Ex vivo gene therapy using intravitreal injection of GDNF-secreting mouse embryonic stem cells in a rat model of retinal degeneration

Purpose: Safe and prolonged drug delivery to the retina is a key obstacle to overcome in the development of new medicines aimed at treating progressive retinal disease. We took advantage of the ability of embryonic stem cells to survive long-term in foreign tissue and used these cells to deliver neuroprotectant molecules to the retina of the rhodopsin TgN S334ter-4 rat model of retinitis pigmentosa (RP). Methods: Mouse embryonic stem (mES) cells, derived from the pluripotent embryonic stem cell line E14TG2a, were genetically engineered to oversecrete the glial cell-derived neurotrophic factor (GDNF). Cell suspensions, containing approximately 200,000 cells and expressing approximately 35ng/106 cells/24 h GDNF, were injected into the vitreous cavity of TgN S334ter rat eyes at postnatal day 21 (P21) without immunosuppression. Histological and immunofluorescence imaging was used to evaluate photoreceptor survival up to P90. Local (vitreous) and systemic (serum) concentrations of GDNF were determined and ocular side effects were monitored. Results: Green fluorescent protein (GFP)-expressing mES cells were observed on the inner limiting membrane of the retina in retinal flatmounts up to P90. In cryostat sections at P45, some GFP-expressing cells had integrated into the inner retina, but did not migrate into the outer nuclear layer. After an initial lag period, the photoreceptor cell counts were significantly higher (p≤0.05) in animals treated with GDNF-secreting mES cells than in untreated animals, principally in the peripheral retina. Several adverse side effects such as tractional detachments and areas of hyperplasia were seen in a minimal number of treated eyes. Abnormally high levels of GDNF in the peripheral circulation were also observed. Conclusions: ES cells engineered to secrete GDNF exerted a neuroprotective effect for at least three months on retinal structure in the TgN S334ter rat model of retinal degeneration. Immunosuppression was not required for this. Several adverse effects were identified which require further investigation to make cell-based delivery of neuroprotection a viable clinical strategy

In the Driver’s Seat: Driving towards a career in cancer prevention research

https://openworks.mdanderson.org/sumexp23/1021/thumbnail.jp

Total Sitting Time and Sitting Pattern in Postmenopausal Women Differ by Hispanic Ethnicity and are Associated With Cardiometabolic Risk Biomarkers.

Background Sedentary behavior is pervasive, especially in older adults, and is associated with cardiometabolic disease and mortality. Relationships between cardiometabolic biomarkers and sitting time are unexplored in older women, as are possible ethnic differences. Methods and Results Ethnic differences in sitting behavior and associations with cardiometabolic risk were explored in overweight/obese postmenopausal women (n=518; mean±SD age 63±6 years; mean body mass index 31.4±4.8 kg/m2). Accelerometer data were processed using validated machine-learned algorithms to measure total daily sitting time and mean sitting bout duration (an indicator of sitting behavior pattern). Multivariable linear regression was used to compare sitting among Hispanic women (n=102) and non-Hispanic women (n=416) and tested associations with cardiometabolic risk biomarkers. Hispanic women sat, on average, 50.3 minutes less/day than non-Hispanic women (P<0.001) and had shorter (3.6 minutes less, P=0.02) mean sitting bout duration. Among all women, longer total sitting time was deleteriously associated with fasting insulin and triglyceride concentrations, insulin resistance, body mass index and waist circumference; longer mean sitting bout duration was deleteriously associated with fasting glucose and insulin concentrations, insulin resistance, body mass index and waist circumference. Exploratory interaction analysis showed that the association between mean sitting bout duration and fasting glucose concentration was significantly stronger among Hispanic women than non-Hispanic women (P-interaction=0.03). Conclusions Ethnic differences in 2 objectively measured parameters of sitting behavior, as well as detrimental associations between parameters and cardiometabolic biomarkers were observed in overweight/obese older women. The detrimental association between mean sitting bout duration and fasting glucose may be greater in Hispanic women than in non-Hispanic women. Corroboration in larger studies is warranted

Atrial thrombi detection prior to pulmonary vein isolation: Diagnostic accuracy of cardiac computed tomography versus transesophageal echocardiography

Background: Patients routinely undergo transesophageal echocardiography (TEE) prior to pulmonary vein isolation (PVI) in order to rule out the presence of intra-atrial thrombi. Cardiac computed tomography (CCT) is also routinely conducted prior to the procedure to determine cardiac anatomy. Although it has been demonstrated that CCT can also rule out intra-atrial thrombi, the use of CCT for thrombi detection is controversial. The primary objective was to determine the utility of CCT for detection of atrial thrombi as compared to TEE. Methods: Patients who underwent PVI between 2010 and 2011 with CTs and TEEs complet­ed within 3 days of each other were retrospectively identified. TEE reports were analyzed, while CCTs were interpreted by a cardiologist specializing in CCTs. Severe spontaneous echo contrast or thrombus detected on TEE were considered positive, as were filling defects found on CCT. Results: A total of 51 patients undergoing PVI (mean age 59.4 ± 9.5 years; 75% male; ejection fraction 60 ± 12%) had both TEE and CCT in timely fashion. By TEE, 0 left atrial ap­pendage (LAA) thrombi were identified with mild to moderate spontaneous echo contrast in 4 patients. By CCT, 2 definite LAA thrombi were identified and thrombi in 4 patients could not be ruled out. Specificity, positive predictive value, and negative predictive value for CCT were 88%, 0%, and 100%, respectively. Conclusions: CCT is an effective tool in ruling out atrial thrombi prior to PVI. TEE should be completed only if CCT is positive

Defining Yield Goals and Management Zones to Minimize Yield and Nitrogen and Phosphorus Fertilizer Recommendation Errors

Three general approaches (minimize soil nutrient variability, yield, and fertilizer recommendation errors) have been used to assess nutrient management zone boundaries. The objective of this study was to determine the influence of different approaches to define management zones and yield goals on minimizing yield variability and fertilizer recommendation errors. This study used soil nutrient and yield information collected from two east-central South Dakota fields between 1995 and 2000. The crop rotation was corn (Zea mays L.) followed by soybean [Glycine max (L.) Merr.]. The four management zone delineation approaches tested were to: (i) sample areas impacted by old homesteads separately from the rest of the field; (ii) separate the field into grid cells; (iii) use geographic information systems or cluster analysis of apparent electrical conductivity, elevation, aspect, and connectedness to identify zones; and (iv) use the Order 1 soil survey. South Dakota fertilizer N and P recommendations were used to calculate fertilizer requirements. This study showed that management zones based on a 4-ha grid cell and an Order 1 soil survey had lower within-zone yield variability than the other methods tested. The best approaches for minimizing recommendation errors were nutrient specific. Nitrogen and P recommendations were improved using multiple years of yield monitor data to develop landscape-specific yield goals, sampling old homesteads separately from the rest of the field, and grid cell soil sampling to fine-tune N and P recommendations

Target Identification : A Challenging Step in Forward Chemical Genetics

Investigation of the genetic functions in complex biological systems is a challenging step in recent year. Hence, several valuable and interesting research projects have been developed with novel ideas to find out the unknown functions of genes or proteins. To validate the applicability of their novel ideas, various approaches are built up. To date, the most promising and commonly used approach for discovering the target proteins from biological system using small molecule is well known a forward chemical genetics which is considered to be more convenient than the classical genetics. Although, the forward chemical genetics consists of the three basic components, the target identification is the most challenging step to chemical biology researchers. Hence, the diverse target identification methods have been developed and adopted to disclose the small molecule bound protein. Herein, in this review, we briefly described the first two parts chemical toolbox and screening, and then the target identifications in forward chemical genetics are thoroughly described along with the illustrative real example case study. In the tabular form, the different biological active small molecules which are the successful examples of target identifications are accounted in this research review.22Yothe

Effects of Climate Change on Water Quality in the Yaquina Estuary, Oregon

As part of a larger study to examine the effect of climate change (CC) on estuarine resources, we simulated the effect of rising sea level, alterations in river discharge, and increasing atmospheric temperatures on water quality in the Yaquina Estuary. Due to uncertainty in the effects of climate change, initial model simulations were performed for different steady river discharge rates that span the historical range in inflow, and for a range of increases in sea level and atmospheric temperature. Model simulations suggest that in the central portion of the estuary (19 km from mouth), a 60-cm increase in sea level will result in a 2-3 psu change in salinity across a broad range of river discharges. For the oligohaline portion of the estuary, salinity increases associated with a rise in sea level of 60 cm are only apparent at low river discharge rates (\u3c 50 m3 s-1). Simulations suggest that the water temperatures near the mouth of the estuary will decrease due to rising sea level, while water temperatures in upriver portions of the estuary will increase due to rising atmospheric temperatures. We present results which demonstrate how the interaction of changes in river discharge, rising sea level, and atmospheric temperature associated with climate change produce non-linear patterns in the response of estuarine salinity and temperature, which vary with location inside the estuary and season. We also will discuss the importance of presenting results in a manner that incorporates uncertainty in climate projections

Local Injection of Aminoglycosides for Prophylaxis Against Infection in Open Fractures

The purpose of this study was to determine the efficacy of local wound cavity injections of aqueous aminoglycosides (gentamicin and tobramycin), in conjunction with systemic antibiotics, to lower the prevalence of infection in patients with open fractures

Methadone-Mediated Autonomic Functioning of Male Patients with Heroin Dependence: The Influence of Borderline Personality Pattern

BACKGROUND: We hypothesize that the population with borderline personality shows different autonomic response to methadone compared to individuals with other personalities. This study applies heart rate variability (HRV) measurements and the Tridimensional Personality Questionnaire (TPQ) to examine this hypothesis. METHODOLOGY/PRINCIPAL FINDINGS: Forty-four male patients with heroin dependence were recruited from a methadone maintenance treatment program. Eight personality patterns were classified according to the TPQ norm used in Taiwan. The borderline pattern (BP, composed of high novelty seeking, high harm avoidance and low reward dependence) and the other personality patterns (OP) were separated into two groups. We compared the HRV profiles between the BP and OP groups. Correlation and regression analysis were performed to clarify relationship between HRV differences and the borderline index (BI, a new concept defined by us, which is calculated as novelty seeking + harm avoidance - reward dependence). The HRV targets investigated included low frequency (LF) power, high frequency (HF) power, total power (TP), normalized LF (LF%), and LF/HF. No baseline HRV parameters showed any inter-group difference. The BP group had a significantly lower ΔHF and a higher ΔLF/HF than the OP group. The personality dimension, reward dependence, showed a negative correlation with ΔLF/HF and ΔLF%. BI was negatively correlated with ΔHF and positively correlated with ΔLF/HF and ΔLF%. CONCLUSIONS/SIGNIFICANCE: Borderline personality individuals show increased sympathetic activity and decreased parasympathetic activity compared to other personalities after taking methadone. The results support the hypothesis that there is an interaction between borderline personality and autonomic modulation