Yersinia pestis genomes reveal plague in Britain 4000 years ago.

Extinct lineages of Yersinia pestis, the causative agent of the plague, have been identified in several individuals from Eurasia between 5000 and 2500 years before present (BP). One of these, termed the 'LNBA lineage' (Late Neolithic and Bronze Age), has been suggested to have spread into Europe with human groups expanding from the Eurasian steppe. Here, we show that the LNBA plague was spread to Europe's northwestern periphery by sequencing three Yersinia pestis genomes from Britain, all dating to ~4000 cal BP. Two individuals were from an unusual mass burial context in Charterhouse Warren, Somerset, and one individual was from a single burial under a ring cairn monument in Levens, Cumbria. To our knowledge, this represents the earliest evidence of LNBA plague in Britain documented to date. All three British Yersinia pestis genomes belong to a sublineage previously observed in Bronze Age individuals from Central Europe that had lost the putative virulence factor yapC. This sublineage is later found in Eastern Asia ~3200 cal BP. While the severity of the disease is currently unclear, the wide geographic distribution within a few centuries suggests substantial transmissibility.

Continuing medical education in emergency plastic surgery for referring physicians: a prospective assessment of educational needs.

BACKGROUND: Continuing medical education for referring physicians is an essential part of raising the profile of plastic surgery and improving patient care. The authors conducted a prospective cohort study to assess the educational needs of emergency and primary care physicians who refer patients to the on-call plastic surgeon. METHODS: The following information was collected for telephone referrals from emergency and primary care physicians over a 1-year period: date, location of referral center, population of referral center, distance between referral center and tertiary care hospital, patient age, presenting problem, anatomical location of the problem, and treatment plan proposed by the plastic surgeon. In addition, the 50 physicians who most frequently referred patients were surveyed to identify which topics they perceived to be of the highest educational utility and which were frequently encountered. RESULTS: There were a total of 1077 referrals to on-call plastic surgeons, mostly for trauma (83 percent) and injuries involved primarily the upper extremity (65 percent) or head and neck regions (26 percent). Five percent or more of all referrals involved mandible, phalangeal, metacarpal, or zygomatico-orbital complex fractures, minor burns, flexor tendon injuries, single digits requiring revision of an amputation, and extensor tendon injuries. Referring physicians reported that the topics of most educational utility were management of hand infections, minor burns, nasal fractures, boxer's fractures, complex facial lacerations, frostbite, metacarpal fractures, and scaphoid fractures. CONCLUSIONS: To have the greatest potential affect on changing physicians' behavior and improving patient care, continuing medical education should focus on traumatic injuries to the upper extremity and head and neck regions. A prioritized list of topics should include management of minor burns, hand fractures, hand infections, nasal infections, and complex facial lacerations.

Inhibition of intravascular thrombosis in murine endotoxemia by targeted expression of hirudin and tissue factor pathway inhibitor analogs to activated endothelium.

We have generated transgenic mice expressing the leech anticoagulant hirudin and human tissue factor pathway inhibitor tethered to the cell surface by fusion with fragments of human CD4 and P-selectin. Expression of the transgenes is under the control of the CD31 (platelet endothelial cell adhesion molecule [PECAM]) promoter, limiting expression to endothelial cells, monocytes, and platelets. In addition, the P-selectin sequence directs expression to secretory granules. Functional cell surface expression only occurs when the cells are activated. In a mouse model of systemic lipopolysaccharide (LPS)-induced endotoxemia, we show that expression of either anticoagulant on activated endothelium inhibits the widespread intravascular thrombosis, thrombocytopenia, and consumptive coagulopathy associated with endotoxemia. Importantly, non- LPS-treated transgenic mice had normal baseline bleeding times. We speculate that targeted delivery of anticoagulants to the endothelium may be a strategy worth pursuing in clinical sepsis to improve efficacy of systemic anticoagulation while minimizing potential hemorrhagic side effects.

In utero gene transfer of human factor IX to fetal mice can induce postnatal tolerance of the exogenous clotting factor.

The fundamental hypotheses behind fetal gene therapy are that it may be possible (1) to achieve immune tolerance of transgene product and, perhaps, vector; (2) to target cells and tissues that are inaccessible in adult life; (3) to transduce a high percentage of rapidly proliferating cells, and in particular stem cells, with relatively low absolute virus doses leading to clonal transgene amplification by integrating vectors; and (4) to prevent early disease manifestation of genetic diseases. This study provides evidence vindicating the first hypothesis; namely, that intravascular prenatal administration of an adenoviral vector carrying the human factor IX (hFIX) transgene can induce immune tolerance of the transgenic protein. Following repeated hFIX protein injection into adult mice, after prenatal vector injection, we found persistence of blood hFIX and absence of hFIX antibodies in 5 of 9 mice. Furthermore, there was substantial hFIX expression after each of 2 reinjections of vector without detection of hFIX antibodies. In contrast, all adult mice that had not been treated prenatally showed a rapid loss of the injected hFIX and the development of high hFIX antibody levels, both clear manifestations of a strong immune reaction.