Strategies for anti-fibrotic therapies.

The fibrotic diseases encompass a wide spectrum of entities including such multisystemic diseases as systemic sclerosis, nephrogenic systemic fibrosis and sclerodermatous graft versus host disease, as well as organ-specific disorders such as pulmonary, liver, and kidney fibrosis. Collectively, given the wide variety of affected organs, the chronic nature of the fibrotic processes, and the large number of individuals suffering their devastating effects, these diseases pose one of the most serious health problems in current medicine and a serious economic burden to society. Despite these considerations there is currently no accepted effective treatment. However, remarkable progress has been achieved in the elucidation of their pathogenesis including the identification of the critical role of myofibroblasts and the determination of molecular mechanisms that result in the transcriptional activation of the genes responsible for the fibrotic process. Here we review the origin of the myofibroblast and discuss the crucial regulatory pathways involving multiple growth factors and cytokines that participate in the pathogenesis of the fibrotic process. Potentially effective therapeutic strategies based upon this new information are considered in detail and the major challenges that remain and their possible solutions are presented. It is expected that translational efforts devoted to convert this new knowledge into novel and effective anti-fibrotic drugs will be forthcoming in the near future. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease

The Decline and Rise of Interstate Migration in the United States: Evidence from the IPUMS, 1850-1990

We examine evidence on trends in interstate migration over the past 150 years, using data from the Integrated Public Use Microdata Series of the U.S. Census (IPUMS). Two measures of migration are calculated. The first considers an individual to have moved if she is residing in a state different from her state of birth. The second considers a family to have moved if it is residing in a state different from the state of birth of one of its young children. The latter measure allows us estimate the timing of moves more accurately. Our results suggest that overall migration propensities have followed a U-shaped trend since 1850, falling until around 1900 and then rising until around 1970. We examine variation in the propensity to make an interstate move by age, sex, race, nativity, region of origin, family structure, and education. Counterfactuals based on probit estimates of the propensity to migrate suggest that the rise in migration of families since 1900 is largely attributable to increased educational attainment. The decline of interstate migration in the late nineteenth century remains to be explained.

Role of protein kinase C-delta in the regulation of collagen gene expression in scleroderma fibroblasts

Working with cultured dermal fibroblasts derived from control individuals and patients with systemic sclerosis (SSc), we have examined the effects of protein kinase C-delta (PKC-delta) on type I collagen biosynthesis and steady-state levels of COL1A1 and COL3A1 mRNAs. Rottlerin, a specific inhibitor of PKC-delta, exerted a powerful, dose-dependent inhibition of type I and type III collagen gene expression in normal and SSc cells. Optimal rottlerin concentrations caused a 70-90% inhibition of type I collagen production, a \u3e80% reduction in COL1A1 mRNA, and a \u3e70% reduction in COL3A1 mRNA in both cell types. In vitro nuclear transcription assays and transient transfections with COL1A1 promoter deletion constructs demonstrated that rottlerin profoundly reduced COL1A1 transcription and that this effect required a 129-bp promoter region encompassing nucleotides -804 to -675. This COL1A1 segment imparted rottlerin sensitivity to a heterologous promoter. Cotransfections of COL1A1 promoter constructs with a dominant-negative PKC-delta expression plasmid showed that suppression of this kinase silenced COL1A1 promoter activity. The results indicate that PKC-delta participates in the upregulation of collagen gene transcription in SSc and suggest that treatment with PKC-delta inhibitors could suppress fibrosis in this disease

Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1

Massive research efforts are now underway to develop a cure for HIV infection, allowing patients to discontinue lifelong combination antiretroviral therapy (ART). New latency-reversing agents (LRAs) may be able to purge the persistent reservoir of latent virus in resting memory CD4+ T cells, but the degree of reservoir reduction needed for cure remains unknown. Here we use a stochastic model of infection dynamics to estimate the efficacy of LRA needed to prevent viral rebound after ART interruption. We incorporate clinical data to estimate population-level parameter distributions and outcomes. Our findings suggest that approximately 2,000-fold reductions are required to permit a majority of patients to interrupt ART for one year without rebound and that rebound may occur suddenly after multiple years. Greater than 10,000-fold reductions may be required to prevent rebound altogether. Our results predict large variation in rebound times following LRA therapy, which will complicate clinical management. This model provides benchmarks for moving LRAs from the lab to the clinic and can aid in the design and interpretation of clinical trials. These results also apply to other interventions to reduce the latent reservoir and can explain the observed return of viremia after months of apparent cure in recent bone marrow transplant recipients and an immediately-treated neonate.Comment: 8 pages main text (4 figures). In PNAS Early Edition http://www.pnas.org/content/early/2014/08/05/1406663111. Ancillary files: SI, 24 pages SI (7 figures). File .htm opens a browser-based application to calculate rebound times (see SI). Or, the .cdf file can be run with Mathematica. The most up-to-date version of the code is available at http://www.danielrosenbloom.com/reboundtimes

The Sources of Regional Variation in the Severity of the Great Depression: Evidence from U.S. Manufacturing, 1919-1937

The impact of the Great Depression was milder in the South Atlantic states, more severe in the Mountain states, and surprisingly uniform across other regions of the country —despite large diiferences in industrial structure. Employing data on 20 manufacturing industries disaggregated by state, we analyze the relative contributions of industry mix and location to regional variations in economic performance. Industrial composition had a significant impact on employment growth, with regions that concentrated on durable goods or inputs to construction faring worse than others. Long-run trends also mattered, and explain much of the South Atlantic's more favorable performance

Mobility patterns of the elderly tourist in Algarve

The present work is part of the Project for Scientific Research and Techno-logical Development "Accessibility for All in Tourism" focuses on modal in-terfaces designed according to the concepts of "Universal Design" and "Age Sensitive Design". In this project 851 surveys were carried out for elderly tourists, who arrived in Algarve (Portugal) through the international Airport of Faro, in the summer of 2018, with a view to understanding their prefer-ences and needs in terms of mobility. It presents the characterization of the senior tourist in Algarve, according to: gender, age, academic qualification, situation in the relation to the profession, nationality, disability and/or disa-bilities that affects mobility and the need to use technical aids to move. It analyses and compares, from the point of view of sustainable mobility, the mobility of the elderly tourist, by gender and age group, in the country where they reside and in the Algarve region. This information is useful for local au-thorities and for transport operators in order to make the mobility of elderly tourists, in Algarve, more sustainable from a social, economic and environ-mental standpoint.The Research Project ACCES4ALL - Accessibility for All in Tourisminfo:eu-repo/semantics/publishedVersio

Clinical Diagnosis of Placenta Accreta and Clinicopathological Outcomes

Objective To investigate the association between the intraoperative diagnosis of placenta accreta at the time of cesarean hysterectomy and pathological diagnosis. Study Design This is a retrospective cohort study of all patients undergoing cesarean hysterectomy for suspected placenta accreta from 2000 to 2016 at Barnes-Jewish Hospital. The primary outcome was the presence of invasive placentation on the pathology report. We estimated predictive characteristics of clinical diagnosis of placenta accreta using pathological diagnosis as the correct diagnosis. Results There were 50 cesarean hysterectomies performed for suspected abnormal placentation from 2000 to 2016. Of these, 34 (68%) had a diagnosis of accreta preoperatively and 16 (32%) were diagnosed intraoperatively at the time of cesarean delivery. Two patients had no pathological evidence of invasion, corresponding to a false-positive rate of 4% (95% confidence interval [CI]: 0.5%, 13.8%) and a positive predictive value of 96% (95% CI: 86.3%, 99.5%). There were no differences in complications among patients diagnosed intraoperatively compared with those diagnosed preoperatively. Conclusion Most patients undergoing cesarean hysterectomy for placenta accreta do have this diagnosis confirmed on pathology. However, since the diagnosis of placenta accreta was made intraoperatively in nearly a third of cesarean hysterectomies, intraoperative vigilance is required as the need for cesarean hysterectomy may not be anticipated preoperatively

Labor-Market Regimes in U.S. Economic History

In much economic analysis it is a convenient fiction to suppose that changes over time in wages and employment are determined by shifts in supply or demand within a more or less competitive market framework Indeed, this framework has been effectively deployed to understand many episodes in American economic history. We argue here, however, that by minimizing the role of labor-market institutions such an approach is incomplete. Drawing on the history of American labor markets over two centuries, we argue that institutions--by which we mean both formal and informal rules that constrain the choices of economic agents--have played a significant role in the determination of wages, employment and other market outcomes over time. The historical evolution of American labor markets can best be characterized as a sequence of relatively stable arrangements punctuated by shifts in institutional regimes. Our narrative emphasizes the importance of understanding the historically contingent role of institutional regimes in conditioning the operation of supply and demand in empirical and policy analysis of the labor market.