Photodynamic drug delivery enhancement in tumours does not depend on leukocyte-endothelial interaction in a human mesothelioma xenograft model

The pre-treatment of tumour neovessels by low-level photodynamic therapy (PDT) improves the distribution of concomitantly administered systemic chemotherapy. The mechanism by which PDT permeabilizes the tumour vessel wall is only partially known. We have recently shown that leukocyte-endothelial cell interaction is essential for photodynamic drug delivery to normal tissue. The present study investigates whether PDT enhances drug delivery in malignant mesothelioma and whether it involves comparable mechanisms of actions.

How reliable is Ki-67 immunohistochemistry in grade 2 breast carcinomas? A QA study of the Swiss Working Group of Breast- and Gynecopathologists

Adjuvant chemotherapy decisions in breast cancer are increasingly based on the pathologist's assessment of tumor proliferation. The Swiss Working Group of Gyneco- and Breast Pathologists has surveyed inter- and intraobserver consistency of Ki-67-based proliferative fraction in breast carcinomas. Methods Five pathologists evaluated MIB-1-labeling index (LI) in ten breast carcinomas (G1, G2, G3) by counting and eyeballing. In the same way, 15 pathologists all over Switzerland then assessed MIB-1-LI on three G2 carcinomas, in self-selected or pre-defined areas of the tumors, comparing centrally immunostained slides with slides immunostained in the different laboratoires. To study intra-observer variability, the same tumors were re-examined 4 months later. Results The Kappa values for the first series of ten carcinomas of various degrees of differentiation showed good to very good agreement for MIB-1-LI (Kappa 0.56–0.72). However, we found very high inter-observer variabilities (Kappa 0.04–0.14) in the read-outs of the G2 carcinomas. It was not possible to explain the inconsistencies exclusively by any of the following factors: (i) pathologists' divergent definitions of what counts as a positive nucleus (ii) the mode of assessment (counting vs. eyeballing), (iii) immunostaining technique, and (iv) the selection of the tumor area in which to count. Despite intensive confrontation of all participating pathologists with the problem, inter-observer agreement did not improve when the same slides were re-examined 4 months later (Kappa 0.01–0.04) and intra-observer agreement was likewise poor (Kappa 0.00–0.35). Conclusion Assessment of mid-range Ki-67-LI suffers from high inter- and intra-observer variability. Oncologists should be aware of this caveat when using Ki-67-LI as a basis for treatment decisions in moderately differentiated breast carcinomas.

Board examination for anatomical pathology in Switzerland: two intense days to verify professional competence

About 15 years ago, the Swiss Society of Pathology has developed and implemented a board examination in anatomical pathology. We describe herein the contents covered by this 2-day exam (autopsy pathology, cytology, histopathology, molecular pathology, and basic knowledge about mechanisms of disease) and its exact modalities, sketch a brief history of the exam, and finish with a concise discussion about the possible objectives and putative benefits weighed against the hardship that it imposes on the candidates.

Postreperfusion cardiac arrest and resuscitation during orthotopic liver transplantation: dynamic visualization and analysis of physiologic recordings

We recently reported on the Multi Wave Animator (MWA), a novel open-source tool with capability of recreating continuous physiologic signals from archived numerical data and presenting them as they appeared on the patient monitor. In this report, we demonstrate for the first time the power of this technology in a real clinical case, an intraoperative cardiopulmonary arrest following reperfusion of a liver transplant graft. Using the MWA, we animated hemodynamic and ventilator data acquired before, during, and after cardiac arrest and resuscitation. This report is accompanied by an online video that shows the most critical phases of the cardiac arrest and resuscitation and provides a basis for analysis and discussion. This video is extracted from a 33-min, uninterrupted video of cardiac arrest and resuscitation, which is available online. The unique strength of MWA, its capability to accurately present discrete and continuous data in a format familiar to clinicians, allowed us this rare glimpse into events leading to an intraoperative cardiac arrest. Because of the ability to recreate and replay clinical events, this tool should be of great interest to medical educators, researchers, and clinicians involved in quality assurance and patient safety.

Resting heart rate and incident heart failure and cardiovascular mortality in older adults: role of inflammation and endothelial dysfunction: the PROSPER study

Resting heart rate is a promising modifiable cardiovascular risk marker in older adults, but the mechanisms linking heart rate to cardiovascular disease are not fully understood. We aimed to assess the association between resting heart rate and incident heart failure (HF) and cardiovascular mortality, and to examine whether these associations might be attributable to systemic inflammation and endothelial dysfunction.

Subclinical thyroid dysfunction and the risk of heart failure in older persons at high cardiovascular risk

Subclinical thyroid dysfunction is common in older people. However, its clinical importance is uncertain.

A high-resolution soil erosion risk map of Switzerland as strategic policy support system

Soil erosion models and soil erosion risk maps are often used as indicators to assess potential soil erosion in order to assist policy decisions. This paper shows the scientific basis of the soil erosion risk map of Switzerland and its application in policy and practice. Linking a USLE/RUSLE-based model approach (AVErosion) founded on multiple flow algorithms and the unit contributing area concept with an extremely precise and high-resolution digital terrain model (2 m × 2 m grid) using GIS allows for a realistic assessment of the potential soil erosion risk, on single plots, i.e. uniform and comprehensive for the agricultural area of Switzerland (862,579 ha in the valley area and the lower mountain regions). The national or small-scale soil erosion prognosis has thus reached a level heretofore possible only in smaller catchment areas or single plots. Validation was carried out using soil loss data from soil erosion damage mappings in the field from long-term monitoring in different test areas. 45% of the evaluated agricultural area of Switzerland was classified as low potential erosion risk, 12% as moderate potential erosion risk, and 43% as high potential erosion risk. However, many of the areas classified as high potential erosion risk are located at the transition from valley to mountain zone, where many areas are used as permanent grassland, which drastically lowers their current erosion risk. The present soil erosion risk map serves on the one hand to identify and prioritise the high-erosion risk areas, and on the other hand to promote awareness amongst farmers and authorities. It was published on the internet and will be made available to the authorities in digital form. It is intended as a tool for simplifying and standardising enforcement of the legal framework for soil erosion prevention in Switzerland. The work therefore provides a successful example of cooperation between science, policy and practice.

Clinical evaluation of the CRIF 4.5/5.5 system for long-bone fracture repair in cattle

OBJECTIVE: To report clinical evaluation of the clamp rod internal fixator 4.5/5.5 (CRIF 4.5/5.5) in bovine long-bone fracture repair. STUDY DESIGN: Retrospective study. ANIMALS: Cattle (n=22) with long-bone fractures. METHODS: Records for cattle with long-bone fractures repaired between 1999 and 2004 with CRIF 4.5/5.5 were reviewed. Quality of fracture repair, fracture healing, and clinical outcome were investigated by means of clinical examination, medical records, radiographs, and telephone questionnaire. RESULTS: Successful long-term outcome was achieved in 18 cattle (82%); 4 were euthanatized 2-14 days postoperatively because of fracture breakdowns. Two cattle had movement of clamps on the rod. Moderate to severe callus formation was evident in 11 cattle 6 months postoperatively. CONCLUSIONS: Movement of clamps on the rod was recognized as implant failure unique to the CRIF. This occurred in cattle with poor fracture stability because of an extensive cortical defect. The CRIF system may not be ideal to treat metacarpal/metatarsal fractures because its voluminous size makes skin closure difficult, thereby increasing the risk of postoperative infections. CLINICAL RELEVANCE: CRIF cannot be recommended for repair of complicated long-bone fractures in cattle.

Tyrosine kinase modulation of protein kinase C activity regulates G protein-linked Ca2+ signaling in leukemic hematopoietic cells

We have used a recombinant mouse pre-B cell line (TonB210.1, expressing Bcr/Abl under the control of an inducible promoter) and several human leukemia cell lines to study the effect of high tyrosine kinase activity on G protein-coupled receptor (GPCR) agonist-stimulated cellular Ca(2+) release and store-operated Ca(2+) entry (SOCE). After induction of Bcr/Abl expression, GPCR-linked SOCE increased. The effect was reverted in the presence of the specific Abl inhibitor imatinib (1microM) and the Src inhibitor PP2 (10microM). In leukemic cell lines constitutively expressing high tyrosine kinase activity, Ca(2+) transients were reduced by imatinib and/or PP2. Ca(2+) transients were enhanced by specific inhibitors of PKC subtypes and this effect was amplified by tyrosine kinase inhibition in Bcr/Abl expressing TonB210.1 and K562 cells. Under all conditions Ca(2+) transients were essentially blocked by the PKC activator PMA. In Bcr/Abl expressing (but not in native) TonB210.1 cells, tyrosine kinase inhibitors enhanced PKCalpha catalytic activity and PKCalpha co-immunoprecipitated with Bcr/Abl. Unlike native TonB210.1 cells, Bcr/Abl expressing cells showed a high rate of cell death if Ca(2+) influx was reduced by complexing extracellular Ca(2+) with BAPTA. Our data suggest that tonic inhibition of PKC represents a mechanism by which high tyrosine kinase activity can enhance cellular Ca(2+) transients and thus exert profound effects on the proliferation, apoptosis and chemotaxis of leukemic cells.