Incidence and Predictors of End Stage Renal Disease among Low-Income Blacks and Whites

We evaluated whether black race is associated with higher incidence of End Stage Renal Disease (ESRD) among a cohort of blacks and whites of similar, generally low socioeconomic status, and whether risk factor patterns differ among blacks and whites and explain the poorly understood racial disparity in ESRD. Incident diagnoses of ESRD among 79,943 black and white participants in the Southern Community Cohort Study (SCCS) were ascertained by linkage with the United States Renal Data System (USRDS) from 2002 through 2009. Person-years of follow up were calculated from date of entry into the SCCS until date of ESRD diagnosis, date of death, or September 1, 2009, whichever occurred first. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for incident ESRD among black and white participants in relation to baseline characteristics. After 329,003 person-years of follow-up, 687 incident cases of ESRD were identified in the cohort. The age-adjusted ESRD incidence rate was 273 (per 100,000) among blacks, 3.5-fold higher than the rate of 78 among whites. Risk factors for ESRD included male sex (HR = 1.6; 95% CI 1.4–1.9), low income (HR = 1.5; 95% CI 1.2–1.8 for income below vs. above $15,000), smoking (HR = 1.2; 95% CI 1.02–1.4) and histories of diabetes (HRs increasing to 9.4 (95% CI 7.4–11.9) among those with ≥20 years diabetes duration) and hypertension (HR = 2.9; 95% CI 2.3–3.7). Patterns and magnitudes of association were virtually identical among blacks and whites. After adjustment for these risk factors, blacks continued to have a higher risk for ESRD (HR = 2.4; 95% CI = 1.9–3.0) relative to whites. The black-white disparity in risk of ESRD was attenuated but not eliminated after control for known risk factors in a closely socioeconomically matched cohort. Further research characterizing biomedical factors, including CKD progression, in ESRD occurrence in these two racial groups is needed.     

GLP2-2G-XTEN: A Pharmaceutical Protein with Improved Serum Half-Life and Efficacy in a Rat Crohn’s Disease Model

Objectives

Glucagon-like peptide 2 (GLP2) is an intestinal growth factor that has been shown to stimulate intestinal growth and reduce disease severity in preclinical models of short bowel syndrome and inflammatory bowel disease. Teduglutide, a recombinant human GLP2 variant (GLP2-2G), has increased half-life and stability as compared to the native GLP2 peptide, but still requires twice daily dosing in preclinical models and daily dosing in the clinic. The goal of this study was to produce and characterize the preclinical pharmacokinetic and therapeutic properties of GLP2-2G-XTEN, a novel, long-acting form of GLP2-2G.

Methodology and Results

A GLP2-2G-XTEN fusion protein with extended exposure profile was produced by genetic fusion of GLP2-2G peptide to XTEN, a long, unstructured, non-repetitive, hydrophilic sequence of amino acids. The serum half-life of GLP2-2G-XTEN in mice, rats and monkeys was 34, 38 and 120 hours, respectively. Intestinotrophic effects were demonstrated in normal rats, where GLP2-2G-XTEN administration resulted in a significant increase in both small intestine weight and length. Efficacy of the GLP2-2G-XTEN protein was compared to that of GLP2-2G peptide in a rat Crohn’s disease model, indomethacin-induced inflammation. Prophylactic administration of GLP2-2G-XTEN significantly increased the length, reduced the number of trans-ulcerations and adhesions, and reduced the TNFα content of the small intestine. GLP2-2G-XTEN demonstrated greater in vivo potency as compared to GLP2-2G peptide, and improvement in histopathology supported the GLP2-2G-XTEN treatment effects.

Conclusions and Significance

GLP2-2G-XTEN is intestinotrophic and demonstrates efficacy in a rat Crohn’s disease model requiring a lower molar dose and less frequent dosing relative to GLP2-2G peptide. Allometric scaling based on pharmacokinetics from mouse, rat and monkey projects a human half-life of 240 hours. These improvements in preclinical pharmacokinetics and dosing indicate that GLP2-2G-XTEN may offer a superior therapeutic benefit for treatment of gastrointestinal diseases including Crohn’s disease.     

Mechanisms underlying the link between cannabis use and prospective memory

While the effects of cannabis use on retrospective memory have been extensively examined, only a limited number of studies have focused on the links between cannabis use and prospective memory. We conducted two studies to examine the links between cannabis use and both time-based and event-based prospective memory as well as potential mechanisms underlying these links. For the first study, 805 students completed an online survey designed to assess cannabis consumption, problems with cannabis use indicative of a disorder, and frequency of experiencing prospective memory failures. The results showed small to moderate sized correlations between cannabis consumption, problems with cannabis use, and prospective memory. However, a series of mediation analyses revealed that correlations between problems with cannabis use and prospective memory were driven by self-reported problems with retrospective memory. For the second study, 48 non-users (who had never used cannabis), 48 experimenters (who had used cannabis five or fewer times in their lives), and 48 chronic users (who had used cannabis at least three times a week for one year) were administered three objective prospective memory tests and three self-report measures of prospective memory. The results revealed no objective deficits in prospective memory associated with chronic cannabis use. In contrast, chronic cannabis users reported experiencing more internally-cued prospective memory failures. Subsequent analyses revealed that this effect was driven by self-reported problems with retrospective memory as well as by use of alcohol and other drugs. Although our samples were not fully characterized with respect to variables such as neurological disorders and family history of substance use disorders, leaving open the possibility that these variables may play a role in the detected relationships, the present findings indicate that cannabis use has a modest effect on self-reported problems with prospective memory, with a primary problem with retrospective memory appearing to underlie this relationship.     

Functional neuronal cells generated by human parthenogenetic stem cells

Parent of origin imprints on the genome have been implicated in the regulation of neural cell type differentiation. The ability of human parthenogenetic (PG) embryonic stem cells (hpESCs) to undergo neural lineage and cell type-specific differentiation is undefined. We determined the potential of hpESCs to differentiate into various neural subtypes. Concurrently, we examined DNA methylation and expression status of imprinted genes. Under culture conditions promoting neural differentiation, hpESC-derived neural stem cells (hpNSCs) gave rise to glia and neuron-like cells that expressed subtype-specific markers and generated action potentials. Analysis of imprinting in hpESCs and in hpNSCs revealed that maternal-specific gene expression patterns and imprinting marks were generally maintained in PG cells upon differentiation. Our results demonstrate that despite the lack of a paternal genome, hpESCs generate proliferating NSCs that are capable of differentiation into physiologically functional neuron-like cells and maintain allele-specific expression of imprinted genes. Thus, hpESCs can serve as a model to study the role of maternal and paternal genomes in neural development and to better understand imprinting-associated brain diseases.     

Myelin-reactive type B T cells and T cells specific for low-affinity MHC-binding myelin peptides escape tolerance in HLA-DR transgenic mice

Genes of the MHC show the strongest genetic association with multiple sclerosis (MS), but the underlying mechanisms have remained unresolved. In this study, we asked whether the MS-associated MHC class II molecules, HLA-DRB1*1501, HLA-DRB5*0101, and HLA-DRB1*0401, contribute to autoimmune CNS demyelination by promoting pathogenic T cell responses to human myelin basic protein (hMBP), using three transgenic (Tg) mouse lines expressing these MHC molecules. Unexpectedly, profound T cell tolerance to the high-affinity MHC-binding hMBP82-100 epitope was observed in all Tg mouse lines. T cell tolerance to hMBP82-100 was abolished upon back-crossing the HLA-DR Tg mice to MBP-deficient mice. In contrast, T cell tolerance was incomplete for low-affinity MHC-binding hMBP epitopes. Furthermore, hMBP82-100-specific type B T cells escaped tolerance in HLA-DRB5*0101 Tg mice. Importantly, T cells specific for low-affinity MHC-binding hMBP epitopes and hMBP82-100-specific type B T cells were highly encephalitogenic. Collectively, the results show that MS-associated MHC class II molecules are highly efficient at inducing T cell tolerance to high-affinity MHC-binding epitope, whereas autoreactive T cells specific for the low-affinity MHC-binding epitopes and type B T cells can escape the induction of T cell tolerance and may promote MS.     

Restricted gene flow in fragmented populations of a wind-pollinated tree

Fragmentation of natural populations can have negative effects at the genetic level, thus threatening their evolutionary potential. Many of the negative genetic impacts of population fragmentation can be ameliorated by gene flow and it has been suggested that in wind-pollinated tree species, high or even increased levels of gene flow are a feature of fragmented populations, although several studies have disputed this. We have used a combination of nuclear microsatellites and allele-specific PCR (AS-PCR) analysis of chloroplast single nucleotide polymorphisms (SNPs) to examine the levels and patterns of genetic diversity and population differentiation in fragmented populations of juniper (Juniperus communis) in Ireland and inform conservation programs for the species. Significant population differentiation was found for both chloroplast and nuclear markers, indicating restricted gene flow, particularly over larger geographic scales. For conservation purposes, the existence of genetically distinct clusters and geographically localised chloroplast haplotypes suggests that the concept of provenance should be taken into account when formulating augmentation or reintroduction strategies. Furthermore, the potential lack of seed dispersal and seedling establishment means that ex-situ approaches to seed and seedling management may have to be considered.