Volvulus with bowel necrosis after laparoscopic appendectomy. Migration of Clip?

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Abstract
About 2.8% of patients develop small bowel obstruction, mostly following an open approach appendectomy. Case Report: we present an 18-year-old girl with acute abdomen 10 days following laparoscopic appendectomy. An emergency laparotomy was performed which revealed bowel necrosis and an impacted slipped clip on the mesenterial side of the bowel with signs of bowel strangulation and necrosis. Bowel resection was carried out with primary enteroenteric anastomosis. We suspect the sharp ends of the open clip allowed it to become lodged in the bowel segment resulting in bowel obstruction and subsequent necrosis. It is possible that the clip migrated or was a failed deployment. To our knowledge, this is the first report of mechanical bowel obstruction after laparoscopic appendectomy caused by aberrant surgical clip.

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Otolaryngology and the Global Burden of Disease

The Global Burden of Disease (GBD) project provides longitudinal analysis of the global burden of otolaryngologic diseases by measuring the all-cause mortality, years of life lost, the years of life lived with disability, and disability-adjusted life years. Hearing loss burden is assessed overall and as sequelae of other diseases, such as otitis media or meningitis. Using these measures, we can appreciate the high prevalence and disability related to hearing loss globally. Other otolaryngologic diseases that contribute to the GBD include otitis media, cleft lip and palate, head and neck cancer, facial trauma, and oral disorders.

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The Small World of Global Otolaryngology

The world is indeed becoming smaller, and the medical field has been transformed by this rapid globalization. As global communication and travel have increased, the Otolaryngology-Head and Neck Surgery community has also become increasingly connected and interwoven across the world, from highly sophisticated tertiary care centers to rural communities in developing countries. As medical professionals, it has always been a part of our fiber to impart information and skills that improve the lives of patients; now, more than ever, it is incumbent upon physicians to share expertise on a global scale.

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Regional Overview of Specific Populations, Workforce Considerations, Training, and Diseases in Latin America

Latin America has significant disparities that make the region vulnerable in the delivery of health care. There is a need to plan comprehensive health care strategies that result in a more robust trained health care workforce, while improving the quality and efficiencies of tertiary public hospitals. This article introduces a survey conducted among otorhinolaryngology leaders in the region that identified the need to strengthen postgraduate programs. Although all countries in Latin America have at least one residency program, more otorhinolaryngology-trained specialists are necessary to address the workforce shortages that are present in about 50% of Latin American countries.

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Bed II Sequence Stratigraphic context of EF-HR and HWK EE archaeological sites, and the Oldowan/Acheulean succession at Olduvai Gorge, Tanzania

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Publication date: Available online 22 April 2018
Source:Journal of Human Evolution
Author(s): Ian G. Stanistreet, Lindsay J. McHenry, Harald Stollhofen, Ignacio de la Torre
Archaeological excavations at EF-HR and HWK EE allow reassessment of Bed II stratigraphy within the Junction Area and eastern Olduvai Gorge. Application of Sequence Stratigraphic methods provides a time-stratigraphic framework enabling correlation of sedimentary units across facies boundaries, applicable even in those areas where conventional timelines, such as tephrostratigraphic markers, are absent, eroded, or reworked. Sequence Stratigraphically, Bed II subdivides into five major Sequences 1 to 5, all floored by major disconformities that incise deeply into the underlying succession, proving that simple "layer cake" stratigraphy is inappropriate. Previous establishment of the Lemuta Member has invalidated the use of Tuff IIA as the boundary between Lower and Middle Bed II, now redefined at the disconformity between Sequences 2 and 3, a lithostratigraphic contact underlying the succession containing the Lower, Middle, and Upper Augitic Sandstones. HWK EE site records Oldowan technology in the Lower Augitic Sandstone at the base of Sequence 3, within Middle Bed II. We suggest placement of recently reported Acheulean levels at FLK W within the Middle Augitic Sandstone, thus emphasizing that handaxes are yet to be found in earlier stratigraphic units of the Olduvai sequence. This would place a boundary between the Oldowan and Acheulean technologies at Olduvai in the Tuff IIB zone or earliest Middle Augitic Sandstone. A major disconformity between Sequences 3 and 4 at and near EF-HR cuts through the level of Tuff IIC, placing the main Acheulean EF-HR assemblage at the base of Sequence 4, within Upper rather than Middle Bed II. Sequence stratigraphic methods also yield a more highly resolved Bed II stratigraphic framework. Backwall and sidewall surveying of archaeological trenches at EF-HR and HWK EE permits definition of "Lake-parasequences" nested within the major Sequences that record downcutting of disconformities associated with lake regression, then sedimentation associated with lake transgression, capped finally by another erosional disconformity or hiatal paraconformity caused by the next lake withdrawal. On a relative time-scale rather than a vertical metre scale, the resulting Wheeler diagram framework provides a basis for recognizing time-equivalent depositional episodes and the position of time gaps at various scales. Relative timing of archaeological assemblage levels can then be differentiated at a millennial scale within this framework.



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Technological behaviour in the early Acheulean of EF-HR (Olduvai Gorge, Tanzania)

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Publication date: Available online 27 April 2018
Source:Journal of Human Evolution
Author(s): Ignacio de la Torre, Rafael Mora
Technological strategies of early humans are discussed in the light of a recently excavated stone tool assemblage from EF-HR, an archaeological site older than 1.33 Ma at Olduvai Gorge, Tanzania. Renewed fieldwork at EF-HR has unearthed a lithic collection containing over 2300 artefacts (including a hundred handaxes in stratigraphic position), which represents one of the largest assemblages for the early Acheulean in East Africa. Our technological study shows co-occurrence of two distinctive reduction sequences in the same assemblage, one aimed at obtaining small flakes and the other focused on the production of large, thick, heavy flakes that were then used as blanks for handaxe shaping. Flaking of small cores is expedient and low intensity, and knapping methods are similar to those observed in earlier Oldowan assemblages. Large Cutting Tools (LCTs) show no evidence of planform and biconvex symmetry, and shaping sequences are brief and discontinuous, indicating short use-lives for handaxes. Bifaces are rare and atypical. Recurrent morphotypes are knives, which are poorly-shaped, scraper-like, large-sized handaxes. Despite the apparent expediency of EF-HR handaxe production, a closer inspection of the interplay between debitage and façonnage stages reveals remarkably standardized procedural patterns. Large Cutting Tool blanks were produced following fixed knapping rules resulting in flakes with a specific morphology and mass distribution. Adapted to the idiosyncrasies of each blank, shaping was almost invariably imposed over the same areas in all LCTs and sought to produce morphotypes that, technologically, are remarkably identical to each other. This strongly supports the existence of mental templates and technical rules that were systematically practiced in LCT production at EF-HR, and underscore the structured nature of technological behaviour at the onset of the Acheulean in East Africa.



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Patterns of lateral enamel growth in Homo naledi as assessed through perikymata distribution and number

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Publication date: Available online 27 April 2018
Source:Journal of Human Evolution
Author(s): Debbie Guatelli-Steinberg, Mackie C. O'Hara, Adeline Le Cabec, Lucas K. Delezene, Donald J. Reid, Matthew M. Skinner, Lee R. Berger
Perikymata, incremental growth lines visible on tooth enamel surfaces, differ in their distribution and number among hominin species, although with overlapping patterns. This study asks: (1) How does the distribution of perikymata along the lateral enamel surface of Homo naledi anterior teeth compare to that of other hominins? (2) When both perikymata distribution and number are analyzed together, how distinct is H. naledi from other hominins? A total of 19 permanent anterior teeth (incisors and canines) of H. naledi were compared, by tooth type, to permanent anterior teeth of other hominins: Australopithecus afarensis, Australopithecus africanus, Paranthropus robustus, Paranthropus boisei, Homo ergaster/Homo erectus, other early Homo, Neandertals, and modern humans, with varying sample sizes. Repeated measures analyses of the percentage of perikymata per decile of reconstructed crown height yielded several statistically significant differences between H. naledi and other hominins. Canonical variates analysis of percentage of perikymata in the cervical half of the crown together with perikymata number revealed that, in 8 of 19 cases, H. naledi teeth were significantly unlikely to be classified as other hominins, while exhibiting least difference from modern humans (especially southern Africans). In a cross-validated analysis, 68% of the H. naledi teeth were classified as such, while 32% were classified as modern human (most often southern African). Of 313 comparative teeth use for this analysis, only 1.9% were classified as H. naledi. What tends to differentiate H. naledi anterior tooth crowns from those of most other hominins, including some modern humans, is strongly skewed perikymata distributions combined with perikymata numbers that fall in the middle to lower ranges of hominin values. H. naledi therefore tends toward a particular combination of these features that is less often seen in other hominins. Implications of these data for the growth and development of H. naledi anterior teeth are considered.



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Mesopithecus pentelicus from the Turolian locality of Kryopigi (Kassandra, Chalkidiki, Greece)

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Publication date: Available online 10 May 2018
Source:Journal of Human Evolution
Author(s): Georgios Lazaridis, Evangelia Tsoukala, Todd C. Rae, Asier Gómez-Olivencia, Doris Nagel, Antonis Bartsiokas
New material of the Mio-Pliocene colobine Mesopithecus from the Turolian locality of Kryopigi (Greece) is described here. It includes a complete skull with the atlas attached and other dental and postcranial elements representing at least five individuals (four males and one female). The material is compared with Mesopithecus delsoni, Mesopithecus pentelicus, Mesopithecus monspessulanus and intermediate forms from more than a dozen Turolian localities of the Greco-Iranian province. These comparisons support the attribution of the Kryopigi material to M. pentelicus. The chronostratigraphic distribution of Mesopithecus species and intermediate forms suggests that the Kryopigi fauna could be dated as younger than the Perivolaki locality with M. delsoni/pentelicus (7.1–7.3 Ma, MN12) and older than the Dytiko localities with M. aff. pentelicus, M. cf. pentelicus and M. cf. monspessulanus (?middle MN13). The dimensions of the atlas are within the distribution of extant colobines. The skull shows bite-marks, probably caused by the hyaena Adcrocuta eximia.



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Reevaluation of ‘endocostal ossifications’ on the Kebara 2 Neanderthal ribs

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Publication date: Available online 10 May 2018
Source:Journal of Human Evolution
Author(s): Daniel García-Martínez, Manuel Campo Martín, Armando González Martín, Óscar Cambra-Moo, Alon Barash, Markus Bastir




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The effect of ontogeny on estimates of KNM-WT 15000's adult body size

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Publication date: Available online 10 May 2018
Source:Journal of Human Evolution
Author(s): Deborah L. Cunningham, Ronda R. Graves, Daniel J. Wescott, Robert C. McCarthy
The Homo erectus specimen KNM-WT 15000 has played a critical role in our understanding of body size evolution. New interpretations suggest that KNM-WT 15000 had a younger age-at-death and a more rapid ontogenetic trajectory than previously suggested. Recent fossil discoveries and new interpretations suggest a wide range of body size and shape variation in H. erectus. Based on these new insights, we argue that KNM-WT 15000's adult stature and body mass could have been much smaller than has been traditionally presented in the literature. Using chimpanzee and modern human growth trajectories, we bracketed the range of possibilities for KNM-WT 15000's adult body size between 160.0 and 177.7 cm (5′3″–5′10″) for stature and 60.0 and 82.7 kg (132–182 lbs.) for body mass. These estimates put KNM-WT 15000 near the mean rather than among the largest known H. erectus specimens.



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A new tephrochronology for early diverse stone tool technologies and long-distance raw material transport in the Middle to Late Pleistocene Kapthurin Formation, East Africa

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Publication date: Available online 10 May 2018
Source:Journal of Human Evolution
Author(s): Nick Blegen, Brian R. Jicha, Sally McBrearty
The Middle to Late Pleistocene (780–10 ka) of East Africa records evidence of significant behavioral change, early fossils of Homo sapiens, and the dispersals of our species across and out of Africa. Studying human evolution in this time period thus requires an extensive and precise chronology relating behavioral evidence from archaeological sequences to aspects of hominin biology and evidence of past environments from fossils and geological sequences. Tephrochronology provides the chronostratigraphic resolution to achieve this through correlation and dating of volcanic ashes. The tephrochronology of the Kapthurin Formation presented here, based on tephra correlations and 40Ar/39Ar dates, provides new ages between 395.6 ± 3.5 ka and 465.3 ± 1.0 ka for nine sites showing diverse blade and Levallois methods of core reduction. These are >110 kyr older than previously known in East Africa. New 40Ar/39Ar dates provide a refined age of 222.5 ± 0.6 ka for early evidence of long-distance (166 km) obsidian transport at the Sibilo School Road Site. A tephra correlation between the Baringo and Victoria basins also provides a new date of ∼100 ka for the Middle Stone Age site of Keraswanin. By providing new and older dates for 11 sites containing several important aspects of hominin behavior and extending the chronology of the Kapthurin Formation forward by ∼130,000 years, the tephrochronology presented here contributes one of the longest and most refined chronostratigraphic frameworks of Middle through Late Pleistocene East Africa. This tephrochronology thus provides the foundation to understand the process of modern human behavioral evolution as it relates to biological and paleoenvironmental circumstances.



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Human-like hip joint loading in Australopithecus africanus and Paranthropus robustus

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Publication date: Available online 27 April 2018
Source:Journal of Human Evolution
Author(s): Timothy M. Ryan, Kristian J. Carlson, Adam D. Gordon, Nina Jablonski, Colin N. Shaw, Jay T. Stock
Adaptations indicative of habitual bipedalism are present in the earliest recognized hominins. However, debate persists about various aspects of bipedal locomotor behavior in fossil hominins, including the nature of gait kinematics, locomotor variability across different species, and the degree to which various australopith species engaged in arboreal behaviors. In this study, we analyze variation in trabecular bone structure of the femoral head using a sample of modern humans, extant non-human hominoids, baboons, and fossil hominins attributed to Australopithecus africanus, Paranthropus robustus, and the genus Homo. We use μCT data to characterize the fabric anisotropy, material orientation, and bone volume fraction of trabecular bone to reconstruct hip joint loading conditions in these fossil hominins. Femoral head trabecular bone fabric structure in australopiths is more similar to that of modern humans and Pleistocene Homo than extant apes, indicating that these australopith individuals walked with human-like hip kinematics, including a more limited range of habitual hip joint postures (e.g., a more extended hip) during bipedalism. Our results also indicate that australopiths have robust femoral head trabecular bone, suggesting overall increased loading of the musculoskeletal system comparable to that imposed by extant apes. These results provide new evidence of human-like bipedal locomotion in Pliocene hominins, even while other aspects of their musculoskeletal systems retain ape-like characteristics.



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A biplanar X-ray approach for studying the 3D dynamics of human track formation

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Publication date: Available online 9 May 2018
Source:Journal of Human Evolution
Author(s): Kevin G. Hatala, David A. Perry, Stephen M. Gatesy
Recent discoveries have made hominin tracks an increasingly prevalent component of the human fossil record, and these data have the capacity to inform long-standing debates regarding the biomechanics of hominin locomotion. However, there is currently no consensus on how to decipher biomechanical variables from hominin tracks. These debates can be linked to our generally limited understanding of the complex interactions between anatomy, motion, and substrate that give rise to track morphology. These interactions are difficult to study because direct visualization of the track formation process is impeded by foot and substrate opacity. To address these obstacles, we developed biplanar X-ray and computer animation methods, derived from X-ray Reconstruction of Moving Morphology (XROMM), to analyze the 3D dynamics of three human subjects' feet as they walked across four substrates (three deformable muds and rigid composite panel). By imaging and reconstructing 3D positions of external markers, we quantified the 3D dynamics at the foot-substrate interface. Foot shape, specifically heel and medial longitudinal arch deformation, was significantly affected by substrate rigidity. In deformable muds, we found that depths measured across tracks did not directly reflect the motions of the corresponding regions of the foot, and that track outlines were not perfectly representative of foot size. These results highlight the complex, dynamic nature of track formation, and the experimental methods presented here offer a promising avenue for developing and refining methods for accurately inferring foot anatomy and gait biomechanics from fossil hominin tracks.



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New hominin postcranial remains from locality OMO 323, Shungura Formation, Lower Omo Valley, southwestern Ethiopia

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Publication date: Available online 27 April 2018
Source:Journal of Human Evolution
Author(s): Guillaume Daver, Gilles Berillon, Caroline Jacquier, Yann Ardagna, Meklit Yadeta, Tiphaine Maurin, Antoine Souron, Cécile Blondel, Yves Coppens, Jean-Renaud Boisserie




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Large mammal diets and paleoecology across the Oldowan–Acheulean transition at Olduvai Gorge, Tanzania from stable isotope and tooth wear analyses

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Publication date: Available online 8 May 2018
Source:Journal of Human Evolution
Author(s): Kevin T. Uno, Florent Rivals, Faysal Bibi, Michael Pante, Jackson Njau, Ignacio de la Torre
The well-dated Pleistocene sediments at Olduvai Gorge have yielded a rich record of hominin fossils, stone tools, and vertebrate faunal remains that, taken together, provide insight to hominin behavior and paleoecology. Since 2008, the Olduvai Geochronology and Archaeology Project (OGAP) has undertaken extensive excavations in Bed II that have yielded a large collection of early Pleistocene stone tools and fossils. The strata of Lower, Middle and Upper Bed II at Olduvai Gorge capture the critical transition from Oldowan to Acheulean technology and therefore provide an opportunity to explore the possible role of biotic and abiotic change during the transition. Here, we analyze newly discovered and existing fossil teeth from Bed II sites using stable isotope and tooth wear methods to investigate the diets of large mammals. We reconstruct the dietary ecology of Bed II mammals and evaluate whether vegetation or hydroclimate shifts are associated with the technological change. Combined isotope and tooth wear data suggest most mammals were C4 grazers or mixed feeders. Carbon isotope data from bulk enamel samples indicate that a large majority of Bed II large mammals analyzed had diets comprising mostly C4 vegetation (>75% of diet), whereas only a small number of individuals had either mixed C3–C4 or mostly C3 diets (<25% C4). Mesowear generally indicates an increase of the abrasiveness of the diet between intervals IIA and IIB (∼1.66 Ma), probably reflecting increased grazing. Microwear indicates more abrasive diets in interval IIA suggesting stronger seasonal differences at the time of death during this interval. This is also supported by the intratooth isotope profiles from Equus oldowayensis molars, which suggest a possible decrease in seasonality across the transition. Neither stable isotope nor tooth wear analyses indicate major vegetation or hydrological change across the Oldowan–Acheulean transition.



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Reconstruction, endocranial form and taxonomic affinity of the early Homo calvaria KNM-ER 42700

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Publication date: Available online 26 April 2018
Source:Journal of Human Evolution
Author(s): Simon Neubauer, Philipp Gunz, Louise Leakey, Meave Leakey, Jean-Jacques Hublin, Fred Spoor
When first described, the small calvaria KNM-ER 42700 from Ileret, Kenya, was considered a late juvenile or young adult and assigned to Homo erectus. However, this species attribution has subsequently been challenged because the specimen's neurocranial shape differs substantially from that of H. erectus adults. Here, (1) we describe the postmortem damage and deformation that could have influenced previous shape analyses, (2) present digital reconstructions based on computed tomographic scans correcting for these taphonomic defects, and (3) analyze the reconstructed endocranial shape and form, considering both static allometry among adults and ontogenetic allometry. To this end, we use geometric morphometrics to analyze the shape of digital endocasts based on landmarks and semilandmarks. Corroborating previous studies of the external surface, we find that the endocranial shape of KNM-ER 42700 falls outside the known adult variation of H. erectus. With an endocranial volume estimate between 721 and 744 ml, size cannot explain its atypical endocranial shape when static allometry within H. erectus is considered. However, the analysis of ontogenetic allometry suggests that it may be a H. erectus individual that is younger than previously thought and had not yet reached adult endocranial shape. Future work should therefore comprehensively review all cranial indicators of its developmental age, including closure of the spheno-occipital synchondrosis. An alternative hypothesis is that KNM-ER 42700 represents an as yet unidentified species of early Homo. Importantly, KNM-ER 42700 should not be included in the adult hypodigm of H. erectus.



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Is there a Developed Oldowan A at Olduvai Gorge? A diachronic analysis of the Oldowan in Bed I and Lower-Middle Bed II at Olduvai Gorge, Tanzania

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Publication date: Available online 8 May 2018
Source:Journal of Human Evolution
Author(s): Tomos Proffitt
Debates regarding the validity of the Developed Oldowan as separate cultural facies within the Oldowan techno-complex have primarily concentrated on the Developed Oldowan B/Acheulean transition, with little attention paid to the validity of the Developed Oldowan A (DOA) as a valid technological differentiation. This study presents a diachronic technological analysis and comparison of Oldowan and DOA lithic assemblages from Olduvai Gorge, Tanzania, dated between 1.84 and 1.6 Ma, to test the validity of Leakey's original distinction between these two cultural facies. The results from this comparative analysis show very few technological differences between the lithic assemblages previously assigned to the DOA and Classic Oldowan. Significant diachronic variation in raw material availability and use is, however, identified between Bed I and Lower/Middle Bed II of Olduvai Gorge, which may go some way to explaining the originally perceived techno-cultural differences. The results suggest an increase in hominin knapping and percussive activities, as well as a clear ability to preferentially select high quality raw materials stratigraphically above Tuff IF. Technological innovation and complexity, however, does not seem to vary significantly between the Classic Oldowan and DOA assemblages. The results of this analysis along with similar studies from the wider eastern African region lead to the conclusion that the term Developed Oldowan A should no longer be used.



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The costs of living at the edge: Seasonal stress in wild savanna-dwelling chimpanzees

Publication date: Available online 21 April 2018
Source:Journal of Human Evolution
Author(s): Erin G. Wessling, Hjalmar S. Kühl, Roger Mundry, Tobias Deschner, Jill D. Pruetz
Adaptations associated with shifting from a predominately forested habitat to a more open environment are considered a crucial step in hominin evolution. Understanding how chimpanzees, one of our closest-living relatives, are exposed to the selection pressures associated with living in a relatively sparse, hot, and dry environment can inform us about the relative importance of potential environmental stressors involved in adaptations to drier environments. We investigated the extent to which chimpanzees living in an extreme savanna habitat experience seasonal variability in either energy balance or thermoregulation (dehydration and heat exposure), as well as whether these potential environmental constraints are taxing to chimpanzee individuals. Specifically, we tested the hypothesis that savanna environments impose seasonally-relevant costs to chimpanzees. To this end, we collected 368 urine samples from one community of chimpanzees at Fongoli, Senegal, and measured c-peptide, creatinine, and cortisol as measures of physiological responses to environmental food, water, and heat constraints, respectively. We then evaluated the influence of climatic and phenological factors on these indicators. Results illustrated significant seasonal variation in all biomarkers, which corresponded to relevant ecological correlates. Furthermore, creatinine but not c-peptide correlated with cortisol levels, suggesting that chimpanzees in this environment endure periods of heat and dehydration stress, but are able to avoid stressful levels of negative energy balance. Using savanna chimpanzees as a referential model, our research lends support to the notion that thermoregulatory challenges were a significant factor in hominin evolution, and suggests these challenges may have overshadowed the challenges of maintaining adequate energetic balance during the expansion of the hominin range from wetter to drier environments.



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Mandibular ramus shape variation and ontogeny in Homo sapiens and Homo neanderthalensis

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Publication date: Available online 30 April 2018
Source:Journal of Human Evolution
Author(s): Claire E. Terhune, Terrence B. Ritzman, Chris A. Robinson
As the interface between the mandible and cranium, the mandibular ramus is functionally significant and its morphology has been suggested to be informative for taxonomic and phylogenetic analyses. In primates, and particularly in great apes and humans, ramus morphology is highly variable, especially in the shape of the coronoid process and the relationship of the ramus to the alveolar margin. Here we compare ramus shape variation through ontogeny in Homo neanderthalensis to that of modern and fossil Homo sapiens using geometric morphometric analyses of two-dimensional semilandmarks and univariate measurements of ramus angulation and relative coronoid and condyle height. Results suggest that ramus, especially coronoid, morphology varies within and among subadult and adult modern human populations, with the Alaskan Inuit being particularly distinct. We also identify significant differences in overall anterosuperior ramus and coronoid shapes between H. sapiens and H. neanderthalensis, both in adults and throughout ontogeny. These shape differences are subtle, however, and we therefore suggest caution when using ramus morphology to diagnose group membership for individual specimens of these taxa. Furthermore, we argue that these morphologies are unlikely to be representative of differences in masticatory biomechanics and/or paramasticatory behaviors between Neanderthals and modern humans, as has been suggested by previous authors. Assessments of ontogenetic patterns of shape change reveal that the typical Neanderthal ramus morphology is established early in ontogeny, and there is little evidence for divergent postnatal ontogenetic allometric trajectories between Neanderthals and modern humans as a whole. This analysis informs our understanding of intraspecific patterns of mandibular shape variation and ontogeny in H. sapiens and can shed further light on overall developmental and life history differences between H. sapiens and H. neanderthalensis.



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An anti-NMDA receptor encephalitis mimicking an HIV encephalitis

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Publication date: Available online 14 May 2018
Source:Clinical Immunology
Author(s): Fatiha Haneche, Sophie Demeret, Dimitri Psimaras, Christine Katlama, Valérie Pourcher
The incidence of HIV associated neurocognitive disorders (HAND) were reduced with the use of antiretroviral therapy. In case of neuropsychiatric symptoms, after elimination of all infections, auto-immune encephalitis could be evocated as a differential diagnosis. We describe a case of anti-N-Methyl-d-Aspartate receptor encephalitis in an HIV-1 infected woman.



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An anti-NMDA receptor encephalitis mimicking an HIV encephalitis

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Publication date: Available online 14 May 2018
Source:Clinical Immunology
Author(s): Fatiha Haneche, Sophie Demeret, Dimitri Psimaras, Christine Katlama, Valérie Pourcher
The incidence of HIV associated neurocognitive disorders (HAND) were reduced with the use of antiretroviral therapy. In case of neuropsychiatric symptoms, after elimination of all infections, auto-immune encephalitis could be evocated as a differential diagnosis. We describe a case of anti-N-Methyl-d-Aspartate receptor encephalitis in an HIV-1 infected woman.



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Impact of Bystander Automated External Defibrillator Use on Survival and Functional Outcomes in Shockable Observed Public Cardiac Arrests.

Author: Pollack, Ross A. BS; Brown, Siobhan P. PhD; Rea, Thomas MD, MPH; Aufderheide, Tom MD; Barbic, David MD; Buick, Jason E. MSc; Christenson, Jim MD; Idris, Ahamed H. MD; Jasti, Jamie BS; Kampp, Michael BS; Kudenchuk, Peter MD; May, Susanne PhD; Muhr, Marc EMT-P; Nichol, Graham MD, MPH; Ornato, Joseph P. MD; Sopko, George MD, MPH; Vaillancourt, Christian MD, MSc; Morrison, Laurie MD, MSc; Weisfeldt, Myron MD; the ROC Investigators
Page: 2104-2113


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Association Between Early Hyperoxia Exposure After Resuscitation From Cardiac Arrest and Neurological Disability: Prospective Multicenter Protocol-Directed Cohort Study.

Author: Roberts, Brian W. MD; Kilgannon, J. Hope MD; Hunter, Benton R. MD; Puskarich, Michael A. MD; Pierce, Lisa BA; Donnino, Michael MD; Leary, Marion RN, MPH, MSN; Kline, Jeffrey A. MD; Jones, Alan E. MD; Shapiro, Nathan I. MD, MPH; Abella, Benjamin S. MD, MPhil; Trzeciak, Stephen MD, MPH
Page: 2114-2124


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Oxygen After Cardiac Arrest: Enough Is Enough?.

Author: McKenzie, Nicole F. MPH, PG Dip (Critical Care), B Nurs, RN; Dobb, Geoffrey J. BSc, MB BS, FRCP, FRCA, FANZCA, FCICM
Page: 2125-2127


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Complement Receptor C5aR1 Plays an Evolutionarily Conserved Role in Successful Cardiac Regeneration.

Author: Natarajan, Niranjana PhD; Abbas, Yamen BS; Bryant, Donald M. PhD; Gonzalez-Rosa, Juan Manuel PhD; Sharpe, Michka BS; Uygur, Aysu PhD; Cocco-Delgado, Lucas H.; Ho, Nhi Ngoc BS; Gerard, Norma P. PhD; Gerard, Craig J. MD, PhD; MacRae, Calum A. MD; Burns, Caroline E. PhD; Burns, C. Geoffrey PhD; Whited, Jessica L. PhD; Lee, Richard T. MD
Page: 2152-2165


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Socioeconomic Status and Cardiovascular Outcomes: Challenges and Interventions.

Author: Schultz, William M. MD; Kelli, Heval M. MD; Lisko, John C. MD; Varghese, Tina MD; Shen, Jia MD; Sandesara, Pratik MD; Quyyumi, Arshed A. MD; Taylor, Herman A. MD; Gulati, Martha MD; Harold, John G. MD; Mieres, Jennifer H. MD; Ferdinand, Keith C. MD; Mensah, George A MD; Sperling, Laurence S. MD
Page: 2166-2178


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Evaluation and Management of Right-Sided Heart Failure: A Scientific Statement From the American Heart Association.

Author: Konstam, Marvin A. MD, Chair; Kiernan, Michael S. MD, MS, FAHA, Co-Chair; Bernstein, Daniel MD; Bozkurt, Biykem MD, PhD, FAHA; Jacob, Miriam MD; Kapur, Navin K. MD; Kociol, Robb D. MD, MS; Lewis, Eldrin F. MD, MPH, FAHA; Mehra, Mandeep R. MD; Pagani, Francis D. MD, PhD, FAHA; Raval, Amish N. MD, FAHA; Ward, Carey MD; On behalf of the American Heart Association Council on Clinical Cardiology; Council on Cardiovascular Disease in the Young; and Council on Cardiovascular Surgery and Anesthesia
Page: e578-e622


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Atrial Fibrillation Burden: Moving Beyond Atrial Fibrillation as a Binary Entity: A Scientific Statement From the American Heart Association.

Author: Chen, Lin Y. MD, MS, FAHA, Chair; Chung, Mina K. MD, FAHA, Vice Chair; Allen, Larry A. MD, MHS, FAHA; Ezekowitz, Michael MBChB, DPhil, FAHA; Furie, Karen L. MD, MPH, FAHA; McCabe, Pamela PhD, RN; Noseworthy, Peter A. MD; Perez, Marco V. MD; Turakhia, Mintu P. MD, MAS; On behalf of the American Heart Association Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; Council on Quality of Care and Outcomes Research; and Stroke Council
Page: e623-e644


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Effects of ceftriaxone-induced intestinal dysbacteriosis on regulatory T cells validated by anaphylactic mice

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Publication date: July 2018
Source:International Immunopharmacology, Volume 60
Author(s): Xia Luo, Zengfeng Pan, Shuang Luo, Qi Liu, Shaowei Huang, Guanghua Yang, Feifei Nong, Yajun Fu, Xiangliang Deng, Lian Zhou
Both probiotics and pathogens in the human gut express pathogen-associated molecular patterns (PAMPs) and die with the release of endotoxin and bacterial DNA, which can stimulate our immune system and cause immune reaction. However, it's interesting and fascinating to address why the normal intestinal flora will not generate immunological rejection like the pathogen does. By investigating the changes in cells and molecules relevant to immune tolerance in mice with ceftriaxone-induced dysbacteriosis, our study discovered that both the Evenness indexes and Shannon Wiener index of intestinal flora showed a decrease in dysbacteriosis mice. Moreover, the proportion of αβ+TCR+CD3+CD4CD8 cells, CD3+γδTCR+ cells and CD4+CD25+FoxP3+ cells in the Peyer's patches (PPs), mesenteric lymph nodes (MLNs) and spleen (SP) and the level of TGF-β1, IL-2, IL-4 and IL-10 in the serum also changed. Intestinal dysbacteriosis in an asthma murine model resulted in enhancement of immunologic response to the allergen ovalbumin (OVA), which was an agent that aggravates asthma symptoms. In summary, it is integral to maintain a certain amount or variety of intestinal microflora for regulatory T cells to act in averting hypersensitivity.



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A systematic review on the frequency of BRCA promoter methylation in breast and ovarian carcinomas of BRCA germline mutation carriers: Mutually exclusive, or not?

Publication date: Available online 14 May 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Shoko Vos, Paul Joannes van Diest, Cathy Beatrice Moelans
BackgroundA considerable number of breast and ovarian carcinomas are due to underlying BRCA gene aberrations. Of these, BRCA germline mutations and BRCA promoter methylation are thought to be mutually exclusive, which could be exploited in clinical practice. However, this paradigm has not been studied extensively and systematically.ObjectiveTo systematically investigate to what extent BRCA promoter methylation has been reported in breast and ovarian carcinomas of BRCA germline mutation carriers.MethodsA comprehensive search on BRCA promoter methylation was performed in PubMed and Embase databases. Two authors independently selected studies, assessed study quality and extracted data according to PRISMA and QUADAS-2 guidelines.Results21 articles met the inclusion criteria. BRCA1 methylation was found in at least 10/276 (3,6%) breast and 2/174 (1,1%) ovarian carcinomas of BRCA germline mutation carriers, and BRCA2 methylation was found in at least 7/131 (5.3%) breast and 0/51 (0.0%) ovarian carcinomas of BRCA germline mutation carriers. Methylation frequencies varied between individual CpG sites. The selected studies showed important differences in methodology and performed in general a limited methylation and incomplete mutation analysis.ConclusionsBRCA methylation is rare in breast and ovarian carcinomas of BRCA germline mutation carriers, although the frequency of BRCA promoter methylation may be underestimated. This could have major implications for clinical practice, including referral for genetic testing and BRCAness analysis for treatment decision-making.



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Micropatterned biodegradable polyesters clicked with CQAASIKVAV promote cell alignment, directional migration, and neurite outgrowth

Publication date: Available online 13 May 2018
Source:Acta Biomaterialia
Author(s): Deteng Zhang, Sai Wu, Jianyong Feng, Yiyuan Duan, Dongming Xing, Changyou Gao
The interplay of microstructures and biological cues is critical to regulate the behaviors of Schwann cells (SCs) in terms of cellular spatial arrangement and directional migration as well as neurite orientation for bridging the proximal and distal stumps of the injured peripheral nervous system. In this study, stripe micropatterns having ridges/grooves of width 20/20 and 20/40 μm were fabricated on the surface of maleimide-functionalized biodegradable poly(ester carbonate) (P(LLA-MTMC)) films by the polydimethylsiloxane mold-pressing method, respectively. The laminin-derived CQAASIKVAV peptides end-capped with an –SH group were then grafted by the thiol-ene click reaction under mild conditions to obtain micropatterned and peptide-grafted films. SCs cultured on these films, especially on the 20/40-μm film, displayed faster and aligned adhesion as well as a larger number of elongated cells with a higher length-to-width (L/W) ratio along the stripe direction than those on the flat-pep film. The migration rate of SCs was significantly enhanced in parallel to the stripe direction with a large net displacement. The micropatterned and peptide-grafted films, especially the 20/40-μm film, could promote SC proliferation and nerve growth factor (NGF) secretion in a manner similar to that of the peptide-grafted planar film. Moreover, the neurites of rat pheochromocytoma 12 (PC12) cells sprouted along the ridges with a longer average length on the micropatterned and peptide-grafted films. The synergistic effect of physical patterns and biological cues was evaluated by considering the results of cell adhesion force; immunofluorescence staining of vinculin; fluorescence staining of F-actin and the nucleus; as well as gene expression of neural cadherin (NCAD), neurocan (NCAN), and myelin protein zero (P0).Statement of significanceThe interplay of microstructures and biological cues is critical to regulate the behaviors of Schwann cells (SCs) and nerve cells, and thereby the regeneration of peripheral nerve system. In this study, the combined micropatterning and CQAASIKVAV grafting endowed the modified P(LLA-MTMC) films with both contact guidance and bioactive chemical cues to enhance cell proliferation, directional alignment and migration, longer net displacement and larger NGF secretion, and stronger neurite outgrowth of SCs and PC12 cells. Hence, the integration of physical micropatterns and bioactive molecules is an effective way to obtain featured biomaterials for the regeneration of nerves and other types of tissues.

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HippoCA3mpal Stem Cell Models Expose Dysfunctional Circuits in Schizophrenia

Publication date: 3 May 2018
Source:Cell Stem Cell, Volume 22, Issue 5
Author(s): Mandy Johnstone, Rana Fetit
In this issue of Cell Stem Cell, Sarkar et al. (2018) describe an efficient method for the generation of human hippocampal pyramidal neurons from stem cells. They developed a compelling in vitro model that recapitulates synaptic connectivity within the hippocampus and showed that cells derived from patients with schizophrenia exhibit abnormal electrical activity.

Teaser

In this issue of Cell Stem Cell, Sarkar et al. (2018) describe an efficient method for the generation of human hippocampal pyramidal neurons from stem cells. They developed a compelling in vitro model that recapitulates synaptic connectivity within the hippocampus and showed that cells derived from patients with schizophrenia exhibit abnormal electrical activity.


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Patient-Derived iPSC-Hypothamic Neurons: The Ultimate Protocol

Publication date: 3 May 2018
Source:Cell Stem Cell, Volume 22, Issue 5
Author(s): Maria Consolata Miletta, Tamas L. Horvath
Several methods for making hypothalamic-like neurons (iHTNs) from human or mouse induced pluripotent stem cells (iPSCs) with varying efficiencies exist. In this issue of Cell Stem Cell, Rajamani et al. (2018) devise a new, efficient method to differentiate iPSCs from super-obese and normal donors into iHTNS and investigate their different molecular profiles and hormone responses.

Teaser

Several methods for making hypothalamic-like neurons (iHTNs) from human or mouse induced pluripotent stem cells (iPSCs) with varying efficiencies exist. In this issue of Cell Stem Cell, Rajamani et al. (2018) devise a new, efficient method to differentiate iPSCs from super-obese and normal donors into iHTNS and investigate their different molecular profiles and hormone responses.


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Crinkle-Cut Brain Organoids

Publication date: 3 May 2018
Source:Cell Stem Cell, Volume 22, Issue 5
Author(s): Madeline A. Lancaster
In large mammalian brains, including those of humans, the surface of the cortex is highly folded. How these convolutions form is still unclear, but recent work in Nature Physics by Karzbrun et al. (2018) supports a mechanism involving differential surface swelling combined with internal constraint.

Teaser

In large mammalian brains, including those of humans, the surface of the cortex is highly folded. How these convolutions form is still unclear, but recent work in Nature Physics by Karzbrun et al. (2018) supports a mechanism involving differential surface swelling combined with internal constraint.


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The Lysosome, Elixir of Neural Stem Cell Youth

Publication date: 3 May 2018
Source:Cell Stem Cell, Volume 22, Issue 5
Author(s): Milos S. Simic, Andrew Dillin
Recently in Science, Leeman et al. find that perturbing lysosomal activity of quiescent NSCs directly impedes their ability to become activated, similar to what happens during aging. Excitingly, they could rejuvenate old quiescent NSCs by enhancing the lysosome pathway, ameliorating their ability to clear protein aggregates and become activated.

Teaser

Recently in Science, Leeman et al. find that perturbing lysosomal activity of quiescent NSCs directly impedes their ability to become activated, similar to what happens during aging. Excitingly, they could rejuvenate old quiescent NSCs by enhancing the lysosome pathway, ameliorating their ability to clear protein aggregates and become activated.


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Mentoring the Next Generation: Hongkui Deng

Publication date: 3 May 2018
Source:Cell Stem Cell, Volume 22, Issue 5

Mentor-mentee relationships are essential for professional development, but developing these interpersonal skills is not often highlighted as a priority in scientific endeavors. In a yearlong series, Cell Stem Cell interviews prominent scientists who have prioritized mentorship over the years. Here, we chat with Dr. Hongkui Deng about his views.



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Blood Development: Hematopoietic Stem Cell Dependence and Independence

Publication date: 3 May 2018
Source:Cell Stem Cell, Volume 22, Issue 5
Author(s): Elaine Dzierzak, Anna Bigas
Evidence of the diversity and multi-layered organization of the hematopoietic system is leading to new insights that may inform ex vivo production of blood cells. Interestingly, not all long-lived hematopoietic cells derive from hematopoietic stem cells (HSCs). Here we review the current knowledge on HSC-dependent cell lineages and HSC-independent tissue-resident hematopoietic cells and how they arise during embryonic development. Classical embryological and genetic experiments, cell fate tracing data, single-cell imaging, and transcriptomics studies provide information on the molecular/cell trajectories that form the complete hematopoietic system. We also discuss the current developmentally informed efforts toward generating engraftable and multilineage blood cells.

Teaser

Dzierzak and Bigas review the current knowledge on molecular/cell trajectories that generate the complete hematopoietic system, informed by classical embryological and genetic experiments, cell fate tracing data, single-cell imaging, and transcriptomics studies. The authors also discuss the current developmentally informed efforts toward generating engraftable and multilineage blood cells.


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Efficient Generation of CA3 Neurons from Human Pluripotent Stem Cells Enables Modeling of Hippocampal Connectivity In Vitro

Publication date: 3 May 2018
Source:Cell Stem Cell, Volume 22, Issue 5
Author(s): Anindita Sarkar, Arianna Mei, Apua C.M. Paquola, Shani Stern, Cedric Bardy, Jason R. Klug, Stacy Kim, Neda Neshat, Hyung Joon Kim, Manching Ku, Maxim N. Shokhirev, David H. Adamowicz, Maria C. Marchetto, Roberto Jappelli, Jennifer A. Erwin, Krishnan Padmanabhan, Matthew Shtrahman, Xin Jin, Fred H. Gage
Despite widespread interest in using human induced pluripotent stem cells (hiPSCs) in neurological disease modeling, a suitable model system to study human neuronal connectivity is lacking. Here, we report a comprehensive and efficient differentiation paradigm for hiPSCs that generate multiple CA3 pyramidal neuron subtypes as detected by single-cell RNA sequencing (RNA-seq). This differentiation paradigm exhibits characteristics of neuronal network maturation, and rabies virus tracing revealed synaptic connections between stem cell-derived dentate gyrus (DG) and CA3 neurons in vitro recapitulating the neuronal connectivity within the hippocampus. Because hippocampal dysfunction has been implicated in schizophrenia, we applied DG and CA3 differentiation paradigms to schizophrenia-patient-derived hiPSCs. We detected reduced activity in DG-CA3 co-culture and deficits in spontaneous and evoked activity in CA3 neurons from schizophrenia-patient-derived hiPSCs. Our approach offers critical insights into the network activity aspects of schizophrenia and may serve as a promising tool for modeling diseases with hippocampal vulnerability.Video Abstract

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Teaser

Sarkar et al. established a differentiation paradigm that generates human CA3 pyramidal neurons from ESCs and iPSCs and recapitulates hippocampal connectivity in vitro. This work reveals reduced levels of activity of schizophrenia-patient-derived neurons, offering opportunities for modeling diseases with hippocampal vulnerability.


https://ift.tt/2IimC9U

Super-Obese Patient-Derived iPSC Hypothalamic Neurons Exhibit Obesogenic Signatures and Hormone Responses

Publication date: 3 May 2018
Source:Cell Stem Cell, Volume 22, Issue 5
Author(s): Uthra Rajamani, Andrew R. Gross, Brooke E. Hjelm, Adolfo Sequeira, Marquis P. Vawter, Jie Tang, Vineela Gangalapudi, Yizhou Wang, Allen M. Andres, Roberta A. Gottlieb, Dhruv Sareen
The hypothalamus contains neurons that integrate hunger and satiety endocrine signals from the periphery and are implicated in the pathophysiology of obesity. The limited availability of human hypothalamic neurons hampers our understanding of obesity disease mechanisms. To address this, we generated human induced pluripotent stem cells (hiPSCs) from multiple normal body mass index (BMI; BMI ≤ 25) subjects and super-obese (OBS) donors (BMI ≥ 50) with polygenic coding variants in obesity-associated genes. We developed a method to reliably differentiate hiPSCs into hypothalamic-like neurons (iHTNs) capable of secreting orexigenic and anorexigenic neuropeptides. Transcriptomic profiling revealed that, although iHTNs maintain a fetal identity, they respond appropriately to metabolic hormones ghrelin and leptin. Notably, OBS iHTNs retained disease signatures and phenotypes of high BMI, exhibiting dysregulated respiratory function, ghrelin-leptin signaling, axonal guidance, glutamate receptors, and endoplasmic reticulum (ER) stress pathways. Thus, human iHTNs provide a powerful platform to study obesity and gene-environment interactions.

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Teaser

Human hypothalamic neurons (HTNs) implicated in obesity have a limited availability. This study describes a reliable method for generating functional hormone-responsive HTNs from multiple normal and obese patient reprogrammed hiPSCs. Obese-patient-induced HTNs retained transcriptome profiles and functional phenotypes of high BMI, exhibiting aberrant obesity-related metabolic and respiratory pathways.


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Spred1 Safeguards Hematopoietic Homeostasis against Diet-Induced Systemic Stress

Publication date: 3 May 2018
Source:Cell Stem Cell, Volume 22, Issue 5
Author(s): Yuko Tadokoro, Takayuki Hoshii, Satoshi Yamazaki, Koji Eto, Hideo Ema, Masahiko Kobayashi, Masaya Ueno, Kumiko Ohta, Yuriko Arai, Eiji Hara, Kenichi Harada, Masanobu Oshima, Hiroko Oshima, Fumio Arai, Akihiko Yoshimura, Hiromitsu Nakauchi, Atsushi Hirao
Stem cell self-renewal is critical for tissue homeostasis, and its dysregulation can lead to organ failure or tumorigenesis. While obesity can induce varied abnormalities in bone marrow components, it is unclear how diet might affect hematopoietic stem cell (HSC) self-renewal. Here, we show that Spred1, a negative regulator of RAS-MAPK signaling, safeguards HSC homeostasis in animals fed a high-fat diet (HFD). Under steady-state conditions, Spred1 negatively regulates HSC self-renewal and fitness, in part through Rho kinase activity. Spred1 deficiency mitigates HSC failure induced by infection mimetics and prolongs HSC lifespan, but it does not initiate leukemogenesis due to compensatory upregulation of Spred2. In contrast, HFD induces ERK hyperactivation and aberrant self-renewal in Spred1-deficient HSCs, resulting in functional HSC failure, severe anemia, and myeloproliferative neoplasm-like disease. HFD-induced hematopoietic abnormalities are mediated partly through alterations to the gut microbiota. Together, these findings reveal that diet-induced stress disrupts fine-tuning of Spred1-mediated signals to govern HSC homeostasis.

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Teaser

Tadokoro et al. show that Spred1 negatively regulates HSC self-renewal in a manner supported by ROCK activity and that Spred1 safeguards HSC homeostasis under high-fat diet (HFD) conditions by regulating HSC self-renewal. The gut microbiota dysbiosis induced by HFD disrupts the fine-tuning of Spred1-mediated signals that govern HSC homeostasis.


https://ift.tt/2IlgHkz

PRC1 Fine-tunes Gene Repression and Activation to Safeguard Skin Development and Stem Cell Specification

Publication date: 3 May 2018
Source:Cell Stem Cell, Volume 22, Issue 5
Author(s): Idan Cohen, Dejian Zhao, Carmit Bar, Victor J. Valdes, Katherine L. Dauber-Decker, Minh Binh Nguyen, Manabu Nakayama, Michael Rendl, Wendy A. Bickmore, Haruhiko Koseki, Deyou Zheng, Elena Ezhkova
Polycomb repressive complexes (PRCs) 1 and 2 are essential chromatin regulators of cell identity. PRC1, a dominant executer of Polycomb-mediated control, functions as multiple sub-complexes that possess catalytic-dependent H2AK119 mono-ubiquitination (H2AK119ub) and catalytic-independent activities. Here, we show that, despite its well-established repressor functions, PRC1 binds to both silent and active genes. Through in vivo loss-of-function studies, we show that global PRC1 function is essential for skin development and stem cell (SC) specification, whereas PRC1 catalytic activity is dispensable. Further dissection demonstrated that both canonical and non-canonical PRC1 complexes bind to repressed genes, marked by H2AK119ub and PRC2-mediated H3K27me3. Interestingly, loss of canonical PRC1, PRC1 catalytic activity, or PRC2 leads to expansion of mechanosensitive Merkel cells in neonatal skin. Non-canonical PRC1 complexes, however, also bind to and promote expression of genes critical for skin development and SC formation. Together, our findings highlight PRC1's diverse roles in executing a precise developmental program.

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Teaser

Cohen et al. show that Polycomb repressive complex 1 (PRC1), a critical chromatin regulator, is essential for skin epithelium morphogenesis and stem cell specification. By coupling in vivo chromatin and transcriptional profiling with loss-of-function studies, the authors show that PRC1 controls skin development through regulation of silent and active genes.


https://ift.tt/2jUPRVC

Retinoid-Sensitive Epigenetic Regulation of the Hoxb Cluster Maintains Normal Hematopoiesis and Inhibits Leukemogenesis

Publication date: 3 May 2018
Source:Cell Stem Cell, Volume 22, Issue 5
Author(s): Pengxu Qian, Bony De Kumar, Xi C. He, Christof Nolte, Madelaine Gogol, Youngwook Ahn, Shiyuan Chen, Zhenrui Li, Hanzhang Xu, John M. Perry, Deqing Hu, Fang Tao, Meng Zhao, Yingli Han, Kate Hall, Allison Peak, Ariel Paulson, Chongbei Zhao, Aparna Venkatraman, Andrew Box, Anoja Perera, Jeffrey S. Haug, Tari Parmely, Hua Li, Robb Krumlauf, Linheng Li
Hox genes modulate the properties of hematopoietic stem cells (HSCs) and reacquired Hox expression in progenitors contributes to leukemogenesis. Here, our transcriptome and DNA methylome analyses revealed that Hoxb cluster and retinoid signaling genes are predominantly enriched in LT-HSCs, and this coordinate regulation of Hoxb expression is mediated by a retinoid-dependent cis-regulatory element, distal element RARE (DERARE). Deletion of the DERARE reduced Hoxb expression, resulting in changes to many downstream signaling pathways (e.g., non-canonical Wnt signaling) and loss of HSC self-renewal and reconstitution capacity. DNA methyltransferases mediate DNA methylation on the DERARE, leading to reduced Hoxb cluster expression. Acute myeloid leukemia patients with DNMT3A mutations exhibit DERARE hypomethylation, elevated HOXB expression, and adverse outcomes. CRISPR-Cas9-mediated specific DNA methylation at DERARE attenuated HOXB expression and alleviated leukemogenesis. Collectively, these findings demonstrate pivotal roles for retinoid signaling and the DERARE in maintaining HSCs and preventing leukemogenesis by coordinate regulation of Hoxb genes.

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Teaser

Hox genes are regulators of HSC maintenance and contributors in leukemogenesis. Li and colleagues elucidate a mechanism for how the retinoid-dependent cis-regulatory element DERARE maintains normal hematopoiesis but prevents leukemogenesis by coordinate regulation of Hoxb cluster genes in a methylation-dependent manner.


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The Dystrophin Glycoprotein Complex Regulates the Epigenetic Activation of Muscle Stem Cell Commitment

Publication date: 3 May 2018
Source:Cell Stem Cell, Volume 22, Issue 5
Author(s): Natasha C. Chang, Marie-Claude Sincennes, Fabien P. Chevalier, Caroline E. Brun, Melanie Lacaria, Jessica Segalés, Pura Muñoz-Cánoves, Hong Ming, Michael A. Rudnicki
Asymmetrically dividing muscle stem cells in skeletal muscle give rise to committed cells, where the myogenic determination factor Myf5 is transcriptionally activated by Pax7. This activation is dependent on Carm1, which methylates Pax7 on multiple arginine residues, to recruit the ASH2L:MLL1/2:WDR5:RBBP5 histone methyltransferase complex to the proximal promoter of Myf5. Here, we found that Carm1 is a specific substrate of p38γ/MAPK12 and that phosphorylation of Carm1 prevents its nuclear translocation. Basal localization of the p38γ/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through β1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38γ/β1-syntrophin interactions are abrogated, resulting in enhanced Carm1 phosphorylation. The resulting progenitors exhibit reduced Carm1 binding to Pax7, reduced H3K4-methylation of chromatin, and reduced transcription of Myf5 and other Pax7 target genes. Therefore, our experiments suggest that dysregulation of p38γ/Carm1 results in altered epigenetic gene regulation in Duchenne muscular dystrophy.

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Teaser

Establishment of cell polarity by the dystrophin complex is required for muscle stem cell asymmetric divisions. Chang et al. identify p38γ MAPK as a critical downstream regulator of satellite stem cell commitment, providing a link between dystrophin and epigenetic gene regulation to mediate asymmetric fates of daughter satellite cells.


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Fasting Activates Fatty Acid Oxidation to Enhance Intestinal Stem Cell Function during Homeostasis and Aging

Publication date: 3 May 2018
Source:Cell Stem Cell, Volume 22, Issue 5
Author(s): Maria M. Mihaylova, Chia-Wei Cheng, Amanda Q. Cao, Surya Tripathi, Miyeko D. Mana, Khristian E. Bauer-Rowe, Monther Abu-Remaileh, Laura Clavain, Aysegul Erdemir, Caroline A. Lewis, Elizaveta Freinkman, Audrey S. Dickey, Albert R. La Spada, Yanmei Huang, George W. Bell, Vikram Deshpande, Peter Carmeliet, Pekka Katajisto, David M. Sabatini, Ömer H. Yilmaz
Diet has a profound effect on tissue regeneration in diverse organisms, and low caloric states such as intermittent fasting have beneficial effects on organismal health and age-associated loss of tissue function. The role of adult stem and progenitor cells in responding to short-term fasting and whether such responses improve regeneration are not well studied. Here we show that a 24 hr fast augments intestinal stem cell (ISC) function in young and aged mice by inducing a fatty acid oxidation (FAO) program and that pharmacological activation of this program mimics many effects of fasting. Acute genetic disruption of Cpt1a, the rate-limiting enzyme in FAO, abrogates ISC-enhancing effects of fasting, but long-term Cpt1a deletion decreases ISC numbers and function, implicating a role for FAO in ISC maintenance. These findings highlight a role for FAO in mediating pro-regenerative effects of fasting in intestinal biology, and they may represent a viable strategy for enhancing intestinal regeneration.

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Mihaylova et al. show that short-term fasting promotes intestinal stem and progenitor cell function in young and aged mice by inducing a robust fatty acid oxidation (FAO) program. PPARδ agonists emulate these effects, showing that fatty acid metabolism has positive effects on young and old ISCs.


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Submucosal Gland Myoepithelial Cells Are Reserve Stem Cells That Can Regenerate Mouse Tracheal Epithelium

Publication date: 3 May 2018
Source:Cell Stem Cell, Volume 22, Issue 5
Author(s): Thomas J. Lynch, Preston J. Anderson, Pavana G. Rotti, Scott R. Tyler, Adrianne K. Crooke, Soon H. Choi, Daniel T. Montoro, Carolyn L. Silverman, Weam Shahin, Rui Zhao, Chandler W. Jensen-Cody, Andrea Adamcakova-Dodd, T. Idil Apak Evans, Weiliang Xie, Yulong Zhang, Hongmei Mou, B. Paul Herring, Peter S. Thorne, Jayaraj Rajagopal, Charles Yeaman, Kalpaj R. Parekh, John F. Engelhardt




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Editorial Board

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Publication date: April 2018
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 32, Issue 2





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Building Blocks of Social Cognition: Mirror, Mentalize, Share?

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Publication date: Available online 14 May 2018
Source:Cortex
Author(s): Daniel Alcalá-López, Kai Vogeley, Ferdinand Binkofski, Danilo Bzdok
During the past decade, novel approaches to study social interaction have expanded and questioned long-standing knowledge about how humans understand others. We aim to portray and reconcile the key psychological processes and neural mechanisms underlying navigation of the social environment. Theoretical accounts mostly revolved around either abstract inferences or embodied simulations, whereas experimental studies mostly focused on theory of mind or mentalizing, empathy, and action imitation. The tension between theories of and experiments on social cognition is systematically revisited to foster new theoretical and empirical studies in the fields. We finally retrace differential impairments in social capacities as a means to re-conceptualize psychopathological disturbance in psychiatry, including schizophrenia, borderline personality, and autism.



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Epinephrine, auto-injectors and anaphylaxis: challenges of dose, depth and device

Publication date: Available online 7 May 2018
Source:Annals of Allergy, Asthma & Immunology
Author(s): Julie Brown
Objectives1. To review epinephrine dosing, site and route of administration, focusing on special populations (patients weighing less that 15 kg, and obese patients). 2. To discuss storage and delivery of epinephrine in pre-hospital and hospital settings.Data SourcesReview of published literature.Study SelectionRelevancy.ResultsThe recommended 0.01 mg/kg (max 0.3-0.5 mg) epinephrine dose in anaphylaxis is based on limited pharmacokinetic data in healthy volunteers. There are no pharmacokinetic or pharmacodynamics studies involving patients in anaphylaxis. When epinephrine auto-injectors (EAIs) are used in infants, the dose increasingly exceeds the recommended dose as weight decreases, although the clinical significance is unclear. Limited data indicate that the intramuscular route and lateral thigh site are superior. Ultrasound studies suggest that 0.15 EAI needles may be too long for many patients under 15 kg and 0.3 mg EAI needles may be too short for obese patients over 30 kg. A newly available 0.1 mg EAI has a lower dose and shorter needle better suited to patients 7.5-15 kg. In some medical settings, vials and syringes may provide a safe, efficient alternative with substantial cost savings over EAIs.ConclusionEAIs should be available in the community with doses and needle depths that meet the needs of all patients. More research on epinephrine pharmacodynamics are needed in children and adults in anaphylaxis, in order to better delineate what optimal doses should be. Optimizing epinephrine dose and delivery has the potential to improve anaphylaxis outcomes and prevent adverse events.



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Angioedema: systemic activation process during prodromes

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Publication date: Available online 3 May 2018
Source:Annals of Allergy, Asthma & Immunology
Author(s): Samuel Luyasu, Delphine Charignon, Denise Ponard, Christian Drouet, Arije Ghannam




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Aldolase: a new crustacea allergen

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Publication date: Available online 2 May 2018
Source:Annals of Allergy, Asthma & Immunology
Author(s): P.M. Gamboa, B. Bartolomé, E. García Lirio, J. Cuesta-Herranz, C. Pastor-Vargas




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Pain inhibits itch, but not in atopic dermatitis?

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Publication date: May 2018
Source:Annals of Allergy, Asthma & Immunology, Volume 120, Issue 5
Author(s): Hjalte H. Andersen, Gil Yosipovitch, Lars Arendt-Nielsen




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Looking into the seeds of time

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Publication date: May 2018
Source:Annals of Allergy, Asthma & Immunology, Volume 120, Issue 5
Author(s): Matthew Greenhawt, Jonathan O'B. Hourihane




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Food allergy to previously tolerated foods: course and patient characteristics

Publication date: Available online 21 April 2018
Source:Annals of Allergy, Asthma & Immunology
Author(s): Liat Nachshon, Michael R. Goldberg, Arnon Elizur, Michael Y. Appel, Michael B. Levy, Yitzhak Katz




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School exposure and asthma

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Publication date: May 2018
Source:Annals of Allergy, Asthma & Immunology, Volume 120, Issue 5
Author(s): Brittany Esty, Wanda Phipatanakul
ObjectiveTo provide a comprehensive overview of common school exposures and the association between school exposures and pediatric asthma morbidity.Data SourcesA comprehensive literature review was performed using PubMed.Study SelectionsFull-length, peer-reviewed studies published in English were considered for review. In vivo, in vitro, and animal studies were excluded. Studies of school exposure to cockroach, mouse, dust mite, dog, cat, molds, pollution, and endotoxin associated with asthma and asthma morbidity were considered.ResultsThe current literature establishes an association between school exposure and pediatric asthma morbidity. There is a need for ongoing research to evaluate the effects of school-based environmental interventions on asthma morbidity.ConclusionIt is evident that the indoor school environment is a significant reservoir of allergens, molds, pollutants, and endotoxin and that there is an association between school exposure and pediatric asthma morbidity. School-based interventions have the potential for substantial individual, community, and public health benefit. It is important that researchers continue to study the health effects associated with school exposures and assess cost-effectiveness of multifaceted school-based interventions.



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Publication date: May 2018
Source:Annals of Allergy, Asthma & Immunology, Volume 120, Issue 5
Author(s): Jonathan I. Silverberg, Kevin R. Patel, Vivek Singam




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Cerebral amyloid angiopathy mimicking central nervous system metastases: a case report

This case describes an unusual presentation of an intracranial hemorrhage first thought to be metastatic disease on computed tomography and magnetic resonance imaging. The healthcare team completed an exhausti...

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Orbital T-cell lymphoma in youngest recorded patient – early diagnosis, management, and successful outcome: a case report and review of the literature

Primary orbital peripheral T-cell lymphoma, not otherwise specified is an exceedingly rare disorder with a very poor outcome, and to the best of our knowledge only a few cases have been reported in the English...

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Carvedilol for Prevention of Chemotherapy-Related Cardiotoxicity: The CECCY Trial

AbstractBackground

Anthracycline (ANT) chemotherapy is associated with cardiotoxicity. Prevention with β-blockers remains controversial.

Objectives

This prospective, randomized, double-blind, placebo-controlled study sought to evaluate the role of carvedilol in preventing ANT cardiotoxicity.

Methods

The authors randomized 200 patients with HER2-negative breast cancer tumor status and normal left ventricular ejection fraction (LVEF) referred for ANT (240 mg/m2) to receive carvedilol or placebo until chemotherapy completion. The primary endpoint was prevention of a ≥10% reduction in LVEF at 6 months. Secondary outcomes were effects of carvedilol on troponin I, B-type natriuretic peptide, and diastolic dysfunction.

Results

Primary endpoint occurred in 14 patients (14.5%) in the carvedilol group and 13 patients (13.5%) in the placebo group (p = 1.0). No differences in changes of LVEF or B-type natriuretic peptide were noted between groups. A significant difference existed between groups in troponin I levels over time, with lower levels in the carvedilol group (p = 0.003). Additionally, a lower incidence of diastolic dysfunction was noted in the carvedilol group (p = 0.039). A nonsignificant trend toward a less-pronounced increase in LV end-diastolic diameter during the follow-up was noted in the carvedilol group (44.1 ± 3.64 mm to 45.2 ± 3.2 mm vs. 44.9 ± 3.6 mm to 46.4 ± 4.0 mm; p = 0.057).

Conclusions

In this largest clinical trial of β-blockers for prevention of cardiotoxicity under contemporary ANT dosage, the authors noted a 13.5% to 14.5% incidence of cardiotoxicity. In this scenario, carvedilol had no impact on the incidence of early onset of LVEF reduction. However, the use of carvedilol resulted in a significant reduction in troponin levels and diastolic dysfunction. (Carvedilol Effect in Preventing Chemotherapy-Induced Cardiotoxicity [CECCY]; NCT01724450)



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Epicardial Adipose Tissue May Mediate Deleterious Effects of Obesity and Inflammation on the Myocardium

Abstract

Epicardial adipose tissue has unique properties that distinguish it from other depots of visceral fat. Rather than having distinct boundaries, the epicardium shares an unobstructed microcirculation with the underlying myocardium, and in healthy conditions, produces cytokines that nourish the heart. However, in chronic inflammatory disorders (especially those leading to heart failure with preserved ejection fraction), the epicardium becomes a site of deranged adipogenesis, leading to the secretion of proinflammatory adipokines that can cause atrial and ventricular fibrosis. Accordingly, in patients at risk of heart failure with preserved ejection fraction, drugs that promote the accumulation or inflammation of epicardial adipocytes may lead to heart failure, whereas treatments that ameliorate the proinflammatory characteristics of epicardial fat may reduce the risk of heart failure. These observations suggest that epicardial adipose tissue is a transducer of the adverse effects of systemic inflammation and metabolic disorders on the heart, and thus, represents an important target for therapeutic interventions.



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Genetic Etiology for Alcohol-Induced Cardiac Toxicity

AbstractBackground

Alcoholic cardiomyopathy (ACM) is defined by a dilated and impaired left ventricle due to chronic excess alcohol consumption. It is largely unknown which factors determine cardiac toxicity on exposure to alcohol.

Objectives

This study sought to evaluate the role of variation in cardiomyopathy-associated genes in the pathophysiology of ACM, and to examine the effects of alcohol intake and genotype on dilated cardiomyopathy (DCM) severity.

Methods

The authors characterized 141 ACM cases, 716 DCM cases, and 445 healthy volunteers. The authors compared the prevalence of rare, protein-altering variants in 9 genes associated with inherited DCM. They evaluated the effect of genotype and alcohol consumption on phenotype in DCM.

Results

Variants in well-characterized DCM-causing genes were more prevalent in patients with ACM than control subjects (13.5% vs. 2.9%; p = 1.2 x10–5), but similar between patients with ACM and DCM (19.4%; p = 0.12) and with a predominant burden of titin truncating variants (TTNtv) (9.9%). Separately, we identified an interaction between TTN genotype and excess alcohol consumption in a cohort of DCM patients not meeting ACM criteria. On multivariate analysis, DCM patients with a TTNtv who consumed excess alcohol had an 8.7% absolute reduction in ejection fraction (95% confidence interval: –2.3% to –15.1%; p < 0.007) compared with those without TTNtv and excess alcohol consumption. The presence of TTNtv did not predict phenotype, outcome, or functional recovery on treatment in ACM patients.

Conclusions

TTNtv represent a prevalent genetic predisposition for ACM, and are also associated with a worse left ventricular ejection fraction in DCM patients who consume alcohol above recommended levels. Familial evaluation and genetic testing should be considered in patients presenting with ACM.



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Cryptogenic Stroke and High-Risk Patent Foramen Ovale: The DEFENSE-PFO Trial

AbstractBackground

Recent reports showing the favorable role of patent foramen ovale (PFO) closure in patients with cryptogenic stroke have raised the issue of selecting optimal candidates.

Objectives

This study, DEFENSE-PFO (Device Closure Versus Medical Therapy for Cryptogenic Stroke Patients With High-Risk Patent Foramen Ovale), evaluated whether the benefits of PFO closure can be determined on the basis of the morphologic characteristics of the PFO, as evaluated by transesophageal echocardiography.

Methods

Patients with cryptogenic stroke and high-risk PFO were divided between a transcatheter PFO closure and a medication-only group. High-risk PFO included PFO with atrial septal aneurysm, hypermobility (phasic septal excursion into either atrium ≥10 mm), or PFO size (maximum separation of the septum primum from the secundum) ≥2 mm. The primary endpoint was a composite of stroke, vascular death, or Thrombolysis In Myocardial Infarction–defined major bleeding during 2 years of follow-up.

Results

From September 2011 until October 2017, 120 patients (mean age: 51.8 years) underwent randomization. PFO size, frequency of septal aneurysm (13.3% vs. 8.3%; p = 0.56), and hypermobility (45.0% vs. 46.7%; p > 0.99) were similar between the groups. All PFO closures were successful. The primary endpoint occurred exclusively in the medication-only group (6 of 60 patients; 2-year event rate: 12.9% [log-rank p = 0.013]; 2-year rate of ischemic stroke: 10.5% [p = 0.023]). The events in the medication-only group included ischemic stroke (n = 5), cerebral hemorrhage (n = 1), Thrombolysis In Myocardial Infarction–defined major bleeding (n = 2), and transient ischemic attack (n = 1). Nonfatal procedural complications included development of atrial fibrillation (n = 2), pericardial effusion (n = 1), and pseudoaneurysm (n = 1).

Conclusions

PFO closure in patients with high-risk PFO characteristics resulted in a lower rate of the primary endpoint as well as stroke recurrence. (Device Closure Versus Medical Therapy for Cryptogenic Stroke Patients With High-Risk Patent Foramen Ovale [DEFENSE-PFO]; NCT01550588)



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Major Adverse Limb Events and Mortality in Patients With Peripheral Artery Disease: The COMPASS Trial

AbstractBackground

Patients with lower extremity peripheral artery disease (PAD) are at increased risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE). There is limited information on the prognosis of patients who experience MALE.

Objectives

Among participants with lower extremity PAD, this study investigated: 1) if hospitalizations, MACE, amputations, and deaths are higher after the first episode of MALE compared with patients with PAD who do not experience MALE; and 2) the impact of treatment with low-dose rivaroxaban and aspirin compared with aspirin alone on the incidence of MALE, peripheral vascular interventions, and all peripheral vascular outcomes over a median follow-up of 21 months.

Methods

We analyzed outcomes in 6,391 patients with lower extremity PAD who were enrolled in the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial. COMPASS was a randomized, double-blind placebo-controlled study of low-dose rivaroxaban and aspirin combination or rivaroxaban alone compared with aspirin alone. MALE was defined as severe limb ischemia leading to an intervention or major vascular amputation.

Results

A total of 128 patients experienced an incident of MALE. After MALE, the 1-year cumulative risk of a subsequent hospitalization was 61.5%; for vascular amputations, it was 20.5%; for death, it was 8.3%; and for MACE, it was 3.7%. The MALE index event significantly increased the risk of experiencing subsequent hospitalizations (hazard ratio [HR]: 7.21; p < 0.0001), subsequent amputations (HR: 197.5; p < 0.0001), and death (HR: 3.23; p < 0.001). Compared with aspirin alone, the combination of rivaroxaban 2.5 mg twice daily and aspirin lowered the incidence of MALE by 43% (p = 0.01), total vascular amputations by 58% (p = 0.01), peripheral vascular interventions by 24% (p = 0.03), and all peripheral vascular outcomes by 24% (p = 0.02).

Conclusions

Among individuals with lower extremity PAD, the development of MALE is associated with a poor prognosis, making prevention of this condition of utmost importance. The combination of rivaroxaban 2.5 mg twice daily and aspirin significantly lowered the incidence of MALE and the related complications, and this combination should be considered as an important therapy for patients with PAD. (Cardiovascular Outcomes for People Using Anticoagulation Strategies [COMPASS]; NCT01776424)



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Psychopharmacology and Cardiovascular Disease

Abstract

This review discusses common mental health disorders and their associations with cardiovascular disease risks. Commonly found mental health disorders include depression, anxiety, and personality types. The link between depression and cardiovascular disease mortality has been established. Depression is also common in patients with heart failure. In addition to discussing psychological disorders, a review of psychotropic drugs is also included. Drugs are described for therapy for depression and anxiety, as well as associations with cardiovascular drug-drug interactions. Drug-drug interactions are more common and potentially dangerous in elderly patients, in whom the conditions often coexist. The most common drug-drug interactions involve the P450 system of enzymes.



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