Efficiency, Safety, Quality, and Empathy: Balancing Competing Perioperative Challenges in the Elderly.

Although baby boomer generation accounts for a little more than 15% of the US population, the cohort represents a disproportionate percentage of patients undergoing surgery. As this group continues to age, a multitude of challenges have arisen in health care regarding the safest and most effective means of providing anesthesia services to these patients. Many elderly patients may be exquisitely sensitive to the effects of anesthesia and surgery and may experience cognitive and physical decline before, during, or after hospital admission. In this review article, the authors briefly examine the physiologic processes underlying aging and explore steps necessary to deliver safe, empathetic care.

Integrative geochronology calibrates the Middle and Late Stone Ages of Ethiopia's Afar Rift.

The Halibee member of the Upper Dawaitoli Formation of Ethiopia's Middle Awash study area features a wealth of Middle and Later Stone Age (MSA and LSA) paleoanthropological resources in a succession of Pleistocene sediments. We introduce these artifacts and fossils, and determine their chronostratigraphic placement via a combination of established radioisotopic methods and a recently developed dating method applied to ostrich eggshell (OES). We apply the recently developed 230Th/U burial dating of OES to bridge the temporal gap between radiocarbon (14C) and 40Ar/39Ar ages for the MSA and provide 14C ages to constrain the younger LSA archaeology and fauna to ∼24 to 21.4 ka. Paired 14C and 230Th/U burial ages of OES agree at ∼31 ka for an older LSA locality, validating the newer method, and in turn supporting its application to stratigraphically underlying MSA occurrences previously constrained only by a maximum 40Ar/39Ar age. Associated fauna, flora, and Homo sapiens fossils are thereby now fixed between 106 ± 20 ka and 96.4 ± 1.6 ka (all errors 2σ). Additional 40Ar/39 results on an underlying tuff refine its age to 158.1 ± 11.0 ka, providing a more precise minimum age for MSA lithic artifacts, fauna, and H. sapiens fossils recovered ∼9 m below it. These results demonstrate how chronological control can be obtained in tectonically active and stratigraphically complex settings to precisely calibrate crucial evidence of technological, environmental, and evolutionary changes during the African Middle and Late Pleistocene.

New geological and palaeontological age constraint for the gorilla-human lineage split.

The palaeobiological record of 12 million to 7 million years ago (Ma) is crucial to the elucidation of African ape and human origins, but few fossil assemblages of this period have been reported from sub-Saharan Africa. Since the 1970s, the Chorora Formation, Ethiopia, has been widely considered to contain ~10.5 million year (Myr) old mammalian fossils. More recently, Chororapithecus abyssinicus, a probable primitive member of the gorilla clade, was discovered from the formation. Here we report new field observations and geochemical, magnetostratigraphic and radioisotopic results that securely place the Chorora Formation sediments to between ~9 and ~7 Ma. The C. abyssinicus fossils are ~8.0 Myr old, forming a revised age constraint of the human-gorilla split. Other Chorora fossils range in age from ~8.5 to 7 Ma and comprise the first sub-Saharan mammalian assemblage that spans this period. These fossils suggest indigenous African evolution of multiple mammalian lineages/groups between 10 and 7 Ma, including a possible ancestral-descendent relationship between the ~9.8 Myr old Nakalipithecus nakayamai and C. abyssinicus. The new chronology and fossils suggest that faunal provinciality between eastern Africa and Eurasia had intensified by ~9 Ma, with decreased faunal interchange thereafter. The Chorora evidence supports the hypothesis of in situ African evolution of the Gorilla-Pan-human clade, and is concordant with the deeper divergence estimates of humans and great apes based on lower mutation rates of ~0.5 × 10(-9) per site per year (refs 13 - 15).

The characteristics and chronology of the earliest Acheulean at Konso, Ethiopia.

The Acheulean technological tradition, characterized by a large (>10 cm) flake-based component, represents a significant technological advance over the Oldowan. Although stone tool assemblages attributed to the Acheulean have been reported from as early as circa 1.6-1.75 Ma, the characteristics of these earliest occurrences and comparisons with later assemblages have not been reported in detail. Here, we provide a newly established chronometric calibration for the Acheulean assemblages of the Konso Formation, southern Ethiopia, which span the time period ∼1.75 to <1.0 Ma. The earliest Konso Acheulean is chronologically indistinguishable from the assemblage recently published as the world's earliest with an age of ∼1.75 Ma at Kokiselei, west of Lake Turkana, Kenya. This Konso assemblage is characterized by a combination of large picks and crude bifaces/unifaces made predominantly on large flake blanks. An increase in the number of flake scars was observed within the Konso Formation handaxe assemblages through time, but this was less so with picks. The Konso evidence suggests that both picks and handaxes were essential components of the Acheulean from its initial stages and that the two probably differed in function. The temporal refinement seen, especially in the handaxe forms at Konso, implies enhanced function through time, perhaps in processing carcasses with long and stable cutting edges. The documentation of the earliest Acheulean at ∼1.75 Ma in both northern Kenya and southern Ethiopia suggests that behavioral novelties were being established in a regional scale at that time, paralleling the emergence of Homo erectus-like hominid morphology.

The geological, isotopic, botanical, invertebrate, and lower vertebrate surroundings of Ardipithecus ramidus.

Sediments containing Ardipithecus ramidus were deposited 4.4 million years ago on an alluvial floodplain in Ethiopia's western Afar rift. The Lower Aramis Member hominid-bearing unit, now exposed across a > 9-kilometer structural arc, is sandwiched between two volcanic tuffs that have nearly identical 40Ar/39Ar ages. Geological data presented here, along with floral, invertebrate, and vertebrate paleontological and taphonomic evidence associated with the hominids, suggest that they occupied a wooded biotope over the western three-fourths of the paleotransect. Phytoliths and oxygen and carbon stable isotopes of pedogenic carbonates provide evidence of humid cool woodlands with a grassy substrate.

Induction of robust cellular and humoral virus-specific adaptive immune responses in human immunodeficiency virus-infected humanized BLT mice.

The generation of humanized BLT mice by the cotransplantation of human fetal thymus and liver tissues and CD34(+) fetal liver cells into nonobese diabetic/severe combined immunodeficiency mice allows for the long-term reconstitution of a functional human immune system, with human T cells, B cells, dendritic cells, and monocytes/macrophages repopulating mouse tissues. Here, we show that humanized BLT mice sustained high-level disseminated human immunodeficiency virus (HIV) infection, resulting in CD4(+) T-cell depletion and generalized immune activation. Following infection, HIV-specific humoral responses were present in all mice by 3 months, and HIV-specific CD4(+) and CD8(+) T-cell responses were detected in the majority of mice tested after 9 weeks of infection. Despite robust HIV-specific responses, however, viral loads remained elevated in infected BLT mice, raising the possibility that these responses are dysfunctional. The increased T-cell expression of the negative costimulator PD-1 recently has been postulated to contribute to T-cell dysfunction in chronic HIV infection. As seen in human infection, both CD4(+) and CD8(+) T cells demonstrated increased PD-1 expression in HIV-infected BLT mice, and PD-1 levels in these cells correlated positively with viral load and inversely with CD4(+) cell levels. The ability of humanized BLT mice to generate both cellular and humoral immune responses to HIV will allow the further investigation of human HIV-specific immune responses in vivo and suggests that these mice are able to provide a platform to assess candidate HIV vaccines and other immunotherapeutic strategies.

The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak.

Aberrant wound-healing responses to injury have been implicated in the development of pulmonary fibrosis, but the mediators directing these pathologic responses have yet to be fully identified. We show that lysophosphatidic acid levels increase in bronchoalveolar lavage fluid following lung injury in the bleomycin model of pulmonary fibrosis, and that mice lacking one of its receptors, LPA1, are markedly protected from fibrosis and mortality in this model. The absence of LPA1 led to reduced fibroblast recruitment and vascular leak, two responses that may be excessive when injury leads to fibrosis rather than to repair, whereas leukocyte recruitment was preserved during the first week after injury. In persons with idiopathic pulmonary fibrosis, lysophosphatidic acid levels in bronchoalveolar lavage fluid were also increased, and inhibition of LPA1 markedly reduced fibroblast responses to the chemotactic activity of this fluid. LPA1 therefore represents a new therapeutic target for diseases in which aberrant responses to injury contribute to fibrosis, such as idiopathic pulmonary fibrosis.

Asa Issie, Aramis and the origin of Australopithecus.

The origin of Australopithecus, the genus widely interpreted as ancestral to Homo, is a central problem in human evolutionary studies. Australopithecus species differ markedly from extant African apes and candidate ancestral hominids such as Ardipithecus, Orrorin and Sahelanthropus. The earliest described Australopithecus species is Au. anamensis, the probable chronospecies ancestor of Au. afarensis. Here we describe newly discovered fossils from the Middle Awash study area that extend the known Au. anamensis range into northeastern Ethiopia. The new fossils are from chronometrically controlled stratigraphic sequences and date to about 4.1-4.2 million years ago. They include diagnostic craniodental remains, the largest hominid canine yet recovered, and the earliest Australopithecus femur. These new fossils are sampled from a woodland context. Temporal and anatomical intermediacy between Ar. ramidus and Au. afarensis suggest a relatively rapid shift from Ardipithecus to Australopithecus in this region of Africa, involving either replacement or accelerated phyletic evolution.

Murine B16 melanomas expressing high levels of the chemokine stromal-derived factor-1/CXCL12 induce tumor-specific T cell chemorepulsion and escape from immune control.

The chemokine, stromal-derived factor-1/CXCL12, is expressed by normal and neoplastic tissues and is involved in tumor growth, metastasis, and modulation of tumor immunity. T cell-mediated tumor immunity depends on the migration and colocalization of CTL with tumor cells, a process regulated by chemokines and adhesion molecules. It has been demonstrated that T cells are repelled by high concentrations of the chemokine CXCL12 via a concentration-dependent and CXCR4 receptor-mediated mechanism, termed chemorepulsion or fugetaxis. We proposed that repulsion of tumor Ag-specific T cells from a tumor expressing high levels of CXCL12 allows the tumor to evade immune control. Murine B16/OVA melanoma cells (H2b) were engineered to constitutively express CXCL12. Immunization of C57BL/6 mice with B16/OVA cells lead to destruction of B16/OVA tumors expressing no or low levels of CXCL12 but not tumors expressing high levels of the chemokine. Early recruitment of adoptively transferred OVA-specific CTL into B16/OVA tumors expressing high levels of CXCL12 was significantly reduced in comparison to B16/OVA tumors, and this reduction was reversed when tumor-specific CTLs were pretreated with the specific CXCR4 antagonist, AMD3100. Memory OVA-specific CD8+ T cells demonstrated antitumor activity against B16/OVA tumors but not B16/OVA.CXCL12-high tumors. Expression of high levels of CXCL12 by B16/OVA cells significantly reduced CTL colocalization with and killing of target cells in vitro in a CXCR4-dependent manner. The repulsion of tumor Ag-specific T cells away from melanomas expressing CXCL12 confirms the chemorepellent activity of high concentrations of CXCL12 and may represent a novel mechanism by which certain tumors evade the immune system.

A CXCR4-dependent chemorepellent signal contributes to the emigration of mature single-positive CD4 cells from the fetal thymus.

Developing thymocytes undergo maturation while migrating through the thymus and ultimately emigrate from the organ to populate peripheral lymphoid tissues. The process of thymic emigration is controlled in part via receptor-ligand interactions between the chemokine stromal-derived factor (SDF)-1, and its cognate receptor CXCR4, and sphingosine 1-phosphate (S1P) and its receptor S1PR. The precise mechanism by which S1P/S1PR and CXCR4/SDF-1 contribute to thymic emigration remains unclear. We proposed that S1P-dependent and -independent mechanisms might coexist and involve both S1P-induced chemoattraction and SDF-1-mediated chemorepulsion or fugetaxis of mature thymocytes. We examined thymocyte emigration in thymi from CXCR4-deficient C57BL/6 embryos in a modified assay, which allows the collection of CD62L(high) and CD69(low) recent thymic emigrants. We demonstrated that single-positive (SP) CD4 thymocytes, with the characteristics of recent thymic emigrants, failed to move away from CXCR4-deficient fetal thymus in vitro. We found that the defect in SP CD4 cell emigration that occurred in the absence of CXCR4 signaling was only partially overcome by the addition of the extrathymic chemoattractant S1P and was not associated with abnormalities in thymocyte maturation and proliferative capacity or integrin expression. Blockade of the CXCR4 receptor in normal thymocytes by AMD3100 led to the retention of mature T cells in the thymus in vitro and in vivo. The addition of extrathymic SDF-1 inhibited emigration of wild-type SP cells out of the thymus by nullifying the chemokine gradient. SDF-1 was also shown to elicit a CXCR4-dependent chemorepellent response from fetal SP thymocytes. These novel findings support the thesis that the CXCR4-mediated chemorepellent activity of intrathymic SDF-1 contributes to SP thymocyte egress from the fetal thymus.

Stratigraphic, chronological and behavioural contexts of Pleistocene Homo sapiens from Middle Awash, Ethiopia.

Clarifying the geographic, environmental and behavioural contexts in which the emergence of anatomically modern Homo sapiens occurred has proved difficult, particularly because Africa lacked adequate geochronological, palaeontological and archaeological evidence. The discovery of anatomically modern Homo sapiens fossils at Herto, Ethiopia, changes this. Here we report on stratigraphically associated Late Middle Pleistocene artefacts and fossils from fluvial and lake margin sandstones of the Upper Herto Member of the Bouri Formation, Middle Awash, Afar Rift, Ethiopia. The fossils and artefacts are dated between 160,000 and 154,000 years ago by precise age determinations using the 40Ar/39Ar method. The archaeological assemblages contain elements of both Acheulean and Middle Stone Age technocomplexes. Associated faunal remains indicate repeated, systematic butchery of hippopotamus carcasses. Contemporary adult and juvenile Homo sapiens fossil crania manifest bone modifications indicative of deliberate mortuary practices.

Remains of Homo erectus from Bouri, Middle Awash, Ethiopia.

The genesis, evolution and fate of Homo erectus have been explored palaeontologically since the taxon's recognition in the late nineteenth century. Current debate is focused on whether early representatives from Kenya and Georgia should be classified as a separate ancestral species ('H. ergaster'), and whether H. erectus was an exclusively Asian species lineage that went extinct. Lack of resolution of these issues has obscured the place of H. erectus in human evolution. A hominid calvaria and postcranial remains recently recovered from the Dakanihylo Member of the Bouri Formation, Middle Awash, Ethiopia, bear directly on these issues. These approximately 1.0-million-year (Myr)-old Pleistocene sediments contain abundant early Acheulean stone tools and a diverse vertebrate fauna that indicates a predominantly savannah environment. Here we report that the 'Daka' calvaria's metric and morphological attributes centre it firmly within H. erectus. Daka's resemblance to Asian counterparts indicates that the early African and Eurasian fossil hominids represent demes of a widespread palaeospecies. Daka's anatomical intermediacy between earlier and later African fossils provides evidence of evolutionary change. Its temporal and geographic position indicates that African H. erectus was the ancestor of Homo sapiens.