Increased physical activity: A protective factor against heart attacks in Puerto Rico

The incidence and potential risk factors of coronary heart disease were assessed in 2,585 rural and 6,208 urban men, aged 45 to 64 years, participating in the Puerto Rico Heart Health Program, a prospective epidemiologic study of coronary heart disease initiated in 1965. An index of daily physical activity and a metabolic equivalent of heaviest activity were estimated from each individual history. Rural men had higher mean levels of overall activity as well as higher levels of heavy activity than urban men. An $\text{8}\text{1}\text{4}$ year follow-up study for coronary heart disease other than angina pectoris was analyzed for relationships with physical activity. Significant inverse associations were found for both urban and rural men. Metabolic equivalent of heaviest activity showed similar results. Although the physical activity index was inversely associated with most known coronary risk factors, multivariate analyses indicated that a significant independent inverse relationship existed with the incidence of coronary heart disease. In Puerto Rico, increased physical activity appears to be a separate protective factor against heart attacks.     

Mechanistic Insights into Self-Reinforcing Processes Driving Abnormal Histogenesis During the Development of Pancreatic Cancer

Pancreatic ductal adenocarcinoma, one of the most feared lethal and painful diseases, is increasing in incidence. The poor prognosis of pancreatic ductal adenocarcinoma–affected patients primarily is owing to our inability to develop effective therapies. Mechanistic studies of genetic, epigenetic, and cell-to-cell signaling events are providing clues to molecular pathways that can be targeted in an attempt to cure this disease. The current review article seeks to draw inferences from available mechanistic knowledge to build a theoretical framework that can facilitate these approaches. This conceptual model considers pancreatic cancer as a tissue disease rather than an isolated epithelial cell problem, which develops and progresses in large part as a result of three positive feedback loops: i) genetic and epigenetic changes in epithelial cells modulate their interaction with mesenchymal cells to generate a dynamically changing process of abnormal histogenesis, which drives more changes; ii) the faulty tissue architecture of neoplastic lesions results in unsynchronized secretion of signaling molecules by cells, which generates an environment that is poor in oxygen and nutrients; and iii) the increased metabolic needs of rapidly dividing cells serve as an evolutionary pressure for them to adapt to this adverse microenvironment, leading to the emergence of resistant clones. We discuss how these concepts can guide mechanistic studies, as well as aid in the design of novel experimental therapeutics.CME Accreditation Statement: This activity (“ASIP 2013 AJP CME Program in Pathogenesis”) has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians.The ASCP designates this journal-based CME activity (“ASIP 2013 AJP CME Program in Pathogenesis”) for a maximum of 48 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose.The incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing with more than 44,000 predicted new cases in the United States and 65,000 in Europe,^1,2 with a 5-year survival of less than 5%. PDAC arises from epithelial cells through an accumulation of genetic and epigenetic alterations in oncogenes and tumor suppressors,^3,4 which contribute to form precursor lesions^5,6 known as pancreatic intraepithelial neoplasias (PanINs) (Figures 1 and ​and2).2). Less frequently, PDAC may progress from two types of cystic lesions: mucinous cystic neoplasms and intraductal papillary mucinous neoplasms. In this process, tumor cells proliferate and secrete molecules that drive their communication with surrounding cells. In the fashion of a self-reinforcing loop, surrounding cells also proliferate and secrete new substances, which initiate new communications among themselves, with other noncancer cell types within the tumor (Figure 3).Open in a separate windowFigure 1Self-reinforcing processes that drive abnormal histogenesis during the development of pancreatic cancer. Diagrammatic representation of positive feedback loops that contribute to pancreatic carcinogenesis involves the progressive genetic and epigenetic changes in epithelial cells, which modulate their interaction with mesenchymal cells to generate a dynamically changing process of abnormal histogenesis to further drive more changes. The faulty tissue architecture of neoplastic lesions results in unsynchronized secretion of signaling molecules by cells, which generates an oxygen- and nutrient-poor environment as a result of aberrant angiogenesis. Finally, the increased metabolic needs of rapidly dividing cells serve as an evolutionary pressure for them to adapt to this adverse microenvironment, leading to the emergence of resistant clones.Open in a separate windowFigure 2Histologic correlates of abnormal histogenesis during pancreatic cancer progression. Neoplastic pancreatic tissue from p48-cre/Kras^G12D transgenic animals were stained using the Masson trichromic method, in which epithelial cells are labeled in red and the extracellular matrix is labeled in blue. This series of micrographs show that from the beginning, pancreatic cancer development involves the tight interaction between epithelial cells and its surrounding mesenchyma. A: PanIN1A lesion formed by cells with normal-shaped nuclei but showing incipient nuclear piling up and increased cytoplasm. B: PanIN1B lesion showing papillary projections formed by cells with normal-looking nuclei with a mucin-containing cytoplasm that displaces nuclei to the base of the lesion. C: PanIN2 lesion with abnormally shaped nuclei and typical papilar projections occupying the duct lumen. D: PanIN2 to 3 lesion showing the typical piling up of nuclei with incipient atypia showing anisokaryosis, poikilokaryosis, and papilar projections. Note that a ring of extracellular matrix surrounds the duct-like structure. E: PanIN3 lesion with extensive atypia showing the surrounding ECM as a dense ring that deforms the ductular structures. F: Multifocal cancerous lesions embedded in a dense desmoplasia.Open in a separate windowFigure 3Epithelial–mesenchymal interactions during the development of pancreatic cancer. The functional co-evolution between pancreatic epithelial cells and their stromal counterparts from early preneoplastic to frank neoplastic lesions is shown. Several growth factors are secreted at abnormal amounts, times, and places to generate abnormal signaling cascades that drive the communication between both the epithelial compartment and the tissue microenvironment. As explained in the text, different growth factors exert their function either in a paracrine or autocrine manner to help form the tumors, desmoplasia, and generate an oxygen- and nutrient-poor tumor bed, impacting the pathobiology of pancreatic cancer and contributing to its resistance and aggressiveness. FGF, fibroblast growth factor; MMP, matrix metalloproteinase; PDGF, platelet-derived growth factor; SDF1, serum derived factor-1; SHH, Sonic hedgehog; VEGF, vascular endothelial growth factor.This extended cellular network generates a dynamic tumor microenvironment that influences genetically heterogeneous tumor cells and selects for highly proliferative and resistant clones. Epithelial and mesenchymal cells each contribute to remodeling the stroma into a dense fibrotic tissue (desmoplasia) enriched in fibrillar collagens, stromal cells, and other migratory cell populations. Accordingly, each component of the developing tumor takes an active role in the process of carcinogenesis. Thus, dissecting the temporal and spatial sequence of events that drives these processes should provide new ways for therapeutically transforming pancreatic cancer from a rapidly fatal to a chronic and treatable, or even curable, disease.     

The conundrum of cryptogenic cirrhosis: Adverse outcomes without treatment options

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Noninvasive Streptococcus pneumoniae Serotypes Recovered from Hospitalized Adult Patients in the United States in 2009 to 2012

This study was conducted to determine the serotype distribution and trends over time of Streptococcus pneumoniae strains associated with noninvasive infections among adult patients ≥18 years of age in the United States (2009 to 2012). A total of 2,927 S. pneumoniae isolates recovered from patients presenting with respiratory infections and obtained mainly (87.0%) from lower respiratory tract specimens (sputum) were included. The levels of the 7-valent pneumococcal conjugate vaccine (PCV7) serotypes remained stable over the 4-year study period (4.6% to 5.5%; P = 0.953). Overall, 13-valent pneumococcal conjugate vaccine (PCV13) serotypes were identified in 32.7% of samples, declining from 33.7% to 35.5% in 2009 to 2011 to 28.2% in 2012 (P = 0.007), with a significant decrease in the levels of serotypes 7F (P = 0.013) and 6A (P = 0.010). The levels of 19A remained constant (15.8% to 17.1%) during 2009 to 2011, dropping to 12.2% in 2012 (P = 0.089). The prevalence of serotypes associated with the 23-valent pneumococcal polysaccharide vaccine (PPSV23), but not PCV13, remained generally stable; however, the prevalence of serotypes 15B and 15C (15B/15C) increased from 2.7% to 6.3% (P = 0.010). The proportion of nonvaccine serotypes increased gradually during the study period (P = 0.044), particularly for serotype 35B (from 3.6% in 2009 to 8.2% in 2012; P = 0.001). Nonsusceptibility rates for penicillin (susceptible breakpoint, ≤2 μg/ml) and clindamycin against PCV7 serotypes decreased over the period. These results suggest the emergence of indirect effects following introduction of PCV13 for infants and young children; continued surveillance is needed to assess the burden of PCV13 serotypes in the adult population after the implementation of age-based recommendations in the United States.