Comparison of Fetal Mesencephalic Grafts, AAV-delivered GDNF, and Both Combined in an MPTP-induced Nonhuman Primate Parkinson’s Model

We combined viral vector delivery of human glial-derived neurotrophic factor (GDNF) with the grafting of dopamine (DA) precursor cells from fetal ventral mesencephalon (VM) to determine whether these strategies would improve the anti-Parkinson's effects in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, an animal model for Parkinson's disease (PD). Both strategies have been reported as individually beneficial in animal models of PD, leading to clinical studies. GDNF delivery has also been reported to augment VM tissue implants, but no combined studies have been done in monkeys. Monkeys were treated with MPTP and placed into four balanced treatment groups receiving only recombinant adeno-associated virus serotype 5 (rAAV5)/hu-GDNF, only fetal DA precursor cells, both together, or a buffered saline solution (control). The combination of fetal precursors with rAAV5/hu-GDNF showed significantly higher striatal DA concentrations compared with the other treatments, but did not lead to greater functional improvement in this study. For the first time under identical conditions in primates, we show that all three treatments lead to improvement compared with control animals

Effects of Neonatal Neural Progenitor Cell Implantation on Adult Neuroanatomy and Cognition in the Ts65Dn Model of Down Syndrome

As much of the aberrant neural development in Down syndrome (DS) occurs postnatally, an early opportunity exists to intervene and influence life-long cognitive development. Recent success using neural progenitor cells (NPC) in models of adult neurodegeneration indicate such therapy may be a viable option in diseases such as DS. Murine NPC (mNPC, C17.2 cell line) or saline were implanted bilaterally into the dorsal hippocampus of postnatal day 2 (PND 2) Ts65Dn pups to explore the feasibility of early postnatal treatment in this mouse model of DS. Disomic littermates provided karyotype controls for trisomic pups. Pups were monitored for developmental milestone achievement, and then underwent adult behavior testing at 14 weeks of age. We found that implanted mNPC survived into adulthood and migrated beyond the implant site in both karyotypes. The implantation of mNPC resulted in a significant increase in the density of dentate granule cells. However, mNPC implantation did not elicit cognitive changes in trisomic mice either neonatally or in adulthood. To the best of our knowledge, these results constitute the first assessment of mNPC as an early intervention on cognitive ability in a DS model

Oxidation-reduction potential of semen: what is its role in the treatment of male infertility?

The diagnosis of male infertility relies largely on conventional semen analysis, and its interpretation has a profound influence on subsequent management of patients. Despite poor correlation between conventional semen parameters and male fertility potential, inclusion of advanced semen quality tests to routine male infertility workup algorithms has not been widely accepted. Oxidative stress is one of the major mediators in various etiologies of male infertility; it has deleterious effects on spermatozoa, including DNA damage. Alleviation of oxidative stress constitutes a potential treatment strategy for male infertility. Measurement of seminal oxidative stress is of crucial role in the identification and monitoring of patients who may benefit from treatments. Various tests including reactive oxygen species (ROS) assay, total antioxidant capacity (TAC) assay or malondialdehyde (MDA) assay used by different laboratories have their own drawbacks. Oxidation-reduction potential (ORP) is a measure of overall balance between oxidants and antioxidants, providing a comprehensive measure of oxidative stress. The MiOXSYS™ System is a novel technology based on a galvanostatic measure of electrons; it presents static ORP (sORP) measures with static referring to the passive or current state of activity between oxidants and antioxidants. Preliminary studies have correlated sORP to poor semen qualities. It is potentially useful in prognostication of assisted reproductive techniques outcomes, screening of antioxidants either in vivo or during IVF cycles, identification of infertile men who may benefit from treatment of oxidative stress, and monitoring of treatment success. The simplified laboratory test requiring a small amount of semen would facilitate clinical application and research in the field. In this paper, we discuss the measurement of ORP by the MiOXSYS System as a real-time assessment of seminal oxidative stress, and argue that it is a potential valuable clinical test that should be incorporated into the male infertility workup and become an important guide to the treatment of oxidative stress-induced male infertility

Building Biocompatible Hydrogels for Tissue Engineering of the Brain and Spinal Cord

Tissue engineering strategies employing biomaterials have made great progress in the last few decades. However, the tissues of the brain and spinal cord pose unique challenges due to a separate immune system and their nature as soft tissue. Because of this, neural tissue engineering for the brain and spinal cord may require re-establishing biocompatibility and functionality of biomaterials that have previously been successful for tissue engineering in the body. The goal of this review is to briefly describe the distinctive properties of the central nervous system, specifically the neuroimmune response, and to describe the factors which contribute to building polymer hydrogels compatible with this tissue. These factors include polymer chemistry, polymerization and degradation, and the physical and mechanical properties of the hydrogel. By understanding the necessities in making hydrogels biocompatible with tissue of the brain and spinal cord, tissue engineers can then functionalize these materials for repairing and replacing tissue in the central nervous system

Hydrogel formulation determines cell fate of fetal and adult neural progenitor cells

Hydrogels provide a unique tool for neural tissue engineering. These materials can be customized for certain functions, i.e. to provide cell/drug delivery or act as a physical scaffold. Unfortunately, hydrogel complexities can negatively impact their biocompatibility, resulting in unintended consequences. These adverse effects may be combated with a better understanding of hydrogel chemical, physical, and mechanical properties, and how these properties affect encapsulated neural cells. We defined the polymerization and degradation rates and compressive moduli of 25 hydrogels formulated from different concentrations of hyaluronic acid (HA) and poly(ethylene glycol) (PEG). Changes in compressive modulus were driven primarily by the HA concentration. The in vitro biocompatibility of fetal-derived (fNPC) and adult-derived (aNPC) neural progenitor cells was dependent on hydrogel formulation. Acute survival of fNPC benefited from hydrogel encapsulation. NPC differentiation was divergent: fNPC differentiated into mostly glial cells, compared with neuronal differentiation of aNPC. Differentiation was influenced in part by the hydrogel mechanical properties. This study indicates that there can be a wide range of HA and PEG hydrogels compatible with NPC. Additionally, this is the first study comparing hydrogel encapsulation of NPC derived from different aged sources, with data suggesting that fNPC and aNPC respond dissimilarly within the same hydrogel formulation

Poor acute outcome in congestive heart failure is associated with increases in the plasma static oxidation–reduction potentials (sORP) in men but not in women

Objectives: In congestive heart failure (CHF), men are younger, more likely to have reduced ejection fraction (HF-rEF), and to be diabetic compared to women. Despite this, sex differences in oxidative stress have yet to be explored in CHF. Methods: Data from 67 males and 63 females hospitalized for CHF were collected. Static oxidation–reduction potential (sORP), a relative indicator of oxidative stress, and capacity ORP (icORP), a relative indicator of antioxidant capacity, were measured from plasma samples. We examined whether sex modified the relationship between ORP and hospital discharge disposition (poor outcome: death, hospice), along with other demographics, medications, and diagnostic parameters. Results: Males with poor outcomes had higher sORP and icORP values than females (P \u3c 0.05). For those with a good outcome, there were no differences between the sexes (P \u3e 0.05). Males were younger and more likely to have HF-rEF and diabetes. Controlling for these variables did not account for the sex differences in ORP measures. Regardless of sex, higher creatinine was related to higher sORP and icORP, while lower magnesium and potassium were related to higher sORP and icORP, respectively. Discussion: Increases in sORP during CHF are partially affected by sex and acute outcomes, but are also related to variables without sexual biases

Oxidation-Reduction Potential as a Biomarker for Severity and Acute Outcome in Traumatic Brain Injury

There are few reliable markers for assessing traumatic brain injury (TBI). Elevated levels of oxidative stress have been observed in TBI patients. We hypothesized that oxidation-reduction potential (ORP) could be a potent biomarker in TBI. Two types of ORP were measured in patient plasma samples: the static state of oxidative stress (sORP) and capacity for induced oxidative stress (icORP). Differences in ORP values as a function of time after injury, severity, and hospital discharge were compared using ANOVAs with significance at p≤0.05. Logit regression analyses were used to predict acute outcome comparing ORP, Injury Severity Score (ISS), Abbreviated Injury Scale (AIS), and Glasgow Coma Scale (GCS). Antioxidant capacity (icORP) on day 4 was prognostic for acute outcomes (p<0.05). An odds ratio of 4.08 was associated with poor acute outcome when icORP > 7.25 μC. IcORP was a better predictor than ISS, AIS, or GCS scores. sORP increased in those with the highest ISS values (p<0.05). Based on these findings ORP is useful biomarker for severity and acute outcome in TBI patients. Changes in ORP values on day 4 after injury were the most prognostic, suggesting that patients’ response to brain injury over time is a factor that determines outcome