Intermittent hypoxia: cause of or therapy for systemic hypertension?

During acute episodes of hypoxia, chemoreceptor-mediated sympathetic activity increases heart rate, cardiac output, peripheral resistance and systemic arterial pressure. However, different intermittent hypoxia paradigms produce remarkably divergent effects on systemic arterial pressure in the post-hypoxic steady state. The hypertensive effects of obstructive sleep apnea (OSA) vs. the depressor effects of therapeutic hypoxia exemplify this divergence. OSA, a condition afflicting 15-25% of American men and 5-10% of women, has been implicated in the pathogenesis of systemic hypertension and is a major risk factor for heart disease and stroke. OSA imposes a series of brief, intense episodes of hypoxia and hypercapnia, leading to persistent, maladaptive chemoreflex-mediated activation of the sympathetic nervous system which culminates in hypertension. Conversely, extensive evidence in animals and humans has shown controlled intermittent hypoxia conditioning programs to be safe, efficacious modalities for prevention and treatment of hypertension. This article reviews the pertinent literature in an attempt to reconcile the divergent effects of intermittent hypoxia therapy and obstructive sleep apnea on hypertension. Special emphasis is placed on research conducted in the nations of the former Soviet Union, where intermittent hypoxia conditioning programs are being applied therapeutically to treat hypertension in patients. Also reviewed is evidence regarding mechanisms of the pro- and anti-hypertensive effects of intermittent hypoxia.     

Stem cell therapy for heart failure:Medical breakthrough,or dead end?

Heart failure continues to be one of the leading causes of morbidity and mortality worldwide.Myocardial infarction is the primary causative agent of chronic heart failure resulting in cardiomyocyte necrosis and the subsequent formation of fibrotic scar tissue.Current pharmacological and non-pharmacological therapies focus on managing symptoms of heart failure yet remain unable to reverse the underlying pathology.Heart transplantation usually cannot be relied on,as there is a major discrepancy between the availability of donors and recipients.As a result,heart failure carries a poor prognosis and high mortality rate.As the heart lacks significant endogenous regeneration potential,novel therapeutic approaches have incorporated the use of stem cells as a vehicle to treat heart failure as they possess the ability to self-renew and differentiate into multiple cell lineages and tissues.This review will discuss past,present,and future clinical trials,factors that influence stem cell therapy outcomes as well as ethical and safety considerations.Preclinical and clinical studies have shown a wide spectrum of outcomes when applying stem cells to improve cardiac function.This may reflect the infancy of clinical trials and the limited knowledge on the optimal cell type,dosing,route of administration,patient parameters and other important variables that contribute to successful stem cell therapy.Nonetheless,the field of stem cell therapeutics continues to advance at an unprecedented pace.We remain cautiously optimistic that stem cells will play a role in heart failure management in years to come.     

Does predation select for or against avian coloniality? A comparative analysis

Some studies have supported predation as a selective pressure contributing to the evolution of coloniality. However, evidence also exists that colonies attract predators, selecting against colonial breeding. Using comparative analyses, we tested the reduced predation hypothesis that individuals aggregate into colonies for protection, and the opposite hypothesis, that breeding aggregations increase predation risk. We used locational and physical characteristics of nests to estimate levels of species' vulnerability to predation. We analysed the Ciconiiformes, a large avian order with the highest prevalence of coloniality, using Pagel's general method of comparative analysis for discrete variables. A common requirement of both hypotheses, that there is correlated evolution between coloniality and vulnerability to predation, was fulfilled in our data set of 363 species. The main predictions of the reduced predation hypothesis were not supported, namely that (1) solitary/vulnerable species are more prone to become colonial than solitary/protected species and (2) colonial/protected species are more likely to evolve towards vulnerability than solitary/protected species. In contrast, the main predictions of the increased predation hypothesis were supported, namely that colonial/vulnerable species are more prone (1) to become protected than solitary/vulnerable species and/or (2) to become solitary than colonial/protected species. This suggests that the colonial/vulnerable state is especially exposed to predation as coloniality may often attract predators rather than provide safety.     

Vascular endothelium: target or victim of cytostatic therapy?

Chemotherapy continues to be the main therapeutic approach in the treatment of hematological malignancies including acute leukemia. Generally, chemotherapy is used to eliminate cancer cells and to restore normal bone marrow function. Simultaneous action of cytostatic drugs on bone marrow angiogenesis decreases the formation of new capillaries and improves therapeutic effect. However, chemotherapeutic agents may also be cytodestructive for cellular elements of other tissues, particularly the vascular endothelium, which can lead to various cardiovascular complications. In this work, we studied the effects of 2 cytostatic drugs, cytosine arabinoside (ara-C) and daunorubicin (DNR), on cultured human vascular (i.e., umbilical) endothelial cells (ECs). Ara-C and DNR were added to cultured cells at concentrations ranging from 1 ng/mL to 100 microg/mL. Drug effects were studied using phase-contrast microscopy, cell viability tests, BRDU incorporation, immunohistochemistry, flow cytometry, and cell cloning. At various concentrations, ara-C and DNR are able to induce morphological and functional changes in cultured cells related to either cytostatic or cytotoxic action. Moreover, ara-C-treated cultured cells displayed significant disturbances in cell adhesion molecule expression and interaction with blood leukocytes. Preliminary data obtained on acute leukemia patients undergoing standard cytostatic therapy ("7+3" regimen) have shown that concentration of the circulating ECs was significantly increased compared with the control group and could be as high as 500-1500 cells/mL of blood. Results obtained suggest that anticancer chemotherapy may induce systemic damage of vascular endothelium related to massive cell loss and (or) alterations of endothelial function.     

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."     

Influenza-virus-induced signaling cascades: targets for antiviral therapy?

Influenza viruses continue to pose a severe threat worldwide, causing thousands of deaths and an enormous economic loss every year. The major problem in fighting influenza is the high genetic variability of the virus, resulting in the rapid formation of variants that escape the acquired immunity against previous virus strains, or have resistance to antiviral agents. Every virus depends on its host cell and, hence, cellular functions that are essential for viral replication might be suitable targets for antiviral therapy. As a result, intracellular signaling cascades induced by the virus, in particular mitogen-activated protein kinase pathways, have recently come into focus.     

Gene therapy for autoimmune diseases: quo vadis?

Biological therapies using antibodies and cytokines are becoming widespread for the treatment of chronic inflammatory autoimmune diseases. However, these treatments have several limitations - such as expense, the need for repeated injections and unwanted side-effects - that can be overcome by genetic delivery. This review summarizes the ingenuity, sophistication and variety of gene-therapy approaches that have been taken in the design of therapeutic molecules and vectors, the engineering of cells and the regulation of gene expression for the targeting of disease outcome. We focus our attention on multiple sclerosis, type 1 diabetes and rheumatoid arthritis.     

Tumor-induced lymphangiogenesis: a target for cancer therapy?

Recent advances in understanding the biology of lymphangiogenesis, the new growth of lymphatic vessels, have cast new light on the molecular basis of metastasis to regional lymph nodes. The receptor tyrosine kinase VEGFR-3 is virtually exclusively expressed on lymphatic but not blood endothelium in the adult, and activation of VEGFR-3 by its ligands VEGF-C and VEGF-D is sufficient to induce lymphangiogenesis. Correlative studies with human tumors and functional studies using animal tumor models show that increased levels of VEGF-C or VEGF-D in tumors lead to enhanced numbers of lymphatic vessels in the vicinity of tumors, which in turn promotes metastasis to regional lymph nodes by providing a greater number of entry sites into the lymphatic system for invading tumor cells. These findings have prompted studies to investigate whether inhibitors of VEGFR-3 activation might represent novel therapeutic agents for the suppression of metastasis. However, a number of points regarding the therapeutic potential of anti-lymphangiogenic treatments in the context of cancer remain to be addressed. The spectrum and relative importance of molecules that induce lymphangiogenesis and the regulation of their expression during tumor progression, the reversibility of tumor-induced lymphangiogenesis, and possible side-effects of anti-lymphangiogenesis-based therapies all need to be investigated. Most importantly, the extent to which lymph node metastases contribute to the formation of metastases in other organs remains to be elucidated. These aspects are the focus of this review, and their investigation should serve as a roadmap to possible translational application.