A Conditioning Lesion Provides Selective Protection in a Rat Model of Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is neurodegenerative disease characterized by muscle weakness and atrophy due to progressive motoneuron loss. The death of motoneuron is preceded by the failure of neuromuscular junctions (NMJs) and axonal retraction. Thus, to develop an effective ALS therapy you must simultaneously preserve motoneuron somas, motor axons and NMJs. A conditioning lesion has the potential to accomplish this since it has been shown to enhance neuronal survival and recovery from trauma in a variety of contexts. rats that received a conditioning lesion was delayed and less severe. These improvements in motor function corresponded to greater motoneuron survival, reduced motor axonopathy, and enhanced NMJ maintenance at disease end-stage. Furthermore, the increased NMJ maintenance was selective for muscle compartments innervated by the most resilient (slow) motoneuron subtypes, but was absent in muscle compartments innervated by the most vulnerable (fast fatigable) motoneuron subtypes.These findings support the development of strategies aimed at mimicking the conditioning lesion effect to treat ALS as well as underlined the importance of considering the heterogeneity of motoneuron sub-types when evaluating prospective ALS therapeutics

Progress in gene therapy for neurological disorders

Diseases of the nervous system have devastating effects and are widely distributed among the population, being especially prevalent in the elderly. These diseases are often caused by inherited genetic mutations that result in abnormal nervous system development, neurodegeneration, or impaired neuronal function. Other causes of neurological diseases include genetic and epigenetic changes induced by environmental insults, injury, disease-related events or inflammatory processes. Standard medical and surgical practice has not proved effective in curing or treating these diseases, and appropriate pharmaceuticals do not exist or are insufficient to slow disease progression. Gene therapy is emerging as a powerful approach with potential to treat and even cure some of the most common diseases of the nervous system. Gene therapy for neurological diseases has been made possible through progress in understanding the underlying disease mechanisms, particularly those involving sensory neurons, and also by improvement of gene vector design, therapeutic gene selection, and methods of delivery. Progress in the field has renewed our optimism for gene therapy as a treatment modality that can be used by neurologists, ophthalmologists and neurosurgeons. In this Review, we describe the promising gene therapy strategies that have the potential to treat patients with neurological diseases and discuss prospects for future development of gene therapy

Omega-3 polyunsaturated fatty acids enhance cytokine production and oxidative stress in a mouse model of preterm labor

Objective: Omega-3 polyunsaturated fatty acid (omega-3 PUFA) supplementation during pregnancy remains controversial. We sought to examine the effects of omega-3 PUFA on inflammation and oxidative stress in vitro and in vivo using a model of preterm labor. Methods: In vivo. Female Swiss Webster mice were fed a normal diet or a 5% fish oil (FO) diet for 3 weeks then mated with normal-fed males. On gestational day 15, dams were injected with either saline (n = 10 per group) or lipopolysaccharide (LPS, intrauterine) (n = 10 per group). Maternal plasma, amniotic fluid, placentas, and uteri were collected 4 h later and assessed for cytokines; maternal plasma and amniotic fluids were analyzed for oxidative stress. In vitro. RAW264.7 mouse macrophage-like cells were treated with either: vehicle, H2O2, docosahexaenoic acid (DHA), or eicosapentaenoic acid (EPA) -(0, -0.1-100 mu M) and analyzed for oxidative stress. Results: In vivo. Administration of the 5% FO diet enhanced LPS-induced cytokines in the placenta (P \u3c 0.05-0.01) and increased tumor necrosis factor-a in the uterus (P \u3c 0.05) and amniotic fluid (P \u3c 0.01) when compared to LPS-treated normal-fed animals. Maternal plasma obtained from FO-fed dams showed higher LPS-induced oxidative stress than control-fed animals (P \u3c 0.035). However, no differences in oxidative stress were observed in the amniotic fluid. In vitro. Treatment of macrophage-like cells with omega-3 PUFA significantly and dose-dependently increased oxidative stress (P \u3c 0.001-0.0001). Conclusions: Supplementation with FO for prior to and during pregnancy significantly increased LPS-induced inflammation in the amniotic fluid, uterus, and placenta and significantly increased maternal systemic oxidative stress in vivo. Likewise, DHA and EPA induced oxidative stress in macrophage-like cells in vitro

investigation of the role of platelets in the aetiopathogenesis of adenomyosis

Research question Do platelets aggregate in adenomyotic lesions and participate in adenomyosis (AD) pathogenesis and related fibrosis? Design Eutopic and ectopic endometrium from 18 patients with AD and endometrium from 23 healthy controls were collected. Immunohistochemical analyses of platelet marker CD41, transforming growth factor β1 (TGF-β1) and vascular endothelial growth factor (VEGF) were performed to investigate aggregation and activation of platelets in the stroma. Picrosirius staining was carried out to evaluate the extent of fibrotic tissue. Results Stroma in the control group showed higher CD41 staining levels than ectopic stroma from patients with AD (p<0.001). In subjects with AD, eutopic stroma expressed more extensive CD41 staining than ectopic stroma (p<0.0001). Stroma in the control group exhibited higher TGF-β1 expression than eutopic and ectopic stroma from AD patients (p<0.001 and p<0.0001). Stroma in the control group also expressed higher VEGF levels than ectopic stroma from subjects with AD (p<0.001). In patients with AD, eutopic stroma showed higher VEGF expression than ectopic stroma (p<0.05). Stroma in ectopic endometrium from AD patients displayed greater picrosirius staining compared to both eutopic stroma from AD patients and stroma in the control group (p<0.0001). Conclusion Our results did not detect a primary role for platelet activation or aggregation in the pathophysiological process of AD. We found higher rates of collagen fibers in adenomyotic lesions, likely to be related to a TGF-β1-independant pathway. Collagen fiber deposition was more extensive in adenomyotic lesions, consistent with fibrosis