Parenchymal pericytes are not the major contributor of extracellular matrix in the fibrotic scar after stroke in male mice

Scar formation after injury of the brain or spinal cord is a common event. While glial scar formation by astrocytes has been extensively studied, much less is known about the fibrotic scar, in particular after stroke. Platelet-derived growth factor receptor ß-expressing (PDGFRß⁺) pericytes have been suggested as a source of the fibrotic scar depositing fibrous extracellular matrix (ECM) proteins after detaching from the vessel wall. However, to what extent these parenchymal PDGFRß⁺ cells contribute to the fibrotic scar and whether targeting these cells affects fibrotic scar formation in stroke is still unclear. Here, we utilize male transgenic mice that after a permanent middle cerebral artery occlusion stroke model have a shift from a parenchymal to a perivascular location of PDGFRß⁺ cells due to the loss of regulator of G-protein signaling 5 in pericytes. We find that only a small fraction of parenchymal PDGFRß⁺ cells co-label with type I collagen and fibronectin. Consequently, a reduction in parenchymal PDGFRß⁺ cells by ca. 50% did not affect the overall type I collagen or fibronectin deposition after stroke. The redistribution of PDGFRß⁺ cells to a perivascular location, however, resulted in a reduced thickening of the vascular basement membrane and changed the temporal dynamics of glial scar maturation after stroke. We demonstrate that parenchymal PDGFRß⁺ cells are not the main contributor to the fibrotic ECM, and therefore targeting these cells might not impact on fibrotic scar formation after stroke.     

Cervical and oral human papillomavirus types in HIV-1 positive and negative women with cervical disease in South Africa

This study tested cervical and oral human papillomavirus (HPV) infection in HIV-1 seropositive (HIV+) and seronegative (HIV-) women to determine any association between infections at both sites and the difference in prevalence of the HPV types infecting these women. Participants were 115 women referred to a colposcopy clinic after diagnosis of abnormal cervical cytology. The women showed low grade cervical intraepithelial neoplasia (CIN1) or high grade disease (CIN2/3) or no CIN based on colposcopy and histology. Typing of HPV in cervical and oral cells was by Roche linear array and included direct sequencing on selected oral samples. Cervical HPV prevalence was 86.5% and 97.1% in HIV- and HIV+ women respectively. With the exception of HPV-45, prominent in HIV+ women, the hierarchy of predominant types were similar in HIV- and HIV+ women. HPV-16 was most prevalent in both HIV+ (41.7%) and HIV- women (38.5%) with CIN2/3. Significantly more HIV+ women had multiple cervical (>1) infections than HIV- women (36.1% vs. 88.2%, P < 0.001) and more oral HPV infections (45.5% and 25% respectively; P = 0.04). The most prevalent oral HPV types were HPV-33, -11, and -72. The majority of women did not have concordant oral and cervical HPV types, reflecting possible independence of infection at the two sites. HIV immune suppression did not impact significantly on the predominant types of cervical HPV infection (except for HPV-45). HIV+ women had more multiple HPV infections and those with severe cervical disease a similar prevalence of HIV-16 but a lower HPV-18 prevalence than HIV- women.     

Human artificial chromosome vectors meet stem cells

The recent emergence of stem cell-based tissue engineering has now opened up new venues for gene therapy. The task now is to develop safe and effective vectors that can deliver therapeutic genes into specific stem cell lines and maintain long-term regulated expression of these genes. Human artificial chromosomes (HACs) possess several characteristics that require gene therapy vectors, including a stable episomal maintenance, and the capacity for large gene inserts. HACs can also carry genomic loci with regulatory elements, thus allowing for the expression of transgenes in a genetic environment similar to the chromosome. Currently, HACs are constructed by a two prone approaches. Using a top-down strategy, HACs can be generated from fragmenting endogenous chromosomes. By a bottom-up strategy, HACs can be created de novo from cloned chromosomal components using chromosome engineering. This review describes the current advances in developing HACs, with the main focus on their applications and potential value in gene delivery, such as HAC-mediated gene expression in embryonic, adult stem cells, and transgenic animals.     

The Dose-Response Effects of Consuming High Fructose Corn Syrup-Sweetened Beverages on Hepatic Lipid Content and Insulin Sensitivity in Young Adults

Increased hepatic lipid content and decreased insulin sensitivity have critical roles in the development of cardiometabolic diseases. Therefore, our objective was to investigate the dose-response effects of consuming high fructose corn syrup (HFCS)-sweetened beverages for two weeks on hepatic lipid content and insulin sensitivity in young (18–40 years) adults (BMI 18–35 kg/m²). In a parallel, double-blinded study, participants consumed three beverages/day providing 0% (aspartame: n = 23), 10% (n = 18), 17.5% (n = 16), or 25% (n = 28) daily energy requirements from HFCS. Magnetic resonance imaging for hepatic lipid content and oral glucose tolerance tests (OGTT) were conducted during 3.5-day inpatient visits at baseline and again at the end of a 15-day intervention. During the 12 intervening outpatient days participants consumed their usual diets with their assigned beverages. Significant linear dose-response effects were observed for increases of hepatic lipid content (p = 0.015) and glucose and insulin AUCs during OGTT (both p = 0.0004), and for decreases in the Matsuda (p = 0.0087) and Predicted M (p = 0.0027) indices of insulin sensitivity. These dose-response effects strengthen the mechanistic evidence implicating consumption of HFCS-sweetened beverages as a contributor to the metabolic dysregulation that increases risk for nonalcoholic fatty liver disease and type 2 diabetes.     

Quantification in Patient Urine Samples of Felbamate and Three Metabolites: Acid Carbamate and Two Mercapturic Acids

PURPOSE: Previously we proposed and provided evidence for the metabolic pathway of felbamate (FBM), which leads to the reactive metabolite, 3-carbamoyl-2-phenylpropion-aldehyde. This aldehyde carbamate was suggested to be the reactive intermediate in the oxidation of 2-phenyl-1,3-propanediol monocarbamate to the major human metabolite 3-carbamoyl-2-phenylpropionic acid. In addition, the aldehyde carbamate was found to undergo spontaneous elimination to 2-phenylpropenal, commonly known as atropaldehyde. Moreover, atropaldehyde was proposed to play a role in the development of toxicity during FBM therapy. Evidence for atropaldehyde formation in vivo was reported with the identification of modified N-acetyl-cysteine conjugates of atropaldehyde in both human and rat urine after FBM administration. Identification of the atropaldehyde-derived mercapturic acids in urine after FBM administration is consistent with the hypothesis that atropaldehyde is formed in vivo and that it reacts with thiol nucleophiles. Based on the hypothesis that the potential for toxicity will correlate to the amount of atropaldehyde formed, we sought to develop an analytic method that would quantify the amount of relevant metabolites excreted in patient urine. METHODS: We summarize the results of an LC/MS method used to quantify FBM, 3-carbamoyl-2-phenylpropionic acid and two atropaldehyde-derived mercapturic acids in the patient population. RESULTS: Analysis was performed on 31 patients undergoing FBM therapy. The absolute quantities of FBM and three metabolites were measured. CONCLUSIONS: This method demonstrated sufficient precision for the identification of patients exhibiting "abnormal" levels of atropaldehyde conjugates and may hold potential for patient monitoring.     

Civic Engagement in California Cannabis Policy Development

ABSTRACT

During the regulatory drafting process, California considered allowing police officers to become licensed owners of cannabis businesses, an action that would have codified a conflict of interest (COI), allowing police to exert influence in two market strata, enforcement and licensure. Up until then, no state specifically excepted law enforcement from COI prohibitions, making California’s proposed medical cannabis regulation unique. We performed two 50-state surveys and examined 298 public comments submitted to the Bureau of Cannabis Control during the initial medical cannabis rulemaking process in June 2017. After public comments, the Bureau withdrew this provision. However, that the exception was even considered is cause for concern in this new area of policy development. The progression from proposed medical cannabis rules to emergency rule adoption and now, into proposed final regulations, highlights the value of civic engagement with the rulemaking process. Jurisdictions should adopt bright-line COI rules within their cannabis codes that limit the relationships that law enforcement may have with the private cannabis markets.     

Bone marrow stem cells and the liver: Are they relevant?

The contribution of bone marrow stem cell responses to liver homeostasis, injury and malignancy is discussed in this review. Pluripotent stem cells or their more committed progenitor progeny are essential to tissue development, regeneration and repair and are widely implicated in the pathogenesis of malignancy. Stem cell responses to injury are the focus of intense research efforts in the hope of future therapeutic manipulation. Stem cells occur within tissues, such as the liver, or arise from extrahepatic sites, in particular, the bone marrow. As the largest reservoir of stem cells in the adult, the bone marrow has been implicated in the stem cell response associated with liver injury. However, in liver injury, the relative contribution of bone marrow stem cells compared to intrahepatic progenitor responses is poorly characterized. Intrahepatic progenitor responses have been recently reviewed elsewhere. In this review, we have summarized liver-specific extrahepatic stem cell responses originating from the bone marrow. The physiological relevance of bone marrow stem cell responses to adult liver homeostasis, injury and malignancy is discussed with emphasis on mechanisms of bone marrow stem cell recruitment to sites of liver injury and its contribution to intrahepatic malignancy.     

Community Monitoring for Youth Violence Surveillance: Testing a Prediction Model

Predictive epidemiology is an embryonic field that involves developing informative signatures for disorder and tracking them using surveillance methods. Through such efforts assistance can be provided to the planning and implementation of preventive interventions. Believing that certain minor crimes indicative of gang activity are informative signatures for the emergence of serious youth violence in communities, in this study we aim to predict outbreaks of violence in neighborhoods from pre-existing levels and changes in reports of minor offenses. We develop a prediction equation that uses publicly available neighborhood-level data on disorderly conduct, vandalism, and weapons violations to predict neighborhoods likely to have increases in serious violent crime. Data for this study were taken from the Chicago Police Department ClearMap reporting system, which provided data on index and non-index crimes for each of the 844 Chicago census tracts. Data were available in three month segments for a single year (fall 2009, winter, spring, and summer 2010). Predicted change in aggravated battery and overall violent crime correlated significantly with actual change. The model was evaluated by comparing alternative models using randomly selected training and test samples, producing favorable results with reference to overfitting, seasonal variation, and spatial autocorrelation. A prediction equation based on winter and spring levels of the predictors had area under the curve ranging from .65 to .71 for aggravated battery, and .58 to .69 for overall violent crime. We discuss future development of such a model and its potential usefulness in violence prevention and community policing.