Biomedical Research Institute Research Articles

Treatment of human astrocytoma U87 cells with silicon dioxide nanoparticles lowers their survival and alters their expression of mitochondrial and cell signaling proteins

Recent evidence suggests silicon dioxide micro- and nanoparticles induce cytotoxic effects on lung cells. Thus, there is an increasing concern regarding their potential health hazard. Nevertheless, the putative toxicity of nanoparticles in mammalian cells has not yet been systematically investigated. We previously noted that several metallic oxide nanoparticles exert differential cytotoxic effects on human neural and nonneural cells. Therefore, we hypothesized that silicon dioxide nanoparticles induce cytotoxicity in U87 cells by lowering their survival by decreasing cell survival signaling and disturbing mitochondrial function. To investigate this hypothesis, we determined the activities of the key mitochondrial enzymes, citrate synthase and malate dehydrogenase, in astrocytoma U87 cells treated with silicon dioxide nanoparticles. In addition, we studied the expression of the mitochondrial DNA-encoded proteins, cytochrome C oxidase II and nicotinamide adenine dinucleotide (NADPH) dehydrogenase subunit 6, and cell signaling pathway protein extracellular signal-regulated kinase (ERK) and phosphorylated ERK in treated U87 cells. The activated form of ERK controls cell growth, differentiation, and proliferation. In parallel, we determined survival of U87 cells after treating them with various concentrations of silicon dioxide nanoparticles. Our results indicated that treatment with silicon dioxide nanoparticles induced decreases in U87 cell survival in a dose-related manner. The activities of citrate synthase and malate dehydrogenase in treated U87 cells were increased, possibly due to an energetic compensation in surviving cells. However, the expression of mitochondrial DNA-encoded cytochrome C oxidase subunit II and NADH dehydrogenase subunit 6 and the cell signaling protein ERK and phosphorylated ERK were altered in the treated U87 cells, suggesting that silicon dioxide nanoparticles induced disruption of mitochondrial DNA-encoded protein expression, leading to decreased mitochondrial energy production and decreased cell survival/proliferation signaling. Thus, our results strongly suggest that the cytotoxicity of silicon dioxide nanoparticles in human neural cells implicates altered mitochondrial function and cell survival/proliferation signaling.

The Rabbit(Oryctolagus cuniculus):A Model for Mammalian Reproduction and Early Embryology

INTRODUCTIONThe rabbit is a valuable animal model for a variety of biomedical research areas including in vitro fertilization, early embryology and organogenesis, neurophysiology, ophthalmology, and cardiovascular research. The rabbit is also used as a model for toxicology studies and analyses of drug effects on embryo and fetal development, as well as for research involving the immune system (e.g., host/pathogen interactions, asthma, arthritis, systemic lupus erythematosus). The rabbit’s most prominent use as a laboratory animal is antibody production; most biomedical research institutions thus provide the infrastructure and veterinary expertise for keeping rabbits. This article discusses current advances in applying modern life science research methods to basic and applied embryological research using the rabbit as a model for early intrauterine development in mammals, including state-of-the-art genomic tools and the sequencing data available (and planned) for the rabbit.

London's biomedical research institute takes shape

London's biomedical research institute takes shape

Global visions for space exploration education

The National Space Biomedical Research Institute (NSBRI), established in 1997 through a National Aeronautics and Space Administration (NASA) competition, is a 12-university consortium dedicated to space life science research and education. NSBRI's Education and Public Outreach Program (EPOP) has partnered with Morehouse School of Medicine (MSM) to support NSBRI-NASA's education mission, which is to strengthen the nation's future science workforce through initiatives that communicate space exploration biology research findings to schools; support undergraduate and graduate programs; fund postdoctoral fellowships; and engage national and international audiences in collegial exchanges that promote global visions for space exploration education. This paper describes select MSM–NSBRI–EPOP activities, including scholarly interchanges with audiences in Austria, Canada, France, China, Greece, Italy, Scotland and Spain. The paper also makes the case for a global space exploration education vision that inspires students, engages educators and informs general audiences about the benefits that space exploration holds for life on Earth.

Singapore Biopolis: Bare Life in the City-State

In late 2003, the Singaporean government launched Biopolis, a life sciences technopole that brings key Singaporean biomedical research institutes together with global and local biotechnology and pharmaceutical companies and governance bodies. The government has allocated generous funding to a range of biomedical research at Biopolis and adjacent academic and clinical institutes. Its stated aim is to make Singapore the Biopolis of Asia, the premier life sciences hub in a region where several much more populous states, notably China, India, and South Korea, are rapidly scaling up public investment in regenerative medicine and genomics. This paper will tease out what is at stake in the creation of Biopolis for the Singaporean state and population and what it can tell us about South East Asian governmentality and its bioeconomic and biopolitical aspirations and anxieties. In particular the paper engages with the implicit utopian vision of a regenerative bioeconomy evident in the Biopolis project. Biopolis is a site which brings together local and imported scientific expertise with the biological productivity of the multi-ethnic Singaporean population, who are understood as surrogates for the SE Asian population more generally. The ultimate aim of Biopolis, I argue, is to recalibrate the relationships between the biological and political life of the Singaporean population, and secure the economic future of the city-state, through the advanced research and development of Asia-specific medical biotechnology.

Singapore Biopolis: Bare Life in the City-State

In late 2003, the Singaporean government launched Biopolis, a life sciences technopole that brings key Singaporean biomedical research institutes together with global and local biotechnology and pharmaceutical companies and governance bodies. The government has allocated generous funding to a range of biomedical research at Biopolis and adjacent academic and clinical institutes. Its stated aim is to make Singapore the Biopolis of Asia, the premier life sciences hub in a region where several much more populous states, notably China, India, and South Korea, are rapidly scaling up public investment in regenerative medicine and genomics. This paper will tease out what is at stake in the creation of Biopolis for the Singaporean state and population and what it can tell us about South East Asian governmentality and its bioeconomic and biopolitical aspirations and anxieties. In particular the paper engages with the implicit utopian vision of a regenerative bioeconomy evident in the Biopolis project. Biopolis is a site which brings together local and imported scientific expertise with the biological productivity of the multi-ethnic Singaporean population, who are understood as surrogates for the SE Asian population more generally. The ultimate aim of Biopolis, I argue, is to recalibrate the relationships between the biological and political life of the Singaporean population, and secure the economic future of the city-state, through the advanced research and development of Asia-specific medical biotechnology.

Is Artificial Gravity An Effective Countermeasure To Microgravity

PURPOSE: It is well known that microgravity can produce substantial losses in muscle mass and strength, bone mass, and orthostatic tolerance. It has been hypothesized that artificial gravity might represent an important countermeasure for preventing such changes. In this context, the primary goal of this study was to test the hypothesis that hypergravity resistance training (HRT) can produce training adaptations similar to those found using a 1 Gz 10 repetition maximum resistance training program. METHODS: Subjects were healthy male subjects who exercised no more than 2-3 times per month prior to the study (N = 18, aged 22.7 ± 0.4 yrs, height 176 ± 2 cm, mass 80 ± 3 kg, means ± S.E.M.). Subjects completed a two-week resistance training program (9 sessions) using either HRT [Space Cycle (SC), n = 9] or free weights (FW, n = 9). Each workout entailed 3 sets of 10 squats at 70, 80, and 90% of pre-training 10 repetition maximum for the 1st, 2nd, and 3rd sets, respectively. Torque-velocity relationships were determined before and after the completion of the two-week resistance training program. Muscle biopsies were taken from the right vastus lateralis shortly before, 4 and 24 hrs after the first and last workouts. RESULTS: The improvements in torque-velocity relationships were similar (∼7-8%) between the two training groups. The muscle biopsy data were used to assess cellular/molecular markers of growth. Analyses demonstrated that there were significant increases (P<0.01) in total RNA for both groups. Both groups also produced acute changes in myogenin mRNA levels, however, comparisons of pre and post training data were not significant. CONCLUSION: This study represents an initial step in testing the HRT hypothesis. Importantly, we found similar adaptations between the HRT and free weight groups, and this offers encouraging evidence for pursuing the potential role of artificial gravity as a countermeasure to microgravity. This work is Supported by the National Space Biomedical Research Institute through NASA MA00403 (VJC) and NIH 2T32AR047752 (VJC) and M01 RR00827.

Profile and role of the members of ethics committees in hospitals and research organisations in Pune, India

Appropriate constitution of ethics committees (EC) is crucial to ensure a high quality review of research proposals. We studied the profile and role of EC members of Pune-based health and research organisations. 52 ethics committee members representing 12 health and bio-medical research institutions in Pune city completed the structured questionnaires. The respondents represented ECs of hospitals (67%), research organisations (23%) and NGOs (10%). The attendance of members at EC meetings was significantly associated with higher qualification (p=0.004), more than 20 years of research experience (p=0.023) and more experience of working with ECs (p=0.032). Most of the chairpersons or secretaries had a medical background (p=0.027), and were more likely to be formally trained in ethics compared to other members (p=0.049) and had more research experience (0.043). Overall, 62% had doctorate degrees and 38% were post-graduates or graduates. Forty four percent had the correct knowledge of ethical principles. A majority (79%) of EC members felt that formal training was necessary and 84% said that there should be networking of the various ECs to share thoughts and experiences. EC members were generally senior in age, highly educated and well-experienced in research. Representation of lawyers, ethicists and non-scientific members needs to be increased. Even with an appropriate EC constitution, the members had sub-optimal understanding of ethical issues and ethical principles. Formal training of EC members in ethics, and networking of ECs, is crucial. The scope of the role of EC members needs to be clearly recognised and understood by the constituting institutes.

Transforming the Culture of Biomedical Research From Compliance to Trustworthiness: Insights From Nonmedical Sectors

To discover ways that the biomedical research community can foster the public's trust essential to sustain the research enterprise, in 2005 the authors and their colleagues convened a group of national leaders from sectors outside of academic science and health care that are also dependent on the public's trust. These leaders provided information about what their sectors do to earn the public's trust that is applicable to academic biomedical research institutions, as well as insights into ways academic research institutions should respond to crises that have the potential to diminish the public's trust. The major strategies they identified for promoting the public's trust were the importance of fostering multiple types of relationships and developing accountability practices that exceed those required by external regulators.In this article, the authors compare these strategies with reports in the literature regarding efforts under way in health care to adapt strategies employed in other sectors to improve the safety of health care. On the basis of what the authors learned from both the national leaders outside of biomedical research and health care and the health care safety literature review, they present a set of recommendations for building and restoring trust, as well as a list of benchmarks for assessing the adequacy of efforts by research institutions to promote the public's trust in biomedical research.

Interview – Perspective on the Application of Pharmacogenomics in the Treatment of Cancer

Professor Roland Wolf (FRSE, FMedSci, FRSA) is the co-director of the Dundee Biomedical Research Institute (Dundee, Scotland, UK) and Honorary Director of the Cancer Research UK Molecular Pharmacology Unit (Dundee, Scotland, UK). His research interests are understanding the pathways that determine the sensitivity of cells to drugs, environmental agents and chemical toxins, particularly molecular and genetic studies on how chemical agents interact with cells, how this influences their therapeutic and toxicological properties and how genetic polymorphisms in the genes involved relate to disease susceptibility, adverse pharmacology and toxicology. Specific current projects focus on preclinical drug development, pharmacogenetics, cancer therapy and chemoprevention. Professor Wolf has published approximately 450 scientific papers in peer reviewed journals. His is a member of many national and international boards and advisory groups and is currently a member of the Scottish Scientific Advisory Council. In 2001, he co-founded a company, CXR Biosciences (Dundee, Scotland, UK), currently comprising of 42 staff. In addition to providing drug discovery and development services, the company has a major focus developing new models for to accelerate the drug development process and reduce attrition when drugs enter man. Professor Wolf has been the recipient of a number of awards including the Gerhard Zbinden award in toxicology, The ISSX European Scientific Achievement award and the Scottish Enterprise award for the individual contributing most to the development of life sciences in Scotland.

Acidic Calponin controls ERK1/2 translocation and l-Caldesmon phosphorylation in fibroblasts

Calponin is an actin binding, troponin-like molecule, first isolated from chicken gizzard smooth muscle cells where it is involved in regulation of contractility. So far there are three known isoforms, basic, acidic and neutral Calponin, each encoded by a separate gene. Expression of the acidic Calponin isoform is, unlike basic Calponin, not restricted to smooth muscle cells but is expressed in a variety of tissues and cell types, especially in the brain. For basic Calponin it is known that the molecule affects smooth muscle cell contractility by regulation of the PKC/ERK signaling pathway. Here we could show that acidic Calponin co-precipitates together with ERK1/2 and PKCalpha in the cultured rat fibroblast cell line REF52.2. Moreover it colocalises with ERK1/2 and PKCalpha in podosome-like structures and at the cell cortex after Phorbol-12,13-Dibutyrate (PDBu) treatment. Knockdown of acidic Calponin expression in these cells results in inhibition of PDBu-mediated ERK1/2 translocation to these structures, whereas PKCalpha targeting is not affected. Both endogenous ERK1/2 activity and phosphorylation of the ERK1/2 substrate l-Caldesmon are blocked by acidic Calponin knockdown, indicating an important role for the acidic Calponin isoform in regulation of ERK1/2 function in REF52.2 cells.Abstract sponsored by John Gergely, Boston Biomedical Research Institute, Watertown 02472, MA, USASupport: NIH grants HL80003, HL86655

Depression Care no Longer Needs to be Earthbound

Depression Care no Longer Needs to be Earthbound

Exposure to titanium dioxide and other metallic oxide nanoparticles induces cytotoxicity on human neural cells and fibroblasts

The use of titanium dioxide (TiO(2)) in various industrial applications (eg, production of paper, plastics, cosmetics, and paints) has been expanding thereby increasing the occupational and other environmental exposure of these nanoparticles to humans and other species. However, the health effects of exposure to TiO(2) nanoparticles have not been systematically assessed even though recent studies suggest that such exposure induces inflammatory responses in lung tissue and cells. Because the effects of such nanoparticles on human neural cells are unknown, we have determined the putative cytotoxic effects of these nanoparticles on human astrocytes-like astrocytoma U87 cells and compared their effects on normal human fibroblasts. We found that TiO(2) micro- and nanoparticles induced cell death on both human cell types in a concentration-related manner. We further noted that zinc oxide (ZnO) nanoparticles were the most effective, TiO(2) nanoparticles the second most effective, and magnesium oxide (MgO) nanoparticles the least effective in inducing cell death in U87 cells. The cell death mechanisms underlying the effects of TiO(2) micro- and nanoparticles on U87 cells include apoptosis, necrosis, and possibly apoptosis-like and necrosis-like cell death types. Thus, our findings may have toxicological and other pathophysiological implications on exposure of humans and other mammalian species to metallic oxide nanoparticles.

Controversies and Consensus: Identifying the Key Issues in Exercise Testing

This discussion was moderated by Ronald J. Oudiz, MD, Associate Professor of Medicine, UCLA School of Medicine and Director, Liu Center for Pulmonary Hypertension, Division of Cardiology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California. Participants included: Hunter C. Champion, MD, PhD, Assistant Professor, Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Robert Naeije, MD, PhD, Professor and Chairman of the Department of Physiology and Pathophysiology at Erasme University Hospital, Brussels, Belgium; Virginia D. Steen, MD, Professor of Medicine and Director of the Rheumatology Fellowship Program, Georgetown University School of Medicine, Washington, DC; and David Systrom, MD, Director, Cardiopulmonary Exercise Lab, Department of Medicine, Pulmonary Critical Care, Massachusetts General Hospital, Boston, Massachusetts.

Occupational Health: Lunar Lung Disease

With the National Aeronautics and Space Administration (NASA) finalizing plans to begin construction on a manned lunar outpost by 2020, the sun is rising on a whole new world of environmental and occupational health. Could longer space missions, reduced gravity, and moondust be a dangerous combination for lunar astronauts’ pulmonary health? Results published in the August 2008 issue of the European Journal of Applied Physiology suggest so. “Moondust has properties similar to silica, a mineral commonly encountered in mining operations known to cause silicosis and other lung problems,” explains principal investigator Kim Prisk, a researcher with the Human Factors and Performance Team at the National Space Biomedical Research Institute. “To be safe we need to know how much dust can get into astronauts’ airways, where it deposits, how long it stays, and just how toxic it might be.” Such information is essential to mission designers who must know what air purification equipment to haul moonward and how extensive post-moonwalk decontamination procedures must be in order to clean up the clingy dust. To determine how much and where moondust might deposit in the lungs, Prisk’s team performed experiments under lunar gravity conditions during parabolic flights aboard NASA’s Microgravity Research Aircraft. Up to six subjects breathed in aerosols (104 particles/mL) of 0.5- or 1-μm polystyrene latex beads (representative of moondust particle sizes) at a constant rate through a mouthpiece. The number of beads entering and leaving the subjects’ breath was measured using a photometer, which revealed how much “dust” remained in subjects’ airways. Compared with terrestrial conditions, lunar gravity reduced the total quantity of 0.5-μm beads settling in the airways by 25% and 1-μm beads by 32%, explains first author Chantal Darquenne, an associate professor in the Department of Medicine at the University of California, San Diego. But while this may seem like good news, further experiments showed that the beads that settled were more likely to do so in the alveoli, clearance from which may be difficult. Whereas particles would be deposited in the upper airways under terrestrial conditions, under lunar conditions they would remain available to be eventually transported deeper into the lung. “NASA is learning that [different] moondusts have toxicologically worrisome properties including reactive surfaces, large surface areas per unit mass, a high content of particles greater than 0.1 μm, and metallic iron impregnation,” says John James, chief toxicologist at the NASA Johnson Space Center in Houston, Texas. “We must be careful not to suppose that there is one level of toxicity for lunar dust,” he adds. “It is likely that there is considerable variability in the size distribution and mineral composition of dust from one location to another. This could mean several-fold variability in the inherent toxicity of the dusts.” “Occupational dust diseases can take decades to develop among exposed workers on Earth, but if the alveoli are more affected on the moon and clearance is reduced, disease could develop more quickly in astronauts—especially if lunar dust proves very toxic,” says David Goldsmith, an associate research professor of environmental and occupational health at The George Washington University in Washington, DC. Emphasizing that we should recognize moondust-exposed astronauts as dusty trades workers in space, he points out that chronic silica exposure can also lead to lung cancer, kidney ailments, and autoimmune diseases in occupationally exposed workers on Earth. He adds, “In space and on Earth these conditions are fully preventable with proper respiratory protection including engineering controls.” This high-flying research may also have a down-to-Earth application. By determining where particles of different size settle in the airways under terrestrial gravity conditions, it may be possible to learn how to deliver drugs accurately to different areas of the lungs.

BROAD INSTITUTE LANDS BIG GIFT

PRONOUNCING THEIR initial investment in the Broad Institute a success, philanthropists Eli and Edythe L. Broad announced on Sept. 4 that they have increased their gift to the Massachusetts biomedical research institute by $400 million to a total of $600 million. “Our investment in the Broad is the largest philanthropic commitment we’ve ever made, and without a doubt it has been the biggest success,” Eli Broad said at a press conference at the institute. He cited, among other things, the 20 mammalian genomes the four-year-old institute has sequenced, the scores of genetic risk factors it has identified for diseases, and the potential new therapeutics it has unearthed. Launched in 2004 as a joint endeavor between Harvard University and MIT, the Broad Institute aims to bring together all kinds of scientists from across the two university communities to tackle big interdisciplinary problems related to various diseases, including cancer, metabolic diseases, and psychiatric conditions. Intrigued by ...

TbRGG2, an Essential RNA Editing Accessory Factor in Two Trypanosoma brucei Life Cycle Stages

In the mitochondria of kinetoplastid protozoa, including Trypanosoma brucei, RNA editing inserts and/or deletes uridines from pre-mRNAs to produce mature, translatable mRNAs. RNA editing is carried out by several related multiprotein complexes known as editosomes, which contain all of the enzymatic components required for catalysis of editing. In addition, noneditosome accessory factors necessary for editing of specific RNAs have also been described. Here, we report the in vitro and in vivo characterization of the mitochondrial TbRGG2 protein (originally termed TbRGGm) and demonstrate that it acts as an editing accessory factor. TbRGG2 is an RNA-binding protein with a preference for poly(U). TbRGG2 protein levels are up-regulated 10-fold in procyclic form T. brucei compared with bloodstream forms. Nevertheless, the protein is essential for growth in both life cycle stages. TbRGG2 associates with RNase-sensitive and RNase-insensitive mitochondrial complexes, and a small fraction of the protein co-immunoprecipitates with editosomes. RNA interference-mediated depletion of TbRGG2 in both procyclic and bloodstream form T. brucei leads to a dramatic decrease in pan-edited RNAs and in some cases a corresponding increase in the pre-edited RNA. TbRGG2 down-regulation also results in moderate stabilization of never-edited and minimally edited RNAs. Thus, our data are consistent with a model in which TbRGG2 is multifunctional, strongly facilitating the editing of pan-edited RNAs and modestly destabilizing minimally edited and never-edited RNAs. This is the first example of an RNA editing accessory factor that functions in the mammalian infective T. brucei life cycle stage.

Seventh Symposium on the Role of the Vestibular Organs in Space Exploration Noordwijk, The Netherlands, June 7–9, 2006

The Seventh Symposium on the Role of the Vestibular Organs in Space Exploration was held at the European Space Technology Centre (ESTEC), in Noordwijk, The Netherlands, on June 7–9, 2006. The host for this conference was the European Space Agency (ESA). The conference was co-sponsored by the National Aeronautics and Space Administration (NASA) and the National Space Biomedical Research Institute (NSBRI). There have been six previous NASA-sponsored symposia in this series. Written proceedings of the first five symposia, held between 1965–1970 in Pensacola, Florida, are available from the NASA Technical Reports Server (http://ntrs.nasa.gov/search.jsp, and enter “Role of Vestibular Organs” as the search term). The Sixth NASA Symposium was held in Portland, Oregon in 2002. The program and abstracts from this meeting were published by the Journal of Vestibular Research as part of Volume 11 (3–5); these abstracts can be accessed through the IOS Press web site (http://iospress.metapress.com/home/main.mpx). In addition, most of the papers from the Sixth Symposium were submitted to the Journal of Vestibular Research and appear as Volume 13 (4–6). Each of the seven Symposia on the Role of the Vestibular Organs in Space Exploration address the adverse physiological effects mediated by the vestibular system in humans exposed to microgravity. A European venue was particularly appropriate for the Seventh Symposium, since the space neurovestibular field has become increasingly international. Researchers from many countries have had the opportunity to conduct experiments on the Russian Mir station, the US Space Shuttle, and the International Space Station. Symposium participants included more than one hundred scientists, flight surgeons, postdoctoral fellows and students from Europe, the US, Canada, Russia and Japan. It was an exciting three day meeting: More than 50 platform presentations and 20 posters were presented, describing results from investigations in spaceflight, parabolic flight, and ground laboratories. Session topics included the vestibulo-ocular reflex, clinical assessment of vestibular disorders, neurophysiology, spatial orientation, spaceflight countermeasures, balance and locomotion, motion sickness, otolith and semicircular canal physiology, and artificial gravity. The meeting concluded with an international panel discussion on challenges and opportunities in space research. We would like to thank the Journal of Vestibular Research for this Special Issue devoted to papers presented at this Symposium. We would also like to thank the presenters who submitted full papers, which underwent peer-review, for this special issue. The web site for the Symposium (http://www.congrex.nl/06a07/) contains the full scientific program; many of the slide presentations and posters are also available at this web site.

In Search of a Holy Grail

“It came out of nowhere and captured the cardiology community by storm.” The cliche seems very appropriate when describing the impact of cardiac resynchronization therapy (CRT) on the treatment of heart failure. CRT improves survival rate in symptomatic patients 1 and is the only nonsurgical technique that provides substantial and stable reverse remodeling in both symptomatic and asymptomatic patients.2,3 The most surprising fact is that this is accomplished through mechanisms that are still unclear and that are not fully elucidated in experimental models. CRT is the only heart failure therapy with a potential to improve survival rate that is not based on neurohormonal modulation. Finally, it represents a challenge to the imaging community, as it establishes a need to measure something that was previously overlooked—dyssynchrony. Article see p 14 Unfortunately, CRT is not universally successful. One third of CRT patients do not feel better,4 and close to 40% of patients do not experience reverse remodeling, which is important because it predicts survival rate.5 This should not be a surprise—treatment of chronic diseases is rarely homogenously beneficial to all the patients. Nevertheless, in the case of CRT, some extra precautions are necessary. CRT is expensive; placement of electrodes may be difficult; and, even in experienced centers, a significant number of patients may require surgical placement. Finally, it is an expensive, healthcare-intensive therapy with extensive follow-up and occasional complications. Thus, there is an ongoing search for practical methods to predict the outcome of CRT and guide its use. Current guidelines use QRS duration (and symptoms) as the principal determinants for implantation, and as noted, this is fairly successful, with two thirds of such patients demonstrating improvement. The real challenge for clinicians comes in two situations: identifying those patients with narrow QRS who are …

Comparison of Noninvasively Determined Hydrogen Ion and Lactate Thresholds During Cycle Exercise

The lactate threshold is a parameter utilized to assess physical fitness, for predicting aerobic performance, and to develop training protocols for endurance athletes. However, this measurement requires invasive blood sampling and produces only intermittent results. Interstitial fluid pH has been measured noninvasively and continuously using near infrared spectroscopy (NIRS) during ischemia, but additional techniques are required to apply this methodology during exercise. PURPOSE: To develop an exercise-based NIRS pH model and to compare H+ threshold from NIRS with lactate threshold from capillary blood sampling in subjects performing a graded exercise cycle protocol. METHODS: Intramuscular pH (pHm) was measured invasively in the flexor digitorum profundus during handgrip exercise in 8 subjects while NIR spectra were collected from a sensor placed on the skin over the muscle. Partial least squares regression was used to obtain a mathematical model relating the two measures. The model was subsequently applied to spectra collected from the vastus lateralis of 10 subjects performing a graded protocol in which the work rate was increased by 50 W every 3 minutes until volitional fatigue. Oxygen consumption (VO2) was measured continuously with a standard metabolic cart, and lactate concentration was measured at the end of each stage with capillary blood from a finger stick. Lactate and H+ thresholds were determined as a function of VO2 using bilinear regression. RESULTS: The root mean square error of prediction for the spectral pHm model was 0.035 pH units. Lactate threshold determined during cycle ergometry was strongly correlated with H+ threshold (R2=0.95) but occurred at higher VO2 (Δ=0.29 ± 0.23 L.min−1). CONCLUSIONS: NIRS can be utilized for noninvasive and continuous measurement of [H+] during incremental cycle exercise to determine a metabolic threshold associated with fitness and athletic performance. Supported by the National Space Biomedical Research Institute through NASA NCC 9-58.