LDL concentration is correlated with the removal from the plasma of a chylomicron-like emulsion in subjects with coronary artery disease

In animal model studies, the uptake of chylomicron remnants after entering in the space of Disse occurs mainly by low-density lipoprotein (LDL) receptor and LDL receptor-related protein (LRP). In subjects, the relative importance of each one of these receptors for the clearance of chylomicron remnants is not fully understood. In our study, LDL cholesterol and apolipoprotein (apo) B were correlated to the plasma kinetics of a chylomicron-like emulsion in 77 subjects (11 women, mean age 58 +/- 12 years) with coronary artery disease (CAD). Their total cholesterol was 227 +/- 25 mg/dl, triglyceride 159 +/- 25 mg/dl, LDL cholesterol 148 +/- 27 mg/dl, HDL cholesterol 40 +/- 9 mg/dl, apo A1 1.80 +/- 0.53 g/l and apo B 1.65 +/- 0.48 g/l. The emulsion was double-labeled with 3H-triolein and 14C-cholesteryl oleate and injected intravenously after 12-h fasting. The decay curves of the radioisotopes were determined from blood samples collected at predetermined intervals during 60 min. A negative correlation between FCR of the emulsion cholesterol esters and LDL cholesterol and apo B plasma concentrations was found (r=-0.4, P=0.005 and r=-0.3, P=0.01, respectively) whereas FCR of the emulsion triglycerides did not correlate with any of the plasma lipids or apolipoprotein parameters. Concluding, in patients with CAD, LDL catabolic pathway significantly influences the removal from plasma of chylomicron remnants.     

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.     

Effusive-Constrictive Pericarditis After Pericardiocentesis: Incidence,Associated Findings,and Natural History

Objectives

This study sought to investigate the incidence, associated findings, and natural history of effusive-constrictive pericarditis (ECP) after pericardiocentesis.

Diarrhea associated with rotavirus in rural Guatemala: a longitudinal study of 24 infants and young children.

A population of 24 infants and young children followed prospectively during the first 3 years of life was studied for the occurrence of rotavirus infection by using enzyme-linked immunosorbent assay to detect virus in stools. Infection with rotavirus was associated with 26 (14.2%) of 183 selected diarrheal episodes. Twenty of the 24 infants and young children had diarrhea associated with rotavirus on at least one occasion and six had two such episodes. Rotavirus infection was documented in over 50% of the dehydrating episodes studied, thus further indicating the importance of rotavirus in this population.     

Implanted hair follicle stem cells form Schwann cells that support repair of severed peripheral nerves

The hair follicle bulge area is an abundant, easily accessible source of actively growing, pluripotent adult stem cells. Nestin, a protein marker for neural stem cells, also is expressed in follicle stem cells and their immediate, differentiated progeny. The fluorescent protein GFP, whose expression is driven by the nestin regulatory element in transgenic mice, served to mark the follicle cell fate. The pluripotent nestin-driven GFP stem cells are positive for the stem cell marker CD34 but negative for keratinocyte marker keratin 15, suggesting their relatively undifferentiated state. These cells can differentiate into neurons, glia, keratinocytes, smooth muscle cells, and melanocytes in vitro. In vivo studies show the nestin-driven GFP hair follicle stem cells can differentiate into blood vessels and neural tissue after transplantation to the subcutis of nude mice. Equivalent hair follicle stem cells derived from transgenic mice with beta-actin-driven GFP implanted into the gap region of a severed sciatic nerve greatly enhance the rate of nerve regeneration and the restoration of nerve function. The follicle cells transdifferentiate largely into Schwann cells, which are known to support neuron regrowth. Function of the rejoined sciatic nerve was measured by contraction of the gastrocnemius muscle upon electrical stimulation. After severing the tibial nerve and subsequent transplantation of hair follicle stem cells, walking print length and intermediate toe spread significantly recovered, indicating that the transplanted mice recovered the ability to walk normally. These results suggest that hair follicle stem cells provide an important, accessible, autologous source of adult stem cells for regenerative medicine.     

Baseline Characteristics of Patients with Symptomatic Carotid Webs: A Matched Case Control Study

Background and purposeThe baseline characteristics of patients with symptomatic carotid web (CaW) are unclear. We investigate demographic and cerebrovascular risk factors in patients with this overlooked stroke etiology.MethodsWe identified consecutive patients diagnosed with symptomatic CaW at a comprehensive stroke center from July 2014-December 2018. These patients were matched at a 1:4 ratio (based on age and NIHSS scores) to create a control group of acute ischemic stroke (AIS) patients with non-CaW etiologies from the local GetWithTheGuidelines stroke database.ResultsThirty patients with symptomatic CaW were compared to 120 AIS patients with non-CaW etiologies. Symptomatic CaW patients were more likely to be female (73.3 vs. 44.2%; p = 0.004) and black (86.7 vs. 64.2%; p = 0.02). Symptomatic CaWs patients had a fewer absolute number of modifiable cerebrovascular risk factors (1.7±1.1 vs. 2.5±1.2; p = 0.002), lower rates of hypertension (43.4 vs. 63.3%; p = 0.04), and a more favorable lipid profile with lower average LDL (89.5±30.3 vs. 111.2±43.7 mg/dL; p = 0.01) and higher average HDL (47.9±11.3 vs. 42.2±13.8 mg/dL; p = 0.01) as compared to strokes with non-CaW etiology. Symptomatic CaW patients were more likely to have a large vessel occlusion (80.0 vs. 51.7%; p = 0.005), despite similar e-ASPECTS between the groups (8.1±2.1 vs. 8.3±2.2; p = 0.30). On multivariable analysis, symptomatic CaW was an independent predictor of independence at discharge (OR 3.72; 95%CI 1.27–10.94).ConclusionA gender and racial predilection of symptomatic CaWs may exist as females and blacks were were found to be more likely affected. Symptomatic CaW patients have a more benign cerebrovascular risk factor profile corroborating the proposed mechanism of local stasis and thromboembolism. Despite presenting more commonly with LVO, symptomatic CaW was associated with good functional outcome, warranting further studies.     

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.     

Brief Report: Health-Related Quality of Life in Preschoolers with Autism Spectrum Disorder is Related to Diagnostic Age and Autistic Symptom Severity

Journal of Autism and Developmental Disorders - We conducted a cross-sectional study to explore whether clinical characteristics and autism diagnostic-traits severity are associated with...