Alternate Edens: History, Evolution, and Origins in UNESCO's Cultural and Scientific History of Mankind.

In 1963, the United Nations Educational, Scientific, and Cultural Organization (UNESCO) published the first volume of its long-awaited cultural and scientific history of mankind. First announced in 1948, the History of Mankind was envisioned as a comprehensive, universal human history, from the evolution of Homo sapiens to the middle of the twentieth century. This article uses editorial conflicts over the site of the cradle of the human species to explore the position of scientific knowledge in world history writing and to examine tensions between different national traditions of expertise at a moment of political and scientific transition.

Archaeology enters the 'atomic age': a short history of radiocarbon, 1946-1960.

Today, the most powerful research technique available for assigning chronometric age to human cultural objects is radiocarbon dating. Developed in the United States in the late 1940s by an alumnus of the Manhattan Project, radiocarbon dating measures the decay of the radioactive isotope carbon-14 (C14) in organic material, and calculates the time elapsed since the materials were removed from the life cycle. This paper traces the interdisciplinary collaboration between archaeology and radiochemistry that led to the successful development of radiocarbon dating in the early 1950s, following the movement of people and ideas from Willard Libby's Chicago radiocarbon laboratory to museums, universities and government labs in the United States, Australia, Denmark and New Zealand. I show how radiocarbon research built on existing technologies and networks in atomic chemistry and physics but was deeply shaped by its original private philanthropic funders and archaeologist users, and ultimately remained to the side of many contemporaneous Cold War scientific and military projects.

The dysphagia stress test for rapid assessment of swallowing difficulties in esophageal conditions.

BACKGROUND: Esophageal dysphagia is a common symptom in gastroenterology practice. Current rapid assessment tools are limited to oropharyngeal dysphagia and do not translate well to esophageal conditions. We aim to create a novel tool, the dysphagia stress test (DST), to evaluate swallowing in patients with esophageal disease characterized by dysphagia. METHODS: Adults with eosinophilic esophagitis (EoE), gastroesophageal reflux disease (GERD), achalasia, and dysphagia not otherwise specified (NOS) participated. Patient controls with non-esophageal diagnoses and healthy controls were also recruited. Participants completed the DST with five bolus challenges: water, applesauce, rice, bread, barium tablet and rated their swallowing difficulty and pain. A study clinician observed and documented water use and refusal of any challenges. Participants also completed measures of esophageal symptoms, hypersensitivity, and symptom anxiety to evaluate the DST validity. Collinearity of bolus challenges guided item reduction. KEY RESULTS: A total of 132 subjects participated. Both control groups and GERD patients had the best swallowing ability, while achalasia, EOE, and dysphagia NOS scored poorer. About 90% of patients were able to attempt or pass each of the bolus challenges, suggesting high acceptability. Construct validity of the DST is evidenced by modest negative correlations with symptom severity, hypersensitivity, and anxiety. The DST does not appear to be influenced by brain-gut processes. Applesauce, rice, and bread demonstrated collinearity; thus, the DST was reduced to three challenges. CONCLUSIONS & INFERENCES: The DST is the first rapid assessment tool designed for gastroenterology clinics with direct observation of swallowing ability across several conditions to mitigate issues related to patient self-report of esophageal symptoms.

Development and validation of a symptom-based activity index for adults with eosinophilic esophagitis.

BACKGROUND & AIMS: Standardized instruments are needed to assess the activity of eosinophilic esophagitis (EoE) and to provide end points for clinical trials and observational studies. We aimed to develop and validate a patient-reported outcome (PRO) instrument and score, based on items that could account for variations in patient assessments of disease severity. We also evaluated relationships between patient assessment of disease severity and EoE-associated endoscopic, histologic, and laboratory findings. METHODS: We collected information from 186 patients with EoE in Switzerland and the United States (69.4% male; median age, 43 y) via surveys (n = 135), focus groups (n = 27), and semistructured interviews (n = 24). Items were generated for the instruments to assess biologic activity based on physician input. Linear regression was used to quantify the extent to which variations in patient-reported disease characteristics could account for variations in patient assessment of EoE severity. The PRO instrument was used prospectively in 153 adult patients with EoE (72.5% male; median age, 38 y), and validated in an independent group of 120 patients with EoE (60.8% male; median age, 40.5 y). RESULTS: Seven PRO factors that are used to assess characteristics of dysphagia, behavioral adaptations to living with dysphagia, and pain while swallowing accounted for 67% of the variation in patient assessment of disease severity. Based on statistical consideration and patient input, a 7-day recall period was selected. Highly active EoE, based on endoscopic and histologic findings, was associated with an increase in patient-assessed disease severity. In the validation study, the mean difference between patient assessment of EoE severity (range, 0-10) and PRO score (range, 0-8.52) was 0.15. CONCLUSIONS: We developed and validated an EoE scoring system based on 7 PRO items that assess symptoms over a 7-day recall period. Clinicaltrials.gov number: NCT00939263.

Liraglutide-induced autoimmune hepatitis.

IMPORTANCE: Use of incretin-based hypoglycemic agents is increasing, but safety data remain limited. We treated a woman with marker-negative autoimmune hepatitis associated with the glucagon-like peptide 1 agonist liraglutide. OBSERVATIONS: A young woman with type 2 diabetes mellitus and vitiligo presented with a 10-day history of acute hepatitis. Other than starting liraglutide therapy 4 months prior, she reported no changes in medication therapy and no use of supplements. At admission, aspartate aminotransferase level was 991 U/L; alanine aminotransferase level, 1123 U/L; total bilirubin level, 9.5 mg/dL; and international normalized ratio, 1.3. Results of a liver biopsy demonstrated interface hepatitis with prominent eosinophils and rare plasma cells. The patient's liraglutide therapy was withheld at discharge but her symptoms worsened. A second biopsy specimen revealed massive hepatic necrosis. She started oral prednisone therapy for presumed liraglutide-induced marker-negative autoimmune hepatitis. CONCLUSIONS AND RELEVANCE: This case represents, to our knowledge, the first report of liraglutide-induced autoimmune hepatitis. Hepatotoxicity may be an incretin analogue class effect with a long latency period. This case raises prescriber awareness about the potential adverse effects of glucagon-like peptide 1 agonists. Postmarketing studies are needed to define the hepatotoxic potential of these agents.

Emerging drugs for eosinophilic esophagitis.

INTRODUCTION: Eosinophilic esophagitis (EoE) has emerged over the past two decades as an important esophageal disorder with significant associated morbidity. The prevalence of EoE now approximates that of commonly recognized gastrointestinal diseases including inflammatory bowel disease. In adults, EoE is now a leading cause of dysphagia and food impaction. Medications, food elimination diets and esophageal dilation are currently utilized for the treatment of EoE. While these approaches are often effective, no pharmaceutical agents have yet been approved by the Food and Drug Administration (FDA). The current medical therapies for EoE primarily consist of topical corticosteroids that have been adopted from formulations designed for pulmonary delivery in patients with asthma and have not been optimized for esophageal delivery. AREAS COVERED: This article focuses on therapeutics being developed for EoE. Several trials have evaluated improved steroid vehicles designed for topical delivery to the esophagus. Novel biologic compounds, including anti-interleukin-5 and anti-interleukin-13, are being evaluated as targeted treatment options in EoE patients. Inhibitors of mast cell-derived prostaglandin D2 (PGD2) are also being studied, based on the concept that mast cells play an important role in EoE pathogenesis. Additional therapies, including immunomodulators, leukotriene antagonists, allergy immunotherapy and angiotensin II receptor blockers, are also examined in this article. EXPERT OPINION: No FDA-approved prescription medications are currently available for EoE patients. Although a number of novel agents are being developed and tested, Phase III clinical trials are scarce. Since EoE is a newly described disease, physicians have an incomplete understanding of the disease's pathogenesis, natural history and disease manifestations. This has led to significant difficulties in determining the most appropriate endpoints of therapy. Clinical trials are hampered by the lack of an accepted, standardized disease activity measure or biomarker by which therapeutic efficacy is assessed. Effective and approved pharmaceutical therapies are eagerly awaited by both physicians and patients for this increasingly recognized and clinically important disease.

Qualitative assessment of patient-reported outcomes in adults with eosinophilic esophagitis.

GOALS: This study aims to qualitatively describe experiences of adult patients diagnosed with eosinophilic esophagitis (EoE). Specifically, we aim to identify disease-specific concerns related to patient-reported outcomes in this population to inform clinical care and assessment. BACKGROUND: EoE is a chronic inflammatory disease of the esophagus and is increasingly recognized as a cause of dysphagia in adults. On the basis of its symptoms, limited and restrictive treatment options and potential for social and psychological impact, it is logical to expect that the health related quality of life of EoE patients would be an important outcome marker for assessment. STUDY: Twenty-four EoE patients participated in semistructured interviews about their illness experiences. Participants also provided demographic and clinical data, and completed the Medical Outcome Study Short Form 12 to assess mental and physical function. RESULTS: Six themes emerged from qualitative analyses which centered around 3 main points: concerns about the illness itself, concerns about swallowing difficulty, and concerns about the impact of EoE on social interactions. Patients were generally open to disclosing their illness status and reported relief at receipt of the EoE diagnosis. EoE patients did not differ from healthy norms for physical well-being, and were similar to comparable illness groups for mental functioning. CONCLUSIONS: Our study demonstrated that EoE has substantial impact on several psychosocial domains that are not adequately addressed by focused assessment of physical complaints of dysphagia. The results support the importance of development of disease-specific instruments pertaining to quality of life in EoE patients.

Thrombospondin-1 is an adipokine associated with obesity, adipose inflammation, and insulin resistance.

OBJECTIVE: We examined the relationship between the expression of thrombospondin (TSP)1, an antiangiogenic factor and regulator of transforming growth factor-beta activity, obesity, adipose inflammation, and insulin resistance. RESEARCH DESIGN AND METHODS: TSP1 gene expression was quantified in subcutaneous adipose tissue (SAT) of 86 nondiabetic subjects covering a wide range of BMI and insulin sensitivity, from visceral adipose (VAT) and SAT from 14 surgical patients and from 38 subjects with impaired glucose tolerance randomized to receive either pioglitazone or metformin for 10 weeks. An adipocyte culture system was also used to assess the effects of pioglitazone and coculture with macrophages on TSP1 gene expression. RESULTS: TSP1 mRNA was significantly associated with obesity (BMI) and insulin resistance (low insulin sensitivity index). Relatively strong positive associations were seen with markers of inflammation, including CD68, macrophage chemoattractant protein-1, and plasminogen activator inhibitor (PAI)-1 mRNA (r >/= 0.46, P = 0.001 for each), that remained significant after controlling for BMI and S(i). However, TSP1 mRNA was preferentially expressed in adipocyte fraction, whereas inflammatory markers predominated in stromal vascular fraction. Coculture of adipocytes and macrophages augmented TSP1 gene expression and secretion from both cell types. Pioglitazone (not metformin) treatment resulted in a 54% decrease (P < 0.04) in adipose TSP gene expression, as did in vitro pioglitazone treatment of adipocytes. CONCLUSIONS: TSP1 is a true adipokine that is highly expressed in obese, insulin-resistant subjects; is highly correlated with adipose inflammation; and is decreased by pioglitazone. TSP1 is an important link between adipocytes and macrophage-driven adipose tissue inflammation and may mediate the elevation of PAI-1 that promotes a prothrombotic state.