenesis, resulting in the progressive separation of myocytes from their blood supply and a condition of interstitial ischemia. The consequence of this process of slow ischemia with nutritional and oxygen deprivation is a progressive myocyte atrophy (or inanition), culminating in cell death, a process that we refer to as inanosis. The studies presented here provide quantitative and semiquantitative evidence to support the concept of the declining proliferative activity as the collagenous matrix increases and the microvascular density decreases.

The eagle ray Aetobatus flagellum (Bloch & Schneider, 1801) is redescribed based on new material from the Persian Gulf (Kuwait), Indonesia and Malaysia. A related but distinct species of Aetobatus from the western North Pacific, previously referred to as A. flagellum, is reported. Aetobatus flagellum is a medium-sized eagle ray which attains about 900 mm DW; males mature at approximately 500 mm DW. Aetobatus flagellum appears to be uncommon and restricted to estuary-influenced waters of the Indo-West Pacific. It is caught as gillnet bycatch where its habit of schooling, combined with probable small litter size, may make it particularly vulnerable to impacts from fisheries.

Objective: To define the musculoskeletal syndrome associated with use of aromatase inhibitors (AIs), specifically, to describe its incidence, time to onset, risk factors, and clinical presentation., Methods: Postmenopausal women with hormone-sensitive, nonmetastatic breast cancer starting AI therapy were enrolled in this prospective cohort study. They underwent complete rheumatologic evaluation and contrast-enhanced magnetic resonance imaging (MRI) of the hands and wrists prior to starting AI, at 3 and 6 months. The primary outcome was change in grip strength., Results: Twenty-eight (54%) of 52 women reported new or worsening musculoskeletal symptoms. Two discontinued AIs due to pain. Mean time to symptom onset was 6 weeks (range 2-18 weeks), and 75% of symptomatic patients developed symptoms by 8 weeks. Later-stage cancer and worse quality of life (QOL) pretreatment were significantly associated with symptom development. Sixty-eight percent of symptomatic subjects had involvement of the hands; however, there was no difference in the mean change in grip strength (-2.9 kg versus -1.3 kg; P = 0.6). Among symptomatic subjects, 46% had evidence of focal tenosynovitis of the hands and feet on examination. Although some symptomatic subjects had new MRI abnormalities, Rheumatoid Arthritis Magnetic Resonance Imaging Scoring did not significantly change., Conclusion: The incidence of AI-associated musculoskeletal syndrome is more than 50%, with most women developing symptoms by 8 weeks. The key finding in symptomatic women was focal tenosynovitis of the hands and feet, without evidence of autoimmune disease or systemic inflammation. Later-stage cancer and poorer QOL were predictive of symptom development., (Copyright © 2012 by the American College of Rheumatology.)

Previously, we reported that fenvalerate (Fen) promotes proliferation of human uterine leiomyoma (UtLM) cells by enhancing progression of cells from G(0)-G(1) to S phase through molecular mechanisms independent of estrogen receptor-α and -β. The cyclin-dependent kinase (CDK) inhibitor p27, which blocks G(1) to S phase transitions and is an important regulator of CDK2, is often decreased in hormonally regulated diseases, including uterine leiomyomas. Therefore, we were interested in whether Fen could regulate the expression of p27 and whether p27 might play a role in Fen-induced cell proliferation. Expression of p27 in Fen-treated UtLM and uterine smooth muscle cells (UtSMCs) was examined. We found that p27 mRNA was significantly downregulated and that protein levels were decreased in both cell types treated with 10 μM Fen for 24 h compared with respective controls. Overexpression of p27 in UtLM cells and UtSMCs using an adenovirus doxycycline (Dox)-regulated Tet-off system abrogated the proliferative effects of Fen, as evidenced by decreased total cell numbers and BrdU incorporation. Fen treatment increased CDK2 mRNA expression levels; however, overexpression of p27 also abolished this effect. In contrast, Dox treatment dramatically restored the above muted responses. Finally, we utilized siRNA to knock down p27 expression. After transfection, mRNA levels of p27 were downregulated in UtLM cells and UtSMCs and total cell numbers and BrdU incorporation increased significantly compared with nontransfected cells. Fen treatment in the presence of p27 silencing enhanced the increased cell counts and BrdU labeling in UtLM cells and UtSMCs. Taken together, these results indicate that p27 downregulation is critical for Fen-induced cell proliferation.

The estrogenic and antiestrogenic potential of perfluorooctanoic acid (PFOA) was assessed using an immature mouse uterotrophic assay and by histologic evaluation of the uterus, cervix and vagina following treatment. Female offspring of CD-1 dams were weaned at 18days old and assigned to groups of equal weight, and received 0, 0.01, 0.1, or 1mg PFOA/kg BW/d by gavage with or without 17-β estradiol (E(2), 500μg/kg/d) from PND 18-20 (n=8/treatment/block). At 24h after the third dose (PND 21), uteri were removed and weighed. Absolute and relative uterine weights were significantly increased in the 0.01mg/kg PFOA only group. Characteristic estrogenic changes were present in all E(2)-treated mice; however, they were minimally visible in the 0.01 PFOA only mice. These data suggest that at a low dose PFOA produces minimal histopathologic changes in the reproductive tract of immature female mice, and does not antagonize the histopathologic effects of E(2)., (Published by Elsevier Inc.)