New Mexico Health Enhancement and Marathon Clinics Research Foundation

Albuquerque, NM, United States

New Mexico Health Enhancement and Marathon Clinics Research Foundation

Albuquerque, NM, United States
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Zhao H.W.,University of California at San Diego | Gu X.Q.,University of California at San Diego | Chailangkarn T.,University of California at San Diego | Perkins G.,University of California at San Diego | And 8 more authors.
Neuroscience | Year: 2015

Monge's disease, also known as chronic mountain sickness (CMS), is a disease that potentially threatens more than 140 million highlanders during extended time living at high altitudes (over 2500m). The prevalence of CMS in Andeans is about 15-20%, suggesting that the majority of highlanders (non-CMS) are rather healthy at high altitudes; however, CMS subjects experience severe hypoxemia, erythrocytosis and many neurologic manifestations including migraine, headache, mental fatigue, confusion, and memory loss. The underlying mechanisms of CMS neuropathology are not well understood and no ideal treatment is available to prevent or cure CMS, except for phlebotomy. In the current study, we reprogrammed fibroblast cells from both CMS and non-CMS subjects' skin biopsies into the induced pluripotent stem cells (iPSCs), then differentiated into neurons and compared their neuronal properties. We discovered that CMS neurons were much less excitable (higher rheobase) than non-CMS neurons. This decreased excitability was not caused by differences in passive neuronal properties, but instead by a significantly lowered Na+ channel current density and by a shift of the voltage-conductance curve in the depolarization direction. Our findings provide, for the first time, evidence of a neuronal abnormality in CMS subjects as compared to non-CMS subjects, hoping that such studies can pave the way to a better understanding of the neuropathology in CMS. © 2014 IBRO.


Phillips G.,University of New Mexico | Reith F.,University of Adelaide | Reith F.,CSIRO | Qualls C.,University of New Mexico | And 3 more authors.
PLoS ONE | Year: 2010

Background: Trace metal analyses in hair are used in archeological, forensic and toxicological investigations as proxies for metabolic processes. We show metallophilic bacteria mediating the deposition of gold (Au), used as tracer for microbial activity in hair post mortem after burial, affecting results of such analyses. Methodology/Principal Findings: Human hair was incubated for up to six months in auriferous soils, in natural soil columns (Experiment 1), soils amended with mobile Au(III)-complexes (Experiment 2) and the Au-precipitating bacterium Cupriavidus metallidurans (Experiment 3), in peptone-meat-extract (PME) medium in a culture of C. metallidurans amended with Au(III)-complexes (Experiment 4), and in non-auriferous soil (Experiment 5). Hair samples were analyzed using scanning electron microscopy, confocal microscopy and inductively coupled plasma-mass spectrometry. In Experiments 1-4 the Au content increased with time (P = 0.038). The largest increase was observed in Experiment 4 vs. Experiment 1 (mean = 1188 vs. 161 μg Kg -1, Fisher's least significance 0.001). The sulfur content, a proxy for hair metabolism, remained unchanged. Notably, the ratios of Au-to-S increased with time (linear trend P = 0.02) and with added Au and bacteria (linear trend, P = 0.005), demonstrating that larger populations of Au-precipitating bacteria and increased availability of Au increased the deposition of Au on the hair. Conclusion/Significance: Interactions of soil biota with hair post mortem may distort results of hair analyses, implying that metal content, microbial activities and the duration of burial must be considered in the interpretation of results of archeological, forensic and toxicological hair analyses, which have hitherto been proxies for pre-mortem metabolic processes. © 2010 Phillips et al.


Udpa N.,University of California at San Diego | Ronen R.,University of California at San Diego | Zhou D.,University of California at San Diego | Liang J.,BGI Americas | And 24 more authors.
Genome Biology | Year: 2014

Background: Although it has long been proposed that genetic factors contribute to adaptation to high altitude, such factors remain largely unverified. Recent advances in high-throughput sequencing have made it feasible to analyze genome-wide patterns of genetic variation in human populations. Since traditionally such studies surveyed only a small fraction of the genome, interpretation of the results was limited.Results: We report here the results of the first whole genome resequencing-based analysis identifying genes that likely modulate high altitude adaptation in native Ethiopians residing at 3,500 m above sea level on Bale Plateau or Chennek field in Ethiopia. Using cross-population tests of selection, we identify regions with a significant loss of diversity, indicative of a selective sweep. We focus on a 208 kbp gene-rich region on chromosome 19, which is significant in both of the Ethiopian subpopulations sampled. This region contains eight protein-coding genes and spans 135 SNPs. To elucidate its potential role in hypoxia tolerance, we experimentally tested whether individual genes from the region affect hypoxia tolerance in Drosophila. Three genes significantly impact survival rates in low oxygen: cic, an ortholog of human CIC, Hsl, an ortholog of human LIPE, and Paf-AHα, an ortholog of human PAFAH1B3.Conclusions: Our study reveals evolutionarily conserved genes that modulate hypoxia tolerance. In addition, we show that many of our results would likely be unattainable using data from exome sequencing or microarray studies. This highlights the importance of whole genome sequencing for investigating adaptation by natural selection. © 2014 Udpa et al.; licensee BioMed Central Ltd.


PubMed | Autonomous University of Madrid, Galileo University and New Mexico Health Enhancement and Marathon Clinics Research Foundation
Type: | Journal: Journal of the neurological sciences | Year: 2016

Icono-diagnosis, the retrospective image-based diagnosis of pathologies, was applied to the canvas Portrait of an Old Man (1595-1600), an attributed self-portrait painted by El Greco. The presence of congenital enophthalmos, strabismus, probable amblyopia and signs of left neglect were found. We assume these sign may be consistent an ischemic event affecting the right middle cerebral artery supply territory. Historically, motor activity was not compromised and the painter was able to return to portraiture. Documental evidence indicates, that a few years later (1608), El Greco suffered another cerebrovascular event resulting in agraphia. The pictorial and historical evidence is consistent with multiple ischemic events resulting in progressive disabilities with fluctuating course characterized by temporary improvements and worsening before his death in 1614.


News Article | November 7, 2016
Site: www.eurekalert.org

To better understand why some people adapt well to life at high altitude while others don't, researchers at University of California San Diego School of Medicine studied red blood cells derived from representatives of both groups living in the Andes Mountains. The study, published November 7 by the Journal of Experimental Medicine, reveals that high-altitude, low-oxygen dwellers prone to chronic mountain sickness produce massive amounts of red blood cells thanks to overproduction of the enzyme SENP1. "In addition to improving the health of millions of people around the world who live above 8,000 feet, information on how Andeans have adapted -- or not adapted -- to high altitude life might teach us how to speed up red blood cell production at lower altitudes, such as in anemia or when blood transfusions are needed rapidly," said senior author Gabriel Haddad, MD, Distinguished Professor and chair of the Department of Pediatrics at UC San Diego School of Medicine and pediatric pulmonologist, physician-in-chief and chief scientific officer at Rady Children's Hospital-San Diego. Chronic mountain sickness affects approximately 20 percent of people who live at high altitudes. One critical aspect of the condition is polycythemia, the overproduction of red blood cells. Some extra red blood cells can be a good thing in high altitude, low oxygen environments -- they help keep blood oxygenated -- but too many thicken blood, increasing a person's risk of heart attack and stroke, even in young adults. In the study, the team, led by Priti Azad, PhD, associate project scientist in Haddad's lab and first author of the study, collected skin cells from people living in the Andes Mountains -- four healthy and five who suffer from chronic mountain sickness -- plus an additional three healthy people who live at sea level, as controls. To produce enough red blood cells from each participant to study them in the lab, the researchers converted the skin cells into a special type of stem cell, called induced pluripotent stem cells (iPSCs). Then, adding a cocktail of growth factors and other molecules, they coaxed the iPSCs into specializing into red blood cells. Multiple samples were tested for each person, for a total of at least 24 iPS cell lines. The researchers exposed the red blood cells to low oxygen conditions that mimic high altitude -- five percent oxygen for three weeks. As a result, red blood cells from healthy sea-level or high altitude-dwelling donors increased a little or not at all. In contrast, numbers of red blood cells from high-altitude dwellers with chronic mountain sickness increased 60-fold. Haddad's team wanted to understand why people with chronic mountain sickness produce so many extra blood cells in response to low oxygen. In a previous study in which the team compared the genomes of high-altitude dwellers with and without chronic mountain sickness, one gene that varied between the two groups stood out -- sentrin-specific protease 1 (SENP1), which is increased in low oxygen in people with chronic mountain sickness but not healthy people. This gene encodes the enzyme SENP1, which acts as a gene regulator by removing small protein tags on transcription factors, other proteins that determine when certain genes are turned on or off. To determine if SENP1 plays a role in high-altitude adaptation, in this study the researchers inhibited the SENP1 gene in chronic mountain sickness patients' iPSCs. As a result, the excessive red blood cell production was reduced by more than 90 percent. On the flip side, when the researchers added extra SENP1 to healthy, adapted highlander iPSCs, red blood cell production increased 30-fold, nearly recapitulating that seen in chronic mountains sickness. Further experiments suggested how SENP1 affects red blood cell production -- elevated levels of the enzyme in chronic mountain sickness in turn boost levels of several other proteins that promote cell division and survival, including VEGF, GATA1 and Bcl-xL. Haddad and Azad are now looking forward to the next phase of their research. "We're interested in determining the early steps in this process -- how low oxygen triggers SENP1 in the first place," Azad said. "We are also investigating how existing altitude sickness medications, such as Diamox, work and whether or not it's through this same mechanism." Co-authors of this study also include: Huiwen W. Zhao, Pedro J. Cabrales, Roy Ronen, Dan Zhou, Orit Poulsen, Yu Hsin Hsiao, Vineet Bafna, UC San Diego; and Otto Appenzeller, New Mexico Health Enhancement and Marathon Clinics Research Foundation.


Zhou D.,University of California at San Diego | Udpa N.,University of California at San Diego | Ronen R.,University of California at San Diego | Stobdan T.,University of California at San Diego | And 23 more authors.
American Journal of Human Genetics | Year: 2013

The hypoxic conditions at high altitudes present a challenge for survival, causing pressure for adaptation. Interestingly, many high-altitude denizens (particularly in the Andes) are maladapted, with a condition known as chronic mountain sickness (CMS) or Monge disease. To decode the genetic basis of this disease, we sequenced and compared the whole genomes of 20 Andean subjects (10 with CMS and 10 without). We discovered 11 regions genome-wide with significant differences in haplotype frequencies consistent with selective sweeps. In these regions, two genes (an erythropoiesis regulator, SENP1, and an oncogene, ANP32D) had a higher transcriptional response to hypoxia in individuals with CMS relative to those without. We further found that downregulating the orthologs of these genes in flies dramatically enhanced survival rates under hypoxia, demonstrating that suppression of SENP1 and ANP32D plays an essential role in hypoxia tolerance. Our study provides an unbiased framework to identify and validate the genetic basis of adaptation to high altitudes and identifies potentially targetable mechanisms for CMS treatment. © 2013 The American Society of Human Genetics.


Lombardi G.,Cayetano Heredia Peruvian University | Lanzirotti A.,University of Chicago | Qualls C.,University of New Mexico | Socola F.,University of Miami | And 2 more authors.
Journal of Biomedicine and Biotechnology | Year: 2012

Mercury is added to the biosphere by anthropogenic activities raising the question of whether changes in the human chromatin, induced by mercury, in a parental generation could allow adaptation of their descendants to mercury. We review the history of Andean mining since pre-Hispanic times in Huancavelica, Peru. Despite the persistent degradation of the biosphere today, no overt signs of mercury toxicity could be discerned in present day inhabitants. However, mercury is especially toxic to the autonomic nervous system (ANS). We, therefore, tested ANS function and biologic rhythms, under the control of the ANS, in 5 Huancavelicans and examined the metal content in their hair. Mercury levels varied from none to 1.014ppm, significantly less than accepted standards. This was confirmed by microfocused synchrotron X-ray fluorescence analysis. Biologic rhythms were abnormal and hair growth rate per year, also under ANS control, was reduced (P 0.001). Thus, evidence of mercurys toxicity in ANS function was found without other signs of intoxication. Our findings are consistent with the hypothesis of partial transgenerational inheritance of tolerance to mercury in Huancavelica, Peru. This would generally benefit survival in the Anthropocene, the man-made world, we now live in. © Copyright 2012 Guido Lombardi et al.


PubMed | University of Turin, University of New Mexico and New Mexico Health Enhancement and Marathon Clinics Research Foundation
Type: | Journal: BioMed research international | Year: 2015

Bioarcheology is cross disciplinary research encompassing the study of human remains. However, lifes activities have, up till now, eluded bioarcheological investigation. We hypothesized that growth lines in hair might archive the biologic rhythms, growth rate, and metabolism during life. Computational modeling predicted the physical appearance, derived from hair growth rate, biologic rhythms, and mental state for human remains from the Roman period. The width of repeat growth intervals (RIs) on the hair, shown by confocal microscopy, allowed computation of time series of periodicities of the RIs to model growth rates of the hairs. Our results are based on four hairs from controls yielding 212 data points and the RIs of six cropped hairs from Zweeloo womans scalp yielding 504 data points. Hair growth was, ten times faster than normal consistent with hypertrichosis. Cant syndrome consists of hypertrichosis, dyschondrosteosis, short stature, and cardiomegaly. Sympathetic activation and enhanced metabolic state suggesting arousal was also present. Two-photon microscopy visualized preserved portions of autonomic nerve fibers surrounding the hair bulb. Scanning electron microscopy found evidence that a knife was used to cut the hair three to five days before death. Thus computational modeling enabled the elucidation of lifes activities 2000 years after death in this individual with Cantu syndrome. This may have implications for archeology and forensic sciences.


Qualls C.,University of New Mexico | Appenzeller O.,New Mexico Health Enhancement and Marathon Clinics Research Foundation
BioMed Research International | Year: 2015

We examine two important measures that can be made in bioarcheology on the remains of human and vertebrate animals. These remains consist of bone, teeth, or hair; each shows growth increments and each can be assayed for isotope ratios and other chemicals in equal intervals along the direction of growth. In each case, the central data is a time series of measurements. The first important measures are spectral estimates in spectral analyses and linear system analyses; we emphasize calculation of periodicities and growth rates as well as the comparison of power in bands. A low frequency band relates to the autonomic nervous system (ANS) control of metabolism and thus provides information about the life history of the individual of archeological interest. Turning to nonlinear system analysis, we discuss the calculation of SM Pinus' approximate entropy (ApEn) for short or moderate length time series. Like the concept that regular heart R-R interval data may indicate lack of health, low values of ApEn may indicate disrupted metabolism in individuals of archeological interest and even that a tipping point in deteriorating metabolism may have been reached just before death. This adds to the list of causes of death that can be determined from minimal data. © 2015 Clifford Qualls and Otto Appenzeller.


PubMed | University of New Mexico and New Mexico Health Enhancement and Marathon Clinics Research Foundation
Type: | Journal: BioMed research international | Year: 2015

We examine two important measures that can be made in bioarcheology on the remains of human and vertebrate animals. These remains consist of bone, teeth, or hair; each shows growth increments and each can be assayed for isotope ratios and other chemicals in equal intervals along the direction of growth. In each case, the central data is a time series of measurements. The first important measures are spectral estimates in spectral analyses and linear system analyses; we emphasize calculation of periodicities and growth rates as well as the comparison of power in bands. A low frequency band relates to the autonomic nervous system (ANS) control of metabolism and thus provides information about the life history of the individual of archeological interest. Turning to nonlinear system analysis, we discuss the calculation of SM Pinus approximate entropy (ApEn) for short or moderate length time series. Like the concept that regular heart R-R interval data may indicate lack of health, low values of ApEn may indicate disrupted metabolism in individuals of archeological interest and even that a tipping point in deteriorating metabolism may have been reached just before death. This adds to the list of causes of death that can be determined from minimal data.

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