Concise Review: Stem Cell Therapies for Amyotrophic Lateral Sclerosis: Recent Advances and Prospects for the Future

Amyotrophic lateral sclerosis (ALS) is a lethal disease involving the loss of motor neurons. Although the mechanisms responsible for motor neuron degeneration in ALS remain elusive, the development of stem cell‐based therapies for the treatment of ALS has gained widespread support. Here, we review the types of stem cells being considered for therapeutic applications in ALS, and emphasize recent preclinical advances that provide supportive rationale for clinical translation. We also discuss early trials from around the world translating cellular therapies to ALS patients, and offer important considerations for future clinical trial design. Although clinical translation is still in its infancy, and additional insight into the mechanisms underlying therapeutic efficacy and the establishment of long‐term safety are required, these studies represent an important first step toward the development of effective cellular therapies for the treatment of ALS. S tem C ells 2014;32:1099–1109Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106861/1/stem1628.pd

APPLICATION OF DIGITAL IMAGE PROCESSING TO ESTIMATE SLAUGHTER VALUE OF BULLS

Glavna svrha našeg istraživanja bila je dokazati da se analiza video slike može upotrijebiti za procjenu sastava polovica u žive stoke. Primjena mikrokompjutora, gdje se obrađuje slika video kamere, nije novost u znanosti o životinjama. Cross i sur. (1) pokušali su predvidjeti sastav područja 9., 10. i 11. rebra u goveda služeći se analiziranjem video slike. Misztal (3) je upotrijebio obradu slike za procjenjivanje sastava polovica u žive stoke. Nove mogućnosti izračunavanja dale su mnogo veću točnost u ovoj metodi, te manje troškove i mnogo bržu obradu digitalnih slika životinja, nego u ranijim istraživanjima. Naš bi pokus morao dati potpunu automatiziranu metodu procjenjivanja uzgojne vrijednosti živih životinja, što bi se mogla izračunati na osnovi predviđene vrijednosti rasjecanja polutki, težine hladnih polovica i dijelova vrijednog mesa. Djelomični koeficijenti regresije svakog pojedinog modela bili su 0.96 Se=6.0 za težinu hladnih polovica, 0.94 Se=6.0 za vrijedno meso i 0.92 Se=6.0 za meso u vrijednim dijelovima, te su bili neznatno viši od onih što su ih dobili Jankowski et al (2) (R=0,48 - 0.94) i Misztal (R=0.86 - 0.91). Visoki djelomični koeficijent regresije (R) svakog modela pokazuje da postoji mogućnost primjene ove metode kao kriterija selekcije, što se temelji na pojedinom testu performance, z- predviđanje klaoničke produktivnosti mesne pasmine

Stem cell technology for neurodegenerative diseases

Over the past 20 years, stem cell technologies have become an increasingly attractive option to investigate and treat neurodegenerative diseases. In the current review, we discuss the process of extending basic stem cell research into translational therapies for patients suffering from neurodegenerative diseases. We begin with a discussion of the burden of these diseases on society, emphasizing the need for increased attention toward advancing stem cell therapies. We then explain the various types of stem cells utilized in neurodegenerative disease research, and outline important issues to consider in the transition of stem cell therapy from bench to bedside. Finally, we detail the current progress regarding the applications of stem cell therapies to specific neurodegenerative diseases, focusing on Parkinson disease, Huntington disease, Alzheimer disease, amyotrophic lateral sclerosis, and spinal muscular atrophy. With a greater understanding of the capacity of stem cell technologies, there is growing public hope that stem cell therapies will continue to progress into realistic and efficacious treatments for neurodegenerative diseases. Ann Neurol 2011;70: 353–361.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86937/1/22487_ftp.pd

Autocrine Production of IGF‐I Increases Stem Cell‐Mediated Neuroprotection

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder resulting in motor neuron (MN) loss. There are currently no effective therapies; however, cellular therapies using neural progenitor cells protect MNs and attenuate disease progression in G93A‐SOD1 ALS rats. Recently, we completed a phase I clinical trial examining intraspinal human spinal stem cell (HSSC) transplantation in ALS patients which demonstrated our approach was safe and feasible, supporting the phase II trial currently in progress. In parallel, efforts focused on understanding the mechanisms underlying the preclinical benefit of HSSCs in vitro and in animal models of ALS led us to investigate how insulin‐like growth factor‐I (IGF‐I) production contributes to cellular therapy neuroprotection. IGF‐I is a potent growth factor with proven efficacy in preclinical ALS studies, and we contend that autocrine IGF‐I production may enhance the salutary effects of HSSCs. By comparing the biological properties of HSSCs to HSSCs expressing sixfold higher levels of IGF‐I, we demonstrate that IGF‐I production augments the production of glial‐derived neurotrophic factor and accelerates neurite outgrowth without adversely affecting HSSC proliferation or terminal differentiation. Furthermore, we demonstrate that increased IGF‐I induces more potent MN protection from excitotoxicity via both indirect and direct mechanisms, as demonstrated using hanging inserts with primary MNs or by culturing with organotypic spinal cord slices, respectively. These findings support our theory that combining autocrine growth factor production with HSSC transplantation may offer a novel means to achieve additive neuroprotection in ALS. Stem Cells 2015;33:1480–1489Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111155/1/stem1933.pd

Impact of inter-hospital transfers on the prevalence of resistant pathogens in a hospital–community system

The spread of resistant bacteria in hospitals is an increasing problem worldwide. Transfers of patients, who may be colonized with resistant bacteria, are considered to be an important driver of promoting resistance. Even though transmission rates within a hospital are often low, readmissions of patients who were colonized during an earlier hospital stay lead to repeated introductions of resistant bacteria into hospitals. We developed a mathematical model that combines a deterministic model for within-hospital spread of pathogens, discharge to the community and readmission, with a hospital–community network simulation of patient transfers between hospitals. Model parameters used to create the hospital–community network are obtained from two health insurance datasets from Germany. For parameter values representing transmission of resistant Enterobacteriaceae, we compute estimates for the single admission reproduction numbers RA and the basic reproduction numbers R0 per hospital–community pair. We simulate the spread of colonization through the network of hospitals, and investigate how increasing connectedness of hospitals through the network influences the prevalence in the hospital–community pairs. We find that the prevalence in hospitals is determined by their RA and R0 values. Increasing transfer rates between network nodes tend to lower the overall prevalence in the network by diluting the high prevalence of hospitals with high R0 to hospitals where persistent spread is not possible. We conclude that hospitals with high reproduction numbers represent a continuous source of risk for importing resistant pathogens for hospitals with otherwise low levels of transmission. Moreover, high risk hospital–community nodes act as reservoirs of pathogens in a densely connected network

Neuromuscular effects of G93A-SOD1 expression in zebrafish

Abstract Background Amyotrophic lateral sclerosis (ALS) is a fatal disorder involving the degeneration and loss of motor neurons. The mechanisms of motor neuron loss in ALS are unknown and there are no effective treatments. Defects in the distal axon and at the neuromuscular junction are early events in the disease course, and zebrafish provide a promising in vivo system to examine cellular mechanisms and treatments for these events in ALS pathogenesis. Results We demonstrate that transient genetic manipulation of zebrafish to express G93A-SOD1, a mutation associated with familial ALS, results in early defects in motor neuron outgrowth and axonal branching. This is consistent with previous reports on motor neuron axonal defects associated with familial ALS genes following knockdown or mutant protein overexpression. We also demonstrate that upregulation of growth factor signaling is capable of rescuing these early defects, validating the potential of the model for therapeutic discovery. We generated stable transgenic zebrafish lines expressing G93A-SOD1 to further characterize the consequences of G93A-SOD1 expression on neuromuscular pathology and disease progression. Behavioral monitoring reveals evidence of motor dysfunction and decreased activity in transgenic ALS zebrafish. Examination of neuromuscular and neuronal pathology throughout the disease course reveals a loss of neuromuscular junctions and alterations in motor neuron innervations patterns with disease progression. Finally, motor neuron cell loss is evident later in the disease. Conclusions This sequence of events reflects the stepwise mechanisms of degeneration in ALS, and provides a novel model for mechanistic discovery and therapeutic development for neuromuscular degeneration in ALS.http://deepblue.lib.umich.edu/bitstream/2027.42/112892/1/13024_2012_Article_367.pd

Regional patient transfer patterns matter for the spread of hospital-acquired pathogens

Pathogens typically responsible for hospital-acquired infections (HAIs) constitute a major threat to healthcare systems worldwide. They spread via hospital (or hospital-community) networks by readmissions or patient transfers. Therefore, knowledge of these networks is essential to develop and test strategies to mitigate and control the HAI spread. Until now, no methods for comparing healthcare networks across different systems were proposed. Based on healthcare insurance data from four German federal states (Bavaria, Lower Saxony, Saxony and Thuringia), we constructed hospital networks and compared them in a systematic approach regarding population, hospital characteristics, and patient transfer patterns. Direct patient transfers between hospitals had only a limited impact on HAI spread. Whereas, with low colonization clearance rates, readmissions to the same hospitals posed the biggest transmission risk of all inter-hospital transfers. We then generated hospital-community networks, in which patients either stay in communities or in hospitals. We found that network characteristics affect the final prevalence and the time to reach it. However, depending on the characteristics of the pathogen (colonization clearance rate and transmission rate or even the relationship between transmission rate in hospitals and in the community), the studied networks performed differently. The differences were not large, but justify further studies