What's New, What's Hot in Solid Organ Transplantation? Summary of the American Transplant Congress 2011.

Breakthroughs in basic and clinical science in solid organ transplantation were presented at the American Transplant Congress 2011. Key areas of presentation included the pathogenesis of late allograft failure, immune regulation and tolerance, pathways in allograft injury, electing appropriate patients for transplantation, determining the best allocation schemes to maximize effective utilization, organ preservation, monitoring the alloimmune response and immunosuppressive management. In this review, we present highlights of the meeting. These presentations demonstrate the exciting promise in translating from the bench to affect patient care.

Clinical implications of advances in the basic science of liver repair and regeneration.

Recent advances in our understanding of the basic mechanisms that control liver regeneration and repair will produce the next generation of therapies for human liver disease. Insights gained from large-scale genetic analysis are producing a new framework within which to plan interventions. Identification of specific molecules that drive regeneration will increase the options for live-donor liver transplantation, and help treat patients with small-for-size syndrome or large tumors who would otherwise have inadequate residual mass after resection. In a complementary fashion, breakthroughs in the ability to manipulate various cell types to adopt the hepatocyte or cholangiocyte phenotype promise to revolutionize therapy for acute liver failure and metabolic liver disease. Finally, elucidating the complex interactions of liver cells with each other and various matrix components during the response to injury is essential for fabricating a liver replacement device. This focused review will discuss how a variety of important scientific advances are likely to impact the treatment of specific types of liver disease.

Evaluating living kidney donors: relationship types, psychosocial criteria, and consent processes at US transplant programs.

We conducted a survey of 132 US kidney transplant programs to examine how they evaluate and select potential living kidney donors, focusing on donor-recipient relationships, psychosocial criteria, and consent processes. There is heterogeneity in donor-recipient relationships that are considered acceptable, although most programs (70%) will not consider publicly solicited donors. Most programs (75%) require a psychosocial evaluation for all potential living donors. Most programs agree that knowledge of financial reward (90%), active substance abuse (86%), and active mental health problems (76%) are absolute contraindications to donation. However, there is greater variability in how other psychosocial issues are considered in the selection process. Consent processes are highly variable across programs: donor and recipient consent for the donor evaluation is presumed in 57% and 76% of programs, respectively. The use of 13 different informed consent elements varied from 65% (alternative donation procedures) to 86% (description of evaluation, surgery and recuperative period) of programs. Forty-three percent use a 'cooling off' period. Findings demonstrate high variability in current practice regarding acceptable donor-recipient relationships, psychosocial criteria, and consent processes. Whether greater consensus should be reached on these donor evaluation practices, especially in the context of more expansive use of living donor kidney transplantation, is discussed.

The medical evaluation of living kidney donors: a survey of US transplant centers.

The use of living donors for kidney transplantation in the United States is common, and long-term studies have demonstrated the safety of donation by young, healthy individuals. However, transplant programs have little data to guide them in deciding which donors are unacceptable, and which characteristics are associated with kidney disease or poor psychosocial outcomes after donation. To document current practices in evaluating potential donors, we surveyed all US kidney transplant programs. Compared to a survey 12 years ago, medical criteria for donation are more inclusive in several areas. All responding programs now accept living unrelated donors. Most programs no longer have an upper age limit to be eligible. Programs are now more likely to accept donors with treated hypertension, or a history of kidney stones, provided that certain additional criteria are met. In contrast, medical criteria for donation are more restrictive in other areas, such as younger donor age and low creatinine clearance. Overall, significant variability remains among transplant programs in the criteria used to evaluate donors. These findings highlight the need for more data on long-term outcomes in various types of donors with potential morbidities related to donation.

Indian hedgehog coordinates endochondral bone growth and morphogenesis via parathyroid hormone related-protein-dependent and -independent pathways.

Indian hedgehog (Ihh) and Parathyroid Hormone-related Protein (PTHrP) play a critical role in the morphogenesis of the vertebrate skeleton. Targeted deletion of Ihh results in short-limbed dwarfism, with decreased chondrocyte proliferation and extensive hypertrophy, features shared by mutants in PTHrP and its receptor. Activation of Ihh signaling upregulates PTHrP at the articular surface and prevents chondrocyte hypertrophy in wild-type but not PTHrP null explants, suggesting that Ihh acts through PTHrP. To investigate the relationship between these factors during development of the appendicular skeleton, mice were produced with various combinations of an Ihh null mutation (Ihh(-/-)), a PTHrP null mutation (PTHrP(-/-)), and a constitutively active PTHrP/Parathyroid hormone Receptor expressed under the control of the Collagen II promoter (PTHrPR*). PTHrPR* rescues PTHrP(-/-) embryos, demonstrating this construct can completely compensate for PTHrP signalling. At 18.5 dpc, limb skeletons of Ihh, PTHrP compound mutants were identical to Ihh single mutants suggesting Ihh is necessary for PTHrP function. Expression of PTHrPR* in chondrocytes of Ihh(-/-) mice prevented premature chondrocyte hypertrophy but did not rescue either the short-limbed dwarfism or decreased chondrocyte proliferation. These experiments demonstrate that the molecular mechanism that prevents chondrocyte hypertrophy is distinct from that which drives proliferation. Ihh positively regulates PTHrP, which is sufficient to prevent chondrocyte hypertrophy and maintain a normal domain of cells competent to undergo proliferation. In contrast, Ihh is necessary for normal chondrocyte proliferation in a pathway that can not be rescued by PTHrP signaling. This identifies Ihh as a coordinator of skeletal growth and morphogenesis, and refines the role of PTHrP in mediating a subset of Ihh's actions.

The Clinical Oncology Information Network (COIN) Project: background, purpose and products.

The Clinical Oncology Information Network (COIN) Project of The Royal College of Radiologists is developing evidence-based practice guidelines, clinical core data sets to audit compliance and a dedicated clinical workstation with a client-server architecture that will collect the data sets as an automatic by-product of the routine delivery of care. Guidelines for the treatment of breast, colorectal, lung and prostate cancer and for the delivery of chemotherapy and radiotherapy will be published in 1999. Version 2 of a demonstrator workstation is in use at the North Middlesex Hospital, London.

Guidance on the creation of evidence-linked guidelines for COIN.

This guidance on the creation of evidence-linked guidelines was issued to the COIN Specially Working Groups charged in 1995 with producing clinical guidelines for breast, colorectral, lung, prostate and testicular cancer and generic guidelines for the delivery of radio- and chemotherapy on behalf of the Faculty of Clinical Oncology of The Royal College of Radiologists and the Joint Council for Clinical Oncology. The first of these guidelines, for lung cancer, is published elsewhere in this issue.

The COIN workstation: state of the future art.

This is a description of the clinical workstation now under development by the Clinical Oncology Information Network (COIN) Project at the Clinical Oncology Centre, North Middlesex Hospital, London, UK. It comprises: introduction; background; technical requirements; design; what the workstation does; how the workstation does it; future plans; glossary; and 26 figures showing screen shots of the workstation in use. The following article sets out the guidance on the creation of evidence-linked guidelines issued to the COIN Specialty Working Groups charged in 1995 with producing clinical guidelines for breast, colorectal, lung, prostate and testicular cancer and generic guidelines for the delivery of radio- and chemotherapy on behalf of the Faculty of Clinical Oncology of The Royal College of Radiologists and the Joint Council for Clinical Oncology. The first of these guidelines, for lung cancer, is published elsewhere in this issue.

Acute right lower quadrant pain in a patient with leukemia.

Typhlitis or neutropenic enterocolitis is a life-threatening, necrotizing process of the cecum whose incidence is increasing. It is usually encountered in patients with leukemia who have recently undergone chemotherapy. Neutropenic enterocolitis presents as fever, abdominal pain, and diarrhea in neutropenic patients. As the incidence of neutropenic enterocolitis increases, emergency physicians must be aware of this rapidly progressive and potentially fatal disease.

Photodynamic therapy inactivates extracellular matrix-basic fibroblast growth factor: insights to its effect on the vascular wall.

PURPOSE: Photodynamic therapy (PDT), the light activation of photosensitizer dyes for the production of oxygen and other free radical moieties without the generation of heat, has been shown to inhibit the development of experimentally induced intimal hyperplasia. The host response to PDT, a form of vascular injury that results in complete vascular wall cell eradication, is devoid of inflammation and proliferation and promotes favorable vascular wall healing. These effects do not result in intimal hyperplasia and are suggestive of PDT-induced changes in the extracellular matrix (ECM). As a model to better understand the biologic consequences of PDT on the vascular wall matrix proteins, the effect of PDT was studied on the powerful matrix-resident mitogen basic fibroblast factor (bFGF) in vitro. METHODS: PDT (5 to 200 J/cm2, 100 mW/cm2, 675 nm) was used with the photosensitizer chloroaluminum sulfonated phthalocyanine (5 micrograms/ml) to inactivate bFGF in vitro while 100 J/cm2 of irradiation was administered 24 hours after 5 mg/ml of the photosensitizer was used in vivo. PDT was used on bFGF in solution and on endothelial cell-derived ECM. Enzyme-linked immunosorbent assay was used to quantitate bFGF in solution after PDT treatment or after extraction from the ECM by collagenase and heparin. Functional activity of matrix-associated bFGF was assessed by smooth muscle cell mitogenesis by 3H-thymidine incorporation. To demonstrate the in vivo relevance of these observations, immunohistochemical analysis of PDT-treated rat carotid arteries was undertaken. RESULTS: PDT eliminated detectable levels of bFGF in solution. PDT of ECM significantly reduced matrix-bound bFGF (1.0 +/- 0.6 vs 27.5 +/- 1.3 pg/ml; p < 0.0001). This reduction in bFGF after PDT of the ECM was associated with a decrease in vascular smooth muscle cell mitogenesis (52.4% +/- 4.6%; p < 0.0001) when plated on PDT-treated matrix compared with nontreated matrix. Quantitative replenishment of exogenous bFGF to PDT-treated matrix restored proliferation to baseline levels. PDT of rat carotid arteries demonstrated a loss of bFGF staining compared with control nontreated arteries. CONCLUSIONS: PDT inactivation of matrix-resident bFGF and possibly other bioactive molecules can provide a mechanism by which PDT suppresses smooth muscle cell proliferation in the vessel wall. This free radical-mediated alteration of matrix may contribute to favorable vascular healing when PDT is used for the inhibition of injury-induced intimal hyperplasia.

Acute myocardial infarction following paclitaxel administration for ovarian carcinoma.

Evidence linking paclitaxel to cardiotoxicity arose from early Phase I trials in which continuous cardiac monitoring was performed because of the high incidence of major hypersensitivity reactions. A variety of cardiac manifestations have been reported, ranging from asymptomatic sinus bradycardia to fatal myocardial infarction. The following case report describes an acute myocardial infarction occurring shortly after paclitaxel therapy.

Differential modulation of vascular endothelial and smooth muscle cell function by photodynamic therapy of extracellular matrix: novel insights into radical-mediated prevention of intimal hyperplasia.

PURPOSE: Photodynamic therapy (PDT) has been demonstrated to inhibit experimental intimal hyperplasia and to lead to expedient reendothelialization but negligible repopulation of the vessel media. The mechanism that underlies the differential ingrowth of cells into PDT-treated vessel segments is not understood. Because the extracellular matrix (ECM) is known to modulate specific cell functions, this study was designed to determine whether PDT of isolated ECM affects the function of endothelial cells (ECs) and smooth muscle cells (SMCs). METHODS: PDT of bovine aortic EC-ECM was performed with chloroaluminum sulfonated phthalocyanine and 675-nm laser light. Control specimens included untreated ECM, ECM-free plates, and ECM exposed to either light or photosensitizer only. Cell function was characterized by attachment, proliferation, and migration of ECs or SMCs that were plated onto identically treated matrixes. RESULTS: SMC attachment (86% +/- 0.4% vs 95% +/- 0.4%), proliferation (46% +/- 0.5% vs 100% +/- 1.4%), and migration (40% +/- 1.0% vs 100% +/- 0.9%) were significantly inhibited after PDT of ECM when compared with untreated ECM (all p < 0.001). In contrast, PDT of ECM significantly enhanced EC proliferation (129% +/- 6.2% vs 100% +/- 6.2%; p < 0.03) and migration (118% +/- 2% vs 100% +/- 0.8; p < 0.01), but did not affect attachment. CONCLUSIONS: This report establishes PDT-induced changes in the ECM with a result of inhibition of SMCs and stimulation of EC functions. It provides insight into how PDT-treated arteries can develop favorable EC repopulation without SMC-derived intimal hyperplasia. These findings may help provide a better understanding of the interactions between cells and their immediate environment in vascular remodeling.

Molecular cloning and chromosomal localization of the key subunit of the human N-methyl-D-aspartate receptor.

A complementary DNA encoding the key subunit of the human N-methyl-D-aspartate (NMDA) receptor (NMDAR1) has been cloned using a probe derived from the rat NMDAR1 cDNA. The cDNA encodes a 938-amino acid protein, which shows 99% amino acid homology with the rat counterpart. Of the 7 of 938 amino acids which are different, three occur in the region of the signal peptide and the others in the extracellular amino-terminal domain preceding the 4 putative transmembrane segments. Expression in Xenopus oocytes demonstrated that the single protein encoded by the cloned cDNA possesses the electrophysiological and pharmacological properties characteristic of the NMDA receptor, including Ca2+ permeability, voltage-dependent Mg2+ block, and inhibition by selective antagonists such as Zn2+ and channel blockers. The high evolutionary conservation in the structure and properties of NMDAR1 argues strongly for the importance of this receptor in functions of glutamate neurotransmission. RNA blot analysis showed abundant expression of mRNA whose size is about 4.5 and 4.8 kilonucleotides. The human gene encoding the NMDAR1 subunit has been mapped to chromosome 9q34.3 by the analyses of blot hybridization of a DNA panel of human/hamster somatic cell hybrids and fluorescence in situ hybridization of human chromosomes.

Audit: the use of radiotherapy for NSCLC in the UK.

A questionnaire on the management of NSCLC was sent to all clinical oncologists in the UK. Responses were received from 121 individuals with at least one representative response from each of 54 British radiotherapy units. Results were then discussed at an open meeting attended by a cross section of clinical oncologists; a synopsis of responses to the questionnaire and discussion at this meeting is contained in this report. A majority of respondents estimated treatment of NSCLC to make up 10%-25% of their work-load. Radical and palliative treatments could be clearly distinguished, and aims of treatment, selection criteria and radiotherapy schedules were consistent with recommendations in the published literature. More than 90% of treatments were with palliative rather than radical intent. Radical treatment schedules could be divided according to dose (< 50 Gy, 50-55 Gy and >55 Gy), number of fractions (< 20, 20, > 20 fractions), overall time < 4/52, 4/52, > 4/52), dose per fraction (> 2.75 Gy, 2.1-2.75 Gy, < or = 2 Gy) and target volume (tumour alone, tumour and hilar nodes, or tumour, hilar and mediastinal nodes). Divided thus, radical techniques fell into three broad groups, each of the three techniques supported by a body of literature. Choice of schedule could be related to a heterogeneous referral pattern and unresolved controversies, identified as debate on the value of treating mediastinal lymphadenopathy with high dose radiation, the value of 'subradical doses' of radiation for microscopic disease, and the relative importance of volume treated, total dose, dose per fraction and overall treatment time in achieving an optimal therapeutic ratio.(ABSTRACT TRUNCATED AT 250 WORDS)