Chronic Melatonin Administration Reduced Oxidative Damage and Cellular Senescence in the Hippocampus of a Mouse Model of Down Syndrome

Previous studies have demonstrated that melatonin administration improves spatial learning and memory and hippocampal long-term potentiation in the adult Ts65Dn (TS) mouse, a model of Down syndrome (DS). This functional benefit of melatonin was accompanied by protection from cholinergic neurodegeneration and the attenuation of several hippocampal neuromorphological alterations in TS mice. Because oxidative stress contributes to the progression of cognitive deficits and neurodegeneration in DS, this study evaluates the antioxidant effects of melatonin in the brains of TS mice. Melatonin was administered to TS and control mice from 6 to 12 months of age and its effects on the oxidative state and levels of cellular senescence were evaluated. Melatonin treatment induced antioxidant and antiaging effects in the hippocampus of adult TS mice. Although melatonin administration did not regulate the activities of the main antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione S-transferase) in the cortex or hippocampus, melatonin decreased protein and lipid oxidative damage by reducing the thiobarbituric acid reactive substances (TBARS) and protein carbonyls (PC) levels in the TS hippocampus due to its ability to act as a free radical scavenger. Consistent with this reduction in oxidative stress, melatonin also decreased hippocampal senescence in TS animals by normalizing the density of senescence-associated â-galactosidase positive cells in the hippocampus. These results showed that this treatment attenuated the oxidative damage and cellular senescence in the brain of TS mice and support the use of melatonin as a potential therapeutic agent for age-related cognitive deficits and neurodegeneration in adults with DS

Galantamine improves olfactory learning in the Ts65Dn mouse model of Down syndrome

Down syndrome (DS) is the most common form of congenital intellectual disability. Although DS involves multiple disturbances in various tissues, there is little doubt that in terms of quality of life cognitive impairment is the most serious facet and there is no effective treatment for this aspect of the syndrome. The Ts65Dn mouse model of DS recapitulates multiple aspects of DS including cognitive impairment. Here the Ts65Dn mouse model of DS was evaluated in an associative learning paradigm based on olfactory cues. In contrast to disomic controls, trisomic mice exhibited significant deficits in olfactory learning. Treatment of trisomic mice with the acetylcholinesterase inhibitor galantamine resulted in a significant improvement in olfactory learning. Collectively, our study indicates that olfactory learning can be a sensitive tool for evaluating deficits in associative learning in mouse models of DS and that galantamine has therapeutic potential for improving cognitive abilities

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

Gene Network Disruptions and Neurogenesis Defects in the Adult Ts1Cje Mouse Model of Down Syndrome

Background: Down syndrome (DS) individuals suffer mental retardation with further cognitive decline and early onset Alzheimer's disease. Methodology/Principal Findings: To understand how trisomy 21 causes these neurological abnormalities we investigated changes in gene expression networks combined with a systematic cell lineage analysis of adult neurogenesis using the Ts1Cje mouse model of DS. We demonstrated down regulation of a number of key genes involved in proliferation and cell cycle progression including Mcm7, Brca2, Prim1, Cenpo and Aurka in trisomic neurospheres. We found that trisomy did not affect the number of adult neural stem cells but resulted in reduced numbers of neural progenitors and neuroblasts. Analysis of differentiating adult Ts1Cje neural progenitors showed a severe reduction in numbers of neurons produced with a tendency for less elaborate neurites, whilst the numbers of astrocytes was increased. Conclusions/Significance: We have shown that trisomy affects a number of elements of adult neurogenesis likely to result in a progressive pathogenesis and consequently providing the potential for the development of therapies to slow progression of, or even ameliorate the neuronal deficits suffered by DS individuals.Chelsee A. Hewitt, King-Hwa Ling, Tobias D. Merson, Ken M. Simpson, Matthew E. Ritchie, Sarah L. King, Melanie A. Pritchard, Gordon K. Smyth, Tim Thomas, Hamish S. Scott and Anne K. Vos

Magnification Effects on Distance Estimation During Robotic Suturing

We aimed to understand the impact of magnification on distance estimation during robotic suturing. Twenty subjects estimated the lengths of various sutures externally, in plain sight, to validate their ability to measure distances. They then robotically repaired a 3-cm cystotomy, suturing 10 mm above and below the incision and 10 mm on either side of the incision. The bladder was removed and distances measured. A total of 20 surgeons were analyzed: 7 residents, 8 fellows, and 5 staff. Specialties comprised four urologists, eight general gynecologists, two urogynecologists, three gynecologic oncologists, and three reproductive endocrinologists. The mean estimation for external suture length was not significant at 10 mm: mean = 9.6 (±3.2) mm (p = 0.59). When comparing these data sets, the externally visualized 10-mm suture versus the suture-to-suture and the suture-to-incision distances were both significantly different (p = 0.002 and p \u3c 0.001, respectively). The mean distance between each suture was 6.5 (±1.8) mm, which was significantly different from the 10-mm goal (p \u3c 0.001, 95 % confidence interval (CI) [−4.4,−2.6]). The mean distance from the suture to the incision was 4.1 (±1.0) mm, which was also statistically significantly different from the goal (p \u3c 0.001, 95 % CI [−6.3,−5.4]). Surgical experience was negatively associated with suture-to-incision distance (r s = −0.53, p = 0.016). Inter-suture distance was also negatively associated with experience (r s = −0.30, p = 0.22), though not statistically significant. In vivo distances are significantly underestimated during robotic suture placement. Interestingly, the most experienced surgeons had the worst distance estimation from the incision to the suture

Magnification Effects on Distance Estimation During Robotic Suturing

We aimed to understand the impact of magnification on distance estimation during robotic suturing. Twenty subjects estimated the lengths of various sutures externally, in plain sight, to validate their ability to measure distances. They then robotically repaired a 3-cm cystotomy, suturing 10 mm above and below the incision and 10 mm on either side of the incision. The bladder was removed and distances measured. A total of 20 surgeons were analyzed: 7 residents, 8 fellows, and 5 staff. Specialties comprised four urologists, eight general gynecologists, two urogynecologists, three gynecologic oncologists, and three reproductive endocrinologists. The mean estimation for external suture length was not significant at 10 mm: mean = 9.6 (±3.2) mm (p = 0.59). When comparing these data sets, the externally visualized 10-mm suture versus the suture-to-suture and the suture-to-incision distances were both significantly different (p = 0.002 and p \u3c 0.001, respectively). The mean distance between each suture was 6.5 (±1.8) mm, which was significantly different from the 10-mm goal (p \u3c 0.001, 95 % confidence interval (CI) [−4.4,−2.6]). The mean distance from the suture to the incision was 4.1 (±1.0) mm, which was also statistically significantly different from the goal (p \u3c 0.001, 95 % CI [−6.3,−5.4]). Surgical experience was negatively associated with suture-to-incision distance (r s = −0.53, p = 0.016). Inter-suture distance was also negatively associated with experience (r s = −0.30, p = 0.22), though not statistically significant. In vivo distances are significantly underestimated during robotic suture placement. Interestingly, the most experienced surgeons had the worst distance estimation from the incision to the suture

Magnification Effects on Distance Estimation During Robotic Suturing

We aimed to understand the impact of magnification on distance estimation during robotic suturing. Twenty subjects estimated the lengths of various sutures externally, in plain sight, to validate their ability to measure distances. They then robotically repaired a 3-cm cystotomy, suturing 10 mm above and below the incision and 10 mm on either side of the incision. The bladder was removed and distances measured. A total of 20 surgeons were analyzed: 7 residents, 8 fellows, and 5 staff. Specialties comprised four urologists, eight general gynecologists, two urogynecologists, three gynecologic oncologists, and three reproductive endocrinologists. The mean estimation for external suture length was not significant at 10 mm: mean = 9.6 (±3.2) mm (p = 0.59). When comparing these data sets, the externally visualized 10-mm suture versus the suture-to-suture and the suture-to-incision distances were both significantly different (p = 0.002 and p \u3c 0.001, respectively). The mean distance between each suture was 6.5 (±1.8) mm, which was significantly different from the 10-mm goal (p \u3c 0.001, 95 % confidence interval (CI) [−4.4,−2.6]). The mean distance from the suture to the incision was 4.1 (±1.0) mm, which was also statistically significantly different from the goal (p \u3c 0.001, 95 % CI [−6.3,−5.4]). Surgical experience was negatively associated with suture-to-incision distance (r s = −0.53, p = 0.016). Inter-suture distance was also negatively associated with experience (r s = −0.30, p = 0.22), though not statistically significant. In vivo distances are significantly underestimated during robotic suture placement. Interestingly, the most experienced surgeons had the worst distance estimation from the incision to the suture