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Hibernation in hominins from Atapuerca, Spain half a million years ago
Abstract
Both animal hibernation and human renal osteodystrophy are characterized by high levels of serum parathyroid hormone. To test the hypothesis of hibernation in an extinct human species, we examined the hominin skeletal collection from Sima de los Huesos, Cave Mayor, Atapuerca, Spain, for evidence of hyperparathyroidism after a thorough review of the literature. We studied the morphology of the fossilized bones by using macrophotography, microscopy, histology and CT scanning. We found trabecular tunneling and osteitis fibrosa, subperiosteal resorption, ‘rotten fence post’ signs, brown tumours, subperiosteal new bone, chondrocalcinosis, rachitic osteoplaques and empty gaps between them, craniotabes, and beading of ribs mostly in the adolescent population of these hominins. Since many of the above lesions are pathognomonic, these extinct hominins suffered annually from renal rickets, secondary hyperparathyroidism, and renal osteodystrophy associated with Chronic Kidney Disease - Mineral and Bone Disorder (CKD-MBD). We suggest these diseases were caused by poorly tolerated hibernation in dark cavernous hibernacula. This is particularly evidenced by the rachitic osteoplaques and the gaps between them in some of the adolescent individuals along with the evidence of healing mainly in the adults. The sublayers in the rachitic osteoplaques indicate bouts of arousal from hibernation. The strong projection of the external lip of the femoral trochlea, the rachitic osteoplaques with the empty gaps between them, the “rotten fence post" sign, and the evidence of annual healing also point to the presence of annually intermittent puberty in this extinct human species. The hypothesis of hibernation is consistent with the genetic evidence and the fact that the SH hominins lived during an extreme glaciation. Alternative hypotheses are examined. The present work will provide a new insight into the physiological mechanism of early human metabolism which could help in determining the life histories and physiologies of extinct human species.
... An emerging body of work suggests that the study of hypometabolic states may be important area of research in humans and applied science more generally (Lee, 2008;Lee et al., 2016;Staples, 2014). In a recent article, Bartsiokas and Arsuaga (2020) review archaeological evidence showing that certain extinct human species living in glacial environments went into hibernation and that the genetic basis and physiology for a hibernation-related hypometabolic state could be preserved in some contemporary humans (Bartsiokas & Arsuaga, 2020). They also discuss historical reports, discussed by Dirks and colleagues, from famine areas in the Pskov region of Russia (east of contemporary Latvia) pertaining to "an almost uninterrupted sleep" (called loijka) during winter; possibly the human equivalent of hibernation, loijka involved entire families of peasants "huddling together on top of huge stoves" to conserve energy and warmth (p 28) (Bartsiokas & Arsuaga, 2020;Dirks et al., 1980). ...
... An emerging body of work suggests that the study of hypometabolic states may be important area of research in humans and applied science more generally (Lee, 2008;Lee et al., 2016;Staples, 2014). In a recent article, Bartsiokas and Arsuaga (2020) review archaeological evidence showing that certain extinct human species living in glacial environments went into hibernation and that the genetic basis and physiology for a hibernation-related hypometabolic state could be preserved in some contemporary humans (Bartsiokas & Arsuaga, 2020). They also discuss historical reports, discussed by Dirks and colleagues, from famine areas in the Pskov region of Russia (east of contemporary Latvia) pertaining to "an almost uninterrupted sleep" (called loijka) during winter; possibly the human equivalent of hibernation, loijka involved entire families of peasants "huddling together on top of huge stoves" to conserve energy and warmth (p 28) (Bartsiokas & Arsuaga, 2020;Dirks et al., 1980). ...
... In a recent article, Bartsiokas and Arsuaga (2020) review archaeological evidence showing that certain extinct human species living in glacial environments went into hibernation and that the genetic basis and physiology for a hibernation-related hypometabolic state could be preserved in some contemporary humans (Bartsiokas & Arsuaga, 2020). They also discuss historical reports, discussed by Dirks and colleagues, from famine areas in the Pskov region of Russia (east of contemporary Latvia) pertaining to "an almost uninterrupted sleep" (called loijka) during winter; possibly the human equivalent of hibernation, loijka involved entire families of peasants "huddling together on top of huge stoves" to conserve energy and warmth (p 28) (Bartsiokas & Arsuaga, 2020;Dirks et al., 1980). Based on emerging data from metabolomic research, Robert Naviaux has suggested that the shutdown state that manifests as severe chronic fatigue syndrome may be a manifestation of a hypometabolic state-similar to dauer-in response to adverse environmental conditions (Naviaux et al., 2016). ...
Asylum-seeking children presenting in the shutdown state have been the subject of much discussion and controversy—on both government and medical system levels—in Australia and in Sweden. In this article, we conceptualize the shutdown state as an evolutionary response to extreme threat. We adopt a neuroscience approach to present five plausible models for explaining this shutdown state, their strengths and shortcomings, and the overlaps between them. Model 1—the sustained autonomic arousal model—draws on polyvagal theory. Model 2—the innate-defence model—draws on research pertaining to animal and human innate defence responses. Model 3—the catatonia model—draws on clinical and research data with patients presenting with catatonia. Model 4—the hypometabolic model—draws on an emerging body of work pertaining to hypometabolic states in animals and humans. Model 5—the defence cascade model of dissociation—draws on clinical research pertaining to human trauma states that present as dissociation. At present, each of the models provides a plausible pathophysiological explanation—or a component of a potential pathophysiological explanation—and none of them, for the moment, has enough evidence to be either accepted or disregarded. We hope that our discussion of the models advances scientific discussion and opens up possibilities for effective treatment.
... In the first and by much the longest phase, mammals exercised a "pure" photoperiodic strategy including, we believe, the ROS-based switch mechanism outlined here. It is possible that elements of this strategy carried, with modifications, into certain early hominin species (14). Yet two factors intrinsic to human evolution gradually complicated this picture. ...
... Given the non-negligible remnant of seasonal modulation in modern man, it is conceivable that a somewhat more extensive version of photoperiodism obtained in an earlier hominid species. Indeed a plausible case has been made that Neanderthals exercised a general photoperiodic capacity (14). Yet even if that preliminary brief should prove true, this only postpones the question why part of the seasonal machinery was diverted into pathology. ...
One of the most striking and least understood aspects of mood disorders involves the “switch process” which drives the dramatic state changes characteristic of bipolar disorder. In this paper we explore the bipolar switch mechanism as deeply grounded in forms of seasonal switching (for example, from summer to winter phenotypes) displayed by many mammalian species. Thus we develop a new and unifying hypothesis that involves four specific claims, all converging to demonstrate a deeper affinity between the bipolar switch process and the light-sensitive (photoperiodic) nonhuman switch sequence than has been appreciated. First, we suggest that rapid eye movement (REM) sleep in both human and nonhuman plays a key role in probing for those seasonal changes in length of day that trigger the organism's characteristic involutional response (in certain animals, hibernation) to shorter days. Second, we claim that this general mammalian response requires the integrity of a neural circuit centering on the anterior bed nucleus of the stria terminalis. Third, we propose that a key molecular mediator of the switch process in both nonhumans and seasonal humans involves reactive oxygen species (ROS) of a particular provenance, namely those created by the enzyme NADPH oxidase (NOX). This position diverges from one currently prominent among students of bipolar disorder. In that tradition, the fact that patients afflicted with bipolar-spectrum disorders display indices of oxidative damage is marshaled to support the conclusion that ROS, escaping adventitiously from mitochondria, have a near-exclusive pathological role. Instead, we believe that ROS, originating instead in membrane-affiliated NOX enzymes upstream from mitochondria, take part in an eminently physiological signaling process at work to some degree in all mammals. Fourth and finally, we speculate that the diversion of ROS from that purposeful, genetically rooted seasonal switching task into the domain of human pathology represents a surprisingly recent phenomenon. It is one instigated mainly by anthropogenic modifications of the environment, especially “light pollution.”
... Przekazanie tej predyspozycji człowiekowi współczesnemu nastąpiło w wyniku krzyżowania się człowieka neandertalskiego z Homo sapiens. W 2020 roku ukazała się praca badaczy hiszpańskich, którzy wykazali, że człowiek neandertalski miał zdolność hibernacji zimowej, o czym świadczą znaleziska w hiszpańskich grotach Atapuerca, gdzie w szkieletach pochodzących sprzed około 500 tysięcy lat stwierdzano cechy zaburzeń układu kostnego i nerek stanowiące konsekwencje okresu hibernacji [39]. Tak więc istnieją powody, aby przypuszczać, że adaptacja klimatyczna człowieka neandertalskiego może stanowić genezę choroby afektywnej sezonowej, głównie depresji zimowej. ...
W bieżącym roku przypada czterdziesta rocznica publikacji artykułu, w którym po raz pierwszy użyto pojęcia choroby afektywnej sezonowej (Seasonal Affective Disorder - SAD). Obecnie SAD uznaje się jako szczególną kategorię choroby afektywnej. W klasyfikacji amerykańskiej Diagnostic and Statistical Manual of Mental Disorders. Fifth edition (DSM-5) sezonowość stanowi „wyznacznik” (specifier, with seasonal pattern) zarówno dla depresji nawracającej czyli tzw. dużego zaburzenia depresyjnego (ang. Major Depressive Disorder – MDD), jak i dla choroby afektywnej dwubiegunowej (CHAD) (ang. Bipolar Disorder). Najbardziej spektakularnym zjawiskiem z kręgu SAD jest depresja zimowa. Jej symptomatologia jest w dużym stopniu podobna do depresji atypowej, charakteryzującej się nadmiarem snu i głodem węglowodanowym. SAD może dotyczyć do 1/5 osób chorujących na depresję nawracającą lub CHAD i częściej występuje u kobiet. SAD można traktować jako ekstremalny przejaw zmian ośrodkowego układu nerwowego (OUN) związanych z okołorocznym rytmem oświetlenia. Różnice sezonowe funkcji OUN dotyczą m.in. sekrecji melatoniny, neuroprzekaźników dopaminy i serotoniny oraz osi podwzgórze-przysadka-nadnercza. W procesach okołodobowych (circadian) oraz około-rocznych (circannual) istotną rolę odgrywa czynność tzw. genów zegarowych (clock genes). SAD może stanowić spuściznę po człowieku neandertalskim. W depresji zimowej efekt leczniczy uzyskuje się za pomocą ekspozycji na jasne światło (bright light therapy – BLT), jak również na światło niebieskie (blue light) oraz za pomocą metody symulacji świtu (dawn simulation). Terapeutyczny efekt fototerapii stwierdzono również w depresji nie-sezonowej. Jako kontrapunkt tego mechanizmu, podjęto zachęcające próby leczenia stanów maniakalnych poprzez ograniczenie światła za pomocą okularów blokujących światło niebieskie (blue-blocking glasses).
... Interestingly, these genes may increase the risk of depression in humans (Nowak and Pawełczyk 2023). The long and wet winter half year in Western Europe within the modelled range of H. heidelbergensis, and the possibility of adaptation to the coldest phase of the year through hibernation (Bartsiokas and Arsuaga 2020), suggest that such genetic traits could have had a role in modulating behaviour. Winter depression, common in contemporary European populations, particularly among women and younger individuals (Dam et al. 1998), may have reduced the mental and physical activity of archaic people, potentially helping them avoid exposure to harsher winter conditions and reducing food demand due to decreased activity. ...
The European populations of Homo heidelbergensis may have contributed to the genetic heritage of modern Eurasians. A better understanding of the possible effects of palaeoenvironmental alterations on the evolution of ancient humans can help to understand the origin of developed traits. For this purpose, the spatiotemporal alterations of physical factors were modelled in Europe for the period of 670–190 ka, covering the existence of Homo heidelbergensis in Europe. The factors included the following: paleoclimatic conditions, climatic suitability values of ancient humans, two prey species, and the European beech. Furthermore, the distribution and features of wood used for toolmaking were also investigated. Finally, changes in the relative mortality risk, the percentage of the body covered by clothing, and daily energy expenditure values in the coldest quarter of the year were modelled. The results suggest that H. heidelbergensis inhabited dominantly temperate regions in Europe where prey such as red deer were present. In the northern regions, European beech trees were abundant. When making wood tools, they preferred relatively light but not the strongest woods, which were readily available in the vicinity of the sites. Although hard and heavy woods were also occasionally used, at a European level, significant changes were observed in the relative mortality risk, the percentage of the body covered by clothing, and daily energy expenditure values during the period of 670–190 ka. However, substantial differences between archaeological sites in these values, indicating somewhat ecological variations, were not found during the studied period.
... Ostatnio badacze hiszpańscy wykazali również, że człowiek neandertalski miał zdolność hibernacji zimowej, o czym świadczą znaleziska w hiszpańskich grotach Atapuerca. W szkieletach pochodzących sprzed około 500 000 lat stwierdzano cechy zaburzeń układu kostnego i nerek stanowiące konsekwencje okresu hibernacji [20]. ...
Choroba afektywna dwubiegunowa (ChAD) zwana również chorobą maniakalno-depresyjną charakteryzuje się okresowym występowaniem biegunowo przeciwnych stanów nastroju, aktywności i motywacji do działania (manii i depresji) niekiedy o ekstremalnym nasileniu. Wytworzenie takich stanów i ich utrzymywanie się w procesie ewolucji może świadczyć o możliwości ich adaptacyjnego charakteru umożliwiającego przystosowanie do niekorzystnej sytuacji zewnętrznej (depresja) oraz mobilizację organizmu w obliczu dostępności zasobów (mania). W artykule główny nacisk jest położony na ewolucyjny aspekt „dwubiegunowości” oraz stanów maniakalnych i hipomaniakalnych. Badania genetyczno-molekularne wskazują, że w przebiegu ewolucji doszło do zachowania genów związanych z predyspozycją do ChAD. W pracy omówiono ewolucyjne koncepcje adaptacyjne ChAD, związane z funkcjonowaniem Homo sapiens w okresie środkowego i późnego plejstocenu, jak również koncepcje „mismatch” związane z nieprzystawalnością czynności mózgu do współczesnych warunków. Przedstawiono ewolucyjne korzyści stanu manii/hipomanii, również w kontekście ich powiązania ze stanami depresji, wskazujące na możliwość związku ze zwiększeniem sukcesu reprodukcyjnego. Jest on następstwem takich cech stanu maniakalnego/hipomaniakalnego, jak zwiększona aktywność eksploracyjna, psychoruchowa i seksualna oraz łatwe podejmowanie ryzyka. Sukces reprodukcyjny może też wiązać się z temperamentem hipertymicznym i cyklotymicznym najczęściej występującymi w ChAD, jako że temperament hipertymiczny często doprowadza do podwyższenia statusu społecznego i tendencji do przywództwa, a temperament cyklotymiczny może zwiększać kreatywność. Przytoczone są przykłady związku między stanem maniakalnym/hipomaniakalnym a zjawiskiem emigracji oraz wpływem na rozwój społeczeństwa amerykańskiego.
... Given that torpor is thought to be an energy-preserving mechanism, it makes sense that the energy spent should be minimized during the whole process, including its exit. Moreover, before they get access to food after arousal, most of the hibernators and daily torpids shall become active (Hume et al. 2002;Cotton and Harlow 2010;Tøien et al. 2011;Gao et al. 2012;Hindle et al. 2015) and, thus, need their energy storages to not be completely exhausted (Dausmann and Warnecke 2016; Bartsiokas and Arsuaga 2020). ...
Torpor is used in small sized birds and mammals as an energy conservation trait. Considerable effort has been put towards elucidating the mechanisms underlying its entry and maintenance, but little attention has been paid regarding the exit. Firstly, we demonstrate that the arousal phase has a stereotyped dynamic: there is a sharp increase in metabolic rate followed by an increase in body temperature and, then, a damped oscillation in body temperature and metabolism. Moreover, the metabolic peak is around two-fold greater than the corresponding euthermic resting metabolic rate. We then hypothesized that either time or energy could be crucial variables to this event and constructed a model from a collection of first principles of physiology, control engineering and thermodynamics. From the model, we show that the stereotyped pattern of the arousal is a solution to save both time and energy. We extended the analysis to the scaling of the use of torpor by endotherms and show that variables related to the control system of body temperature emerge as relevant to the arousal dynamics. In this sense, the stereotyped dynamics of the arousal phase necessitates a certain profile of these variables which is not maintained as body size increases.
... The reality is that different species of humans, like other animals, often adapt in different directions. One fascinating example is the possibility that Neanderthals hibernated (Bartsiokas and Arsuaga 2020). This is far from a ridiculous suggestion as Neanderthals may have adapted to resource shortfalls much like the fat-tailed dwarf lemur. ...
In Hidden Depths, Professor Penny Spikins explores how our emotional connections have shaped human ancestry. Focusing on three key transitions in human origins, Professor Spikins explains how the emotional capacities of our early ancestors evolved in response to ecological changes, much like similar changes in other social mammals. For each transition, dedicated chapters examine evolutionary pressures, responses in changes in human emotional capacities and the archaeological evidence for human social behaviours. Starting from our earliest origins, in Part One, Professor Spikins explores how after two million years ago, movement of human ancestors into a new ecological niche drove new types of collaboration, including care for vulnerable members of the group. Emotional adaptations lead to cognitive changes, as new connections based on compassion, generosity, trust and inclusion also changed our relationship to material things. Part Two explores a later key transition in human emotional capacities occurring after 300,000 years ago. At this time changes in social tolerance allowed ancestors of our own species to further reach out beyond their local group and care about distant allies, making human communities resilient to environmental changes. An increasingly close relationship to animals, and even to cherished possessions, appeared at this time, and can be explained through new human vulnerabilities and ways of seeking comfort and belonging. Lastly, Part Three focuses on the contrasts in emotional dispositions arising between ourselves and our close cousins, the Neanderthals. Neanderthals are revealed as equally caring yet emotionally different humans, who might, if things had been different, have been in our place today. This new narrative breaks away from traditional views of human evolution as exceptional or as a linear progression towards a more perfect form. Instead, our evolutionary history is situated within similar processes occurring in other mammals, and explained as one in which emotions, rather than ‘intellect’, were key to our evolutionary journey. Moreover, changes in emotional capacities and dispositions are seen as part of differing pathways each bringing strengths, weaknesses and compromises. These hidden depths provide an explanation for many of the emotional sensitivities and vulnerabilities which continue to influence our world today.
... They seem to have benefited from physical adaptations to their particular environments and ecology that are notably different, such as increased levels of brown fat (Sazzini et al. 2014) and adaptations to a high protein diet (Ben-Dor et al. 2016), and seem to have been better suited to short sprints rather than running for long periods (Higgins and Ruff 2011). They may even have undergone something similar to hibernation to escape resource shortages in winter months (Bartsiokas and Arsuaga 2020). Their brains also developed differently (Gunz et al. 2010). ...
In Hidden Depths, Professor Penny Spikins explores how our emotional connections have shaped human ancestry. Focusing on three key transitions in human origins, Professor Spikins explains how the emotional capacities of our early ancestors evolved in response to ecological changes, much like similar changes in other social mammals. For each transition, dedicated chapters examine evolutionary pressures, responses in changes in human emotional capacities and the archaeological evidence for human social behaviours. Starting from our earliest origins, in Part One, Professor Spikins explores how after two million years ago, movement of human ancestors into a new ecological niche drove new types of collaboration, including care for vulnerable members of the group. Emotional adaptations lead to cognitive changes, as new connections based on compassion, generosity, trust and inclusion also changed our relationship to material things. Part Two explores a later key transition in human emotional capacities occurring after 300,000 years ago. At this time changes in social tolerance allowed ancestors of our own species to further reach out beyond their local group and care about distant allies, making human communities resilient to environmental changes. An increasingly close relationship to animals, and even to cherished possessions, appeared at this time, and can be explained through new human vulnerabilities and ways of seeking comfort and belonging. Lastly, Part Three focuses on the contrasts in emotional dispositions arising between ourselves and our close cousins, the Neanderthals. Neanderthals are revealed as equally caring yet emotionally different humans, who might, if things had been different, have been in our place today. This new narrative breaks away from traditional views of human evolution as exceptional or as a linear progression towards a more perfect form. Instead, our evolutionary history is situated within similar processes occurring in other mammals, and explained as one in which emotions, rather than ‘intellect’, were key to our evolutionary journey. Moreover, changes in emotional capacities and dispositions are seen as part of differing pathways each bringing strengths, weaknesses and compromises. These hidden depths provide an explanation for many of the emotional sensitivities and vulnerabilities which continue to influence our world today.
... If Smith et al.'s (2018) findings reflect a wider pattern this could indicate over-wintering when substantially reduced mobility helped balance energetic demands of late-term gestation, birth, and lactation (Nowell, 2021). Claims for species-wide physiological hibernation (Bartsiokas & Arsuaga, 2020) however, are hard to reconcile with evidence of some winter hunting and movement. ...
Despite a remarkably persistent pop culture image of Neanderthals as semi-upright, hairy, cavemen wielding clubs, science provides us with a different picture. There is no doubt that the evolutionary forces that shaped Neanderthals and Homo sapiens differed, but recent evidence of interbreeding tells us that our anatomy and physiology were compatible and differences in physical appearance were not an obstacle to social interaction. Similarities in growth and development indicate that, like us, Neanderthals also gave birth to helpless young, and imply complex social lives necessary to support reproduction and protracted phases of offspring development. Of course, some uncertainty will always surround the behaviors of extinct species, but we can be sure that Neanderthals had sex and successfully reproduced for hundreds of thousands of years, and the archeological record and DNA evidence can illuminate behaviors that are invisible anatomically. In this chapter, we synthesize diverse data, theories, and models to reconsider aspects of Neanderthal sexual and reproductive behavior, and contextualize inferences within our current understanding of their physical characteristics, life-ways, and genomics.
... It seems most likely that humans would have required both controlled fire and tailored clothing to withstand the hyper-cold climate of Beringia (but see Bartsiokas and Arsuaga 2020). However, if Denisovans could survive in the mountains of Tibet, they might have had the necessary biological, if not cultural, adaptations for life in the Arctic. ...
The study of the peopling of the Americas has been transformed in the past decade by astonishing progress in paleogenomic research. Ancient genomes now show that Native American ancestors were formed in Siberia or the Amur region by admixture of ca. 15–30% Ancient North Eurasian genes with those of East Asians. The Anzick infant, buried with Clovis bifaces at 12,900 cal BP, belonged to a group that was ancestral to later Native Central and South Americans. Fishtail points, derived from Clovis, mark the arrival and rapid expansion of Clovis-descended Paleoindians across South America, also evident in the sharp increase of radiocarbon dates, continent-wide, at 13,000–12,500 cal BP. In both North and South America, extinction of most genera of megafauna was virtually simultaneous with Paleoindian expansion. Human hunting must have been involved, perhaps in concert with other indirect impacts. Contrary to the alternative bolide impact theory, there is no evidence of a dramatic human population decline after 12,800 cal BP. Ancient genomes show that divergent lithic traditions after 13,000 cal BP need not be attributed to a separate Pacific Rim migration stream. Several recent finds raise the possibility that pre-Clovis people might have reached the Americas before 20,000 cal BP, but these precursors must have either failed to thrive, or were ultimately replaced by proto-Clovis or Clovis people. Consilient paleogenomic and archaeological data indicate that initial colonization by Paleoindian ancestors of living Native Americans occurred after 14,500 cal BP.
... Likewise, a single-nucleotide polymorphism in the DIO2 gene of Neanderthals [53] that resulted in a decreased capacity for conversion of T4 to T3 could have affected key developmental programmes and could potentially explain the significant phenotypical differences between Neanderthals and Homo sapiens despite their closeness in terms of genetic ancestry [53,54]. Most importantly, this variant may have enabled Neanderthals to hibernate and survive long and cold winters [55] (if this evidence is further confirmed), but when archaic humans switched to a high-carbohydrate diet, the variant became disadvantageous, as it is associated with an increased risk of diabetes [56,57]. These findings strongly indicate that even small changes in TH signalling might have an enormous effect on development, growth, and metabolism, and should be of utmost significance for the adaptive responses of Homo sapiens to environmental changes. ...
Thyroid hormone (TH) signalling is a universally conserved pathway with pleiotropic actions that is able to control the development, metabolism, and homeostasis of organisms. Using evidence from paleoecology/palaeoanthropology and data from the physiology of modern humans, we try to assess the natural history of TH signalling and its role in human evolution. Our net thesis is that TH signalling has likely played a critical role in human evolution by facilitating the adaptive responses of early hominids to unprecedently challenging and continuously changing environments. These ancient roles have been conserved in modern humans, in whom TH signalling still responds to and regulates adaptations to present-day environmental and pathophysiological stresses, thus making it a promising therapeutic target.
... The induction of an induced torporlike state in humans, which has been suggested as a countermeasure for space travel as far back as the 1960s [18] would therefore effectively address both of the challenges outlined above, by minimising nutrient, O 2 and H 2 O consumption for long-term space travel and protecting against radiation damage [3,19]. Interestingly, a recent study of the bones of early humans shows evidence of seasonal variation in bone growth and patterns of lesions that are consistent with those found in hibernating mammals indicating that our ancestors may have adapted to hibernating during extreme cold periods [20]. While modern humans have ceased to employ hibernation as a survival mechanism, controlled therapeutic hypothermia has been used in medicine to successfully lower mortality rates and improve the neurological function of patients that have suffered from acute trauma, cardiac arrest or stroke [21]. ...
The development of the Artemis programme with the goal of returning to the moon is spurring technology advances that will eventually take humans to Mars and herald a new era of interplanetary space travel. However, long-term space travel poses unique challenges including exposure to ionising radiation from galactic cosmic rays and potential solar particle events, exposure to microgravity and specific nutritional challenges arising from earth independent exploration. Ionising radiation is one of the major obstacles facing future space travel as it can generate oxidative stress and directly damage cellular structures such as DNA, in turn causing genomic instability, telomere shortening, extracellular-matrix remodelling and persistent inflammation. In the gastrointestinal tract (GIT) this can lead to leaky gut syndrome, perforations and motility issues, which impact GIT functionality and affect nutritional status. While current countermeasures such as shielding from the spacecraft can attenuate harmful biological effects, they produce harmful secondary particles that contribute to radiation exposure. We hypothesised that induction of a torpor-like state would confer a radioprotective effect given the evidence that hibernation extends survival times in irradiated squirrels compared to active controls. To test this hypothesis, a torpor-like state was induced in zebrafish using melatonin treatment and reduced temperature, and radiation exposure was administered twice over the course of 10 days. The protective effects of induced-torpor were assessed via RNA sequencing and qPCR of mRNA extracted from the GIT. Pathway and network analysis were performed on the transcriptomic data to characterise the genomic signatures in radiation, torpor and torpor + radiation groups. Phenotypic analyses revealed that melatonin and reduced temperature successfully induced a torpor-like state in zebrafish as shown by decreased metabolism and activity levels. Genomic analyses indicated that low dose radiation caused DNA damage and oxidative stress triggering a stress response, including steroidal signalling and changes to metabolism, and cell cycle arrest. Torpor attenuated the stress response through an increase in pro-survival signals, reduced oxidative stress via the oxygen effect and detection and removal of misfolded proteins. This proof-of-concept model provides compelling initial evidence for utilizing an induced torpor-like state as a potential countermeasure for radiation exposure.
... Until we are able to more broadly understand the current variation of BAT across a range of climates and PALs, we will not be able to infer the potential thermoregulatory role this heat-producing tissue may have played among Neanderthals and potentially enabled Neanderthal hibernation. 135 Furthermore, determining the genetic underpinnings of BAT and other physiological cold climate adaptations (such as the hunting response) could prove highly valuable for identifying similar markers in Neanderthal ancient DNA. This exciting area of research will be critical for accurately assessing modern human and Neanderthal capacities for coping with cold climates. ...
A large body of work focuses on the unique aspects of Neanderthal anatomy, inferred physiology, and behavior to test the assumption that Neanderthals were hyper‐adapted to living in cold environments. This research has expanded over the years to include previously unexplored and potentially adaptive features such as brown adipose tissue and fire‐usage. Here we review the current state of knowledge of Neanderthal cold adaptations along morphological, physiological, and behavioral lines. While highlighting foundational as well as recent work, we also emphasize key areas for future research. Despite thriving in a variety of climates, it is well‐accepted that Neanderthals appear to be the most cold‐adapted of known fossil hominin groups; however, there are still many unknowns. There is a great deal yet to be uncovered about the nature and manifestation of Neanderthal adaptation and how the synergy of biology and culture helped buffer them against extreme and variable environments.
Genes of Neanderthal ancestry are believed to have become incorporated in the modern Homo sapiens genome via hybridisation and introgression. Although the majority have been eliminated from the population by natural selection due to Dobzhansky–Muller incompatibilities, some of them nevertheless remain, suggesting they have been selected for and have some adaptive value. The current work examines hypotheses explaining the emergence of depressive symptoms and disorders from an evolutionary standpoint. Neither the incentive hypothesis nor any social hypothesis (social position hypothesis, attachment hypothesis, social navigation hypothesis) accommodates any evidence of archaic introgression. However, the immunological hypothesis, corroborated by a considerable body of research, treats depressive symptoms as part of immunologic response. According to the hypothesis, infections have placed a considerable selective pressure on humans. Upon arrival in Eurasia from Africa, Homo sapiens was confronted with unknown pathogenic microorganisms. In contrast, the Neanderthals populating Eurasia had already been adapting to them for millennia. Introgression of Neanderthal man alleles of genes associated with the immunological response has already been demonstrated in Homo sapiens, and may well increase the fitness of newcomers. Such inclusion of genes connected with depressive symptoms may explain why archaic alleles are still present in the gene pool of modern humans.
Found in all organisms, pyruvate dehydrogenase complexes (PDC) are the keystones of prokaryotic and eukaryotic energy metabolism. In eukaryotic organisms these multi-component megacomplexes provide a crucial mechanistic link between cytoplasmic glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle. As a consequence, PDCs also influence the metabolism of branched chain amino acids, lipids and, ultimately, oxidative phosphorylation (OXPHOS). PDC activity is an essential determinant of the metabolic and bioenergetic flexibility of metazoan organisms in adapting to changes in development, nutrient availability and various stresses that challenge maintenance of homeostasis. This canonical role of the PDC has been extensively probed over the past decades by multidisciplinary investigations into its causal association with diverse physiological and pathological conditions, the latter making the PDC an increasingly viable therapeutic target. Here we review the biology of the remarkable PDC and its emerging importance in the pathobiology and treatment of diverse congenital and acquired disorders of metabolic integration.
The interface of sexual behavior and evolutionary psychology is a rapidly growing domain, rich in psychological theories and data as well as controversies and applications. With nearly eighty chapters by leading researchers from around the world, and combining theoretical and empirical perspectives, The Cambridge Handbook of Evolutionary Perspectives on Sexual Psychology is the most comprehensive and up-to-date reference work in the field. Providing a broad yet in-depth overview of the various evolutionary principles that influence all types of sexual behaviors, the handbook takes an inclusive approach that draws on a number of disciplines and covers nonhuman and human psychology. It is an essential resource for both established researchers and students in psychology, biology, anthropology, medicine, and criminology, among other fields. Volume 4: Controversies, Applications, and Nonhuman Primate Extensions addresses controversies and unresolved issues; applications to health, law, and pornography; and non-human primate evolved sexual psychology.
Pleistocene climatic fluctuations could play an important role in the development of the human phylogenetic line of Neanderthals. The aim of this study was to model how the climate-based physiological, cognitive, and vector-borne disease risk stressors for humans could vary in Europe by area and time from the Lower Palaeolithic era to the extinction of Neanderthals. For this purpose, the climatic requirements of the ancient humans were reconstructed based on the Early, Middle and Upper Palaeolithic occurrences of humans in Europe and its wider geographical environment for 8 Palaeolithic times and further six health and cold adaptation-related factors were also modelled. The adaptation of European human populations to the cool and volatile Pleistocene climate of Europe could gradually happen. While the Middle Palaeolithic humans in Europe lived in areas with long and medium-long vegetation periods and low or middle January mortality risk, in the late Palaeolithic the Neanderthal populations may have settled in areas with short ones. In January, these northern regions in the Late Palaeolithic era could be characterized by relatively high mortality risk. While the ancient humans of the Middle Palaeolithic era lived in such regions where the length of the thermal comfort season could be relatively long, the late Pleistocene humans of Europe occupied such regions where the thermal comfort season could be very short, and these humans should cover a large part of their body surface. However, the model results suggest that both humans of the Middle and Late Palaeolithic era should wear clothes in the coldest period of the winter in Europe. The Upper Palaeolithic populations could be less affected by such tick-borne diseases as Lyme borreliosis than the Early or the Middle Palaeolithic populations.
In this chapter, the diversity of heterotherms, where they live and how they differ from each other is covered in detail. When data from free-ranging animals were available these were used preferentially, but information on captive animals is also included. As the extent of available data differs substantially among taxa, the information provided reflects what is known about a specific group to a large extent. To put the information on heterothermic endotherms into context with other organisms, I will address terrestrial ectotherms first.
After 34 years of research and findings in the Middle Pleistocene site of the Sima de los Huesos (SH) of the Sierra de Atapuerca (Burgos, Spain), we present an update of the estimation of the number of individuals (ENI) identified in the SH hominin assemblage. The last ENI, published in 2004, was 28. Although the number of specimens recovered has almost doubled since then and more complete information is now available, this new analysis suggests that the ENI is 29. Some individuals are still represented by only one or a few teeth and the upper and lower jaws of various individuals have not been completed. We suggest that the amateur cavers, who accessed the SH site for years looking for bear fossils, destroyed a significant number of hominin fossils. Despite this, we have a good picture of the group of hominins represented in the SH assemblage. Because complete corpses were accumulated in SH and it is a closed cavity, it is expected that a significant number of hominin fossils remains to be discovered. According to the previous estimates, the representation of females is greater than that of males. However, the observed sex ratio is not significantly different from the 1:1 ratio. With the exception of the possible presence of a child individual, most of the remaining 28 individuals are teenagers or young adults (24/28 = 0.857). The ages of death of SH hominins appear to conform to a catastrophic profile.
Neanderthals are a Late Pleistocene hominin adapted to cool high‐latitudes environments. Popular views on how Neanderthals adapted to these environments have changed over time. While once thought of as a largely scavenging hominin, Neanderthals are now accepted to be competent hunters who sourced a major part of their nutrition from ungulates. Neanderthal diet appears to be highly terrestrial but there are difficulties ruling out a contribution of marine foods in many regions. While the important role of large and medium ungulates in debates about Neanderthal diet has largely been settled, recent discussions about Neanderthal diet have explored the extent of their diet varied, the role of minor foods (plant, small mammal and marine foods) and dietary flexibility.
Key Concepts
• Zooarchaeology mortality profiles show Neanderthals were competent hunters.
• Neanderthals predominantly relied on large‐ and medium‐sized ungulates.
• There is little clear evidence of Neanderthal hunting methods, important but this is also the case for the earliest modern human in Europe. Neanderthals appear to have relied on thrown or thrusted spears, which were both hafted and unhafted.
• Plants played a crucial role in diet, even though meat was nutritionally much more important.
• Important questions remain concerning how diet was processed and how much diet varied.
Three adaptive hypotheses have been forwarded to explain the distinctive Neanderthal face: (i) an improved ability to accommodate high anterior bite forces, (ii) more effective conditioning of cold and/or dry air and, (iii) adaptation to facilitate greater ventilatory demands. We test these hypotheses using three-dimensional models of Neanderthals, modern humans, and a close outgroup (Homo heidelbergensis), applying finite-element analysis (FEA) and computational fluid dynamics (CFD). This is the most comprehensive application of either approach applied to date and the first to include both. FEA reveals few differences between H. heidelbergensis, modern humans, and Neanderthals in their capacities to sustain high anterior tooth loadings. CFD shows that the nasal cavities of Neanderthals and especially modern humans condition air more efficiently than does that of H. heidelbergensis, suggesting that both evolved to better withstand cold and/or dry climates than less derived Homo. We further find that Neanderthals could move considerably more air through the nasal pathway than could H. heidelbergensis or modern humans, consistent with the propositions that, relative to our outgroup Homo, Neanderthal facial morphology evolved to reflect improved capacities to better condition cold, dry air, and, to move greater air volumes in response to higher energetic requirements.
A recent study conducted the first genome-wide scan for selection in Inuit from Greenland using SNP chip data. Here, we report that selection in the region with the second most extreme signal of positive selection in Greenlandic Inuit favored a deeply divergent haplotype that is closely related to the sequence in the Denisovan genome, and was likely introgressed from an archaic population. The region contains two genes, WARS2 and TBX15, and has previously been associated with adipose tissue differentiation and body-fat distribution in humans. We show that the adaptively introgressed allele has been under selection in a much larger geographic region than just Greenland. Furthermore, it is associated with changes in expression of WARS2 and TBX15 in multiple tissues including the adrenal gland and subcutaneous adipose tissue, and with regional DNA methylation changes in TBX15.
The fossil population structure of the cave bear from the Mokrica cave was evaluated to provide new data concerning the behaviour and mortality of this extinct species. Age at death was estimated for 128 different individuals by analysing cementum increments, root formation and crown wear of left M, teeth. After the frequency distribution of specimens through one-year intervals, the mortality trends can be estimated for various lifetime periods, and interpreted in accordance with data for present-day bears. The original death assemblage was presumably juvenile-dominated. Extremely fragile molars of less than 6 month old cubs did not get preserved. Yearlings are the most numerous age class in the fossil population from the Mokrica cave. Mortality drastically dropped after cave bears survived their first hibernation in the second winter. The lowest mortality rate was observed in the 9-15 years age group, when cave bears would be expected to be in their prime. The oldest age recorded by cementum analysis is approximately 30 years, which indicates that the maximum life span was similar to present-day bears. Study of dental tissues shows that the mortality in the cave was seasonally restricted - the majority of deaths in the cave occured during winter and in early spring. Sex structure of the fossil population has been studied on the sample of 750 canines. The significantly higher proportion of mates in the group of older juveniles and subadults could be explained by the fact that the weaning period is more critical for mates also in present-day bears. In young adults and prime adults the mortality was presumably higher in females. The sex structure of adult bears, especially in the sample of older individuals, indicates that the Mokrica cave was used as winter den mostly by solitary males.
A genetic mutation in prehistoric apes may underlie today's pandemic of obesity and diabetes
The indigenous people of Greenland, the Inuit, have lived for a long time in the extreme conditions of the Arctic, including
low annual temperatures, and with a specialized diet rich in protein and fatty acids, particularly omega-3 polyunsaturated
fatty acids (PUFAs). A scan of Inuit genomes for signatures of adaptation revealed signals at several loci, with the strongest
signal located in a cluster of fatty acid desaturases that determine PUFA levels. The selected alleles are associated with
multiple metabolic and anthropometric phenotypes and have large effect sizes for weight and height, with the effect on height
replicated in Europeans. By analyzing membrane lipids, we found that the selected alleles modulate fatty acid composition,
which may affect the regulation of growth hormones. Thus, the Inuit have genetic and physiological adaptations to a diet rich
in PUFAs.
Significance
The middle Pleistocene Sima de los Huesos (SH) fossil collection provides the rare opportunity to thoroughly characterize the postcranial skeleton in a fossil population, comparable only to that obtained in the study of the Neandertal hypodigm and recent (and fossil) modern humans. The SH paleodeme can be characterized as relatively tall, wide, and muscular individuals, who are less encephalized than both Neandertals and modern humans. Some (but not all) Neandertal derived traits are present, which phylogenetically links this population with Neandertals. Thus, the full suite of Neandertal features did not arise all at once, and the evolution of the postcranial skeleton could be characterized as following a mosaic pattern.
Evidence of interpersonal violence has been documented previously in Pleistocene mem- bers of the genus Homo, but only very rarely has this been posited as the possible manner of death. Here we report the earliest evidence of lethal interpersonal violence in the hominin fossil record. Cranium 17 recovered from the Sima de los Huesos Middle Pleistocene site shows two clear perimortem depression fractures on the frontal bone, interpreted as being produced by two episodes of localized blunt force trauma. The type of injuries, their location, the strong similarity of the fractures in shape and size, and the different orientations and im- plied trajectories of the two fractures suggest they were produced with the same object in face-to-face interpersonal conflict. Given that either of the two traumatic events was likely lethal, the presence of multiple blows implies an intention to kill. This finding shows that the lethal interpersonal violence is an ancient human behavior and has important implications for the accumulation of bodies at the site, supporting an anthropic origin.
It is eighteen years since the human fossils recovered from the TD6 level of the Gran Dolina cave site, in Sierra de Atapuerca (Burgos, northern Spain) were assigned to a new hominin species, Homo antecessor. This review summarizes the main results obtained from the study of these fossils during this period. The increase of the African and Eurasian fossil record, as well as the application of new methodological approaches, has led to competing interpretations about its hypothetical phylogenetic position and possible evolutionary scenarios. At present, we can argue that this species is defined by a unique mosaic of primitive traits for the Homo clade, a certain number of derived features present in modern humans, a significant suite of derived features shared with Neandertals and their ancestors in the European Middle Pleistocene (in particular with the Atapuerca-Sima de los Huesos hominins), and some derived features shared with the Chinese Middle Pleistocene hominins. From this evidence, we suggest that a speciation event could have occurred in Africa/Western Eurasia, originating a new Homo clade. Homo antecessor, most probably dated to the MIS 21, could be a side branch of this clade placed at the westernmost region of the Eurasian continent.
We present the case of a preterm 6-month-old African American infant who developed craniosynostosis secondary to rickets. This child developed rickets and macrocephaly by the age of 6 months. His head continued to enlarge, and a 3D CT obtained when the child was 2 years old revealed metopic and bilateral coronal craniosynostosis. This CT suggested increased intracranial pressure, and therefore, corrective cranial vault reconstruction was performed. Craniosynostosis secondary to rickets is rarely reported, but since neither rickets nor craniosynostosis is a reportable disease, the exact incidence of both diseases is unknown. Craniosynostosis should be suspected in any rachitic child with an abnormal head circumference or shape and craniofacial CT evaluation should be performed, so that a corrective surgery can be performed at an appropriate age.
As modern humans migrated out of Africa, they encountered many new environmental conditions, including greater temperature extremes, different pathogens and higher altitudes. These diverse environments are likely to have acted as agents of natural selection and to have led to local adaptations. One of the most celebrated examples in humans is the adaptation of Tibetans to the hypoxic environment of the high-altitude Tibetan plateau. A hypoxia pathway gene, EPAS1, was previously identified as having the most extreme signature of positive selection in Tibetans, and was shown to be associated with differences in haemoglobin concentration at high altitude. Re-sequencing the region around EPAS1 in 40 Tibetan and 40 Han individuals, we find that this gene has a highly unusual haplotype structure that can only be convincingly explained by introgression of DNA from Denisovan or Denisovan-related individuals into humans. Scanning a larger set of worldwide populations, we find that the selected haplotype is only found in Denisovans and in Tibetans, and at very low frequency among Han Chinese. Furthermore, the length of the haplotype, and the fact that it is not found in any other populations, makes it unlikely that the haplotype sharing between Tibetans and Denisovans was caused by incomplete ancestral lineage sorting rather than introgression. Our findings illustrate that admixture with other hominin species has provided genetic variation that helped humans to adapt to new environments.
Seventeen Middle Pleistocene crania from the Sima de los Huesos site (Atapuerca, Spain)
are analyzed, including seven new specimens. This sample makes it possible to thoroughly
characterize a Middle Pleistocene hominin paleodeme and to address hypotheses
about the origin and evolution of the Neandertals. Using a variety of techniques, the
hominin-bearing layer could be reassigned to a period around 430,000 years ago.
The sample shows a consistent morphological pattern with derived Neandertal features
present in the face and anterior vault, many of which are related to the masticatory
apparatus. This suggests that facial modification was the first step in the evolution of
the Neandertal lineage, pointing to a mosaic pattern of evolution, with different anatomical
and functional modules evolving at different rates.
Excavations of a complex of caves in the Sierra de Atapuerca in northern Spain have unearthed hominin fossils that range in age from the early Pleistocene to the Holocene. One of these sites, the 'Sima de los Huesos' ('pit of bones'), has yielded the world's largest assemblage of Middle Pleistocene hominin fossils, consisting of at least 28 individuals dated to over 300,000 years ago. The skeletal remains share a number of morphological features with fossils classified as Homo heidelbergensis and also display distinct Neanderthal-derived traits. Here we determine an almost complete mitochondrial genome sequence of a hominin from Sima de los Huesos and show that it is closely related to the lineage leading to mitochondrial genomes of Denisovans, an eastern Eurasian sister group to Neanderthals. Our results pave the way for DNA research on hominins from the Middle Pleistocene.
A review of the topic, along with a case report illustrating dramatic radiographic changes in the mandible of a patient on long term hemodialysis
It is generally accepted that the earliest human ancestors grew more like apes than like humans today. If they did so, and we are now different, when, how and why did our modern growth patterns evolve? Originally published in 2003, this book focuses on species within the genus Homo to investigate the evolutionary origins of characteristic human patterns and rates of craniofacial and postcranial growth and development, and to explore unique ontogenetic patterns within each fossil species. Experts examine growth patterns found within available Plio-Pleistocene hominid samples, and analyse variation in ontogenetic patterns and rates of development in recent modern humans in order to provide a comparative context for fossil hominid studies. Presenting studies of some of the newer juvenile fossil specimens and information on Homo antecessor, this book will provide a rich data source with which anthropologists and evolutionary biologists can address the questions posed above.
Recent chronological studies of the Sima de los Huesos (SH) hominin fossil site, Atapuerca, Spain, have established a close minimum age of at least 430 ka for sedimentary material immediately overlying the human remains. However, a firm maximum age limit still needs to be established for the SH fossils in order to better constrain the timing for the onset of Neandertal speciation. In the present study, we address this important chronological gap at SH by providing direct ages for the sediment deposits that host, and immediately underlie, the hominin fossils. Depositional ages were obtained using single-grain thermally-transferred optically stimulated luminescence (TT-OSL), a technique that has yielded reliable ‘extended-range’ luminescence chronologies at several independently dated Atapuerca sites. Four single-grain TT-OSL depositional ages of 453 ± 56 ka, 437 ± 38 ka, 457 ± 41 ka and 460 ± 39 ka were obtained for the red clay lithostratigraphic units (LU-5 and LU-6) found underlying and encasing the SH hominin bones. A Bayesian age-depth model was constructed using previously published chronologies, as well as the new single-grain TT-OSL ages for LU-5 and LU-6, in order to derive combined age estimates for individual lithostratigraphic units preserved at SH. The combined modeled ranges reveal that the hominin-bearing layer (LU-6) was deposited between 455 ± 17 ka and 440 ± 15 ka (mean lower and upper boundary 68.2% probability range ± 1σ uncertainty, respectively), with a mean age of 448 ± 15 ka. These new bracketing ages suggest that the hominin fossils at SH were most likely deposited within Marine Isotope Stage (MIS) 12, enabling more precise temporal constraint on the early evolution of the Neandertal lineage. The SH fossils represent the oldest reliably dated hominin remains displaying Neandertal features across Eurasia. These Neandertal features are first observed in the facial skeleton, including the mandible and teeth, as well as the temporomandibular joint, and appear consistently across the SH collection. Our chronological findings suggest that the appearance of these Neandertal traits may have been associated with the climatic demise of MIS 12 and the ecological changes that occurred in Iberia during this period. Other Middle Pleistocene hominin fossils from Europe dated to MIS 12–11, or later, show different morphological trends, with some lacking Neandertal specializations. The latest SH dating results enable improved temporal correlations with these contrasting hominin records from Europe, and suggest a complex picture for hominin evolution during the Middle Pleistocene.
Nutritional rickets remains a global public health problem, despite effective and inexpensive means to prevent and treat the disease. It is most prevalent in the infant/toddler age groups and the adolescent, but vitamin D deficiency is also prevalent in women of child bearing age, resulting in babies being born with low vitamin D stores and the mothers having inadequate vitamin D in breast milk, thus exacerbating the risk for rickets in these infants. In a number of subtropical developing countries, rickets appears to be due to low-dietary calcium intakes (?200. mg/day) rather than vitamin D deficiency. Biochemically these children are differentiated from those with vitamin D deficiency by having markedly elevated serum 1,25-dihydroxyvitamin D concentrations and high fractional intestinal calcium absorption. Nutritional rickets represents the outcome of a spectrum of causes ranging from vitamin D deficiency on one hand to dietary calcium deficiency on the other, while in between low dietary intakes and vitamin D insufficiency combine to cause the disease.
Description:
The Kidney Disease: Improving Global Outcomes (KDIGO) 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) is a selective update of the prior CKD-MBD guideline published in 2009. The guideline update and the original publication are intended to assist practitioners caring for adults with CKD and those receiving long-term dialysis.
Methods:
Development of the guideline update followed an explicit process of evidence review and appraisal. The approach adopted by the Work Group and the evidence review team was based on systematic reviews of relevant trials, appraisal of the quality of the evidence, and rating of the strength of recommendations according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Searches of the English-language literature were conducted through September 2015 and were supplemented with targeted searches through February 2017. Final modification of the guidelines was informed by a public review process involving numerous stakeholders, including patients, subject matter experts, and industry and national organizations.
Recommendations:
The update process resulted in the revision of 15 recommendations. This synopsis focuses primarily on recommendations for diagnosis of and testing for CKD-MBD and treatment of CKD-MBD that emphasizes decreasing phosphate levels, maintaining calcium levels, and addressing elevated parathyroid hormone levels in adults with CKD stage G3a to G5 and those receiving dialysis. Key elements include basing treatment on trends in laboratory values rather than a single abnormal result and being cautious to avoid hypercalcemia when treating secondary hyperparathyroidism.
Mineralization of bone matrix depends on adequate supplies of not only vitamin D but also calcium and phosphorus and the presence of alkaline phosphatase and a normal pH. If there is deficiency of these substances for any reason or if there is severe acidosis, then mineralization of bone will be defective. This results in rickets in childhood and osteomalacia in adults. Radiographically, rickets is evident by bone deformity caused by softening and metaphyseal abnormalities where endochondral ossification is defective. The pathognomonic feature of osteomalacia is the Looser zone (pseudofracture).Many different diseases that result in rickets and osteomalacia (vitamin D deficiency, calcium deficiency, hypophosphatemia, hypophosphatasia, and acidemia) may have similar radiographic appearances. There may be distinguishing features (e.g., dense bones and extraskeletal ossification in X-linked hypophosphatemia (XLH); subperiosteal bone erosions in hyperparathyroidism secondary to vitamin D deficiency; arterial and soft tissue calcification related to phosphate retention in chronic kidney disease).Radiographs remain the most important imaging technique for the diagnosis of metabolic bone disease. Radionuclide scanning and other techniques (ultrasound, computed tomography, magnetic resonance imaging) have a role in localizing tumors that produce fibroblastic growth factor 23 and induce hypophosphatemic ("oncogenic") osteomalacia; Ga-68 DOTATOC positron emission tomography/computed tomography is currently the optimum imaging technique for localizing such tumors. In some cases (two tumor sites demonstrated) venous hormone sampling may provide further localizing information. Multidetector computed tomography is well suited to demonstrate the intraspinal ossification, which is a rare, but recognized, complication of the enthesopathy associated with XLH osteomalacia.
The alterations of urine flow and composition during hypothermia were studied in unanesthetized rats and ground squirrels. One ureter or the urethra was cannulated in some animals for continuous urine collection. Within 5–10 minutes of the onset of cooling, the urine flow diminished to an almost immeasurable level and then recovered to a level lower than the precooling one. This diminution may be due to the stimulation of the sympathetic nervous system. As the body temperature was further lowered, urine flow progressively decreased. Both water and solute diuresis, if already under way before the onset of hypothermia, were also reduced during hypothermia without increase in solute concentration. However, any infusion of fluid during hypothermia augmented the urine flow. This augmented urine flow was not inhibited by injected Pituitrin. During hypothermia the renal blood flow was quantitatively greatly reduced, while the changes in the hematocrit ratio or in the refractive index of plasma were not consistent. These facts suggest that decrease in glomerular filtration rate, which follows the reduction in renal blood flow, may be the main cause for this great reduction in urine flow during hypothermia. The solute concentration of the urine formed during hypothermia was more independent of the urine flow, so that the normal volume-concentration relationship is upset, suggesting that water and solute reabsorptions are dissociated. When 0.50 m NaCl solution was infused during hypothermia, a large amount of dilute urine was excreted, probably due to the inability of tubules to reabsorb the water and chloride loads presented. The hypothermic animals also failed to concentrate urea in the urine. Reducing substances were excreted. The excretion of phenolsulfonephthalein (PSP), in terms either of the percentage return in the urine after intravenous administration or of the blood plasma clearance, was also lowered during hypothermia. Urine/plasma concentration ratio of chloride or PSP was lower during hypothermia. These suggest that tubular functions, both reabsorptive and secretory, are depressed during hypothermia. During hibernation the urine flow was similarly slow and the urine was dilute.
Assessment of development is an important component of age estimation in juveniles. One area that has not been fully investigated as a possible aging method is the development of the frontal sinus. The frontal sinuses form when the ectocranial table of the frontal bone separates from the endocranial table forming an air pocket in the bone. The endocranial table ceases growth with the brain, while the ectocranial table is displaced anteriorly as the facial bones continue growth. In order to examine growth and the utility of the frontal sinuses for age estimation, 392 radiographs were examined (♀=159 and ♂=233) from the Juvenile Radiograph Database at North Carolina State University and the Patricia Database from Mercyhurst University. The sample included individuals who range in age from 0 to 18 years old. Anterior view radiographs were examined and were then grouped based upon the presence or absence of the frontal sinus. Based on this, individuals were divided into four age categories. A one-way ANOVA was performed to test whether developmental phase was related to age. Results from the ANOVA show that developmental phase is significantly related to age (p <.0001). An ordinal logistic regression was conducted to examine whether developmental phase could be used to predict age. The results of the logistic regression suggest that developmental phase is an accurate indicator of age (p <.0001, df = 1, Chi-Squared = 537.2428); however, the age ranges received can be quite wide and should be utilized alongside other established methods of age estimation. This article is protected by copyright. All rights reserved.
The definition and classification of chronic kidney disease (CKD) have evolved over time, but current international guidelines define this condition as decreased kidney function shown by glomerular filtration rate (GFR) of less than 60 mL/min per 1·73 m², or markers of kidney damage, or both, of at least 3 months duration, regardless of the underlying cause. Diabetes and hypertension are the main causes of CKD in all high-income and middle-income countries, and also in many low-income countries. Incidence, prevalence, and progression of CKD also vary within countries by ethnicity and social determinants of health, possibly through epigenetic influence. Many people are asymptomatic or have non-specific symptoms such as lethargy, itch, or loss of appetite. Diagnosis is commonly made after chance findings from screening tests (urinary dipstick or blood tests), or when symptoms become severe. The best available indicator of overall kidney function is GFR, which is measured either via exogenous markers (eg, DTPA, iohexol), or estimated using equations. Presence of proteinuria is associated with increased risk of progression of CKD and death. Kidney biopsy samples can show definitive evidence of CKD, through common changes such as glomerular sclerosis, tubular atrophy, and interstitial fibrosis. Complications include anaemia due to reduced production of erythropoietin by the kidney; reduced red blood cell survival and iron deficiency; and mineral bone disease caused by disturbed vitamin D, calcium, and phosphate metabolism. People with CKD are five to ten times more likely to die prematurely than they are to progress to end stage kidney disease. This increased risk of death rises exponentially as kidney function worsens and is largely attributable to death from cardiovascular disease, although cancer incidence and mortality are also increased. Health-related quality of life is substantially lower for people with CKD than for the general population, and falls as GFR declines. Interventions targeting specific symptoms, or aimed at supporting educational or lifestyle considerations, make a positive difference to people living with CKD. Inequity in access to services for this disease disproportionally affects disadvantaged populations, and health service provision to incentivise early intervention over provision of care only for advanced CKD is still evolving in many countries.
Rickets is a clinical syndrome that occurs in children as a result of a failure of or delay in mineralization of the growth plate of growing bones. There are numerous causes, the majority of which can be grouped into three major categories-those which primarily result in a failure to maintain normal calcium homeostasis; those which primarily affect phosphate homeostasis; and those which directly inhibit the mineralization process. Globally, rickets due to nutritional causes remains the most frequent form of the disease seen. Despite readily accessible and effective means to eradicate rickets globally, the disease remains a major public health problem in many countries, not only in temperate regions of the world but also in tropical and subtropical countries. In many developed countries, the promotion of exclusive breast-feeding during the first six months of life and the concerns about the long-term effect of sunlight exposure during this period have exacerbated the risks of vitamin D deficiency in the young infant. In some subtropical countries, social customs play an important role in preventing adequate vitamin D status not only in the young infant but also in the pregnant and lactating mother. In a number of developing countries, low dietary calcium intakes appear to play a major role in the pathogenesis of rickets in older children. Recent studies have helped to provide an all-embracing concept of the interaction of vitamin D and calcium intakes in the pathogenesis of rickets.
Vitamin D deficiency may occur as a consequence of simple nutritional deficiency, due to malabsorption states, chronic liver disease which affects hydroxylation at the 25 position, and chronic renal disease in which the active metabolite 1,25(OH)2D is not produced. Consequently, a large variety of diseases may result in vitamin D deficiency. Mineralization of bone matrix depends on the presence of adequate supplies of not only vitamin D, in the form of its active metabolite 1,25(OH)2D, but also calcium and phosphorus and the presence of alkaline phosphatase and a normal pH. If there is deficiency of these substances for any reason, or if there is severe acidosis, then mineralization of bone will be defective. This results in rickets in childhood and osteomalacia in adults. Radiographically, rickets is evident by bone deformity caused by softening and metaphyseal abnormalities where endochondral ossification is defective. Radiographs remain the most important imaging technique for the diagnosis of metabolic bone disease; radionuclide scans may be more sensitive for identifying Looser's zones (pseudofractures). Radionuclide scanning (indium-111-labeled ocreotide; PET CT) and other techniques (ultrasound, computed tomography, magnetic resonance imaging) have a role in localizing tumors that induce hypophosphatemic (oncogenic) osteomalacia. Multidetector computed tomography (MDCT) is particularly well suited to demonstrate the intraspinal ossification, which is a rare, but recognized, complication of the enthesopathy associated with XLH-linked osteomalacia.
Several evolutionary changes have led to uric acid levels being much higher in humans than in other mammals. Uric acid is the end product of purine metabolism in hominoids, including humans, due to the genetic loss of uricase activity during the Miocene epoch, and this is the main cause of the increased uric acid in hominoids. Additional factors that have contributed to increased levels of uric acid are the high renal tubular reabsorption of uric acid and the previous loss of the ability to synthesise vitamin C in hominoids. Several hypotheses have been proposed on the evolutionary advantage of increased serum uric acid levels in hominoids, although the biological reasons for this increase remain unclear. The large current increase in uric acid levels in humans in developed countries is mainly influenced by dietary factors and lifestyle changes.
Key Concepts
Uric acid (UA) is the end product of purine metabolism in humans due to the loss of uricase activity by various mutations of its gene during the Miocene epoch.
Loss of uricase activity led to humans having higher UA levels than other mammals.
The high renal tubular reabsorption of UA and the previous loss of the ability to synthesise vitamin C may have also contributed to increased levels of UA in humans.
The biological reason for the loss of uricase activity and increased levels of UA in humans and certain primates is unknown.
UA is one of the most important antioxidants in human biological fluids.
UA probably has neuroprotective activity.
The current large increase in UA levels in humans in developed countries is mainly influenced by eating habits and lifestyle changes.
Hyperuricaemia can cause gout and uric lithiasis, and is associated with hypertension, metabolic syndrome, renal disease and cardiovascular disease.
Radiologic skeletal surveys in 117 patients with severe chronic renal disease revealed periosteal neostosis (periosteal new bone formation) in 10 patients (8.5%). Periosteal neostosis occurred in varied locations and was always accompanied by subperiosteal resorption in finger bones, and in 9 of 10 cases by osteosclerotic changes in the central skeleton. The most common finding in iliac crest biopsies, obtained from 8 patients, was osteoid excess (osteomalacia). The combination of periosteal neostosis, subperiosteal resorption, osteosclerosis, and osteoid excess may be a manifestation of secondary hyperparathyroidism, with high bone turnover and sustained ability to produce mineralized bone.
The literature contains many articles on primary premature craniosynostosis (PCS). There are allusions to secondary PCS and some key articles are found in which PCS is attributed to some other disease entity or considered a part of another well known syndrome. Based on a review of the literature and our own cases, we have attempted to present the many conditions associated with or considered an integral part of PCS.
The resulting craniofacial deformities secondary to PCS are numerous and variable. The pathogenesis and etiology are really not known. Therefore, no one classification will satisfy every need. Our proposed classification is presented simply to call attention to the many conditions in which PCS has been found.
Information on craniosynostosis in this paper updates “Craniosynostosis: Diagnosis, Evaluation, and Management” (Cohen MM Jr: New York: Raven Press, 1986). It also discusses recent developments that were included in the book but need further explanation or emphasis. Subjects discussed are: epidemiology, etiology, sutural biology, growth and development, neurological and psychosocial aspects, surgery, cloverleaf skulls, craniosynostosis syndromes, and prenatal diagnosis. Under the subject of etiology, fetal head constraint, maternal thyroid disease, calcified cephalohematoma, teratogens, and delayed suture closure and Wormian bones are considered. An updating of 15 cloverleaf skull conditions includes four monogenic disorders, two chromosomal disorders, one disruption, one iatrogenic condition, and seven syndromes of unknown cause. Newly recognized disorders with cloverleaf skull include Beare-Stevenson cutis gyratum syndrome and Say-Poznanski syndrome. Craniosynostosis syndromes and associations discussed include acrocraniofacial dysostosis, Apert syndrome, Beare-Stevenson cutis gyratum syndrome, Calabro syndrome, calvarial hyperostosis, chromosomal craniostenosis, Cole-Carpenter type osteogenesis imperfecta, Crouzon syndrome, Curry-Jones syndrome, Curry variant of Carpenter syndrome, cutis aplasia and cranial stenosis, Fontaine-Farriaux syndrome, Gomex-López-Hernández syndrome, Hersh syndrome, hyper-IgE syndrome and craniostenosis, hypomandibular faciocranial dysostosis, Marfanoid features and craniostenosis, Pfeiffer-type cardiocranial syndrome, Pfeiffer-type dolichocephalosyndactyly, and Say-Barber syndrome.
Rickets and osteomalacia are the subadult and adult expressions of a disease in which the underlying problem is a failure to mineralize bone protein (osteoid). The most common cause of this disease is a physiological deficiency in vitamin D. The associated problems include deformed bones and this condition is well known in pre-modern medical texts and documents as a fairly common cause of morbidity. Given these facts, it is surprising that the literature on palaeopathology provides very little evidence of this disease in archaeological human skeletal samples.The medieval sample (N=687) of human remains from Wharram Percy, North Yorkshire, England contains a remarkable subsample of eight burials in which a spectrum of pathological features is expressed. The subsample includes infants ranging in age from 3 to 18 months at the time of death.Ten abnormal bone features were identified in the subsample, including: (i) cranial vault porosity; (ii) orbital roof porosity; (iii) deformation of the mandibular ramus; (iv) deformation of arm bones; (v) deformation of leg bones; (vi) flared costo-chondral ends of ribs; (vii) irregular and porous cortex of the costo-chondral ends of the ribs; (viii) abnormality of the growth plates of long bones; (ix) irregular and porous surfaces of the metaphyseal cortex; (x) thickening of the long bones, particularly in the metaphyseal areas. Not all of these features were found in all of the cases. Nevertheless, the overall pattern of skeletal abnormality fits well with the anatomical and radiological conditions associated with rickets. © 1998 John Wiley & Sons, Ltd.
The deposits of Biśnik Cave yielded numerous bear remains from sediments dated to the MIS 8–MIS 3 interval. This situation allowed examination of the paleoecology of Ursus spelaeus over time, compared with two other species of bears: Ursus deningeri and Ursus arctos, also present in fossil material from Biśnik Cave. The stable isotope ratios (δ13C, δ18O) in tooth enamel were applied in combination with examination of seasonal deposition of dental cementum. The δ13C values showed the diet of each bear species stayed in the range of C3 plants. Results for U. spelaeus showed a wider range of δ13C values than for U. deningeri or U. arctos. The values are relatively negative in comparison to fossil bears from other European sites. Low δ13C values observed in bears from Biśnik Cave could be linked to a canopy effect and document a forested environment for these bears. No correlation between δ18O and δ13C values was noted. The cementum analysis revealed that season of death of all species was winter and all studied specimens died during hibernation. The highest mortality concerned mostly individuals below 4 years old and the highest individual aged was U. deningeri.
The skull radiographs of 68 patients undergoing dialysis for chronic renal failure were reviewed for evidence of renal osteodystrophy. Four patients (6%) were positive and the unusually severe changes seen in one patient are described in detail. The changes seen in the skull in renal failure, both before and after treatment, are discussed.