Archaeological and molecular evidence for ancient chickens in Central Asia.

The origins and dispersal of the chicken across the ancient world remains one of the most enigmatic questions regarding Eurasian domesticated animals. The lack of agreement concerning timing and centers of origin is due to issues with morphological identifications, a lack of direct dating, and poor preservation of thin, brittle bird bones. Here we show that chickens were widely raised across southern Central Asia from the fourth century BC through medieval periods, likely dispersing along the ancient Silk Road. We present archaeological and molecular evidence for the raising of chickens for egg production, based on material from 12 different archaeological sites spanning a millennium and a half. These eggshells were recovered in high abundance at all of these sites, suggesting that chickens may have been an important part of the overall diet and that chickens may have lost seasonal egg-laying.

Neural response during prefrontal theta burst stimulation: Interleaved TMS-fMRI of full iTBS protocols.

BACKGROUND: Left prefrontal intermittent theta-burst stimulation (iTBS) has emerged as a safe and effective transcranial magnetic stimulation (TMS) treatment protocol in depression. Though network effects after iTBS have been widely studied, the deeper mechanistic understanding of target engagement is still at its beginning. Here, we investigate the feasibility of a novel integrated TMS-fMRI setup and accelerated echo planar imaging protocol to directly observe the immediate effects of full iTBS treatment sessions. OBJECTIVE/HYPOTHESIS: In our effort to explore interleaved iTBS-fMRI feasibility, we hypothesize that TMS will induce acute BOLD signal changes in both the stimulated area and interconnected neural regions. METHODS: Concurrent TMS-fMRI with full sessions of neuronavigated iTBS (i.e. 600 pulses) of the left dorsolateral prefrontal cortex (DLPFC) was investigated in 18 healthy participants. In addition, we conducted four TMS-fMRI sessions in a single patient on long-term maintenance iTBS for bipolar depression to test the transfer to clinical cases. RESULTS: Concurrent TMS-fMRI was feasible for iTBS sequences with 600 pulses. During interleaved iTBS-fMRI, an increase of the BOLD signal was observed in a network including bilateral DLPFC regions. In the clinical case, a reduced BOLD response was found in the left DLPFC and the subgenual anterior cingulate cortex, with high variability across individual sessions. CONCLUSIONS: Full iTBS sessions as applied for the treatment of depressive disorders can be established in the interleaved iTBS-fMRI paradigm. In the future, this experimental approach could be valuable in clinical samples, for demonstrating target engagement by iTBS protocols and investigating their mechanisms of therapeutic action.

Subtle Introgression Footprints at the End of the Speciation Continuum in a Clade of Heliconius Butterflies.

Quantifying gene flow between lineages at different stages of the speciation continuum is central to understanding speciation. Heliconius butterflies have undergone an adaptive radiation in wing color patterns driven partly by natural selection for local mimicry. Color patterns are also known to be used as assortative mating cues. Therefore, wing pattern divergence is considered to play a role in speciation. A corollary is that mimicry between closely related species may be associated with hybridization and interfere with reproductive isolation. Here, we take a multifaceted approach to explore speciation history, species boundaries, and traits involved in species differentiation between the two closely related species, Heliconius hecale and Heliconius ismenius. We focus on geographic regions where the two species mimic each other and contrast this with geographic regions where they do not mimic each other. To examine population history and patterns of gene flow, we tested and compared a four-population model accounting for linked selection. This model suggests that the two species have remained isolated for a large part of their history, yet with a small amount of gene exchange. Accordingly, signatures of genomic introgression were small except at a major wing pattern allele and chemosensing genes and stronger in the mimetic populations compared with nonmimetic populations. Behavioral assays confirm that visual confusion exists but that short-range cues determine strong sexual isolation. Tests for chemical differentiation between species identified major differences in putative pheromones which likely mediate mate choice and the maintenance of species differences.

Chemical Modification of Biomarkers through Accelerated Degradation: Implications for Ancient Plant Identification in Archaeo-Organic Residues.

Biochemical and biomolecular archaeology is increasingly used to elucidate the consumption, use, origin, and trade of plants in the past. However, it can be challenging to use biomarkers to identify the taxonomic origin of archaeological plants due to limited knowledge of molecular survival and degradation for many key plant compounds in archaeological contexts. To gain a fundamental understanding of the chemical alterations associated with chemical degradation processes in ancient samples, we conducted accelerated degradation experiments with essential oil derived from cedar (Cedrus atlantica) exposed to materials commonly found in the archaeological record. Using GC-MS and multivariate analysis, we detected a total of 102 compounds across 19 treatments that were classified into three groups. The first group comprised compounds that were abundant in fresh cedar oil but would be unlikely to remain in ancient residues due to rapid degradation. The second group consisted of compounds that remained relatively stable or increased over time, which could be potential biomarkers for identifying cedar in archaeological residues. Compounds in the third group were absent in fresh cedar oil but were formed during specific experiments that could be indicative for certain storage conditions. These results show that caution is warranted for applying biomolecular profiles of fresh plants to ancient samples and that carefully designed accelerated degradation experiments can, at least in part, overcome this limitation.

Hand or foot train-of-four tests and surgical site muscle relaxation assessed with multiple motor evoked potentials: A prospective observational study.

BACKGROUND: Intra-operative muscle relaxation is often required in orthopaedic surgery and the hand train-of-four (TOF) test is usually used for its quantification. However, even though full muscle relaxation is claimed by anaesthesiologists based on a TOF count of zero, surgeons observe residual muscle activity. OBJECTIVE: The aim of the study was to assess if hand or foot TOF adequately represents intra-operative muscle relaxation compared with multiple motor evoked potentials. DESIGN: Prospective observational study. SETTING: A single-centre study performed between February 2016 and December 2018 at the Balgrist University Hospital, Zurich, Switzerland. PATIENTS: Twenty patients scheduled for elective lumbar spinal fusion were prospectively enrolled in this study after giving written informed consent. INTERVENTIONS: To assess neuromuscular blockade (NMB) with the intermediate duration nondepolarising neuromuscular blocking agent rocuronium, hand TOF (adductor pollicis) and foot TOF (flexor hallucis brevis) monitoring, and muscle motor evoked potentials (MMEPs) from the upper and lower extremities were assessed prior to surgery under general anaesthesia. Following baseline measurements, muscle relaxation was performed with rocuronium until the spinal surgeon observed sufficient relaxation for surgical intervention. At this timepoint, NMB was assessed by TOF and MMEP. MAIN OUTCOME MEASURES: The primary outcome was to determine the different effect of rocuronium on muscle relaxation comparing hand and foot TOF with the paraspinal musculature assessed by MMEP. RESULTS: Hand TOF was more resistant to NMB and had a shorter recovery time than foot TOF. When comparing MMEPs, muscle relaxation occurred first in the hip abductors, and the paraspinal and deltoid muscles. The most resistant muscle to NMB was the abductor digiti minimi. Direct comparison showed that repetitive MMEPs simultaneously recorded from various muscles at the upper and lower extremities and from paraspinal muscles reflect muscle relaxation similar to TOF testing. CONCLUSION: Hand TOF is superior to foot TOF in assessing muscle relaxation during spinal surgery. Hand TOF adequately represents the degree of muscle relaxation not only for the paraspinal muscles but also for all orthopaedic surgical sites where NMB is crucial for good surgical conditions. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03318718).

Improved Diagnosis of Cervical Spondylotic Myelopathy with Contact Heat Evoked Potentials.

The aim of this study was to reveal the sensitivity and responsiveness of contact heat evoked potentials (CHEPs) to assess cervical spondylotic myelopathy (CSM). A total of 81 patients with clinically and radiologically confirmed spinal cord compression were reviewed. All patients underwent full clinical examinations with combined recordings of segmental CHEPs and somatosensory evoked potentials (dSSEPs) compared with healthy controls. Cross-sectional area, maximal canal compression, and maximal spinal cord compression were determined based on T2-weighted MRI. CHEPs exhibited the highest sensitivity (∼ 95%) to disclose at-level impairments in CSM patients. Normally appearing rostral segments above the level of lesion were impaired in 17% of patients. Comparatively, dSSEPs were less affected (24%) and predominantly impaired at and below the level of CSM. Longitudinal evaluation revealed that CHEPs became progressively impaired in parallel with clinical deterioration. CHEPs were sensitive to CSM, revealing evidence of impaired neurophysiology at and below the radiographic level of stenosis. The changes observed above the level of CSM suggest neurophysiological deficits beyond the focally damaged area. Deteriorating CHEPs were observed in a cohort of patients with worsening neurological symptoms, indicating their responsiveness to track CSM. The present study highlights the value of incorporating CHEPs into the diagnosis and prognosis of CSM.

Markers of Protection in Children and Adolescents Six to Fourteen Years After Primary Hepatitis B Vaccination in Real Life: A Pilot Study.

BACKGROUND: Not many data are available on long-term immunity against hepatitis B (HB) for children vaccinated under real-life conditions. METHODS: Two hundred and thirty-two children and adolescents vaccinated 6-14 years earlier in pediatric practices were examined for conditions of vaccination and markers of protection as anti-HBs, anamnestic response to a booster dose and cell-mediated immunity. RESULTS: Fifty-six percent of the participants were vaccinated according to the German vaccination recommendations (group 1). In 44.0% (group 2), these recommendations were not followed. Anti-HBs concentrations of ≥10 IU/L were found in 53.1% of group 1 and 45.1% of group 2 participants. A booster dose resulted in 91 of 99 participants in having an anamnestic response, in 3 (5.9%) of group 1 and 5 (10.4%) of group 2 anti-HBs remained below 10 IU/L. In group 1, postbooster anti-HBs concentration was inversely correlated with time since the last vaccination. Cellular immune responses were seen in only 5% of revaccinated individuals before the booster, increasing to 30% thereafter. CONCLUSIONS: Under real-life conditions about half of vaccinees have lost protecting antibodies 6-14 years after vaccination in infancy, but in approximately 90% of them, immune memory was demonstrated. However, as memory may wane, revaccination at a time when boostability is still present might be considered.

LTßR expression on hematopoietic cells regulates acute inflammation and influences maturation of myeloid subpopulations.

Lymphotoxin beta-receptor (LTßR) is involved in the formation and maintenance of secondary lymphoid structures, as well as in the regulation of inflammatory responses. Because LTßR lymphoid structure formation continues to develop in infants, we compared two different chimera models: one using adult mice and the other using a transplantation model of neonatal mice. To elucidate the function of LTßR on lymphoid and non-lymphoid cells, we generated bone marrow chimeras on the wild type C57Bl/6 and the LTßR-deficient (LTßR(-/-)) background, and reconstituted the mice with bone marrow cells reciprocally. These chimeric mice were analyzed in the experimental model of acute dextran sulfate sodium-induced colitis. Interestingly, both models revealed not only equal reconstitution levels but also similar immunological responses: LTßR expression on stromal cells is essential for lymph node formation, whereas LTBR on hematopoietic cells is crucial for a decrease in inflammation. In addition, mice lacking LTßR on hematopoietic cells revealed (a) an increase of immature granulocytic cells in the spleen and (b) a reduced proportion of myeloid cells in peripheral blood and spleen expressing CD11b(+)Ly6C(+)Ly6G(-) (myeloid-derived suppressor cells expression profile). In conclusion, LTßR expression on hematopoietic cells seems to be involved in the down-regulation of acute inflammatory reactions paralleled by the appearance of immature myeloid cells.

Test performance characteristics of Anti-HEV IgG assays strongly influence hepatitis E seroprevalence estimates.

Hepatitis E virus (HEV) seroprevalences of 0.3%-53% were reported from industrialized countries. Because these estimates may be influenced by detection assays, this study compares 3 frequently used tests for HEV detection: the MP Diagnostics HEV immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA), the Axiom Diagnostics HEV IgG enzyme immunoassay (EIA), and the Mikrogen recomLine HEV IgG assay. Sera from 200 healthy healthcare workers and 30 individuals with acute HEV infection were analyzed. Among the healthy individuals, HEV IgG was found in 4.5% by the MP Diagnostics assay, in 29.5% by the Axiom Diagnostics assay, and in 18% by the Mikrogen assay. Among individuals with acute HEV infection, positive results were obtained for 83.3%, 100%, and 96.7%, respectively. Thus, the 3 assays show clear differences in diagnostic sensitivity.

Mouse ß-defensin 14 (Defb14) promotes tumor growth by inducing angiogenesis in a CCR6-dependent manner.

ß-Defensins are known for their antimicrobial activity and belong to the molecular barrier of the innate immune system against invading pathogens. In addition, it has been shown that some members of the ß-defensin superfamily have the capacity to promote local innate inflammatory and systemic adaptive immune responses, mediated in part by the interaction with CCR6. We found that mouse ß-defensin 14 (mBD14, Defb14), a newly identified member of the mouse ß-defensin superfamily, is expressed in mouse fibrosarcoma tumor tissue. Tumor cells overexpressing mBD14 demonstrated enhanced solid tumor growth in syngeneic C57BL/6 mice concomitant with increased vascularization of these tumors. Furthermore, mBD14-overexpressing tumors demonstrated increased expression of proangiogenic MIP-2 (CXCL2) ex vivo. In contrast, vascular endothelial growth factor expression was not affected. Cellular analysis of tumor-infiltrating leukocytes revealed a significant increase of CCR6(+) B220(+) lymphocytes in solid tumors derived from mBD14-overexpressing tumor cells. Enhanced tumor growth of mBD14-overexpressing fibrosarcomas was abolished in CCR6-deficient mice, which was paralleled by decreased infiltration of CCR6(+) B220(+) lymphocytes, indicating the requirement of CCR6 expression on host cells. Previously, the interaction of activated, LTαß(+), lymphocytes with lymphotoxin ß-receptor-expressing fibrosarcoma tumor cells has been identified as a new CXCL2-dependent proangiogenic pathway. Coexpression of a soluble lymphotoxin ß-receptor:Ig fusion protein, an inhibitor of CXCL2-dependent angiogenesis, in mBD14-overexpressing fibrosarcoma tumor cells abolished enhanced solid tumor growth. Thus, we conclude that mBD14 expression by tumor-infiltrating host cells results in the chemoattraction of CCR6(+) B220(+) lymphocytes, which in turn initiates a proangiogenic pathway leading to enhanced angiogenesis and organized tumor tissue development.

Lymphotoxin-beta receptor activation on macrophages ameliorates acute DSS-induced intestinal inflammation in a TRIM30α-dependent manner.

Our previous studies indicated that LTßR activation mainly by T cell derived LTα1ß2 is crucial for the control and down-regulation of intestinal inflammation. In order to dissect the cellular and molecular role of LTßR activation in the experimental model of DSS-induced intestinal inflammation, we have generated cell type-specific LTßR-deficient mice with specific ablation of LTßR expression on macrophages/neutrophils (LTßR((flox/flox))×LysM-Cre). These mice develop an exacerbated intestinal inflammation in our experimental model indicating that LTßR expression on macrophages/neutrophils is responsible for the control and down-regulation of the inflammatory reaction. These results were verified by adoptive transfer experiments of BMDM from wild-type and LTßR-deficient mice. Furthermore, transfer of activated CD4+ T cells derived from wild-type mice, but not from LTßR ligand-deficient mice attenuated the signs of intestinal inflammation. Finally, we demonstrate that LTßR activation on BMDM results in induction of TRIM30α, a negative regulator of NFκB activation. Concordantly, ablation of LTßR signaling results in the inability to induce TRIM30α expression concomitant with an increased expression of pro-inflammatory cytokines in our experimental model. Taken together, our data demonstrate that LTßR activation on macrophages by CD4+ T cell derived LTαß controls the pro-inflammatory response by activation of a TRIM30α-dependent signaling pathway, crucial for the down-regulation of the inflammatory response in this experimental model.

Lymphotoxin ß receptor activation on macrophages induces cross-tolerance to TLR4 and TLR9 ligands.

Our previous studies indicated that lymphotoxin ß receptor (LTßR) activation controls and downregulates inflammatory reactions. In this study, we report that LTßR activation on primary mouse macrophages results in induction of tripartite motif containing (TRIM) 30α, which negatively regulates NF-κB activation induced by TLR signaling. LTßR activation results in a downregulation of proinflammatory cytokine and mediator expression upon TLR restimulation, demonstrating that LTßR signaling is involved in the induction of TLR cross-tolerance. Specific knockdown experiments using TRIM30α-specific small interfering RNA abolished the LTßR-dependent induction of TRIM30α and LTßR-mediated TLR cross-tolerance. Concordantly, LTßR activation on bone marrow-derived macrophages induced cross-tolerance to TLR4 and TLR9 ligands in vitro. Furthermore, we have generated cell type-specific LTßR-deficient mice with ablation of LTßR expression on macrophages/neutrophils (LTßR(flox/flox) × LysM-Cre). In bone marrow-derived macrophages derived from these mice LTßR-induced cross-tolerance to TLR4 and TLR9 ligands was impaired. Additionally, mice with a conditional ablation of LTßR expression on macrophages (LTßR(flox/flox) × LysM-Cre) are resistant to LTßR-induced TLR4 tolerance in vivo. Collectively, our data indicate that LTßR activation on macrophages by T cell-derived lymphotoxin α(1)ß(2) controls proinflammatory responses by activation of a TRIM30α-controlled, counterregulatory signaling pathway to protect against exacerbating inflammatory reactions.

Dissociative symptoms in patients with schizophrenia: relationships with childhood trauma and psychotic symptoms.

OBJECTIVE: This study sought to examine the stability of dissociative symptoms in patients with schizophrenia spectrum disorders as well as relationships between psychotic symptoms, childhood trauma, and dissociation. METHOD: One hundred forty-five patients with schizophrenia spectrum disorders (72% schizophrenia, 67% men) were examined at admission to inpatient treatment and 3 weeks later using the Positive and Negative Syndrome Scale, the Childhood Trauma Questionnaire, and the Dissociative Experiences Scale. RESULTS: Dissociative symptoms significantly decreased over time (mean, 19.2 vs 14.1; P < .001). The best predictor of dissociative symptoms at admission was the Positive and Negative Syndrome Scale positive subscale (F(inc)(3,64) = 3.66, P = .017), whereas childhood sexual abuse best predicted dissociation when patients were stabilized (F(inc)(10,80) = 2.00, P = .044). CONCLUSION: Dissociative symptoms in patients with schizophrenia spectrum disorders are related to childhood trauma. Dissociation seems to be state dependent in this diagnostic group. Moreover, diagnostic interviews, in addition to the Dissociative Experiences Scale, should be considered to avoid measurement artifacts.

Detection of hepatitis E virus (HEV) from porcine livers in Southeastern Germany and high sequence homology to human HEV isolates.

BACKGROUND: Hepatitis E virus (HEV) has been identified as an emerging cause of infectious hepatitis over the last years in developed countries. In contrast to travel associated hepatitis E, zoonotic sources of infection are suspected for autochthonous cases in Europe. OBJECTIVE: Since pigs are known reservoirs of HEV, we tested porcine livers sold as food in Southeastern Germany for the presence of hepatitis E virus RNA. STUDY DESIGN: We purchased 200 porcine liver samples in 81 butcher shops and grocery stores in Regensburg, Germany. Nucleic acid preparations were tested for the presence of HEV RNA by quantitative real-time PCR (RT-qPCR). HEV isolates from positive samples were characterized by partial sequencing of ORF1 and ORF2 regions in the HEV genome and by phylogenetic analysis. RESULTS: Specimens from eight (4%) of 200 purchased pig livers had detectable HEV RNA amounts. Sequence determination and phylogenetic analysis allowed two novel isolates to be classified as HEV genotype 3, subgenotype 3a (swR437) and 3c (swR269), respectively. Both novel swine HEV isolates showed high sequence homology to isolates obtained from patients with acute HEV infection from the same geographic region. CONCLUSIONS: These results support the suggested role of undercooked pig products in food as a source of zoonotic HEV infection for humans. It remains to be clarified if this mechanism of transmission is responsible for the surprisingly high anti-HEV IgG prevalence recently observed in some European countries and the USA.

Randomized, placebo-controlled study of a new botulinum toxin type a for treatment of glabellar lines: efficacy and safety.

BACKGROUND: A new botulinum toxin type A (BoNT-A) has been assessed in the United States for treatment of glabellar lines. In April 2009, the US FDA approved the Biologics License Application for a new US formulation of BoNT-A (Dysport [abobotulinum toxin A]; Medicis Aesthetics Inc., Scottsdale, AZ). OBJECTIVE: To compare efficacy and safety of a single treatment of BoNT-A with placebo in subjects with moderate to severe glabellar lines. METHODS AND MATERIALS: One hundred fifty-eight subjects with moderate to severe glabellar lines were randomized 2:1 to receive 50 U of BoNT-A (n=105) or placebo (n=53). Responders were defined as having no or mild glabellar lines at 30 days posttreatment according to investigator and subject assessments (co-primary endpoint) using the validated Glabellar Line Scale Score at maximum frown. Subject diaries were used to document onset of effect. When conducting the research, the authors conformed to the ethical guidelines of the 1975 Declaration of Helsinki. RESULTS: According to investigator assessment, the proportion of responders to BoNT-A at Day 30 was 89.5%, versus 7.5% for placebo (p<.001); according to subject assessment, the proportion of responders was 75.7%, versus 9.8% for placebo (p<.001). CONCLUSION: A single treatment with BoNT-A (50 U) was significantly superior to placebo in the correction of moderate to severe glabellar lines, with comparable tolerability.

[The SS dentist Dr. Willy Frank. A biography]. / Der SS-Zahnarzt Dr. Willy Frank. Eine Biographie.

In his role as leading SS dentist in the concentration camp Auschwitz-Birkenau Dr. Willy Frank was involved in the worst crimes of World War II: In the early summer of 1944 the so called "Hungarian Action" commenced. It planned the extermination of around 450 000 Hungarian Jews within only a few months. Some twenty years later he was sentenced during the Frankfurt Auschwitz Trials to seven years of imprisonment on grounds of his participation in the selection and gassing of the Jews. Before that he had been able to resume his professional worksince 1947 unchecked.