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Dermatofibrosarcoma protuberans (DFSP) is a rare, CD34+ mesenchymal neoplasm that classically involves the dermis. A COL1A1::PDGFB t(17;22) translocation is present in 91.4% to 96% of cases, resulting in aberrant proliferation due to tyrosine kinase hyperactivity. Here, we present a postmenopausal woman with a CD34-positive spindle cell neoplasm of the breast without cutaneous involvement, lacking muscle marker expression, STAT6 expression, and 13q14 deletion by fluorescence in situ hybridization (FISH). Although the classic PDGFB translocation was not detected by FISH, the overall features were highly suspicious for DFSP. Subsequent RNA-based next-generation sequencing revealed an EMILIN2::PDGFD fusion. A literature review showed that PDGFD fusions can be detected in up to 55% PDGFB FISH negative cases, with EMILIN2::PDGFD fusion highly associated with fibrosarcomatous transformation. This holds important diagnostic and prognostic information as fibrosarcomatous-DFSP is associated with higher recurrence and metastatic potential. The tumor was completely resected with clear margins, showed no fibrosarcomatous areas, and no evidence of recurrence is documented 2 years since resection. This review and case report adds to the literature regarding PDGFD -translocation positive DFSP as a differential diagnosis of CD34-positive spindle cell tumors of the breast, while emphasizing the prognostic importance of EMILIN2::PDGFD fusions., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

BK viremia is endemic among kidney transplant recipients (KTRs). Incidence, risk factors, outcomes, and clinical management of detectable versus high BK viremia have not been considered previously in KTR in the modern era. This observational study examined KTR transplanted between January 1, 2009 and December 31, 2016. Any BK viral load in the serum constituted detectable BK viremia and ≥10 3 copies/ml constituted high viremia. Among 1193 KTRs, the cumulative probability of developing detectable and high BK viremia within 2 years posttransplant were 27.8% and 19.6%, respectively. Significant risk factors for detectable BK viremia included recipient age (HR 1.02 [95% CI: 1.01, 1.03]) and donor age (HR 1.01 [95% CI: 1.00, 1.02]). Recipient age also predicted high BK viremia (HR 1.02 [95% CI: 1.01, 1.03]), whereas White race (HR 0.70 [95% CI: 0.52, 0.95]), nondepleting induction therapy (HR 0.61 [95% CI: 0.42, 0.89]), and delayed graft function (HR 0.61 [95% CI: 0.42, 0.88]) were protective. Mean estimated glomerular filtration rates were 4.28 ml/min/1.72 m 2 (95% CI: 2.71, 5.84) lower with detectable BK viremia. Although low viral load was usually not acted upon at first presentation, antiproliferative dose reductions were the most common initial management. BK viremia remains a common early complication in a modern cohort of KTRs. These findings highlight the benefit of early BKV monitoring in addition to intensive clinical management. Clinical responses beyond first positive BK viremia tests, and their implications for graft outcomes, merit further investigation., (© 2022 Wiley Periodicals LLC.)

Imaging subclinical atherosclerosis identifies individuals at higher risk of cardiovascular disease through direct visualization before events occur so that preventative measures can be taken. Coronary artery calcium (CAC) scans are the most widely used and studied to identify subclinical atherosclerosis and are most useful in men older than 40 years and women older than 50 years. Coronary computed tomography angiography has high prognostic value and might be the best modality for assessing subclinical atherosclerosis with incremental increase in predictive value over CAC. Ankle-brachial indexes are specific markers for cardiovascular risk but are a less sensitive tool for risk assessment., Competing Interests: Disclosure Dr J.K. Logan and Dr M.P. Ayers have nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Acute retinal artery occlusion (RAO) is an urgent ophthalmic condition often indicative of future ischemic pathology. Patients diagnosed at an outpatient retina clinic must present to an emergency department (ED) or primary care clinic to obtain a systemic workup. We review the overall compliance and suspected delay in completing the required testing., Design: Retrospective cohort study METHODS: Patients presenting with a symptomatic RAO from June 2009 to January 2019 at a vitreoretinal practice (The Retina Institute, St. Louis, MO) were included. Documentation of carotid vasculature and echocardiographic imaging was requested from the patient's primary care physician (PCP), cardiologist, or neurologist. Time to workup (TTW) from RAO diagnosis to receiving appropriate workup and site of workup (ED vs. outpatient setting) were recorded., Results: One hundred forty-seven patients were included. A total of 132 (89.8%) patients were documented as having completed at least one type of cardiovascular or carotid imaging. Seventy-seven patients (52.3%) were documented to have completed both carotid and echocardiographic imaging. Following RAO diagnosis, 97 (66.0%) patients were referred to an outpatient facility while 35 (23.8%) were evaluated at an ED. Mean TTW through an ED setting vs. outpatient was 2.20 days (1.10 STDM, range 0-29) vs.13.6 days (2.23 STDM, range 0-149) respectively (p=0.003)., Conclusion: Our study gives objective data to the delay suspected in referring patients with acute symptomatic RAO for outpatient workup. We recommend all outpatient ophthalmology and retina practices establish a relationship with a comprehensive or primary stroke center to facilitate urgent testing through an emergency department., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

O-linked β-N-acetylglucosamine (O-GlcNAc) is a single sugar post-translational modification (PTM) of intracellular proteins linking nutrient flux through the Hexosamine Biosynthetic Pathway (HBP) to the control of cis-regulatory elements in the genome. Aberrant O-GlcNAcylation is associated with the development, progression, and alterations in gene expression in cancer. O-GlcNAc cycling is defined as the addition and subsequent removal of the modification by O-GlcNAc Transferase (OGT) and O-GlcNAcase (OGA) provides a novel method for cells to regulate various aspects of gene expression, including RNA polymerase function, epigenetic dynamics, and transcription factor activity. We will focus on the complex relationship between phosphorylation and O-GlcNAcylation in the regulation of the RNA Polymerase II (RNAP II) pre-initiation complex and the regulation of the carboxyl-terminal domain of RNAP II via the synchronous actions of OGT, OGA, and kinases. Additionally, we discuss how O-GlcNAcylation of TATA-box binding protein (TBP) alters cellular metabolism. Next, in a non-exhaustive manner, we will discuss the current literature on how O-GlcNAcylation drives gene transcription in cancer through changes in transcription factor or chromatin remodeling complex functions. We conclude with a discussion of the challenges associated with studying O-GlcNAcylation and present several new approaches for studying O-GlcNAc regulated transcription that will advance our understanding of the role of O-GlcNAc in cancer.

The sources of the stone used to construct Stonehenge around 2500 BCE have been debated for over four centuries. The smaller "bluestones" near the center of the monument have been traced to Wales, but the origins of the sarsen (silcrete) megaliths that form the primary architecture of Stonehenge remain unknown. Here, we use geochemical data to show that 50 of the 52 sarsens at the monument share a consistent chemistry and, by inference, originated from a common source area. We then compare the geochemical signature of a core extracted from Stone 58 at Stonehenge with equivalent data for sarsens from across southern Britain. From this, we identify West Woods, Wiltshire, 25 km north of Stonehenge, as the most probable source area for the majority of sarsens at the monument., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Archaeological evidence indicates that pig domestication had begun by ∼10,500 y before the present (BP) in the Near East, and mitochondrial DNA (mtDNA) suggests that pigs arrived in Europe alongside farmers ∼8,500 y BP. A few thousand years after the introduction of Near Eastern pigs into Europe, however, their characteristic mtDNA signature disappeared and was replaced by haplotypes associated with European wild boars. This turnover could be accounted for by substantial gene flow from local European wild boars, although it is also possible that European wild boars were domesticated independently without any genetic contribution from the Near East. To test these hypotheses, we obtained mtDNA sequences from 2,099 modern and ancient pig samples and 63 nuclear ancient genomes from Near Eastern and European pigs. Our analyses revealed that European domestic pigs dating from 7,100 to 6,000 y BP possessed both Near Eastern and European nuclear ancestry, while later pigs possessed no more than 4% Near Eastern ancestry, indicating that gene flow from European wild boars resulted in a near-complete disappearance of Near East ancestry. In addition, we demonstrate that a variant at a locus encoding black coat color likely originated in the Near East and persisted in European pigs. Altogether, our results indicate that while pigs were not independently domesticated in Europe, the vast majority of human-mediated selection over the past 5,000 y focused on the genomic fraction derived from the European wild boars, and not on the fraction that was selected by early Neolithic farmers over the first 2,500 y of the domestication process., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Importance: Dermatofibrosarcoma protuberans (DFSP) may have a deceptively benign clinical appearance, including a nonprotuberant presentation. Patients with DFSP often perceive misdiagnoses and delays in receiving a diagnosis. Use of existing, patient-designed Facebook patient support groups (FBSGs) to recruit large numbers of patients with rare diseases may be an effective novel research method., Objectives: To collaborate with patients with rare disease through social media and answer questions important to both patients and the medical field, including sources of diagnostic delay, risk of recurrence, and flat presentation of DFSP., Design, Setting, and Participants: A multiple-choice survey created by a team of medical practitioners and patients with DFSP was administered to 214 patients with DFSP or family members from international DFSP FBSGs and a nonprofit foundation patient database via Lime Survey from October 30 to November 20, 2015. The survey asked questions designed to determine risk of recurrence and metastasis, surgical outcomes, sources of diagnostic delay, symptoms of recurrence, number of recurrences, scar size, and number of clinicians seen before biopsy. Statistical analysis was performed from January 1, 2016, to April 1, 2019., Main Outcomes and Measures: The study goal was to collect at least 200 survey responses., Results: Of 214 survey respondents (169 females and 45 males; mean [SD] age, 40.7 [12.1] years; range, <1 to 72 years), 199 were patients with DFSP and 15 were family members. Delays occurred between the patient noticing the DFSP lesion and receiving a diagnosis of DFSP (median, 4 years; range, <1 to 42 years). Most patients (112 [52.3%]) believed that they received a misdiagnosis at some point: by dermatologists (35 of 107 [32.7%]), primary care clinicians (80 of 107 [74.8%]), or another type of physician (27 of 107 [25.2%]). The most frequent prebiopsy clinical suspicion included cyst (101 [47.2%]), lipoma (30 [14.0%]), and scar (17 [7.9%]). Many patients first noticed their DFSP as a flat plaque (87 of 194 [44.8%]). Of these lesions, 73.6% (64 of 87) became protuberant eventually. Surgical treatments included Mohs micrographic surgery (56 of 194 [28.9%]), wide local excision (122 of 194 [62.9%]), and conservative excision (16 of 194 [8.2%]). The reported rate of recurrence was 5.4% (3 of 56) for Mohs micrographic surgery, 7.4% (9 of 122) for wide local excision, and 37.5% (6 of 16) for conservative excision. The higher rate of recurrence for conservative excision was significant (P = .001); there was no significant difference in the rate of recurrence between Mohs micrographic surgery and wide local excision (P = .76)., Conclusions and Relevance: This study reports what appears to be disease-relevant statistics from the largest survey of patients with DFSP to date. Because of the dissonance between the name of the neoplasm and its clinical presentation, the alternative term dermatofibrosarcoma, often protuberant is proposed. This study suggests that FBSGs are useful tools in medical research, providing rapid access to large numbers of patients with rare diseases and enabling synergistic collaborations between patients and medical researchers.

The great henge complexes of southern Britain are iconic monuments of the third millennium BCE, representing great feats of engineering and labor mobilization that hosted feasting events on a previously unparalleled scale. The scale of movement and the catchments that the complexes served, however, have thus far eluded understanding. Presenting the largest five-isotope system archeological dataset ( 87 Sr/ 86 Sr, δ 34 S, δ 18 O, δ 13 C, and δ 15 N) yet fully published, we analyze 131 pigs, the prime feasting animals, from four Late Neolithic (approximately 2800 to 2400 BCE) complexes to explore the networks that the feasts served. Because archeological evidence excludes continental contact, sources are considered only in the context of the British Isles. This analysis reveals wide-ranging origins across Britain, with few pigs raised locally. This finding demonstrates great investment of effort in transporting pigs raised elsewhere over vast distances to supply feasts and evidences the very first phase of pan-British connectivity.

The addition of a single β-d-GlcNAc sugar ( O -GlcNAc) by O -GlcNAc-transferase (OGT) and O -GlcNAc removal by O -GlcNAcase (OGA) maintain homeostatic O -GlcNAc levels on cellular proteins. Changes in protein O -GlcNAcylation regulate cellular differentiation and cell fate decisions, but how these changes affect erythropoiesis, an essential process in blood cell formation, remains unclear. Here, we investigated the role of O -GlcNAcylation in erythropoiesis by using G1E-ER4 cells, which carry the erythroid-specific transcription factor GATA-binding protein 1 (GATA-1) fused to the estrogen receptor (GATA-1-ER) and therefore undergo erythropoiesis after β-estradiol (E 2 ) addition. We observed that during G1E-ER4 differentiation, overall O -GlcNAc levels decrease, and physical interactions of GATA-1 with both OGT and OGA increase. RNA-Seq-based transcriptome analysis of G1E-ER4 cells differentiated in the presence of the OGA inhibitor Thiamet-G (TMG) revealed changes in expression of 433 GATA-1 target genes. ChIP results indicated that the TMG treatment decreases the occupancy of GATA-1, OGT, and OGA at the GATA-binding site of the lysosomal protein transmembrane 5 ( Laptm5 ) gene promoter. TMG also reduced the expression of genes involved in differentiation of NB4 and HL60 human myeloid leukemia cells, suggesting that O -GlcNAcylation is involved in the regulation of hematopoietic differentiation. Sustained treatment of G1E-ER4 cells with TMG before differentiation reduced hemoglobin-positive cells and increased stem/progenitor cell surface markers. Our results show that alterations in O -GlcNAcylation disrupt transcriptional programs controlling erythropoietic lineage commitment, suggesting a role for O -GlcNAcylation in regulating hematopoietic cell fate., (© 2019 Zhang et al.)

Context: - Patients with rare tumors have difficulty finding reliable information about their disease. Facebook patient support groups allow patients to educate one another., Objective: - To investigate how these patients perceive the value of pathologists, both in Facebook groups and real-world patient care., Design: - Survey links were posted in 12 Facebook patient groups: 6 with an active pathologist member (angiosarcoma, epithelioid hemangioendothelioma, epithelioid sarcoma, dermatofibrosarcoma protuberans [×2], and desmoid fibromatosis), and 6 without "active" pathologist involvement (aggressive angiomyxoma, chondrosarcoma, Ewing sarcoma, leiomyosarcoma, liposarcoma, and osteosarcoma)., Results: - A total of 542 people responded (403 were patients): 264 from groups with a pathologist, and 278 from groups without active pathologist involvement. Of groups with an active pathologist, respondents agreed the pathologist's posts helped them better understand their disease (107 of 119; 90%) and relieved some of their disease-related anxiety (92 of 119; 77%). And for these groups 98% (117 of 119) of respondents agreed that having a pathologist in their group was a good thing; 83% (192 of 232) wanted more pathologists involved. More respondents from groups with an active pathologist (219 of 236; 93%) than without one (215 of 252; 85%) agreed: "pathologists are an important part of the patient care team for patients with cancer and other rare tumors" ( P = .008)., Conclusions: - This study is the first to evaluate the impact of pathologist interaction with Facebook patient support groups and to assess perceptions about the specialty of pathology from a large group of patients with rare tumors. Pathologist involvement in Facebook patient groups appears to positively influence patient perception of the importance of pathologists. We hope these data will encourage more pathologists to participate in Facebook patient support groups.

Sequence-selective intercalation of pyrene into the chain-folds of a random, binary copolyimide under fast-exchange conditions results in the development of self-similar structure in the diimide region of the 1 H NMR spectrum. The resulting spectrum can be described by the mathematics of fractals, an approach that is rationalised in terms of a dynamic summation of ring-current shielding effects produced by pyrene molecules intercalating into the chain at progressively greater distances from each "observed" diimide residue. The underlying set of all such summations is found to be a defined mathematical fractal namely the fourth-quarter Cantor set, within which the observed spectrum is embedded. The pattern of resonances predicted by a geometric construction of the fourth-quarter Cantor set agrees well with the observed spectrum.

This corrects the article DOI: 10.1038/nature25738.

From around 2750 to 2500 bc, Bell Beaker pottery became widespread across western and central Europe, before it disappeared between 2200 and 1800 bc. The forces that propelled its expansion are a matter of long-standing debate, and there is support for both cultural diffusion and migration having a role in this process. Here we present genome-wide data from 400 Neolithic, Copper Age and Bronze Age Europeans, including 226 individuals associated with Beaker-complex artefacts. We detected limited genetic affinity between Beaker-complex-associated individuals from Iberia and central Europe, and thus exclude migration as an important mechanism of spread between these two regions. However, migration had a key role in the further dissemination of the Beaker complex. We document this phenomenon most clearly in Britain, where the spread of the Beaker complex introduced high levels of steppe-related ancestry and was associated with the replacement of approximately 90% of Britain's gene pool within a few hundred years, continuing the east-to-west expansion that had brought steppe-related ancestry into central and northern Europe over the previous centuries.

Animal models of erythropoiesis have been, and will continue to be, important tools for understanding molecular mechanisms underlying the development of this cell lineage and the pathophysiology associated with various human erythropoietic diseases. In this regard, the mouse is probably the most valuable animal model available to investigators. The physiology and short gestational period of mice make them ideal for studying developmental processes and modeling human diseases. These attributes, coupled with cutting-edge genetic tools such as transgenesis, gene knockouts, conditional gene knockouts, and genome editing, provide a significant resource to the research community to test a plethora of hypotheses. This review summarizes the mouse models available for studying a wide variety of erythroid-related questions, as well as the properties inherent in each one.

The aim of this study was to use electronic health care records (EHRs) to examine retrospectively the incidence of and attributes associated with dental implant failures necessitating implant removal in a large cohort of patients treated in the student clinics of a U.S. dental school over three and a half years. EHRs were searched for all patients who received dental implants between July 1, 2011, and December 31, 2014. Characteristics of patients and implants that were actively removed due to irrevocable failure of any etiology ("failure cohort") during this period were compared to those of all other patients who received dental implants during the same time frame ("reference cohort"). Differences in the frequency distribution of various characteristics between the failure and reference cohorts were compared. Of a total 6,129 implants placed in 2,127 patients during the study period, 179 implants (2.9%) in 120 patients (5.6%) were removed. In the multivariate analysis, presence of a removable (OR=2.86) or fixed temporary prosthesis (OR=3.71) was statistically significantly associated with increased risk for implant failure. In contrast, antibiotic coverage (pre- and post-surgery OR=0.16; post-surgery only OR=0.38) and implants of certain manufacturers were associated with lower risk of implant failure. In this sizeable cohort of patients receiving care in dental student clinics, the review of EHRs facilitated identification of multiple variables associated with implant failure resulting in removal; however, these findings do not suggest causative relationships. The adopted analytical approach can enhance quality assurance measures and may contribute to the identification of true risk factors for dental implant failure.

A geostatistical model to predict human skeletal oxygen isotope values (δ 18 O p ) in Britain is presented here based on a new dataset of Chalcolithic and Early Bronze Age human teeth. The spatial statistics which underpin this model allow the identification of individuals interpreted as 'non-local' to the areas where they were buried (spatial outliers). A marked variation in δ 18 O p is observed in several areas, including the Stonehenge region, the Peak District, and the Yorkshire Wolds, suggesting a high degree of human mobility. These areas, rich in funerary and ceremonial monuments, may have formed focal points for people, some of whom would have travelled long distances, ultimately being buried there. The dataset and model represent a baseline for future archaeological studies, avoiding the complex conversions from skeletal to water δ 18 O values-a process known to be problematic.

Fetal hemoglobin is a major genetic modifier of the phenotypic heterogeneity in patients with sickle cell disease and certain β-thalassemias. Normal levels of fetal hemoglobin postnatally are approximately 1% of total hemoglobin. Patients who have hereditary persistence of fetal hemoglobin, characterized by elevated synthesis of γ-globin in adulthood, show reduced disease pathophysiology. Hereditary persistence of fetal hemoglobin is caused by β-globin locus deletions (deletional hereditary persistence of fetal hemoglobin) or γ-globin gene promoter point mutations (non-deletional hereditary persistence of fetal hemoglobin). Current research has focused on elucidating the pathways involved in the maintenance/reactivation of γ-globin in adult life. To better understand these pathways, we generated new β-globin locus yeast artificial chromosome transgenic mice bearing the (A)γ-globin -175 T > C or -195 C > G hereditary persistence of fetal hemoglobin mutations to model naturally occurring hereditary persistence of fetal hemoglobin. Adult -175 and -195 mutant β-YAC mice displayed a hereditary persistence of fetal hemoglobin phenotype, as measured at the mRNA and protein levels. The molecular basis for these phenotypes was examined by chromatin immunoprecipitation of transcription factor/co-factor binding, including YY1, PAX1, TAL1, LMO2, and LDB1. In -175 HPFH versus wild-type samples, the occupancy of LMO2, TAL1 and LDB1 proteins was enriched in HPFH mice (5.8-fold, 5.2-fold and 2.7-fold, respectively), a result that concurs with a recent study in cell lines showing that these proteins form a complex with GATA-1 to mediate long-range interactions between the locus control region and the (A)γ-globin gene. Both hereditary persistence of fetal hemoglobin mutations result in a gain of (A)γ-globin activation, in contrast to other hereditary persistence of fetal hemoglobin mutations that result in a loss of repression. The mice provide additional tools to study γ-globin gene expression and may reveal new targets for selectively activating fetal hemoglobin., (© 2016 by the Society for Experimental Biology and Medicine.)

Synthetically straightforward conditions have been developed for the preparation of poly(bis 2,2,2-trifluoroethoxy)phosphazene with low PDI (<1.15) at high conversion (75-99%) and on a multigram scale. A combination of 31 P NMR and GPC analyses demonstrate that molecular weight increases linearly as a function of monomer consumption, exhibiting first order kinetics with respect to monomer concentration up to high monomer conversion. Thus, the molecular weight can be controlled by varying the initiator (H 2 O) to monomer ratio.

Protein motions control enzyme catalysis through mechanisms that are incompletely understood. Here NMR (13)C relaxation dispersion experiments were used to monitor changes in side-chain motions that occur in response to activation by phosphorylation of the MAP kinase ERK2. NMR data for the methyl side chains on Ile, Leu, and Val residues showed changes in conformational exchange dynamics in the microsecond-to-millisecond time regime between the different activity states of ERK2. In inactive, unphosphorylated ERK2, localized conformational exchange was observed among methyl side chains, with little evidence for coupling between residues. Upon dual phosphorylation by MAP kinase kinase 1, the dynamics of assigned methyls in ERK2 were altered throughout the conserved kinase core, including many residues in the catalytic pocket. The majority of residues in active ERK2 fit to a single conformational exchange process, with kex ≈ 300 s(-1) (kAB ≈ 240 s(-1)/kBA ≈ 60 s(-1)) and pA/pB ≈ 20%/80%, suggesting global domain motions involving interconversion between two states. A mutant of ERK2, engineered to enhance conformational mobility at the hinge region linking the N- and C-terminal domains, also induced two-state conformational exchange throughout the kinase core, with exchange properties of kex ≈ 500 s(-1) (kAB ≈ 15 s(-1)/kBA ≈ 485 s(-1)) and pA/pB ≈ 97%/3%. Thus, phosphorylation and activation of ERK2 lead to a dramatic shift in conformational exchange dynamics, likely through release of constraints at the hinge.

Objective: To compare noise reduction of commercially available ear-level hearing protection (muffs/inserts) to that of firearm muzzle suppressors., Setting: Experimental sound measurements under consistent environmental conditions., Subjects: None., Study Design and Methods: Muzzle suppressors for 2 pistol and 2 rifle calibers were tested using the Bruel & Kjaer 2209 sound meter and Bruel & Kjaer 4136 microphone calibrated with the Bruel & Kjaer Pistonphone using Military-Standard 1474D placement protocol. Five shots were recorded unsuppressed and 10 shots suppressed under consistent environmental conditions. Sound reduction was then compared with the real-world noise reduction rate of the best available ear-level protectors., Results: All suppressors offered significantly greater noise reduction than ear-level protection, usually greater than 50% better. Noise reduction of all ear-level protectors is unable to reduce the impulse pressure below 140 dB for certain common firearms, an international standard for prevention of sensorineural hearing loss., Conclusion: Modern muzzle-level suppression is vastly superior to ear-level protection and the only available form of suppression capable of making certain sporting arms safe for hearing. The inadequacy of standard hearing protectors with certain common firearms is not recognized by most hearing professionals or their patients and should affect the way hearing professionals counsel patients and the public.

Background: Natural human psychological phenomena, such as depression, anxiety, delusions, hallucinations and dementia, are documented across the ages in both fictional and non-fictional works. We asked whether 'dissociative amnesia' was similarly documented throughout history., Method: We advertised in three languages on more than 30 Internet web sites and discussion groups, and also in print, offering US$1000 to the first individual who could find a case of dissociative amnesia for a traumatic event in any fictional or non-fictional work before 1800., Results: Our search generated more than 100 replies; it produced numerous examples of ordinary forgetfulness, infantile amnesia and biological amnesia throughout works in English, other European languages, Latin, Greek, Arabic, Sanskrit and Chinese before 1800, but no descriptions of individuals showing dissociative amnesia for a traumatic event., Conclusions: If dissociative amnesia for traumatic events were a natural psychological phenomenon, an innate capacity of the brain, then throughout the millennia before 1800, individuals would presumably have witnessed such cases and portrayed them in non-fictional works or in fictional characters. The absence of cases before 1800 cannot reasonably be explained by arguing that our ancestors understood or described psychological phenomena so differently as to make them unrecognizable to modern readers because spontaneous complete amnesia for a major traumatic event, in an otherwise lucid individual, is so graphic that it would be recognizable even through a dense veil of cultural interpretation. Therefore, it appears that dissociative amnesia is not a natural neuropsychological phenomenon, but instead a culture-bound syndrome, dating from the nineteenth century.

Objective: This survey was conducted to better understand women's experiences with hormonal contraception and their interest in and attitudes toward gaining direct access to oral contraception (OC), patch, ring or emergency contraception (EC) in pharmacies., Method: A nationally representative telephone survey of 811 women aged 18-44 years who were at risk for unintended pregnancy was conducted in the United States., Results: It was found that 68% of women in the United States said they would use pharmacy access to OC, patch, ring and/or EC. Likely users include women not using contraception who would begin using hormonal contraceptives (41%) if they were available directly in pharmacies, and OC, patch or ring users who were interested in obtaining their method this way (66%). Over half of the women (55%) said they would be more likely to use EC if they were available directly in pharmacies. Interest in pharmacy access is higher among uninsured and low-income women. Support for pharmacy access hinges on pharmacist screening, with 63% of women agreeing that OC, patch and ring should be available without prescription if pharmacists screen women for medically safe use., Conclusion: Most women in the United States believe that hormonal contraception should be available without prescription and would personally use pharmacy access. Seventeen to 22 million women constitute the potential market for pharmacy access to hormonal contraceptives in the United States. Women's enthusiasm for pharmacy access suggests that the pharmacy is an important site for the provision of sexual health education, screening and supplies.

The authors offer a new, integrative conceptualization of the relational self based on a synthesis of recent approaches to the self and significant others. This conceptualization provides a sharper and fuller definition of the relational self than does any existing approach alone and a common framework to interpret findings from separate literatures. The authors then present 5 propositions and evidence to support the thesis that relational selves exert a pervasive influence on interpersonal life. Specifically, relational selves (a) shape a wide range of psychological processes and outcomes, (b) exert their influence automatically, (c) serve basic orientation and meaning functions, (d) provide continuity and context-specific variability in personality, and (e) carry implications for psychological well-being. Discussion focuses on remaining issues and implications for future research.

The basolateral amygdala complex has been implicated in the formation and utilization of cocaine-cue associations in rat models of cue-induced reinstatement to cocaine-seeking behavior. We have previously demonstrated the importance of dopamine inputs to the basolateral amygdala complex in the reinstatement of cocaine-seeking behavior following chronic cocaine self-administration. Here we show that selective blockade of amygdalar dopamine D1 and D2 receptors during acquisition of cocaine-cue associations has distinctive effects on subsequent conditioned-cued cocaine-seeking behavior. Male, Sprague-Dawley rats were first trained to self-administer i.v. cocaine on a fixed ratio 1 schedule for 5 days. Subjects then received bilateral, intra-basolateral amygdala complex infusions of a dopamine D1 receptor antagonist (SCH23390, 0.25-2.0 microg/side; experiment 1), a dopamine D2 receptor antagonist (raclopride, 0.625-5.0 microg/side; experiment 2), or vehicle just prior to a single classical conditioning session, during which a light+tone cue was discretely paired with passive infusions of cocaine in the absence of lever responding. Following five additional days of cocaine self-administration and 7-10 days of extinction training, animals underwent multiple tests for cue-induced reinstatement. SCH23390 (2.0 microg/side), administered at the time of cocaine-cue association only, produced an attenuation of reinstatement to cue-induced cocaine-seeking behavior. In contrast, low doses of raclopride potentiated, while a higher dose of raclopride attenuated cue-induced reinstatement. These results demonstrate unique contributions of D1 vs. D2 receptors in mediating dopamine inputs within the basolateral amygdala complex during the formation of cocaine-stimulus associations that are critical for cue-induced reinstatement.

Rationale: Gender differences exist in the patterns of drug taking in cocaine addiction, suggesting that the propensity to relapse varies between men and women. Previous reports have shown sex differences in both cocaine-primed and conditioned-cued reinstatement of cocaine-seeking behavior, including recent evidence that the estrous cycle influences the level of conditioned-cued reinstatement. However, the influence of the estrous cycle on cocaine-primed reinstatement has not been examined., Objective: Accordingly, we assessed the influence of sex and estrous cycle status on cocaine-primed reinstatement of drug-seeking behavior in Sprague-Dawley rats., Methods: Intact male and female rats were trained to lever press to self-administer intravenous cocaine (0.5 mg/kg every infusion; fixed ratio 1, 20-s time-out following each infusion), followed by prolonged extinction training, and subsequently tested for the ability of a cocaine-priming injection (0, 5, or 10 mg/kg i.p.) to reinstate extinguished cocaine seeking (i.e., nonreinforced lever responding)., Results: Despite no differences in cocaine intake between male and female rats, females responded more on the cocaine-paired lever during self-administration and extinction relative to males. Subsequently, both males and females exhibited a dose-dependent cocaine-primed reinstatement of extinguished drug-seeking behavior. Moreover, females in estrus exhibited significantly higher reinstatement than either males or non-estrus females, following a high-dose (10 mg/kg) cocaine prime., Conclusions: Estrus females display heightened sensitivity to the motivational and/or stimulant effects of cocaine, suggesting that hormonal state modulates drug craving and propensity for drug relapse in cocaine addicts.

The present study tested the hypothesis that separate neural substrates mediate cocaine relapse elicited by drug-associated contextual stimuli vs explicit conditioned stimuli (CSs) and cocaine. Specifically, we investigated the involvement of the dorsal hippocampus (DH), basolateral amygdala (BLA), and dorsomedial prefrontal cortex (dmPFC) in contextual reinstatement of cocaine-seeking behavior and the involvement of the DH in explicit CS- and cocaine-induced reinstatement. Rats were trained to self-administer cocaine in a distinct context or in the presence of CSs paired explicitly with cocaine infusions. Responding of context-trained rats was then extinguished in the previously cocaine-paired or an alternate context, whereas responding of explicit CS-trained rats was extinguished in the absence of the CSs. Subsequently, the target brain regions or anatomical control regions were functionally inactivated using tetrodotoxin (0 or 5 ng/side), and cocaine-seeking behavior (ie, nonreinforced responses) was assessed in the cocaine-paired context, in the alternate context, in the presence of the explicit CSs, or following cocaine priming (10 mg/kg, i.p.). DH inactivation abolished contextual, but failed to alter explicit CS- or cocaine-induced, reinstatement of cocaine-seeking behavior. BLA or dmPFC inactivation also abolished contextual reinstatement. Conversely, inactivation of the control brain regions failed to alter contextual reinstatement. In conclusion, the DH, BLA, and dmPFC play critical roles in contextual reinstatement. Previous findings suggest that the BLA is critical for explicit CS-induced, but not cocaine-primed, reinstatement and the dmPFC is critical for both explicit CS-induced and cocaine-primed reinstatement. Thus, distinct but partially overlapping neural substrates mediate context-induced, explicit CS-induced, and cocaine-primed reinstatement of extinguished cocaine-seeking behavior.

Orbitofrontal cortex (OFC) damage elicits impulsivity and perseveration, and impairments in OFC function may underlie compulsive drug seeking in cocaine users. To test this hypothesis, we assessed the effects of fiber-sparing lesions or functional inactivation of OFC subregions on cocaine seeking in rats. Rats were trained to lever press for intravenous cocaine (0.20 mg/infusion) paired with the presentations of light plus tone stimuli. Responding was then allowed to extinguish. Rats received bilateral NMDA (0.1 M) or sham lesions of the lateral OFC (lOFC) or medial OFC (mOFC) before self-administration training (experiment 1) or muscimol plus baclofen (0.1 and 1.0 mM) or vehicle infusions into the lOFC or mOFC before reinstatement testing (experiment 2). The effects of these manipulations on reinstatement of cocaine seeking (i.e., responding on the previously cocaine-paired lever) were assessed in the presence of the light plus tone stimuli or after a cocaine priming injection (10 mg/kg, i.p.). Post-training lOFC inactivation impaired conditioned cue-induced reinstatement, whereas other manipulations failed to alter this behavior. This suggests that the lOFC plays a critical role in assessing the current motivational significance of cocaine-conditioned stimuli or in using this information to guide cocaine-seeking behavior if stimulus-reward learning takes place before lOFC damage. OFC inactivation failed to alter cocaine-primed reinstatement. However, lOFC lesions augmented cocaine-primed reinstatement in a perseverative manner, whereas mOFC lesions attenuated cocaine-primed reinstatement, suggesting that prolonged cell loss in OFC subregions may modulate the propensity for cocaine seeking in a subregion-specific manner.

Inhibitors of proteases prevent tumor-associated matrix degradation, affecting tumor growth, angiogenesis and metastasis. Our study was designed to investigate the effect of inhibition of matrix metalloproteinases (MMPs) on the growth of experimental hemangiomas, using the model of murine endothelioma eEnd.1 cells. In nude mice, these cells generate hemangiomas, consisting mostly of host-recruited endothelial cells, whose growth requires the activity of MMPs. In vitro, eEnd.1 cells produce factors that recruit endothelial cells and stimulate them to release MMPs. Over-expression of TIMP-2, following retrovirus-mediated gene transfer, decreased tumor growth in vivo. The infected clone CR1, which produces high levels of TIMP-2 (as assessed by Northern blot, ELISA and reverse zymography), formed slow-growing tumors that did not grow beyond 0.4 g, while clone 1H, which produces little TIMP-2, grew not dissimilarly to mock-infected cells and parental e.End.1 cells. Histologically, control tumors presented the features of cavernous hemangiomas, while CR1 tumors had a more solid pattern, showing foci of apoptotic cells. In vitro, TIMP-2 over-expression had no autocrine anti-proliferative effect on endothelioma cells but reduced their ability to recruit endothelial cells. CR1 cells lacked the capacity of mock-infected or parental eEnd.1 cells to stimulate endothelial cell motility and invasiveness. Antibodies against TIMP-2 restored the ability of CR1 to induce endothelial cell invasion. We conclude that, in this model, genetic increase of TIMP-2 inhibits tumor growth, apparently by affecting the recruitment and organization of host endothelial cells by the transformed cells., (Copyright 2001 Wiley-Liss, Inc.)