Predictive value and limitations of animal models for human transplantation: do we need more models for facial transplantation?

Animal models have traditionally provided the basis for preliminary investigation of new techniques prior to trials taking place in human subjects. The timing of when to proceed with human trials is difficult, as the accuracy of preclinical models can only be determined with hindsight. This review outlines the progression from transplantation in animal models to man. Now that many transplant procedures are well established, it is possible to assess the predictive value and limitations of animal models. These results are of great importance in the current debate about composite tissue allotransplantation (CTA) and in particular facial transplantation. This progression of CTA from animal models to man is outlined and compared with early renal, cardiac, and liver transplants. There is some evidence to suggest that animal models may have been misleading in CTA and that this has effectively delayed the transition to humans. The role for animal models in facial transplantation, which is currently making the step to clinical trials, is discussed.     

Intracranial circulation: pulse-sequence considerations in three- dimensional (volume) MR angiography

The technique and feasibility of magnetic resonance (MR) angiography of intracranial vessels were studied in 35 healthy volunteers. Variations in image orientation, repetition time (TR), and flip angle were evaluated to determine their effects on flow-related enhancement. Gradient modifications--including echo time (TE), motion compensation, bandwidth, and field of view--were also studied in an effort to reduce motion-induced phase shifts. Results indicated that a FISP (fast imaging with steady precession) sequence with a TR of 50 msec, TE of 15 msec, velocity compensation in the read and section-select directions, acceleration compensation in the read direction, anisotropic volume, and a 1.25-mm partition thickness produced three-dimensional angiographic MR images that were accurate and reproducible in the depiction of the major intracranial vessels. Difficulties with field of view, persistent signal void secondary to higher-order motion, and spatial resolution remain major problems requiring additional study.     

AlphaV beta3 (αvβ3) integrin inhibition reduces leukocyte–endothelium interaction in a pressure-induced reperfusion model

The leukocyte-endothelium interaction is known to contribute to reperfusion injury, which is considered to participate in the pathophysiology of pressure ulcers, and integrin alphaV beta3 (alphavbeta3) has been shown to mediate the processes of cellular adhesion in various types of cells. This study aims to clarify leukocyte behavior in our original microcirculatory pressure-induced reperfusion model, which can visualize the microcirculation in vivo. We also estimated the effect of alphavbeta3 integrin inhibition on the reduction of the leukocyte-endothelium interaction. Mice with dorsal skinfold chambers were divided into three groups: the baseline group (n=6), in which animals received no compression; the compression-reperfusion group (n=6), in which animals underwent 2-hour compression of the dorsal skin, followed by release, and the inhibitor-treated group (n=7), in which an alphavbeta3 inhibitor, CP4715, was administered in addition to the compression-release procedure. Staining with rhodamine 6G quantitatively visualized leukocyte behavior under the intravital fluorescent microscope. Compression-reperfusion induced a significant increase in rolling, sticking, and extravasation of the leukocytes. Treatment with the inhibitor strikingly reduced leukocyte sticking and extravasation. The present experiment has provided evidence that alphavbeta3 inhibition reduces leukocyte-endothelium interaction in our original pressure-induced reperfusion model.     

Lymphocytes capable of mediating delayed-type hypersensitivity reactions accumulate within sponge matrix allografts

The rejection of sponge matrix allografts across H-2 barriers has generally been found to contain specifically sensitized cytotoxic T cells to donor alloantigen. There is one exception: sponge matrix allografts that differ only with respect to class II alloantigens do not contain specifically sensitized cytotoxic T cells. We therefore investigated the capacity of infiltrating cells removed from sponge matrix allografts to generate delayed hypersensitivity reactions after exposure to fresh alloantigen in a footpad assay. Cells infiltrating class I and II allografts were equally capable of eliciting delayed footpad reactions when injected with specific donor alloantigen into the footpads of naive responder strain mice. Allosensitized T-lymphocyte clones of helper or cytotoxic type were also capable of initiating delayed-type hypersensitivity (DTH) reactions in vivo. We conclude that rejecting allografts across class I or II alloantigenic barriers are infiltrated by cells capable of effecting DTH reactions, in addition to their capacity to exert specific helper or specific cytotoxic reactions. The results also support that both helper and cytotoxic T cells can participate in allospecific DTH reactions.     

Raf-1 kinase,epidermal growth factor receptors,and mutant ras proteins in colonic carcinomas

Epidermal growth factor receptors (EGFR) andras mutations are known to play a significant role in controlling cell growth and tumor promotion. Both of them transmit mitogenic signals to the nucleus by activation of Raf-1 kinase. In this study, the expression of EGFR and mutant Ras proteins, and, for the first time, the expression, phosphorylation and kinase activity of Raf-1 kinase have been determined in paired samples of colorectal cancer and mucosa. The tumor and mucosa samples did not differ significantly with regard to Raf-1 kinase content and activity. A major difference between tumors and mucosa was found, however, in the phosphorylation of Raf-1. Most of the mucosa samples (13/20), but only 1/20 of the cancer samples, contained hyperphosphorylated Raf-1. EGFR were significantly (p=0.0025) decreased in the tumors. The decreased phosphorylation of Raf-1 in colonic carcinomas could be the result of activation of Raf-1 phosphatases or inactivation of kinases phosphorylating Raf-1. New forms of treatment based on EGFR overexpression do not seem to be suitable for the majority of colonic cancers.This work was supported by the state of Baden-Württemberg (Verbundforschungsprojekt: Aufklärung von Mechanismen der Tumorentstehung und Tumorabwehr).     

Bipolar disorder in children and adolescents: obstacles to early diagnosis and future directions

Aim: This article reviews research centred around juvenile bipolar disorder with particular reference to diagnostic difficulties. Putative deficits are scrutinized with respect to trait likelihood and the roles of neuropsychology and neuroimaging in enhancing our understanding of juvenile bipolar disorder are discussed. Methods: Search terms including childhood, adolescent, youth and juvenile combined with the terms ‘bipolar disorder’, mania, depression and hypomania were used to identify relevant studies in MEDLINE and PsychLit. Results: Over recent years research into this relatively new disorder has increased phenomenally. Key issues within the field include diagnostic specificity, the heritability of the disorder, the impact of comorbidity and the implications of neuropsychological and neuroimaging findings. Conclusion: Despite concerning controversies in literature the diagnosis of bipolar disorder in children and adolescents as compared with adults, promising future research directions include better neurological characterization of the disorder through the application of findings from clinical populations, neuropsychological and neuroimaging research.     

Analysis of ischemia-reperfusion injury in a microcirculatory model of pressure ulcers

The aim of this study was to establish a pressure ulcer model that visualizes the microcirculation, and to examine the participation of ischemia-reperfusion injury in the pathophysiology of pressure ulcers. An original system composed of a new skin fold chamber and compression device allowed loading quantitative vertical stress to the skin. An intravital microscopic technique enabled direct visualization of the microcirculation in the physiological condition and in response to pressure application. To estimate the effect of ischemia-reperfusion injury, animals were divided into two groups: the compression-release group (n = 8), in which the animals received four cycles of compression-release which consisted of 2 hours of compression followed by 1 hour of pressure release; and the compression alone group (n = 8) in which the animals underwent continuous compression for 8 hours. Functional capillary density was quantified before the compression procedure and on day 1 (35 hours) after the first evaluation. The cyclic compression-release procedure significantly decreased functional capillary density as compared to continuous compression, indicating that in our experimental setting repetition of ischemia-reperfusion cycle more severely damaged the microcirculation than single prolonged ischemic insult. This finding supports the significant contribution of ischemia-reperfusion injury to the pathophysiology of pressure ulcers at the level of dynamic in vivo microcirculation.     

The effect of perioperative beta-blockade on the pulmonary function of patients undergoing major arterial surgery.

INTRODUCTION: Concern about the potential detrimental side-effects of beta-blockade on pulmonary function often dissuades against their perioperative use in patients undergoing major arterial surgery (especially in those with chronic obstructive pulmonary disease (COPD)). In this study we aimed to establish prospectively the clinical relevance of these concerns. METHODS: After ethics committee approval and individual informed consent, the pulmonary function of twenty patients (mean age 68.7 years (range 43-82), 11 males) scheduled to undergo non-emergency major vascular surgery was studied by recording symptoms and spirometry before and after institution of effective beta-blockade. Fifteen patients (75%) had significant smoking histories (mean pack years/patient=50), while 12 (60%) had COPD. RESULTS: All patients tolerated effective beta-blockade satisfactorily without developing either subjective deterioration in symptoms or significant change on spirometry. The mean change in FEV1 following adequate beta-blockade was 0.05+/-0.24 liters (95% CI -0.06 to +1.61), p=0.35, giving a mean percentage change of 3.18%+/-11.66 (95% CI -2.26 to 8.62). CONCLUSIONS: Previously held concerns about worsening pulmonary function through the short-term use of beta-blockers should not dissuade their perioperative usage in patients with peripheral vascular disease. Furthermore, the accuracy of pulmonary function tests in preoperative assessment and risk stratification also appears unaffected by this therapy.     

What should nurse teachers be doing? A preliminary study

There is little doubt that the role of the nurse teacher is complex and multifaceted in nature. The apparently conflicting demands of NHS trusts and education in the United Kingdom, at the time of integration of nurse education into the higher education sector, further complicates the role. This recognition underlines the need to capture and measure key aspects of nurse teacher function in order to maximize educational gain. Using a comprehensive literature review, focus group discussions and a small number of individual semi-structured interviews, this preliminary study explored the issue of teacher workload, from the perspective of the principal stakeholders in nurse and higher education. Competing research and clinical practice objectives for nurse teachers are identified against a background of changing health care provision, reduced availability of placements and an increased need for evidence-based practice.     

Quantitative MRI studies for assessment of multiple sclerosis.

Although magnetic resonance imaging (MRI) is a valuable aid in the initial diagnosis of multiple sclerosis (MS), quantitatively MRI has been disappointing in staging and evaluating therapy protocols by means of serial examinations. In this study, image processing algorithms were developed for the global analysis of MR images of the cerebrum. Limited three-dimensional segmentation was achieved through histogram analysis by these algorithms, which are essentially operator independent. The effects of coil response and tip angles, patient positioning, and interslice gap thicknesses were examined for 10 MS patients with repeated examinations for a total of 72 images. Effects of technique and instrumentation errors were approximately 6%, and agreement between two independent operators for measuring the total MR pixel sum from periventricular effusions and intense MS plaques was better than 97% with a standard deviation of 2.9%.