Cervidae antlers exploited to manufacture prehistoric tools and hunting implements as a reliable source of ancient DNA.

Antler is one of the primary animal raw materials exploited for technical purposes by the hunter-gatherer groups of the Eurasian Upper Palaeolithic (UP) all over the ecological range of deers, and beyond. It was exhaustively employed to produce one of the most critical tools for the survival of the UP societies: hunting weapons. However, antler implements can be made from diverse deer taxa, with different ecological requirements and ethological behaviours. Identifying the antler's origin at a taxonomic level is thus essential in improving our knowledge of humans' functional, practical and symbolic choices, as well as the human-animal interface during Prehistoric times. Nevertheless, palaeogenetics analyses have focused mainly on bone and teeth, with genetic studies of antler generally focused on modern deer conservation. Here we present the results of the first whole mitochondrial genome ancient DNA (aDNA) analysis by means of in-solution hybridisation capture of antlers from pre-Holocene archaeological contexts. We analysed a set of 50 Palaeolithic and Neolithic (c. 34-8ka) antler and osseous objects from South-Western Europe, Central Europe, South-Western Asia and the Caucasus. We successfully obtained aDNA, allowing us to identify the exploited taxa and demonstrate the archaeological relevance of those finds. Moreover, as most of the antlers were sampled using a minimally-invasive method, further analyses (morphometric, technical, genetic, radiometric and more) remain possible on these objects.

More than urns: A multi-method pipeline for analyzing cremation burials.

Burial rites of archaeological populations are frequently interpreted based on cremated remains of the human body and the urn they were deposited in. In comparison to inhumations, information about the deceased is much more limited and dependent on fragmentation, selection of body regions, taphonomic processes, and excavation techniques. So far, little attention has been paid to the context in which urns are buried. In this study, we combined archaeological techniques with anthropology, computed tomography, archaeobotany, zooarchaeology, geochemistry and isotopic approaches and conducted a detailed analysis on a case study of two Late Bronze Age urns from St. Pölten, Austria (c. 1430 and 1260 cal. BCE). The urns were recovered en-bloc and CT-scanned before the micro-excavation. Osteological and strontium isotope analysis revealed that the cremated remains comprised a young adult female and a child that died at the age of 10-12 years. Both individuals had been subject to physiological stress and were likely local. Animal bones burnt at different temperatures suggested different depositional pathways into the urn and pit as part of the pyre, food offerings, and unintentional settlement debris. Eight wild plant and five crop plant species appeared as part of the local landscape, as food offerings and fire accelerants. Sediment chemistry suggests that pyre remains were deposited around the urns during burial. Multi-element geochemistry, archaeobotany, and zooarchaeology provide insights into the Late Bronze Age environment, the process of cremation, the gathering of bones and final funerary deposition.

A 41,500 year-old decorated ivory pendant from Stajnia Cave (Poland).

Evidence of mobiliary art and body augmentation are associated with the cultural innovations introduced by Homo sapiens at the beginning of the Upper Paleolithic. Here, we report the discovery of the oldest known human-modified punctate ornament, a decorated ivory pendant from the Paleolithic layers at Stajnia Cave in Poland. We describe the features of this unique piece, as well as the stratigraphic context and the details of its chronometric dating. The Stajnia Cave plate is a personal 'jewellery' object that was created 41,500 calendar years ago (directly radiocarbon dated). It is the oldest known of its kind in Eurasia and it establishes a new starting date for a tradition directly connected to the spread of modern Homo sapiens in Europe.

New perspectives on Neanderthal dispersal and turnover from Stajnia Cave (Poland).

The Micoquian is the broadest and longest enduring cultural facies of the Late Middle Palaeolithic that spread across the periglacial and boreal environments of Europe between Eastern France, Poland, and Northern Caucasus. Here, we present new data from the archaeological record of Stajnia Cave (Poland) and the paleogenetic analysis of a Neanderthal molar S5000, found in a Micoquian context. Our results demonstrate that the mtDNA genome of Stajnia S5000 dates to MIS 5a making the tooth the oldest Neanderthal specimen from Central-Eastern Europe. Furthermore, S5000 mtDNA has the fewest number of differences to mtDNA of Mezmaiskaya 1 Neanderthal from Northern Caucasus, and is more distant from almost contemporaneous Neanderthals of Scladina and Hohlenstein-Stadel. This observation and the technological affinity between Poland and the Northern Caucasus could be the result of increased mobility of Neanderthals that changed their subsistence strategy for coping with the new low biomass environments and the increased foraging radius of gregarious animals. The Prut and Dniester rivers were probably used as the main corridors of dispersal. The persistence of the Micoquian techno-complex in South-Eastern Europe infers that this axis of mobility was also used at the beginning of MIS 3 when a Neanderthal population turnover occurred in the Northern Caucasus.

Issues of theory and method in the analysis of Paleolithic mortuary behavior: A view from Shanidar Cave.

Mortuary behavior (activities concerning dead conspecifics) is one of many traits that were previously widely considered to have been uniquely human, but on which perspectives have changed markedly in recent years. Theoretical approaches to hominin mortuary activity and its evolution have undergone major revision, and advances in diverse archeological and paleoanthropological methods have brought new ways of identifying behaviors such as intentional burial. Despite these advances, debates concerning the nature of hominin mortuary activity, particularly among the Neanderthals, rely heavily on the rereading of old excavations as new finds are relatively rare, limiting the extent to which such debates can benefit from advances in the field. The recent discovery of in situ articulated Neanderthal remains at Shanidar Cave offers a rare opportunity to take full advantage of these methodological and theoretical developments to understand Neanderthal mortuary activity, making a review of these advances relevant and timely.

A switch to a raltegravir containing regimen does not lower platelet reactivity in HIV-infected individuals.

OBJECTIVE: Platelet hyperreactivity and increased platelet-monocyte aggregation (PMA) are associated with increased cardiovascular risk and inflammation. In a previous cross-sectional study, individuals using a raltegravir (RAL)-based regimen were found to have reduced platelet reactivity and PMA compared with other antiretroviral regimens. Our aim was to investigate whether switching from a nonintegrase inhibitor regimen to a RAL-based regimen reduces platelet reactivity or PMA. DESIGN: An investigator initiated, single-centre, prospective randomized, open-label, blinded endpoint trial. METHODS: Forty HIV-infected adults using a nonintegrase inhibitor containing regimen with undetectable viral load were randomized to either continue their regimen or switch to a RAL-based regimen for 10 weeks, continuing the same backbone. The primary outcome was the change in platelet reactivity at week 10, which was determined as the expression of the platelet activation marker P-selectin and binding of fibrinogen before and after ex-vivo stimulation with different platelet agonists. Secondary outcomes included PMA, plasma markers of platelet activation and markers of inflammation and immune cell activation. RESULTS: Twenty-one participants were enrolled in the continuation group and 19 in the RAL group. Baseline characteristics were comparable between groups. There were no differences in the change in platelet reactivity to either platelet agonist at week 10, nor in plasma markers of platelet activation. PMA, C-reactive protein, T-cell activation (CD38HLA-DR) and monocyte (CD14CD16) subsets. CONCLUSION: Switching a nonintegrase inhibitor containing regimen to a RAL-based regimen does not reduce platelet reactivity, platelet-leukocyte aggregation, inflammation and immune activation in virologically suppressed HIV-infected individuals. CLINICAL TRIAL NUMBER: NCT02383355.

Ancient genomes show social and reproductive behavior of early Upper Paleolithic foragers.

Present-day hunter-gatherers (HGs) live in multilevel social groups essential to sustain a population structure characterized by limited levels of within-band relatedness and inbreeding. When these wider social networks evolved among HGs is unknown. To investigate whether the contemporary HG strategy was already present in the Upper Paleolithic, we used complete genome sequences from Sunghir, a site dated to ~34,000 years before the present, containing multiple anatomically modern human individuals. We show that individuals at Sunghir derive from a population of small effective size, with limited kinship and levels of inbreeding similar to HG populations. Our findings suggest that Upper Paleolithic social organization was similar to that of living HGs, with limited relatedness within residential groups embedded in a larger mating network.

Cognitive functioning, wellbeing and brain correlates in HIV-1 infected patients on long-term combination antiretroviral therapy.

OBJECTIVE: The objective of the current study is to integrate results from extensive neuropsychological assessment, subjective wellbeing reports and structural neuroimaging findings in successfully treated HIV-infected patients in comparison with a HIV-negative control group. DESIGN: A cross-sectional study. METHODS: Neuropsychological functioning and self-reported wellbeing were assessed in a group of 102 virologically suppressed HIV-infected patients on combination antiretroviral therapy (cART) and 56 controls. Both groups underwent magnetic resonance (MR) examinations and grey matter, white matter and subcortical volumes were determined. Brain parenchymal fraction (BPF) was calculated as an estimated measure of global brain atrophy. RESULTS: HIV-infected patients showed worse information processing speed (P = 0.01) and motor function (P = 0.03) than controls. Also, higher levels of anxiety and depressive symptoms, somatic and cognitive complaints, sleep problems and health distress were found, as well as lower levels of general health perceptions, social functioning and energy (P < 0.05). No differences in wellbeing reports were found between patients on regimens containing either efavirenz or nevirapine and patients on cART without these drugs (P > 0.05). Patients had a smaller BPF (P = 0.04) and thalamus (P = 0.05) than controls. A lower BPF was related to worse motor function and information processing speed in the patients. A smaller thalamus volume was related to lower motor function in the patient group and lower speed of information processing in the controls. CONCLUSION: No profound deficits were found in the current study. The present results demonstrate that HIV has a minor impact on brain, cognition and wellbeing among HIV-infected patients who are otherwise healthy and maintained on a good control of cART.

New chronology for Ksâr 'Akil (Lebanon) supports Levantine route of modern human dispersal into Europe.

Modern human dispersal into Europe is thought to have occurred with the start of the Upper Paleolithic around 50,000-40,000 y ago. The Levantine corridor hypothesis suggests that modern humans from Africa spread into Europe via the Levant. Ksâr 'Akil (Lebanon), with its deeply stratified Initial (IUP) and Early (EUP) Upper Paleolithic sequence containing modern human remains, has played an important part in the debate. The latest chronology for the site, based on AMS radiocarbon dates of shell ornaments, suggests that the appearance of the Levantine IUP is later than the start of the first Upper Paleolithic in Europe, thus questioning the Levantine corridor hypothesis. Here we report a series of AMS radiocarbon dates on the marine gastropod Phorcus turbinatus associated with modern human remains and IUP and EUP stone tools from Ksâr 'Akil. Our results, supported by an evaluation of individual sample integrity, place the EUP layer containing the skeleton known as "Egbert" between 43,200 and 42,900 cal B.P. and the IUP-associated modern human maxilla known as "Ethelruda" before ∼ 45,900 cal B.P. This chronology is in line with those of other Levantine IUP and EUP sites and demonstrates that the presence of modern humans associated with Upper Paleolithic toolkits in the Levant predates all modern human fossils from Europe. The age of the IUP-associated Ethelruda fossil is significant for the spread of modern humans carrying the IUP into Europe and suggests a rapid initial colonization of Europe by our species.

Long-term treatment with tenofovir: prevalence of kidney tubular dysfunction and its association with tenofovir plasma concentration.

BACKGROUND: Monitoring of side effects of long-term HIV treatment has become increasingly important. Tenofovir disoproxil fumarate (TDF), a first-line treatment option, is associated with kidney tubular dysfunction (KTD). Our objective was to further investigate the prevalence and risk factors of KTD, in particular its association with TDF plasma concentration in HIV-infected patients treated with TDF for at least one year. METHODS: An observational cross-sectional single-centre study was conducted. KTD was defined as the presence of at least two of the following criteria: urinary α1-microglobulin/creatinine ratio >15 mg/10 mmol; fractional excretion (FE) of phosphate >20% in the presence of hypophosphataemia; FE of uric acid >10% in the presence of hypouricaemia and glucosuria. Multivariate logistic regression was used to study which variable was associated with KTD. RESULTS: A total of 161 HIV patients were included. Abnormalities in tubular function were observed in 101 patients (62.7%), while 17 patients (10.6%) fulfilled the definition of KTD. Urinary α1-microglobulin/creatinine ratio was the most sensitive parameter to detect KTD. Multivariate logistic regression showed TDF plasma concentration to be the only variable associated with KTD. Post hoc analysis showed a stronger association between the product of TDF plasma concentration and TDF exposure and KTD. CONCLUSIONS: Parameters of KTD are frequently observed in patients on long-term TDF-containing combination antiretroviral therapy. KTD is associated with higher TDF plasma concentrations. A stronger association between the product of TDF plasma concentration and TDF exposure and KTD could suggest cumulative toxicity. A causative role for elevated TDF plasma concentration in development of KTD cannot be demonstrated in this cross-sectional analysis. Longitudinal research is needed to investigate the development and clinical relevance of KTD.

High-dose vitamin D3 supplementation is a requisite for modulation of skin-homing markers on regulatory T cells in HIV-infected patients.

Vitamin D(3) is known to have an effect on the immune function. We investigated the immunomodulatory capability of vitamin D(3) in HIV-infected patients and studied the expression of chemokine receptors on regulatory T cells (Treg). Vitamin D(3)-deficient HIV-1-seropositive subjects were treated with cholecalciferol (vitamin D(3)) at a dose of 800 IU daily for 3 months (n=9) or 25,000 IU weekly for 2 months (n=7). Peripheral blood mononuclear cells (PBMCs) were isolated and analyzed for skin-homing (CCR4 and CCR10) and gut-homing (CCR9 and integrin α(4)ß(7)) marker expression on Treg, by flow cytometry, before and after supplementation. Serum 25(OH)D(3) and parathyroid hormone (PTH) levels were determined at baseline and after the treatment period. Weekly doses of 25,000 IU cholecalciferol effectively achieved the optimal target serum 25(OH)D(3) concentration of >75 nmol/liter (30 ng/ml) in HIV-infected patients. High-dose cholecalciferol supplementation differentially influenced skin-homing markers on Treg with an increased level of CCR10 expression and while a reduction in CCR4 expression level was observed together with a lower percentage of Treg expressing CCR4. For both dosing regimens, there were no significant differences in the expression of gut-homing markers, CCR9, and integrin α(4)ß(7). High-dose vitamin D(3) supplementation is needed to reverse vitamin D(3) deficiency in HIV-infected individuals and this results in modulation of skin-homing markers but not gut-homing markers expression on Treg. At a standard dose of 800 IU/day, vitamin D(3) is not effective in achieving an optimal 25(OH)D(3) concentration in patients with an underlying T cell dysfunction and is unable to exert any immunomodulatory effects.

Vitamin D deficiency among HIV type 1-infected individuals in the Netherlands: effects of antiretroviral therapy.

Vitamin D regulates bone metabolism but has also immunoregulatory properties. In HIV-infected patients bone disorders are increasingly observed. Furthermore, low 1,25(OH)(2)D(3) levels have been associated with low CD4(+) counts, immunological hyperactivity, and AIDS progression rates. Few studies have examined the vitamin D status in HIV-infected patients. This study will specifically focus on the effects of antiretroviral agents on vitamin D status. Furthermore, the effect of vitamin D status on CD4 cell recovery after initiation of HAART will be evaluated. Among 252 included patients the prevalence of vitamin D deficiency (<35 nmol/liter from April to September and <25 nmol/liter from October to March) was 29%. Female sex, younger age, dark skin, and NNRTI treatment were significant risk factors in univariate analysis, although in multivariate analyses skin pigmentation remained the only independent risk factor. Median 25(OH)D(3) levels were significantly lower in white NNRTI-treated patients [54.5(27.9-73.8) nmol/liter] compared to white PI-treated patients [77.3 (46.6-100.0) nmol/liter, p = 0.007], while among nonwhites no difference was observed. Both PI- and NNRTI-treated patients had significantly higher blood PTH levels than patients without treatment. Moreover, NNRTI treatment puts patients at risk of elevated PTH levels (>6.5 pmol/liter). Linear regression analysis showed that vitamin D status did not affect CD4 cell recovery after initiation of HAART. In conclusion, 29% of the HIV-1-infected patients had vitamin D deficiency, with skin color as an independent risk factor. NNRTI treatment may add more risk for vitamin D deficiency. Both PI- and NNRTI-treated patients showed higher PTH levels and might therefore be at risk of bone problems. Evaluation of 25(OH)D(3) and PTH levels, especially in NNRTI-treated and dark skinned HIV-1-infected patients, is necessary to detect and treat vitamin D deficiency early.

Nevirapine plasma concentrations are still detectable after more than 2 weeks in the majority of women receiving single-dose nevirapine: implications for intervention studies.

BACKGROUND: Single-dose nevirapine is a highly cost-effective strategy to reduce perinatal HIV-1 transmission. Its major disadvantage is the selection of nevirapine resistance in 20% to 30% of women, probably attributable to the long elimination half-life of nevirapine. To develop intervention strategies, it is important to know the interpatient variability in nevirapine half-life in women receiving a single dose of nevirapine. METHODS: HIV-negative, healthy, nonpregnant Dutch women were eligible for this study. After administration of a single 200-mg dose of nevirapine to the subjects, blood was sampled for measurement of nevirapine twice a week for a total of 21 days. Nevirapine plasma levels were determined by a validated high-performance liquid chromatography method with a lower limit of quantification of 0.15 mg/L. The primary end point was the first sample with an undetectable nevirapine concentration. RESULTS: Forty-four subjects participated. The median age, height, and body weight (interquartile range) were 26 (21-33) years, 1.72 (1.68-1.75) m, and 64 (59-75) kg, respectively. The median elimination half-life of nevirapine was 56.7 hours, with a range of 25.6 to 164 hours. The time to the first undetectable nevirapine plasma concentration was 10 days in 4 subjects, 14 days in 12 subjects, 17 days in 12 subjects, and 21 days in 9 subjects. In the remaining 7 subjects, nevirapine was still detectable on day 21, the last day of sampling. Time to an undetectable nevirapine plasma concentration was influenced by oral contraceptive use but not by age, height, body weight, body surface area, alcohol use, or smoking. CONCLUSIONS: Most women who received a single 200-mg nevirapine dose still had detectable plasma concentrations of nevirapine after more than 2 weeks. This information is valuable for designing intervention studies to prevent the development of nevirapine resistance.