Mucopolysaccharidosis type I is an inborn error of glycosaminoglycan catabolism with phenotypes ranging from severe (Hurler syndrome) to attenuated (Hurler–Scheie and Scheie syndromes). Cardiovascular involvement is common and contributes significantly to morbidity and mortality. We conducted a retrospective analysis of the prevalence and natural history of cardiac abnormalities in treatment-naïve individuals enrolled in the international Mucopolysaccharidosis Type I Registry. Interrogation of echocardiography data (presence of cardiac valve regurgitation and/or stenosis; measurements of left ventricular chamber dimensions in diastole and systole, diastolic left ventricular posterior wall and interventricular septal thicknesses and ventricular systolic function (shortening fraction)) showed that mitral regurgitation was the most common and earliest finding for individuals with both severe (58.3%, median age 1.2 years) and attenuated (74.2%, median age 8.0 years) disease. Left-sided valve stenosis was also common in individuals with attenuated disease (mitral 30.3%; aortic 25%). Abnormal ventricular wall and septal thickness (Z-scores ≥2) were observed early in both phenotypes. Z-scores for diastolic left ventricular posterior wall and interventricular septal thicknesses increased with age in the severe phenotype (annualised slopes of 0.2777 [p = 0.037] and 0.3831 [p = 0.001], respectively); a similar correlation was not observed in the attenuated phenotype (annualised slopes of −0.0401 [p = 0.069] and −0.0029 [p = 0.875], respectively). Decreased cardiac ventricular systolic function (defined as shortening fraction <28%) was uncommon but, when noted, was more frequent in infants with the severe phenotype. While cardiac abnormalities occur early in both severe and attenuated mucopolysaccharidosis type I, the pattern of valve dysfunction and progression of ventricular abnormalities vary by phenotype.

Subcutaneous adipose tissue (scAT) and peripheral blood mononuclear cells (PBMC) play a significant role in obesity-associated systemic low-grade inflammation. High-fat diet (HFD) is known to induce inflammatory changes in both scAT and PBMC. However, the time course of the effect of HFD on these systems is still unknown. The aim of the present study was to determine the time course of the effect of HFD on PBMC and scAT. New Zealand white rabbits were fed HFD for 5 or 10 weeks (i.e. HFD-5 and HFD-10) or regular chow (i.e. control (CNT)-5 and CNT-10). Thereafter, metabolic and inflammatory parameters of PBMC and scAT were quantified. HFD induced hyperfattyacidaemia in HFD-5 and HFD-10 groups, with the development of insulin resistance in HFD-10, while no changes were observed in scAT lipid metabolism and inflammatory status. HFD activated the inflammatory pathways in PBMC of HFD-5 group and induced modified autophagy in that of HFD-10. The rate of fat oxidation in PBMC was directly associated with the expression of inflammatory markers and tended to inversely associate with autophagosome formation markers in PBMC. HFD affected systemic substrate metabolism, and the metabolic, inflammatory and autophagy pathways in PBMC in the absence of metabolic and inflammatory changes in scAT. Dietary approaches or interventions to avert HFD-induced changes in PBMC could be essential to prevent metabolic and inflammatory complications of obesity and promote healthier living.

OBJECTIVES/SPECIFIC AIMS: The current treatment for amyotrophic lateral sclerosis (ALS) includes systemic delivery of neurotrophic factors (NTFs). Although this approach may seem theoretically sound, NTF efficacy within the central nervous system (CNS) is largely limited by the blood-brain barrier. Thus, a cell-based approach, which allows for targeted delivery of molecular therapies locally from the CNS, could lead to a paradigm shift in the field. METHODS/STUDY POPULATION: The Windebank and Staff group at Mayo Clinic completed a Phase I dose-escalation safety trial of autologous, adipose-derived mesenchymal stem cells (adMSCs) in an effort to move toward personalized medical treatment of ALS. The adMSCs were injected into the intrathecal space by lumbar puncture in 27 patients and the results showed an excellent safety profile across a range of doses. The team is moving forward with this idea by using gene-editing technology to develop clinical-grade, genetically modified autologous MSCs. The patient-derived adMSCs are modified at defined “safe-harbor” regions of the human genome through transcription activator-like effector nuclease (TALEN) technology. RESULTS/ANTICIPATED RESULTS: Our results show that electroporating adMSCs with plasmid DNA leads to efficient GFP or TALEN transgene expression, but yields low cell survival and a low rate of genetic modification. DISCUSSION/SIGNIFICANCE OF IMPACT: It can be concluded that: (1) TALEN technology may be used to target safe harbor loci for gene integration to produce therapeutic adMSC for ALS. (2) Primary barriers to adMSC modification are inefficient TALEN and donor template uptake, low cutting efficiency, and poor cell survival after electroporation. Future directions include optimizing the protocol to obtain 48 base pairs in the homology arms and increasing transfection efficiency.

Scholarship by Barbara Harris, James Daybell and others has recently highlighted the role played by elite women as custodians of dynastic memory in early modern England. The Dissolution of the Monasteries interrupted the commemorative process and constituted a threat to the mausoleums of the elite. Moving or rebuilding tombs represented, to some extent, a decision to remake or even to rewrite the family's history, a process which it is often assumed was at this time controlled by men. This article, however, through the example of the Howard family, demonstrates that women were equally involved; it investigates why this was so and the mechanics of the processs.

Prenatal tobacco exposure (PTE) has a well-documented association with disruptive behavior in childhood, but the neurocognitive effects of exposure that underlie this link are not sufficiently understood. The present study was designed to address this gap, through longitudinal follow-up in early childhood of a prospectively enrolled cohort with well-characterized prenatal exposure. Three-year-old children (n = 151) were assessed using a developmentally sensitive battery capturing both cognitive and motivational aspects of self-regulation. PTE was related to motivational self-regulation, where children had to delay approach to attractive rewards, but not cognitive self-regulation, where children had to hold information in mind and inhibit prepotent motor responses. Furthermore, PTE predicted motivational self-regulation more strongly in boys than in girls, and when propensity scores were covaried to control for confounding risk factors, the effect of PTE on motivational self-regulation was significant only in boys. These findings suggest that PTE's impact on neurodevelopment may be greater in boys than in girls, perhaps reflecting vulnerability in neural circuits that subserve reward sensitivity and emotion regulation, and may also help to explain why PTE is more consistently related to disruptive behavior disorders than attention problems.

Green tea catechins (GTC) reduce UV radiation (UVR)-induced inflammation in experimental models, but human studies are scarce and their cutaneous bioavailability and mechanism of photoprotection are unknown. We aimed to examine oral GTC cutaneous uptake, ability to protect human skin against erythema induced by a UVR dose range and impact on potent cyclo-oxygenase- and lipoxygenase-produced mediators of UVR inflammation, PGE2 and 12-hydroxyeicosatetraenoic acid (12-HETE), respectively. In an open oral intervention study, sixteen healthy human subjects (phototype I/II) were given low-dose GTC (540 mg) with vitamin C (50 mg) daily for 12 weeks. Pre- and post-supplementation, the buttock skin was exposed to UVR and the resultant erythema quantified. Skin blister fluid and biopsies were taken from the unexposed and the UVR-exposed skin 24 h after a pro-inflammatory UVR challenge (three minimal erythema doses). Urine, skin tissue and fluid were analysed for catechin content and skin fluid for PGE2 and 12-HETE by liquid chromatography coupled to tandem MS. A total of fourteen completing subjects were supplement compliant (twelve female, median 42·5 years, range 29–59 years). Benzoic acid levels were increased in skin fluid post-supplementation (P= 0·03), and methylated gallic acid and several intact catechins and hydroxyphenyl-valerolactones were detected in the skin tissue and fluid. AUC analysis for UVR erythema revealed reduced response post-GTC (P= 0·037). Pre-supplementation, PGE2 and 12-HETE were UVR induced (P= 0·003, 0·0001). After GTC, UVR-induced 12-HETE reduced from mean 64 (sd 42) to 41 (sd 32) pg/μl (P= 0·01), while PGE2 was unaltered. Thus, GTC intake results in the incorporation of catechin metabolites into human skin associated with abrogated UVR-induced 12-HETE; this may contribute to protection against sunburn inflammation and potentially longer-term UVR-mediated damage.