Recent advances in basic and translational stroke research.

Since 1998, the biannual International Symposium on Neuroprotection and Neurorepair, also known as the Magdeburg Meeting series, has provided a platform for the discussion of recent advances in basic and translational stroke research. The 2010 meeting reviewed highly relevant topics, including astrogliosis and microgliosis, neuroimmunological processes, cell-based therapies, novel imaging approaches, mechanisms of poststroke regeneration and metabolic phenomena in neuroprotection. It further focused on common pitfalls and opportunities in the translational process, from preclinical research to clinical application.

Simultaneous genome-wide inference of physical, genetic, regulatory, and functional pathway components.

Biomolecular pathways are built from diverse types of pairwise interactions, ranging from physical protein-protein interactions and modifications to indirect regulatory relationships. One goal of systems biology is to bridge three aspects of this complexity: the growing body of high-throughput data assaying these interactions; the specific interactions in which individual genes participate; and the genome-wide patterns of interactions in a system of interest. Here, we describe methodology for simultaneously predicting specific types of biomolecular interactions using high-throughput genomic data.

Quantitative analysis of fitness and genetic interactions in yeast on a genome scale.

Global quantitative analysis of genetic interactions is a powerful approach for deciphering the roles of genes and mapping functional relationships among pathways. Using colony size as a proxy for fitness, we developed a method for measuring fitness-based genetic interactions from high-density arrays of yeast double mutants generated by synthetic genetic array (SGA) analysis. We identified several experimental sources of systematic variation and developed normalization strategies to obtain accurate single- and double-mutant fitness measurements, which rival the accuracy of other high-resolution studies.

Minocycline to improve neurologic outcome in stroke (MINOS): a dose-finding study.

Background And Purpose: Minocycline is a promising anti-inflammatory and protease inhibitor that is effective in multiple preclinical stroke models. We conducted an early phase trial of intravenous minocycline in acute ischemic stroke.

Methods: Following an open-label, dose-escalation design, minocycline was administered intravenously within 6 hours of stroke symptom onset in preset dose tiers of 3, 4.

Peri-hemorrhagic degeneration accompanies stereotaxic collagenase-mediated cortical hemorrhage in mouse.

The cortex is a key brain region vulnerable to intracerebral hemorrhage (ICH) associated with stroke and head trauma. Animal models of ICH, via blood or collagenase infusion, have been developed most commonly to target the striatum. Here, we show that stereotaxic injection of collagenase type IV into two sites of the right cortex of adult C57BL6 mice produced hemorrhage to the cortex, subcortical white matter and hippocampus at day 1 post-injury, followed by cortical volume decrement by day 7.

Undone Science: Charting Social Movement and Civil Society Challenges to Research Agenda Setting.

"Undone science" refers to areas of research that are left unfunded, incomplete, or generally ignored but that social movements or civil society organizations often identify as worthy of more research. This study mobilizes four recent studies to further elaborate the concept of undone science as it relates to the political construction of research agendas. Using these cases, we develop the argument that undone science is part of a broader politics of knowledge, wherein multiple and competing groups struggle over the construction and implementation of alternative research agendas.

Repurposing an old drug to improve the use and safety of tissue plasminogen activator for acute ischemic stroke: minocycline.

Tissue plasminogen activator (tPA) is the only drug approved by the United States Food and Drug Administration for treatment of acute ischemic stroke. Because the drug must be used soon after symptom onset and is associated with intracerebral hemorrhage, tPA remains underutilized. Research has therefore focused on identifying other drugs that can be used concomitantly with tPA to improve the odds of a favorable recovery and to reduce the risk of intracerebral hemorrhage.

Estradiol suppresses tissue androgens and prostate cancer growth in castration resistant prostate cancer.

Background: Estrogens suppress tumor growth in prostate cancer which progresses despite anorchid serum androgen levels, termed castration resistant prostate cancers (CRPC), although the mechanisms are unclear. We hypothesize that estrogen inhibits CRPC in anorchid animals by suppressing tumoral androgens, an effect independent of the estrogen receptor.

Methods: The human CRPC xenograft LuCaP 35V was implanted into orchiectomized male SCID mice and established tumors were treated with placebo, 17beta-estradiol or 17beta-estradiol and estrogen receptor antagonist ICI 182,780.

Metal chelation by the common 2-amino-2-deoxy-, 2-N-acetylamino-2-deoxy-, and 2-deoxy-hexoses.

The chelating properties of the common aldohexoses d-glucose, d-mannose, and d-galactose are characteristically modified in 2-substituted derivatives. The 2-amino-2-deoxy-aldohexoses provide mono- and bis-metallisable anionic ligands after their reaction with metal probes of the Pd(II)N(2) type (N(2) = bidentate nitrogen ligand). The 2-amino function reliably participates in metal binding of the, mostly pyranoidic, carbohydrate chelators.

Repurposing an old drug to improve the use and safety of tissue plasminogen activator for acute ischemic stroke: minocycline.

There is only 1 US Food and Drug Administration-approved drug for acute ischemic stroke: tissue plasminogen activator (tPA). Due to a short time window and fear of intracerebral hemorrhage (ICH), tPA remains underutilized. There is great interest in developing combination drugs to use with tPA to improve the odds of a favorable recovery and to reduce the risk of ICH.

Improving modified Rankin Scale assessment with a simplified questionnaire.

Background And Purpose: The modified Rankin Scale (mRS) is a popular primary stroke outcome measure, but its usefulness is limited by suboptimal reliability (inter-rater agreement).

Methods: We developed and tested the reliability of a simplified mRS questionnaire (smRSq) in 50 patients after stroke seen in outpatient clinics. Randomly chosen paired raters administered the smRSq within 20 minutes of each other and the ratings were blinded until the end of this study.

Human cord blood progenitors with high aldehyde dehydrogenase activity improve vascular density in a model of acute myocardial infarction.

Unlabelled: Human stem cells from adult sources have been shown to contribute to the regeneration of muscle, liver, heart, and vasculature. The mechanisms by which this is accomplished are, however, still not well understood. We tested the engraftment and regenerative potential of human umbilical cord blood-derived ALDH(hi)Lin(-), and ALDH(lo)Lin(-) cells following transplantation to NOD/SCID or NOD/SCID beta2m null mice with experimentally induced acute myocardial infarction.

A telestroke network enhances recruitment into acute stroke clinical trials.

Background And Purpose: Acute stroke clinical trials are conducted primarily at academic medical centers. As a result, patients living in rural areas are excluded from participation, results may not be generalizable to nonacademic settings, and studies may be slow to recruit subjects. Telemedicine can provide rural patients with emergency neurovascular consultation.

Toward cell therapy using placenta-derived cells: disease mechanisms, cell biology, preclinical studies, and regulatory aspects at the round table.

Among the many cell types that may prove useful to regenerative medicine, mounting evidence suggests that human term placenta-derived cells will join the list of significant contributors. In making new cell therapy-based strategies a clinical reality, it is fundamental that no a priori claims are made regarding which cell source is preferable for a particular therapeutic application. Rather, ongoing comparisons of the potentiality and characteristics of cells from different sources should be made to promote constant improvement in cell therapies, and such comparisons will likely show that individually tailored cells can address disease-specific clinical needs.

Therapeutic targets and limits of minocycline neuroprotection in experimental ischemic stroke.

Background: Minocycline, a second-generation tetracycline with anti-inflammatory and anti-apoptotic properties, has been shown to promote therapeutic benefits in experimental stroke. However, equally compelling evidence demonstrates that the drug exerts variable and even detrimental effects in many neurological disease models. Assessment of the mechanism underlying minocycline neuroprotection should clarify the drug's clinical value in acute stroke setting.

Who's in favor of translational cell therapy for stroke: STEPS forward please?

A consortium of translational stem cell and stroke experts from multiple academic institutes and biotechnology companies, under the guidance of the government (FDA/NIH), is missing. Here, we build a case for the establishment of this consortium if cell therapy for stroke is to advance from the laboratory to the clinic.

Telestroke 10 years later--'telestroke 2.0'.

Background: The lack of physicians with specialty stroke training represents a significant challenge to the future of stroke. This deficit limits both quality stroke care and clinical research initiatives.

Methods: The use of telemedicine for stroke ('telestroke') has been an attempt to overcome this shortage and extend stroke expertise to locations which lack coverage.

Minocycline and tissue-type plasminogen activator for stroke: assessment of interaction potential.

Background And Purpose: New treatment strategies for acute ischemic stroke must be evaluated in the context of effective reperfusion. Minocycline is a neuroprotective agent that inhibits proteolytic enzymes and therefore could potentially both inactivate the clot lysis effect and decrease the damaging effects of tissue-type plasminogen activator (t-PA). This study aimed to determine the effect of minocycline on t-PA clot lysis and t-PA-induced hemorrhage formation after ischemia.

The impact of incomplete knowledge on evaluation: an experimental benchmark for protein function prediction.

Motivation: Rapidly expanding repositories of highly informative genomic data have generated increasing interest in methods for protein function prediction and inference of biological networks. The successful application of supervised machine learning to these tasks requires a gold standard for protein function: a trusted set of correct examples, which can be used to assess performance through cross-validation or other statistical approaches. Since gene annotation is incomplete for even the best studied model organisms, the biological reliability of such evaluations may be called into question.

Retrospective correction for T1-weighting bias in T2 values obtained with various spectroscopic spin-echo acquisition schemes.

Localized tissue transverse relaxation time (T(2)) is obtained by fitting a decaying exponential to the signals from several spin-echo experiments at different echo times (TE). Unfortunately, time constraints in magnetic resonance spectroscopy (MRS) often mandate in vivo acquisition schemes at short repetition times (TR), that is, comparable with the longitudinal relaxation constant (T(1)). This leads to different T(1)-weighting of the signals at each TE.

Anomaly in aortic arch alters pathological outcome of transient global ischemia in Rhesus macaques.

We investigated a non-human primate (NHP) transient global ischemia (TGI) model which was induced by clipping the arteries originating from the aortic arch. Previously we demonstrated that our TGI model in adult Rhesus macaques (Macaca mulatta) results in marked neuronal cell loss in the hippocampal region, specifically the cornu Ammonis (CA1) region. However, we observed varying degrees of hippocampal cell loss among animals.

Amnion: a potent graft source for cell therapy in stroke.

Regenerative medicine is a new field primarily based on the concept of transplanting exogenous or stimulating endogenous stem cells to generate biological substitutes and improve tissue functions. Recently, amnion-derived cells have been reported to have multipotent differentiation ability, and these cells have attracted attention as a novel cell source for cell transplantation therapy. Cells isolated from amniotic membrane can differentiate into all three germ layers, have low immunogenicity and anti-inflammatory function, and do not require the destruction of human embryos for their isolation, thus circumventing the ethical debate commonly associated with the use of human embryonic stem cells.

Human progenitor cells with high aldehyde dehydrogenase activity efficiently engraft into damaged liver in a novel model.

Unlabelled: Human cord blood stem cells (hCBSCs) have been reported to generate hepatocyte-like cells and thus hold promise for repairing damaged liver. However, the frequency of hCBSC-derived hepatocytes varies tremendously between different studies, and it is still controversial as to whether hCBSC-derived cells can transdifferentiate into hepatocytes or simply fuse to recipient hepatocytes. We used the beta-glucuronidase-deficient nonobese diabetic/severe combined immunodeficient/mucopolysaccharidosis type VII (NOD/SCID/MPSVII) mouse model for better identification of engrafted cells.

Revascularization of ischemic limbs after transplantation of human bone marrow cells with high aldehyde dehydrogenase activity.

The development of cell therapies to treat peripheral vascular disease has proven difficult because of the contribution of multiple cell types that coordinate revascularization. We characterized the vascular regenerative potential of transplanted human bone marrow (BM) cells purified by high aldehyde dehydrogenase (ALDH(hi)) activity, a progenitor cell function conserved between several lineages. BM ALDH(hi) cells were enriched for myelo-erythroid progenitors that produced multipotent hematopoietic reconstitution after transplantation and contained nonhematopoietic precursors that established colonies in mesenchymal-stromal and endothelial culture conditions.

Directing experimental biology: a case study in mitochondrial biogenesis.

Computational approaches have promised to organize collections of functional genomics data into testable predictions of gene and protein involvement in biological processes and pathways. However, few such predictions have been experimentally validated on a large scale, leaving many bioinformatic methods unproven and underutilized in the biology community. Further, it remains unclear what biological concerns should be taken into account when using computational methods to drive real-world experimental efforts.