Calcific uremic arteriolopathy: Pathophysiology, reactive oxygen species and therapeutic approaches

Calcific uremic arteriolopathy (CUA)/calciphylaxis is an important cause of morbidity and mortality in patients with chronic kidney disease requiring renal replacement. Once thought to be rare, it is being increasingly recognized and reported on a global scale. The uremic milieu predisposes to multiple metabolic toxicities including increased levels of reactive oxygen species and inflammation. Increased oxidative stress and inflammation promote this arteriolopathy by adversely affecting endothelial function resulting in a prothrombotic milieu and significant remodeling effects on vascular smooth muscle cells. These arteriolar pathological effects include intimal hyperplasia, inflammation, endovascular fibrosis and vascular smooth muscle cell apoptosis and differentiation into bone forming osteoblast-like cells resulting in medial calcification. Systemic factors promoting this vascular condition include elevated calcium, parathyroid hormone and hyperphosphatemia with consequent increases in the calcium × phosphate product. The uremic milieu contributes to a marked increased in upstream reactive oxygen species—oxidative stress and subsequent downstream increased inflammation, in part, via activation of the nuclear transcription factor NFκB and associated downstream cytokine pathways. Consitutive anti-calcification proteins such as Fetuin-A and matrix GLA proteins and their signaling pathways may be decreased, which further contributes to medial vascular calcification. The resulting clinical entity is painful, debilitating and contributes to the excess morbidity and mortality associated with chronic kidney disease and end stage renal disease. These same histopathologic conditions also occur in patients without uremia and therefore, the term calcific obliterative arteriolopathy could be utilized in these conditions

Onset of deglacial warming in West Antarctica driven by local orbital forcing

The cause of warming in the Southern Hemisphere during the most recent deglaciation remains a matter of debate[superscript 1,2]. Hypotheses for a Northern Hemisphere trigger, through oceanic redistributions of heat, are based in part on the abrupt onset of warming seen in East Antarctic ice cores and dated to 18,000 years ago, which is several thousand years after high-latitude Northern Hemisphere summer insolation intensity began increasing from its minimum, approximately 24,000 years ago[superscript 3,4]. An alternative explanation is that local solar insolation changes cause the Southern Hemisphere to warm independently[superscript 2,5]. Here we present results from a new, annually resolved ice-core record from West Antarctica that reconciles these two views. The records show that 18,000 years ago snow accumulation in West Antarctica began increasing, coincident with increasing carbon dioxide concentrations, warming in East Antarctica and cooling in the Northern Hemisphere[superscript 6] associated with an abrupt decrease in Atlantic meridional overturning circulation[superscript 7]. However, significant warming in West Antarctica began at least 2,000 years earlier. Circum-Antarctic sea-ice decline, driven by increasing local insolation, is the likely cause of this warming. The marine-influenced West Antarctic records suggest a more active role for the Southern Ocean in the onset of deglaciation than is inferred from ice cores in the East Antarctic interior, which are largely isolated from sea-ice changes.Keywords: Last glacial period, Carbon Dioxide, High resolution, Chronology, Ice core, Circulation, Abrupt climate change, Atmospheric Co2, Greenland, Polar ic

Precise interpolar phasing of abrupt climate change during the last ice age

The last glacial period exhibited abrupt Dansgaard–Oeschger climatic oscillations, evidence of which is preserved in a variety of Northern Hemisphere palaeoclimate archives¹. Ice cores show that Antarctica cooled during the warm phases of the Greenland Dansgaard–Oeschger cycle and vice versa[superscript 2,3], suggesting an interhemispheric redistribution of heat through a mechanism called the bipolar seesaw[superscript 4–6]. Variations in the Atlantic meridional overturning circulation (AMOC) strength are thought to have been important, but much uncertainty remains regarding the dynamics and trigger of these abrupt events[superscript 7–9]. Key information is contained in the relative phasing of hemispheric climate variations, yet the large, poorly constrained difference between gas age and ice age and the relatively low resolution of methane records from Antarctic ice cores have so far precluded methane-based synchronization at the required sub-centennial precision[superscript 2,3,10]. Here we use a recently drilled high-accumulation Antarctic ice core to show that, on average, abrupt Greenland warming leads the corresponding Antarctic cooling onset by 218 ± 92 years (2σ) for Dansgaard–Oeschger events, including the Bølling event; Greenland cooling leads the corresponding onset of Antarctic warming by 208 ± 96 years. Our results demonstrate a north-to-south directionality of the abrupt climatic signal, which is propagated to the Southern Hemisphere high latitudes by oceanic rather than atmospheric processes. The similar interpolar phasing of warming and cooling transitions suggests that the transfer time of the climatic signal is independent of the AMOC background state. Our findings confirm a central role for ocean circulation in the bipolar seesaw and provide clear criteria for assessing hypotheses and model simulations of Dansgaard–Oeschger dynamics

Centennial-scale changes in the global carbon cycle during the last deglaciation

Global climate and the concentration of atmospheric carbon dioxide (CO2) are correlated over recent glacial cycles. The combination of processes responsible for a rise in atmospheric CO2 at the last glacial termination (23,000 to 9,000 years ago), however, remains uncertain. Establishing the timing and rate of CO2 changes in the past provides critical insight into the mechanisms that influence the carbon cycle and helps put present and future anthropogenic emissions in context. Here we present CO2 and methane (CH4) records of the last deglaciation from a new high-accumulation West Antarctic ice core with unprecedented temporal resolution and precise chronology. We show that although low-frequency CO2 variations parallel changes in Antarctic temperature, abrupt CO2 changes occur that have a clear relationship with abrupt climate changes in the Northern Hemisphere. A significant proportion of the direct radiative forcing associated with the rise in atmospheric CO2 occurred in three sudden steps, each of 10 to 15 parts per million. Every step took place in less than two centuries and was followed by no notable change in atmospheric CO2 for about 1,000 to 1,500 years. Slow, millennial-scale ventilation of Southern Ocean CO2-rich, deep-ocean water masses is thought to have been fundamental to the rise in atmospheric CO2 associated with the glacial termination, given the strong covariance of CO2 levels and Antarctic temperatures. Our data establish a contribution from an abrupt, centennial-scale mode of CO2 variability that is not directly related to Antarctic temperature. We suggest that processes operating on centennial timescales, probably involving the Atlantic meridional overturning circulation, seem to be influencing global carbon-cycle dynamics and are at present not widely considered in Earth system models

11β-hydroxysteroid dehydrogenase blockade prevents age-induced skin structure and function defects

Glucocorticoid (GC) excess adversely affects skin integrity, inducing thinning and impaired wound healing. Aged skin, particularly that which has been photo-exposed, shares a similar phenotype. Previously, we demonstrated age-induced expression of the GC-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in cultured human dermal fibroblasts (HDFs). Here, we determined 11β-HSD1 levels in human skin biopsies from young and older volunteers and examined the aged 11β-HSD1 KO mouse skin phenotype. 11β-HSD1 activity was elevated in aged human and mouse skin and in PE compared with donor-matched photo-protected human biopsies. Age-induced dermal atrophy with deranged collagen structural organization was prevented in 11β-HSD1 KO mice, which also exhibited increased collagen density. We found that treatment of HDFs with physiological concentrations of cortisol inhibited rate-limiting steps in collagen biosynthesis and processing. Furthermore, topical 11β-HSD1 inhibitor treatment accelerated healing of full-thickness mouse dorsal wounds, with improved healing also observed in aged 11β-HSD1 KO mice. These findings suggest that elevated 11β-HSD1 activity in aging skin leads to increased local GC generation, which may account for adverse changes occurring in the elderly, and 11β-HSD1 inhibitors may be useful in the treatment of age-associated impairments in dermal integrity and wound healing

WAIS Divide Deep ice core 0-68 ka WD2014 chronology

The West Antarctic Ice Sheet (WAIS) Divide deep ice core WD2014 chronology, consisting of ice age, gas age, delta-age and uncertainties therein. The West Antarctic Ice Sheet Divide (WAIS Divide, WD) ice core is a newly drilled, high-accumulation deep ice core that provides Antarctic climate records of the past ~68 ka at unprecedented temporal resolution. The upper 2850 m (back to 31.2 ka BP; Sigl et al., 2015, Sigl et al., 2016) have been dated using annual-layer counting based on counting of annual layers observed in the chemical, dust and electrical conductivity records. The measurements were interpreted manually and with the aid of two automated methods. We validated the chronology by comparing of the cosmogenic isotope records of 10Be from WAIS Divide and 14C for IntCal13. We demonstrated that over the Holocene WD2014 was consistently accurate to better than 0.5% of the age. The chronology for the deep part of the core (below 2850m; 67.8-31.2 ka BP; Buizert et al., 2015) is based on stratigraphic matching to annual-layer-counted Greenland ice cores using globally well-mixed atmospheric methane. We calculate the WD gas age-ice age difference (Delta age) using a combination of firn densification modeling, ice-flow modeling, and a data set of d15N-N2, a proxy for past firn column thickness. The largest Delta age at WD occurs during the Last Glacial Maximum, and is 525 +/- 120 years. We synchronized the WD chronology to a linearly scaled version of the layer-counted Greenland Ice Core Chronology (GICC05), which brings the age of Dansgaard-Oeschger (DO) events into agreement with the U/Th absolutely dated Hulu Cave speleothem record

Shifts in Greenland interannual climate variability lead Dansgaard-Oeschger abrupt warming by hundreds of years

During the Last Glacial Period (LGP), Greenland experienced approximately thirty abrupt warming phases, known as Dansgaard-Oeschger (D-O) Events, followed by cooling back to baseline glacial conditions. Studies of mean climate change across warming transitions reveal indistinguishable phase-offsets between shifts in temperature, dust, sea salt, accumulation and moisture source, thus preventing a comprehensive understanding of the “anatomy” of D-O cycles (Capron et al,. 2021). One aspect of abrupt change that has not been systematically assessed is how high-frequency, interannual-scale climatic variability surrounding mean temperature changes across D-O transitions. Here, we utilize the EGRIP ice core high-resolution water isotope record, a proxy for temperature and atmospheric circulation, to quantify the amplitude of 7–15 year isotopic variability for D-O events 2–13, the Younger Dryas and the Bølling-Allerød. On average, cold stadial periods consistently exhibit greater variability than warm interstadial periods. Most notably, we often find that reductions in the amplitude of the 7–15 year band led abrupt D-O warmings by hundreds of years. Such a large phase offset between two climate parameters in a Greenland ice core has never been documented for D-O cycles. However, similar centennial lead times have been found in proxies of Norwegian Sea ice cover relative to abrupt Greenland warming (Sadatzki et al., 2020). Using HadCM3, a fully coupled general circulation model, we assess the effects of sea ice on 7–15 year temperature variability at EGRIP. For a range of stadial and interstadial conditions, we find a strong relationship in line with our observations between colder simulated mean temperature and enhanced temperature variability at the EGRIP location. We also find a robust correlation between year-to-year North Atlantic sea-ice fluctuations and the strength of interannual-scale temperature variability at EGRIP. Thus, both paleoclimate proxy evidence and model simulations suggest that sea ice plays a substantial role in high-frequency climate variability prior to D-O warming. This provides a clue about the anatomy of D-O Events and should be the target of future sea-ice model studies