Inverted altitude Flashcards
(26 cards)
Isolated a 50-nucleotide DNA sequence from the human EPO gene that drove hypoxia-inducible transcription in Hep3B cells; mutations of that sequence abolished the hypoxic response, leading to the discovery of HIF-1.
Semenza and Wang (1992)
Discovery of the hypoxic regulator
Used tamoxifen-inducible, ubiquitous Cre to delete HIF-2α or HIF-1α postnatally in mice; only HIF-2α deletion caused anemia responsive to EPO and blunted renal EPO induction, demonstrating HIF-2’s in vivo role in erythropoiesis.
Gruber et al (2007)
Establishing the role of Hif isoforms
Measured pulmonary vascular resistance with a balloon-tipped catheter in 8 men during 8 h isocapnic hypoxia, 3 h euxia, then re-hypoxia; PVR rose and fell in parallel with inspired PO₂, characterizing dynamic HPV.
Dorrington et al (1997)
Characterising the pulmonary response
In 22 healthy lowlanders at 4340 m, gave IV iron vs placebo on day 3 and measured PASP by echo: iron reduced PASP by 6 mmHg, placebo did not; in CMS highlanders, venesection–induced iron deficiency increased PASP by 9 mmHg, showing iron/HIF-dependence.
Smith, Talbot et al (2009)
Effect of iron on pulmonary arterial pressure
Randomized 48 non-anemic COPD patients to ferric carboxymaltose vs placebo; after 1 week measured SpO₂, 6MWD, breathlessness, QoL: iron improved 6MWD and breathlessness but not SpO₂ or QoL.
Santer et al (2020)
Effect of iron on phsyiological outcomes
Tracked ventilatory responses to CO₂ and O₂ in lowlanders over 6 weeks at altitude, altitude-residing lowlanders, and natives: lowlanders’ CO₂ sensitivity rose progressively; natives had blunted hypoxic response,
Forster et al (1971)
Ventilatory responses in acclimatised and adapted individuals
In goats with one carotid body perfused extracorporeally, perfused hypoxic blood for 6 h under isocapnia: ventilation progressively rose and persisted after normoxia, proving carotid-body hypoxia alone drives acclimatization.
Busch et al (1985)
Peripheral driver of acclimatisation
Used tamoxifen-inducible knockouts of PHD2, HIF-1α, and HIF-2α to test hypoxic ventilatory response and carotid-body proliferation in mice: PHD2 KO increased HVR; HIF-2α deletion (not HIF-1α) blocked the enhanced HVR and CB proliferation, identifying PHD2–HIF-2α as key.
Hodson et al (2016)
Role of PHD2 and Hif in the ventilatory response
Compared hemoglobin in Tibetans and Aymara at high altitude: Tibetans showed no marked Hb increase whereas Aymara did, revealing a blunted erythropoietic response in Tibetans due to genetic adaptation.
Beall et al (1998)
Hct in high altitude populaions
GWAS in Tibetans vs Han Chinese identified EPAS1 under strong selection; EPAS1 genotype was associated with ∼1 g/dL lower Hb in homozygotes, replicated at 4300 m, implicating EPAS1 in Tibetan adaptation.
Beall et al (2010)
Natural selection in high altitude populations
Assessed associations of compound EPAS1 and PHD1 variants with hemoglobin in highlanders.
Some studies showed lower Hb in homozygous patients for the compound variant, others showed lower Hb only when the PHD2 variants were associated with positively selected HIF2alpha variants
Petousi et al (2014)
Natural selection in high altitude populations
Surveyed prevalence of chronic mountain sickness in Tibetans, Europeans, Han, and Andeans: Tibetans had the lowest CMS rate, linked to lower Hb and blunted pulmonary hypertensive response, underscoring durable adaptation.
Moore et al (2021)
CMS in high altitude populations
Measured pulmonary artery pressure and resistance at rest and during maximal exercise in 5 Tibetans at 3658 m: values were within sea-level norms and little changed when subjects breathed a hypoxic gas mixture. Near maximal exercise increased CO three-fold but did not elevate PVR.
Groves et al (1985)
Pulmonary response in Tibetans
Reported LP opening pressures in 24 Indian soldiers moving between sea level and high altitude: indicative of increased ICP; one of the earliest recorded cases of HACE
Singh et al (1969)
Early recorded cases of HACE
Described 12 severe altitude‐illness cases dominated by neurological signs; necropsy in 2 fatalities showed widespread petechiae and hemorrhage, establishing HACE as distinct from AMS.
Housten and Dickenson (1975)
Establishing HACE as a distinct condition
Used T2-weighted MRI in 9 HACE patients vs 6 controls at high altitude: intense white-matter signal in HACE revealed vasogenic edema, especially in the splenium of the corpus callosum.
Hackett et al (1998)
Clinical feature of HACE
Applied susceptibility-weighted 3 T MRI in 3 HACE and 3 AMS patients: HACE patients showed extensive microbleeds not seen in AMS, indicating distinct microvascular pathology.
Kallenberg et al (2008)
Clinical distinguisher of HACE
Followed 8 HACE patients with MRI over months–years: persistent and coalescing microbleeds in white matter demonstrated long-term sequelae of cerebral edema; also observed evidence of cytotoxic oedema
Hackett et al (2019)
Long term effect of HACE
Exposed 30 non-acclimatized mountaineers (16 HAPE history) to controlled hypoxia; measured pulmonary capillary pressure (PCP): PCP ≥ 19 mmHg predicted HAPE, linking elevated PCP to risk.
Maggiorini et al (2001)
PCP and HAPE
Screened > 400 lowlanders for exaggerated HPV; selected high-HPV and control groups for 48 h at 4559 m: only 13% of high-HPV subjects developed HAPE, showing exaggerated HPV is an imperfect surrogate.
Dehnert et al (2015)
HPV and HAPE
Measured exhaled NO over 4 h of hypoxic exposure in HAPE-susceptible vs controls: susceptible individuals had lower NO, implicating reduced NO bioavailability in HAPE vulnerability.
Bush et al (2001)
NO bioavailability and HAPE
Assayed BAL nitrate/nitrite in mountaineers who did or did not develop HAPE: HAPE-susceptible had lower NO metabolites, supporting a role for impaired NO signaling in HAPE pathogenesis.
Swenson et al (2002)
NO bioavailability in HAPE
Ganglioside GM1, which is known to alleviate brain injury, protects HACE in rats by muting inflammatory cytokines
Gong et al (2018)
Animal model in HACE research
Expedition to the Peruvian Andes; identified elevated RBC numbers as an acute physiologic response rather than an inherited condition.
Viault (1890)
Initial characterisation of erythrocytosis
