Benefits of Public R&D in U.S. Agriculture: Spill-Ins, Extension and Roads

This paper uses panel data for the 1980-2004 period to estimate the contributions of public research to US agricultural productivity growth. Local and social internal rates of return are estimated accounting for the effects of R & D spill-in, extension activities and road density. R & D spill-in proxies were constructed based on both geographic proximity and production profile to examine the sensitivity of the rates of return to these alternatives. We find that extension activities, road density, and R & D spill-ins, play an important role in enhancing the benefit of public R & D investments. We also find that the local internal rates of return, although high, have declined through time along with investments in extension, while the social rates have not. Yet, the social rates of return are not robust to the choice of spill-in proxy

Infections in recipients of liver homografts.

Seventeen patients received liver homografts between 1963 and May, 1968. The eight treated before July, 1967, died within 34 days; seven had progressive infections with gram-negative bacilli, Candida albicans and cytomegalovirus. The infections were similar to but more fulminating than those after renal homotransplantation. In nine later cases, there was more discriminating donor selection, improved immunosuppression, and better organ preservation. In the first five of these nine patients, all infants, lobar hepatic gangrene apparently secondary to delayed right hepatic arterial thrombosis developed. Two died within a few days, two and three and a half months after transplantation. The three who did not die immediately subsequently had multiple bacteremias, fungemias and cytomegalovirus pulmonary infections. One of these children is alive twelve months after transplantation; the others died after four and a half and six months. In contrast, the last four patients, in whom septic liver infarctions were avoided, have been free of serious infections for two to five and a half months

Education about death and dying during surgical residency

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29314/1/0000379.pd

Genomic Expression Libraries for the Identification of Cross-Reactive Orthopoxvirus Antigens

Increasing numbers of human cowpox virus infections that are being observed and that particularly affect young non-vaccinated persons have renewed interest in this zoonotic disease. Usually causing a self-limiting local infection, human cowpox can in fact be fatal for immunocompromised individuals. Conventional smallpox vaccination presumably protects an individual from infections with other Orthopoxviruses, including cowpox virus. However, available live vaccines are causing severe adverse reactions especially in individuals with impaired immunity. Because of a decrease in protective immunity against Orthopoxviruses and a coincident increase in the proportion of immunodeficient individuals in today's population, safer vaccines need to be developed. Recombinant subunit vaccines containing cross-reactive antigens are promising candidates, which avoid the application of infectious virus. However, subunit vaccines should contain carefully selected antigens to confer a solid cross-protection against different Orthopoxvirus species. Little is known about the cross-reactivity of antibodies elicited to cowpox virus proteins. Here, we first identified 21 immunogenic proteins of cowpox and vaccinia virus by serological screenings of genomic Orthopoxvirus expression libraries. Screenings were performed using sera from vaccinated humans and animals as well as clinical sera from patients and animals with a naturally acquired cowpox virus infection. We further analyzed the cross-reactivity of the identified immunogenic proteins. Out of 21 identified proteins 16 were found to be cross-reactive between cowpox and vaccinia virus. The presented findings provide important indications for the design of new-generation recombinant subunit vaccines

Efficacy and Safety/Toxicity Study of Recombinant Vaccinia Virus JX-594 in Two Immunocompetent Animal Models of Glioma

The purpose of this study was to investigate the oncolytic potential of the recombinant, granulocyte macrophage colony-stimulating factor (GM-CSF)-expressing vaccinia virus (VV) JX-594 in experimental malignant glioma (MGs) in vitro and in immunocompetent rodent models. We have found that JX-594 killed all MG cell lines tested in vitro. Intratumoral (i.t.) administration of JX-594 significantly inhibited tumor growth and prolonged survival in rats-bearing RG2 intracranial (i.c.) tumors and mice-bearing GL261 brain tumors. Combination therapy with JX-594 and rapamycin significantly increased viral replication and further prolonged survival in both immunocompetent i.c. MG models with several animals considered “cured” (three out of seven rats >120 days, terminated experiment). JX-594 infected and killed brain tumor-initiating cells (BTICs) from patient samples grown ex vivo, and did so more efficiently than other oncolytic viruses MYXV, Reovirus type-3, and VSVΔM51. Additional safety/toxicity studies in nontumor-bearing rodents treated with a supratherapeutic dose of JX-594 demonstrated GM-CSF-dependent inflammation and necrosis. These results suggest that i.c. administered JX-594 triggers a predictable GM-CSF-mediated inflammation in murine models. Before proceeding to clinical trials, JX-594 should be evaluated in the brains of nonhuman primates and optimized for the viral doses, delivery routes as well as the combination agents (e.g., mTOR inhibitors)

Adverse Events Post Smallpox-Vaccination: Insights from Tail Scarification Infection in Mice with Vaccinia virus

Adverse events upon smallpox vaccination with fully-replicative strains of Vaccinia virus (VACV) comprise an array of clinical manifestations that occur primarily in immunocompromised patients leading to significant host morbidity/mortality. The expansion of immune-suppressed populations and the possible release of Variola virus as a bioterrorist act have given rise to concerns over vaccination complications should more widespread vaccination be reinitiated. Our goal was to evaluate the components of the host immune system that are sufficient to prevent morbidity/mortality in a murine model of tail scarification, which mimics immunological and clinical features of smallpox vaccination in humans. Infection of C57BL/6 wild-type mice led to a strictly localized infection, with complete viral clearance by day 28 p.i. On the other hand, infection of T and B-cell deficient mice (Rag1−/−) produced a severe disease, with uncontrolled viral replication at the inoculation site and dissemination to internal organs. Infection of B-cell deficient animals (µMT) produced no mortality. However, viral clearance in µMT animals was delayed compared to WT animals, with detectable viral titers in tail and internal organs late in infection. Treatment of Rag1−/− with rabbit hyperimmune anti-vaccinia serum had a subtle effect on the morbidity/mortality of this strain, but it was effective in reduce viral titers in ovaries. Finally, NUDE athymic mice showed a similar outcome of infection as Rag1−/−, and passive transfer of WT T cells to Rag1−/− animals proved fully effective in preventing morbidity/mortality. These results strongly suggest that both T and B cells are important in the immune response to primary VACV infection in mice, and that T-cells are required to control the infection at the inoculation site and providing help for B-cells to produce antibodies, which help to prevent viral dissemination. These insights might prove helpful to better identify individuals with higher risk of complications after infection with poxvirus

T Cell-Dependence of Lassa Fever Pathogenesis

Lassa virus (LASV), the causative agent of Lassa fever (LF), is endemic in West Africa, accounting for substantial morbidity and mortality. In spite of ongoing research efforts, LF pathogenesis and mechanisms of LASV immune control remain poorly understood. While normal laboratory mice are resistant to LASV, we report that mice expressing humanized instead of murine MHC class I (MHC-I) failed to control LASV infection and develop severe LF. Infection of MHC-I knockout mice confirmed a key role for MHC-I-restricted T cell responses in controlling LASV. Intriguingly we found that T cell depletion in LASV-infected HHD mice prevented disease, irrespective of high-level viremia. Widespread activation of monocyte/macrophage lineage cells, manifest through inducible NO synthase expression, and elevated IL-12p40 serum levels indicated a systemic inflammatory condition. The absence of extensive monocyte/macrophage activation in T cell-depleted mice suggested that T cell responses contribute to deleterious innate inflammatory reactions and LF pathogenesis. Our observations in mice indicate a dual role for T cells, not only protecting from LASV, but also enhancing LF pathogenesis. The possibility of T cell-driven enhancement and immunopathogenesis should be given consideration in future LF vaccine development

Study protocol: Determinants of participation and quality of life of adolescents with cerebral palsy: a longitudinal study (SPARCLE2)

<p>Abstract</p> <p>Background</p> <p>Children and adults with impairments such as cerebral palsy have lower participation in life situations than able-bodied people. Less is known about their subjective perception of their lives, called their quality of life.</p> <p>During adolescence, rapid physical and psychological changes occur; although these may be more difficult for disabled than for able-bodied adolescents, little research has examined the lives of disabled adolescents.</p> <p>In 2003-4 a European Union funded project, SPARCLE, visited 818 children aged 8-12 years with cerebral palsy, sampled from population-based registers in nine European regions. The quality of life reported by these disabled children was similar to that of the general population but their participation was lower; levels of participation varied between countries even for children with similar severity of cerebral palsy.</p> <p>We are currently following up these children, now aged 13-17 years, to identify (i) to what extent contemporaneous factors (pain, impairment, psychological health and parental stress) predict their participation and quality of life, (ii) what factors modify how participation and quality of life at age 8-12 years are associated with participation and quality of life in adolescence, and (iii) whether differences between European countries in participation and quality of life can be explained by variations in environmental factors.</p> <p>Methods/Design</p> <p>Trained researchers will visit families to administer questionnaires to capture the adolescents' type and severity of impairment, socio-demographic characteristics, participation, quality of life, psychological health, pain, environmental access and parental stress. We will use multivariable models (linear, logistic or ordinal) to assess how adolescent participation, quality of life, psychological health, pain, environmental access and parental stress, vary with impairment and socio-demographic characteristics and, where possible, how these outcomes compare with general population data. For participation and quality of life, longitudinal analyses will assess to what extent these are predicted by corresponding levels in childhood and what factors modify this relationship. Structural equation modelling will be used to identify indirect relationships mediated by other factors.</p