Ribosome display and affinity maturation: from antibodies to single V-domains and steps towards cancer therapeutics

Vascular endothelium is an important site for a wide array of immunological processes such as inflammation, atherosclerosis and allograft rejection. Culture methods of mouse vascular endothelium would provide an important in vitro correlate to immunological murine in vivo models. We describe a simple method to culture mouse vascular endothelium from thoracic aorta. Our cultured cells express typical phenotypic (CD105, CD31, CD106), morphological and ultrastructural (intercellular junctions, Weibel-Palade bodies) markers of vascular endothelium. They also possess functional receptors for uptake and processing of acetylated low-density lipoproteins. The mouse vascular endothelium within our system expresses high levels of MHC class I and MHC class II after activation with IFN-gamma. In addition, these cells express the accessory molecules CD80 and CD54, while they lack constitutive expression of CD86 and CD40, providing them the means to function as antigen presenting cells. Alloreactive CD4(+) and CD8(+) T lymphocytes demonstrate evidence of DNA synthesis after co-culture with activated vascular endothelium indicating their commitment to proliferation. In conclusion, we describe a simple culture system to isolate and grow mouse vascular endothelium, which provides a powerful tool to study biological interactions in vitro.     

Geneticists' views on science policy formation and public outreach

Though much research about the public's views of scientists, genetic research and its moral, ethical, and social implications exists, little has been done to investigate how scientists view their own role(s) in public discussions and policy formation related to genetic research and technologies. We interviewed 20 academic geneticists in the United States about their perceptions of the roles they and others (e.g., professional societies, the public, ethicists, and elected officials) do and should play in the formation of science policy, the communication of science to the public, and the public discussions of moral and ethical issues raised by scientific advances. The participants in our study thought that scientists should be more actively involved in public outreach and science policy formation, but frequently they felt ill-equipped and unsupported by their peers and institutions to pursue these activities. Furthermore, many were skeptical of or did not trust elected officials--who they consider uninformed about the issues and too driven by political agendas--to formulate sound science policy. They do, however, have faith in the ability of scientific societies to influence policy effectively, and some thought that societies should play a larger role, both in science policy and as a liaison between scientists and the public. Finally, participants offered suggestions for increasing the involvement and influence of scientists in science-policy formation and public discourse.     

Rapid odor conditioning in newborn rabbits: amnesic effect of hypothermia.

Rabbit pups are completely dependent on a maternal pheromone for the release of suckling behavior. However, if the mother is perfumed prior to nursing, pups will learn to respond to the novel odor with the characteristic nipple-search behavior in just one 3-4 min nursing episode. In a first investigation of the processes underlying this recently developed learning paradigm, time-dependent effects of hypothermia on retention of the task could be demonstrated. Thus pups whose whole body was cooled to a mouth temperature of 7 degrees C immediately after conditioning (n = 10) and tested 24 h later for 3 min on a perfumed fur did not differ significantly in their search response from naive, untreated controls (n = 10). In contrast, pups cooled 4 h after conditioning (n = 10) demonstrated clear retention of the learned response and searched as vigorously as conditioned but uncooled animals (n = 10). As pups of all groups demonstrated normal nipple-search behavior when tested on a lactating doe, the deficits associated with immediate cooling appear to have been specific to the learning task and time of treatment.     

Drug usage guidelines, Part 2: Analysis of program outcome

The effect of integrating a Drug Usage Guidelines (DUG) program with a hospital formulary system was analyzed. Significant changes were observed in both the number of requests submitted to the P & T Committee and the number of drugs added to the formulary after implementation of the DUG program. Failure to follow the DUG submission protocol, particularly with respect to the requirement for supportive clinical data from the primary literature, led to delayed consideration and eventual withdrawal of several highly promoted drug products. The initial involvement of physicians in the planning and implementation of the DUG program has been an important factor in the continued success of the program.     

Scleroderma renal crisis

Scleroderma renal crisis (SRC) is a rare but life-threatening complication of systemic sclerosis (SSc) characterized by malignant hypertension and acute kidney injury. Historically, SRC was the leading cause of death in SSc. However, with the advent of angiotensin converting enzyme (ACE) inhibitors, mortality rates have decreased significantly. Nevertheless, one-year outcomes remain poor, with over 30% mortality and 25% of patients remaining dialysis-dependent. There is an urgent need to improve early recognition and treatment, and to identify novel treatments to improve outcomes of SRC. In this chapter, the clinical features, classification, pathophysiology, differential diagnosis, management and outcomes of SRC are presented. Specific issues relating to pregnancy, prophylactic ACE inhibition and management of essential hypertension are also discussed.     

Affective spectrum disorder: does antidepressant response identify a family of disorders with a common pathophysiology?

Response to pharmacologic treatments may identify groups of disorders with a common pathophysiology. The authors applied a treatment-response model, based on four classes of antidepressants (tricyclic types, monoamine oxidase inhibitors, serotonin uptake inhibitors, and atypical agents), to the medical literature. The model identified eight disorders that may share a pathophysiologic abnormality: major depression, bulimia, panic disorder, obsessive-compulsive disorder, attention deficit disorder with hyperactivity, cataplexy, migraine, and irritable bowel syndrome. Phenomenologic and family studies support this grouping. If the model is validated, this family of disorders, which the authors term "affective spectrum disorder," would represent one of the most prevalent diseases in the population.     

Joint working. Local differences

The interface between social care and primary healthcare remains underdeveloped. Where joint working is effective, it is the result of co-operation, trust and mutual respect. Successful local networks take account of professional autonomy.     

A comparison of four ultraviolet sources to alter graft-versus-host responses

Graft-versus-host disease (GVHD) is a major contributor to the morbidity and mortality associated with allogeneic bone marrow transplantation. Direct ultraviolet B (UVB) irradiation of bone marrow and spleen cell allografts in mice using broadband lamps is known to abolish alloreactive responses which would normally cause GVHD. Using a histoincompatible murine model, we have extended these observations by comparing the physical spectrum of four UV sources (the Philips TUV8W, TL12 and TL01, and the Spectronics XX15B) with in vitro assessment of bone marrow progenitor cell damage and suppression of lymphocyte proliferation and in vivo comparison of the effect on GVHD of the TL12 and XX15B and on the rate of engraftment with the TL12. At doses of uv found to abolish lymphocyte proliferation (2.5, 7, 12 and 1000 J m(-2) with the TUV8W, XX15B, TL12 and TL01 lamps) colony-forming unit granulocyte-macrophage (CFU-GM) proliferation was reduced to 81%, 71%, 79% and 62%, respectively. At an optimal dose found to suppress GVHD (100 J m(-2) integrated radiant energy from 200-320 nm for the TL12 and XX15B) CFU-GM proliferation showed a reduction of 98% with the XX15B and 86% with the TL12. At this radiant energy with the TL12, the rate of bone marrow engraftment was impaired with 72% marrow cellularity at 2 weeks, decreasing to 48% after 200 J m(-2). Our results with this model demonstrate that broadband UVB irradiation of bone marrow permits transplantation across a major histocompatibility barrier. Furthermore we have provided in vitro evidence that narrowband UVB or UVC might potentially be applied to this model.