Pleiotrophin Gene Therapy for Peripheral Ischemia: Evaluation of Full-Length and Truncated Gene Variants

Pleiotrophin (PTN) is a growth factor with both pro-angiogenic and limited pro-tumorigenic activity. We evaluated the potential for PTN to be used for safe angiogenic gene therapy using the full length gene and a truncated gene variant lacking the domain implicated in tumorigenesis. Mouse myoblasts were transduced to express full length or truncated PTN (PTN or T-PTN), along with a LacZ reporter gene, and injected into mouse limb muscle and myocardium. In cultured myoblasts, PTN was expressed and secreted via the Golgi apparatus, but T-PTN was not properly secreted. Nonetheless, no evidence of uncontrolled growth was observed in cells expressing either form of PTN. PTN gene delivery to myocardium, and non-ischemic skeletal muscle, did not result in a detectable change in vascularity or function. In ischemic hindlimb at 14 days post-implantation, intramuscular injection with PTN-expressing myoblasts led to a significant increase in skin perfusion and muscle arteriole density. We conclude that (1) delivery of the full length PTN gene to muscle can be accomplished without tumorigenesis, (2) the truncated PTN gene may be difficult to use in a gene therapy context due to inefficient secretion, (3) PTN gene delivery leads to functional benefit in the mouse acute ischemic hindlimb model.     

Predicting Child Outcomes at the End of Kindergarten from the Quality of Pre-Kindergarten Teacher–Child Interactions and Instruction

Publicly funded prekindergartens are programs that most states use to promote school readiness, especially of 4-year-old children at risk for academic problems due to poverty. Despite large public expenditures, these programs have not been widely evaluated. We examined 240 randomly selected pre-kindergarten programs in six states with mature programs that serve large numbers of children, and evaluated specific aspects of classroom quality and children's academic achievement in both the pre-kindergarten and kindergarten year for over 700 children. Results showed that, on average, pre-kindergarten teachers were moderately responsive and sensitive, but were less successful in engaging children in learning specific skills. Both sensitive and stimulating interactions with the teacher and the instructional quality aspects of the pre-kindergarten classroom predicted the acquisition of language, pre-academic, and social skills through the end of the kindergarten year.     

Late‐life rapamycin treatment reverses age‐related heart dysfunction

Rapamycin has been shown to extend lifespan in numerous model organisms including mice, with the most dramatic longevity effects reported in females. However, little is known about the functional ramifications of this longevity‐enhancing paradigm in mammalian tissues. We treated 24‐month‐old female C57BL/6J mice with rapamycin for 3 months and determined health outcomes via a variety of noninvasive measures of cardiovascular, skeletal, and metabolic health for individual mice. We determined that while rapamycin has mild transient metabolic effects, there are significant benefits to late‐life cardiovascular function with a reversal or attenuation of age‐related changes in the heart. RNA‐seq analysis of cardiac tissue after treatment indicated inflammatory, metabolic, and antihypertrophic expression changes in cardiac tissue as potential mechanisms mediating the functional improvement. Rapamycin treatment also resulted in beneficial behavioral, skeletal, and motor changes in these mice compared with those fed a control diet. From these findings, we propose that late‐life rapamycin therapy not only extends the lifespan of mammals, but also confers functional benefits to a number of tissues and mechanistically implicates an improvement in contractile function and antihypertrophic signaling in the aged heart with a reduction in age‐related inflammation.     

Unhealthy Days and Quality of Life in Irish Patients with Diabetes

Objectives

To study the determinants of health-related quality of life (HRQoL) in Irish patients with diabetes using the Centres for Disease Controls'' (CDC''s) ‘Unhealthy Days’ summary measure and to assesses the agreement between this generic HRQoL measure and the disease-specific Audit of Diabetes Dependant Quality of Life (ADDQoL) measure.

Research Design and Methods

Data were analysed from the Diabetes Quality of Life Study, a cross-sectional study of 1,456 people with diabetes in Ireland (71% response rate). Unhealthy days were assessed using the CDC''s ‘Unhealthy days’ summary measure. Quality of life (QoL) was also assessed using the ADDQoL measure. Analyses were conducted primarily using logistic regression. The agreement between the two QoL instruments was measured using the kappa co-efficient.

Results

Participants reported a median of 2 unhealthy days per month. In multivariate analyses, female gender (P = 0.001), insulin use (P = 0.030), diabetes complications (P = <0.001) were significantly associated with more unhealthy days. Older patients had fewer unhealthy days per month (P = 0.003). Agreement between the two measures of QoL (unhealthy days measure and ADDQoL) was poor, Kappa = 0.234

Conclusions

The findings highlight the determinants of HRQoL in patients with diabetes using a generic HRQoL summary measure. The ‘Unhealthy Days’ and the ADDQoL have poor agreement, therefore the ‘Unhealthy Days’ summary measure may be assessing a different construct. Nonetheless, this study demonstrates that the generic ‘Unhealthy Days’ summary measure can be used to detect determinants of HRQoL in patients with diabetes.     

Minimal Erythema Dose (MED) Testing

Ultraviolet radiation (UV) therapy is sometimes used as a treatment for various common skin conditions, including psoriasis, acne, and eczema. The dosage of UV light is prescribed according to an individual''s skin sensitivity. Thus, to establish the proper dosage of UV light to administer to a patient, the patient is sometimes screened to determine a minimal erythema dose (MED), which is the amount of UV radiation that will produce minimal erythema (sunburn or redness caused by engorgement of capillaries) of an individual''s skin within a few hours following exposure. This article describes how to conduct minimal erythema dose (MED) testing. There is currently no easy way to determine an appropriate UV dose for clinical or research purposes without conducting formal MED testing, requiring observation hours after testing, or informal trial and error testing with the risks of under- or over-dosing. However, some alternative methods are discussed.