Ventricular fibrillation: one spiral or many?

Ventricular fibrillation is the major cause of sudden cardiac death, the leading cause of death in the industrialized world; however, the mechanisms for its onset are not well understood. To further understand the dynamics of fibrillation at and near its onset, we compared spatial and temporal variability of mean interactivation intervals in a stable canine model for ventricular fibrillation. Temporal variability was very small, suggesting that the relevant physiological parameters remained constant during our experiments. Spatial variability was usually significantly larger and appeared incompatible with the dynamics of a single, meandering spiral wave. This confirmed recent results that a single spiral wave cannot generate ventricular fibrillation. Thus the onset of fibrillation is a multistage process, with spiral-wave breakdown providing a crucial step in the quasi-periodic route to fibrillation.     

The skeletal muscle satellite cell: stem cell or son of stem cell?

The concept of the adult tissue stem cell is fundamental to models of persistent renewal in functionally post-mitotic tissues. Although relatively ignored by stem cell biology, skeletal muscle is a prime example of an adult tissue that can generate terminally differentiated cells uniquely specialized to carry out tissue-specific functions. This capacity is attributed to satellite cells, a population of undifferentiated, quiescent precursors that become activated to divide and differentiate in response to the demands of growth or damage. The aim of this review is to discuss the role of the satellite cell as an adult tissue-specific stem cell. We examine evidence for the presence of behaviourally and phenotypically distinct subpopulations of precursor within the satellite cell pool. Further, we speculate on the possible identity, origins and relevance of multipotent muscle stem cells, a population with both myogenic and hematopoietic potentials that has been isolated from whole muscle. Taken together, current evidence suggests the possibility that the regenerative compartment of adult skeletal muscle may conform to an archetypal stem cell-based hierarchy, maintained within a stem cell niche. It therefore remains to be seen whether all satellite cells are skeletal muscle-specific stem cells, or whether some or all are the progeny of an as yet unidentified muscle stem cell.     

Chagas heart disease pathogenesis: one mechanism or many?

Chagas heart disease (CHD), caused by the protozoan parasite Trypanosoma cruzi, is the leading cause of infectious myocarditis in the world. The etiology of CHD is unclear and multiple mechanisms have been proposed to explain the pathogenesis of the disease. This review describes the proposed mechanisms of CHD pathogenesis and evaluates the historical significance and evidence supporting each. Although the majority of CHD-related pathologies are currently attributed to parasite persistence in the myocardium and autoimmunity, there is strong evidence that CHD develops as a result of additive and even synergistic effects of several distinct mechanisms rather than one factor.     

Prolonged clonal growth: escape route or route to extinction?

Many plant species have the capability to reproduce sexually as well as clonally. The balance between clonal reproduction and sexual reproduction varies between different species. It was estimated that 66.5% of all central European flora may form independent but genetically identical daughter plants. Also within species there is great variation in the ratio clonal/sexual reproduction. Clonal reproduction can be considered as an alternative life cycle loop that allows persistence of a species in the absence of the ability to complete the normal life cycle (i.e. seed production, germination and recruitment). Plant populations exhibiting prolonged clonal growth have been referred to as 'remnant populations'. A remnant population in general is defined as \"a population capable of persistence during extended time periods despite a negative population growth rate (λ<1) due to longlived life stages and life cycles, including loops, that allow population persistence without completion of the whole life cycle\". Here we argue that prolonged and nearly exclusive clonal growth through environmental suppression of sexual reproduction can ultimately lead to local sexual extinction and to monoclonal populations of a species, and that this may imply significant consequences for population viability. Especially obligate or mainly outcrossing clonal plant species may be vulnerable for sexual extinction. We argue that the consequences of reduced sexual recruitment in clonally propagating plants may be understudied and underestimated and that a re-evaluation of current ideas on clonality may be necessary.     

Planar cell polarity: one or two pathways?

In multicellular organisms, cells are polarized in the plane of the epithelial sheet, revealed in some cell types by oriented hairs or cilia. Many of the underlying genes have been identified in Drosophila melanogaster and are conserved in vertebrates. Here we dissect the logic of planar cell polarity (PCP). We review studies of genetic mosaics in adult flies - marked cells of different genotypes help us to understand how polarizing information is generated and how it passes from one cell to another. We argue that the prevailing opinion that planar polarity depends on a single genetic pathway is wrong and conclude that there are (at least) two independently acting processes. This conclusion has major consequences for the PCP field.     

Hematopoietic stem cell gene therapy: dead or alive?

Despite some reports of toxicity in recent clinical trials, many scientists believe that the use of gene therapy in the treatment of congenital genetic defects and acquired disorders has too much potential to abandon. Hematopoietic stem cells (HSCs) have been primary targets for gene therapy owing to their capacity for differentiation and self-renewal, whereby multiple cell lineages can potentially be corrected for the lifetime of an individual. These efforts represent a long-term investment towards broadening physicians' treatment options for patients whose diseases, in particular certain immunodeficiencies, are fatal and where no other therapy is available. We review the recent progress and clinical triumphs as well as the reported toxicity related to insertional mutagenesis. We also discuss the current risk-to-benefit estimates and future strategies to reduce the risks and allow full realization of clinical potential. Scientists are continually revising protocols: going both from "bench to bedside" and, as strikingly demonstrated by HSC gene therapy, from "bedside to bench."     

Mesencephalic fifth nucleus cell responses to thyroid hormone: one population or two?

Hypophysectomized Rana pipiens tadpoles 3-6 months old were placed in dl-thyroxine (T4) solutions of 4 to 200 micrograms/l for 1-18 days and fixed 1 day after removal from the hormone solution. Exposure times varied inversely with T4 concentration. Mesencephalic fifth nucleus (M-V) cells were counted on both sides, and cell and nuclear sizes were drawn and measured for each tadpole. Changes in M-V cell characteristics correlated well with T4 exposure times and concentrations, as did changes in external tadpole morphology. All T4 concentrations were effective. Cells and nuclei were distinctly larger in all T4-treated groups. The changes were greatest for cell sizes, less for nuclear dimensions, and still less for nucleo-cytoplasmic ratios. Significant changes were seen for minimum and maximum sizes as well as for the mean values. The greatest mean changes were seen at dosages of 50 micrograms/l for 7-9 days. Mean M-V cell numbers are significantly smaller in hypophysectomized tadpoles than in controls (about 420 vs. 650). Thyroid hormone treatment of the hypophysectomized animals abolishes much of the deficit, though M-V cell deaths at the higher concentrations and longer treatment times reduce the apparent increase in numbers. Are the additional cells obtained through cell division, or do they represent a preexisting subpopulation of prospective M-V cells that require stimulation by thyroid hormone for their full differentiation?     

Neural stem cells as biological minipumps: a faster route to cell therapy for the CNS?

One strategy for the use of neural stem cells (NSCs) in treating neurological disorders is as transplantable "biological minipumps", in which genetically engineered neural stem cells serve as sources of secreted therapeutic (neuroprotective or tumoricidal) agents. Neural stem cells are highly mobile within the brain and demonstrate a tropism for various types of central nervous system (CNS) pathology, making them promising candidates for targeted gene delivery vehicles. Although neural stem cells have also been proposed as a potential source of replacement neurons and astrocytes to repopulate injured or degenerating neural circuits, the challenges involved in rebuilding damaged brain architecture are substantial and remain an active area of investigation. In contrast, the use of NSCs as biological minipumps does not rely on neuronal differentiation, axonal targeting, or synaptogenesis. This strategy may be a faster route to cell-based therapy of the CNS and is poised to move into human clinical trials. This review considers two types of neurologic disease that may be suitable targets for this alternative approach to NSC therapy: glial brain tumors and traumatic brain injury. We examine some of the key scientific and technical issues that must be addressed for the successful use of NSCs as minipumps.     

Preventing aging with stem cell rejuvenation: Feasible or infeasible?

Characterized by dysfunction of tissues, organs, organ systems and the whole organism, aging results fromthe reduced function of effective stem cell populations. Recent advances in aging research have demonstrated that old tissue stem cells can be rejuvenated for the purpose of maintaining the old-organ function by youthful re-calibration of the environment where stem cells reside. Biochemical cues regulating tissue stem cell function include molecular signaling pathways that interact between stem cells themselves and their niches. Historically, plasma fractions have been shown to contain factors capable of controlling age phenotypes; subsequently, signaling pathways involved in the aging process have been identified. Consequently, modulation of signaling pathways such as Notch/Delta, Wnt, transforming growth factor-β, JAK/STAT, mammalian target of rapamycin and p38 mitogen-activated protein kinase has demonstrated potential to rejuvenate stem cell function leading to organismic rejuvenation. Several synthetic agents and natural sources, such as phytochemicals and flavonoids, have been proposed to rejuvenate old stem cells by targeting these pathways. However, several concerns still remain to achieve effective organismic rejuvenation in clinical settings, such as possible carcinogenic actions; thus, further research is still required.     

Neurogenesis: is the adult stem cell young or old?

Stem cell biology is one of the most exciting, controversial, and debated fields in science today. It has been suggested that neuronal replacement therapy using stem cell transplants may be one possible answer to a host of neuropathological disorders including spinal cord injury, stroke, and neurodegenerative diseases. Important sources for stem cells include the developing embryo and adult central nervous system, but will these populations of cells exhibit similar behavior and responses to stimuli? This review will discuss some important similarities and differences between the embryonic and adult stem cell, as well as the basis for developing therapeutic approaches for stem cell replacement.     

Giant cell formation: the way to cell death or cell survival?

The study of giant cells in populations of different tumor cells and evaluation of their role in cancer development is an expanding field. The formation of giant cells has been shown to be followed by mitotic catastrophe, apoptosis, necrosis, and other types of cell elimination. Reports also demonstrate that giant cells can escape cell death and give rise to new cancer cells. However, it is not known if the programmed cell death is involved in this type of cell cycle disorders. Here we describe principal events that are observed during giant cell formation. We also consider the role of giant cells in cancer development, taking into account both published work and our own recent data in this field.     

Epithelial stem cells of the lung: privileged few or opportunities for many?

Most reviews of adult stem cells focus on the relatively undifferentiated cells dedicated to the renewal of rapidly proliferating tissues, such as the skin, gut and blood. By contrast, there is mounting evidence that organs and tissues such as the liver and pancreatic islets, which turn over more slowly, use alternative strategies, including the self-renewal of differentiated cells. The response of these organs to injury may also reveal the potential of differentiated cells to act as stem cells. The lung shows both slow turnover and rapid repair. New experimental approaches, including those based on studies of embryonic development, are needed to identify putative lung stem cells and strategies of lung homeostasis and repair.     

From cell to movement: to what answers does EMG really contribute?

This paper aims to address some of the possibilities and limitations of EMG technologies available to date. Considerable progress has been achieved in this field during the last 30 years and EMG signals can be easily obtained on different levels beginning at the cell membrane and ending with the global EMG associated with the movement itself. Different aspects from cell to movement have been considered in this paper. Highly selective needle EMG for the detection of the processes at the membrane is discussed as well as high spatial resolution EMG which gives non-invasive access to the acquisition of the single motor unit activity. On the highest level of muscles, an expert system is introduced as a novel approach to support the interpretation of muscular co-ordination as detected by conventional surface EMG. While there is a high potential in the newly developed EMG methodologies, it is a big challenge to utilize these methodologies in order to obtain detailed, repeatable, reliable--and meaningful--results. However, the risk of over- and misinterpretation has to be carefully considered. In this paper, this risk is exemplified in situations dealing with muscle fatigue, conduction velocity and cross-talk. Despite all the new possibilities available, the authors recommend that EMG with its inherent strengths and limitations should still be diligently, but carefully, used.     

Cardiac biointerventions: whatever happened to stem cell and gene therapy?

ABSTRACT: Angiogenic gene therapy and stem cell administration represent two "biologic" interventions for the treatment of cardiac disease that were first introduced more than 15 years ago but still have not achieved approval for clinical use for the treatment of myocardial ischemia and heart failure. Challenges that have been encountered in the clinical testing of these new treatment strategies have included a lack of placebo controls in phase I surgical trials and the incorporation of potentially ineffectual agent delivery via intracoronary routes. Although enthusiasm for these approaches may therefore have ebbed, new refinements in these technologies and insights into their appropriate clinical testing suggest that a resurgence of interest in these "biointerventions" may be expected in the near future.     

From co-expression to co-regulation: how many microarray experiments do we need?

Background  

Cluster analysis is often used to infer regulatory modules or biological function by associating unknown genes with other genes that have similar expression patterns and known regulatory elements or functions. However, clustering results may not have any biological relevance.