GDNF Secreting Human Neural Progenitor Cells Protect Dying Motor Neurons, but Not Their Projection to Muscle, in a Rat Model of Familial ALS

Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease characterized by rapid loss of muscle control and eventual paralysis due to the death of large motor neurons in the brain and spinal cord. Growth factors such as glial cell line derived neurotrophic factor (GDNF) are known to protect motor neurons from damage in a range of models. However, penetrance through the blood brain barrier and delivery to the spinal cord remains a serious challenge. Although there may be a primary dysfunction in the motor neuron itself, there is also increasing evidence that excitotoxicity due to glial dysfunction plays a crucial role in disease progression. Clearly it would be of great interest if wild type glial cells could ameliorate motor neuron loss in these models, perhaps in combination with the release of growth factors such as GDNF.Human neural progenitor cells can be expanded in culture for long periods and survive transplantation into the adult rodent central nervous system, in some cases making large numbers of GFAP positive astrocytes. They can also be genetically modified to release GDNF (hNPC(GDNF)) and thus act as long-term 'mini pumps' in specific regions of the rodent and primate brain. In the current study we genetically modified human neural stem cells to release GDNF and transplanted them into the spinal cord of rats over-expressing mutant SOD1 (SOD1(G93A)). Following unilateral transplantation into the spinal cord of SOD1(G93A) rats there was robust cellular migration into degenerating areas, efficient delivery of GDNF and remarkable preservation of motor neurons at early and end stages of the disease within chimeric regions. The progenitors retained immature markers, and those not secreting GDNF had no effect on motor neuron survival. Interestingly, this robust motor neuron survival was not accompanied by continued innervation of muscle end plates and thus resulted in no improvement in ipsilateral limb use.The potential to maintain dying motor neurons by delivering GDNF using neural progenitor cells represents a novel and powerful treatment strategy for ALS. While this approach represents a unique way to prevent motor neuron loss, our data also suggest that additional strategies may also be required for maintenance of neuromuscular connections and full functional recovery. However, simply maintaining motor neurons in patients would be the first step of a therapeutic advance for this devastating and incurable disease, while future strategies focus on the maintenance of the neuromuscular junction

Insect herbivory releases more nutrients in warmer and drier forests

Climate, forest successional stage, and soil substrate age can alter herbivore communities and their effects on biogeochemical cycling, but the size and spatial variability of these effects are poorly quantified. To address this knowledge gap, we established a globally distributed network of 50 broadleaved old-growth forests across six continents, encompassing well-constrained local-scale gradients in mean annual temperature (MAT), mean annual precipitation (MAP), succession, and soil substrate age. We used this network to investigate how these variables impact insect foliar herbivory and the associated carbon, nitrogen, phosphorus, and silica fluxes in forest ecosystems. Over 1 to 2 years, we measured stand-level foliar biomass production, leaf-level herbivory, and foliar element concentrations. At the global scale, insect herbivores liberated higher amounts of elements from the canopies of warmer and drier sites than those of cooler and wetter sites with patterns for phosphorus being most pronounced. MAT exerted a stronger influence over insect-mediated element fluxes than MAP. Foliar biomass production and leaf-level herbivory responses to MAT and MAP were mainly responsible for the observed changes in insect-mediated element fluxes; we also observed minor effects of foliar phosphorus concentration on phosphorus fluxes. Local-scale trends were mixed and successional stage or soil substrate age did not appear to influence insect herbivore-mediated element fluxes. These results demonstrate that climate effects on plant-herbivore interactions are stronger at large than small scales, at which herbivory rates and nutrient fluxes appear to be more strongly affected by a diversity of non-climate factors

Persistent Expression of Notch2 Delays Gonadotrope Differentiation

Copyright © 2006 by The Endocrine SocietyNormal pituitary gland development requires coordination between maintenance of progenitor cell pools and selection of progenitors for differentiation. The spatial and temporal expression of Notch2 during pituitary development suggested that it could control progenitor cell differentiation in the pituitary. Consistent with this idea, Notch2 is not expressed in Prop1 mutants, and anterior pituitary progenitors in Prop1 mutants appear to be unable to transition from proliferation to differentiation properly, resulting in anterior lobe failed cell specification and evolving hypoplasia. To test the function of Notch2 directly, we used the GSU subunit promoter to express activated NOTCH2 persistently in pre-gonadotropes and pre-thyrotropes of transgenic mice. At birth, there is a small reduction in the population of fully differentiated thyrotropes and almost no fully differentiated gonadotropes. The temporal and spatial expression of Hey1 suggests that it could be a mediator of this effect. Gonadotropes complete their differentiation program eventually, although expression of LH and FSH is mutually exclusive with NOTCH2 transgene expression. This demonstrates that activated Notch2 is sufficient to delay gonadotrope differentiation, and it supports the hypothesis that Notch2 regulates progenitor cell differentiation in the pituitary gland.Lori T. Raetzman, Bayly S. Wheeler, Shelley A. Ross, Paul Q. Thomas and Sally A. Campe

Outcomes With Femoral IABP in Heart Failure and Acute Myocardial Infarction-Related Cardiogenic Shock.

BACKGROUND: Intra-aortic balloon pump (IABP) insertion has not been shown to improve mortality rates in acute myocardial infarction-related cardiogenic shock (AMI-CS) but is increasingly used in heart failure-related cardiogenic shock (HF-CS). OBJECTIVE: We sought to compare IABP-related outcomes in patients with HF-CS and AMI-CS. METHODS: The Cardiogenic Shock Working Group registry was queried for patients with CS receiving femoral IABPs as the first temporary mechanical circulatory support (tMCS) device. Patients were divided into those with AMI-CS or HF-CS and were excluded if they received the IABP in conjunction with venoarterial extracorporeal membrane oxygenation (VA-ECMO) or another device concomitantly. Outcomes, including rates of native heart survival (NHS) (ie, weaned from IABP and discharged), heart replacement therapy (HRT) (ie, bridge to durable left ventricular assist device or heart transplant), need for another tMCS device, and death, were recorded and compared between the 2 cohorts. RESULTS: In total, 886 patients were supported by IABPs as the first tMCS device; of these, 407 (45.6%) had HF-CS and 384 (43.3%) had AMI-CS. Those with HF-CS were younger but had higher burdens of cardiovascular comorbidities than those with AMI-CS. Among the HF-CS cohort, 33.2% had NHS, and 26.7% were bridged to HRT without another tMCS device. In the AMI-CS cohort, 43.4% had NHS and 2.1% were bridged to HRT without another tMCS device. Mortality rates were higher in AMI-CS group (36.4% vs 20.6%; P \u3c 0.001). Complication rates were higher in those with AMI-CS and in those needing another tMCS device. CONCLUSION: Patients with HF-CS were more likely to have a favorable outcome with IABPs than those with AMI-CS