Tacticity in chiral phononic crystals.

The study of vibrational properties in engineered periodic structures relies on the early intuitions of Haüy and Boscovich, who regarded crystals as ensembles of periodically arranged point masses interacting via attractive and repulsive forces. Contrary to electromagnetism, where mechanical properties do not couple to the wave propagation mechanism, in elasticity this paradigm inevitably leads to low stiffness and high-density materials. Recent works transcend the Haüy-Boscovich perception, proposing shaped atoms with finite size, which relaxes the link between their mass and inertia, to achieve unusual dynamic behavior at lower frequencies, leaving the stiffness unaltered. Here, we introduce the concept of tacticity in spin-spin-coupled chiral phononic crystals. This additional layer of architecture has a remarkable effect on their dispersive behavior and allows to successfully realize material variants with equal mass density and stiffness but radically different dynamic properties.

Balancing efficacy and toxicity of kidney transplant immunosuppression.

Late renal allograft loss is mainly the result of progressive histological damage. Both underimmunosuppression (rejection phenomena) and overimmunosuppression (calcineurin inhibitor nephrotoxicity) contribute to the progression of chronic histological damage. The current study was performed to elucidate the complementary impact of immune and nonimmune phenomena on renal allograft histology and function. By performing protocol biopsies, it was demonstrated that clinical and subclinical acute cellular rejection phenomena continue to play important roles, despite the use of the powerful combination of tacrolimus, mycophenolate mofetil, and steroids. Next to immune phenomena, the importance of nonimmune factors in renal allograft histological evolution was shown in protocol biopsy studies. Both in adult and in pediatric renal allograft recipients, the characteristics of the donor kidney (donor age, size discrepancy) appeared to be major determinants of the histological and functional evolution. This impact of donor characteristics was not only important in the immediate peritransplantation period, it was also shown that higher donor age increased the risk for progressive posttransplant histological injury and calcineurin inhibitor nephrotoxicity. Systemic levels of tacrolimus, if kept within a relatively narrow target window, were not associated with a risk for calcineurin inhibitor nephrotoxicity. However, we observed a significant association between renal allograft histology and P-glycoprotein (ABCB1) gene polymorphisms and expression, suggesting a role of this protein in the individual susceptibility to calcineurin inhibitor nephrotoxicity. Finally, the interplay between immune and nonimmune phenomena was demonstrated by the association between donor origin (deceased versus living) and local renal complement gene expression, by using whole-genome expression microarrays.

Quantification of material nonlinearity in relation to microdamage density using nonlinear reverberation spectroscopy: Experimental and theoretical study.

High amplitude vibrations induce amplitude dependence of the characteristic resonance parameters (i.e., resonance frequency and damping factor) in materials with microscopic damage features as a result of the nonlinear constitutive relation at the damage location. This paper displays and quantifies results of the nonlinear resonance technique, both in time (signal reverberation) and in frequency (sweep) domains, as a function of sample crack density. The reverberation spectroscopy technique is applied to carbon fiber reinforced plastic (CFRP) composites exposed to increasing thermal loading. Considerable gain in sensitivity and consistent interpretation of the results for nonlinear signatures in comparison with the linear characteristics are obtained. The amount of induced damage is quantified by analyzing light optical microscopy images of several cross-sections of the CFRP samples using histogram equalization and grayscale thresholding. The obtained measure of crack density is compared to the global macroscopic nonlinearity of the sample and explicitly confirms that the increase in nonlinearity is linked to an increased network of cracks. A change from 1% to 3% in crack density corresponds to a tenfold increase in the signature of nonlinearity. Numerical simulations based on a uniform distribution of a hysteretic nonlinear constitutive relation within the sample support the results.

Localization, etiology and impact of calcium phosphate deposits in renal allografts.

Hypercalcemia, hypophosphatemia and renal phosphate wasting are common after kidney transplantation. Animal data suggest that these alterations in mineral metabolism may contribute to calcium phosphate (CaPhos) deposition in the kidney and renal dysfunction. We tested the hypothesis that CaPhos deposition is highly prevalent in the early posttransplant period and is related to a disturbed mineral metabolism. For this purpose, biomarkers of mineral metabolism and renal calcium and phosphorus handling were prospectively assessed in 201 renal transplant recipients. CaPhos deposits were observed in 4.6, 30.4 and 24.7% of protocol biopsies obtained at the time of engraftment, and 3 and 12 months thereafter, respectively. In multivariate logistic regression analysis, high calcium and low serum phosphorus levels were independently associated with renal CaPhos deposition at month 3. The extent of CaPhos deposition correlated significantly with the severity of mineral metabolism disturbances. Renal function after a mean follow-up of 33 months was similar in patients with and without CaPhos deposition at month 3. In conclusion, our data demonstrate that CaPhos deposition is highly prevalent in the early posttransplant period and suggest that a disordered mineral metabolism is implicated in its pathogenesis. The clinical relevance of CaPhos deposition remains to be established.

TuBaFrost: European virtual tumor tissue banking.

TuBaFrost is a consortium responsible for the task to create a virtual European human frozen tumor tissue bank, composed of high quality frozen tumor tissue collections with corresponding accurate diagnosis stored in European cancer centers and universities, searchable on the Internet, providing rules for access and use and a code of conduct to comply with the various legal and ethical regulations in European countries. Such infrastructure would enlarge tissue availability and accessibility in large amounts of specified or even rare tumor samples. Design of an infrastructure for European residual tissue banking with the described characteristics, clear focus points emerge that can be broken down in dedicated subjects: (1) standardization and quality assurance (QA) to avoid inter-institute quality variation; (2) law and ethics enabling exchange of tissue samples possible between institutes in the different European countries, where law and ethics are characterized by a strong variability; (3) rules for access, with sufficient incentives for collectors; (4) central database application containing innovations on search and selection procedures; (5) support when needed with histology images; and (6) Internet access to search and upload, with in addition a solid website giving proper information on the procedures, intentions and activities not only to the scientific community, but also to the general public. One consortium decision, part of the incentives for collectors, had major impact on the infrastructure; custodianship over the tissues as well as the tissues stay with the collector institute. Resulting in specimens that are not given to an organization, taking decisions on participation of requests, but instead the local collected tissues stay very easy to access by the collector and allows autonomous negotiation between collector and requestor on cooperation, coauthorship in publication or compensation in costs. Thereby, improving availability of large amounts of high quality samples of a highly specified or rare tumor types and contact opportunities for cooperation with other institutes.

Virtual microscopy in virtual tumor banking.

Many systems have already been designed and successfully used for sharing histology images over large distances, without transfer of the original glass slides. Rapid evolution was seen when digital images could be transferred over the Internet. Nowadays, sophisticated virtual microscope systems can be acquired, with the capability to quickly scan large batches of glass slides at high magnification and compress and store the large images on disc, which subsequently can be consulted through the Internet. The images are stored on an image server, which can give simple, easy to transfer pictures to the user specifying a certain magnification on any position in the scan. This offers new opportunities in histology review, overcoming the necessity of the dynamic telepathology systems to have compatible software systems and microscopes and in addition, an adequate connection of sufficient bandwidth. Consulting the images now only requires an Internet connection and a computer with a high quality monitor. A system of complete pathology review supporting biorepositories is described, based on the implementation of this technique in the European Human Frozen Tumor Tissue Bank (TuBaFrost).

TuBaFrost 6: virtual microscopy in virtual tumour banking.

Many systems have already been designed and successfully used for sharing histology images over large distances, without transfer of the original glass slides. Rapid evolution was seen when digital images could be transferred over the Internet. Nowadays, sophisticated Virtual Microscope systems can be acquired, with the capability to quickly scan large batches of glass slides at high magnification and compress and store the large images on disc, which subsequently can be consulted through the Internet. The images are stored on an image server, which can give simple, easy to transfer pictures to the user specifying a certain magnification on any position in the scan. This offers new opportunities in histology review, overcoming the necessity of the dynamic telepathology systems to have compatible software systems and microscopes and in addition, an adequate connection of sufficient bandwidth. Consulting the images now only requires an Internet connection and a computer with a high quality monitor. A system of complete pathology review supporting bio-repositories is described, based on the implementation of this technique in the European Human Frozen Tumor Tissue Bank (TuBaFrost).

TuBaFrost 1: Uniting local frozen tumour banks into a European network: an overview.

TuBaFrost is the consortium responsible for the creation of a virtual European human frozen tumour tissue bank: a collection of high quality frozen residual, accurately classified tumour tissue samples, which are stored in European cancer centres and universities. This virtual tissue bank, searchable on the internet, has rules for access and use, and a code of conduct to comply with the various legal and ethical regulations in European countries. The easy accessibility and the European scale of the bank will result in the availability of a large number of samples even of rarer tumour types. Standardisation of collection, storage and quality control throughout the network is achieved minimising inter-institutional variability. A website providing access to upload, search and request samples is a key tool of the tissue bank. The search engine makes use of virtual microscopy. An overview of the development of the European virtual frozen tissue bank infrastructure is described in this paper. The various key aspects are described in more detail in a series of articles to appear in this Journal.

TuBaFrost 2: Standardising tissue collection and quality control procedures for a European virtual frozen tissue bank network.

Tumour Bank Networking presents a great challenge for oncological research as in order to carry out large-scale, multi-centre studies with minimal intrinsic bias, each tumour bank in the network must have some fundamental similarities and be using the same standardised and validated procedures. The European Human Frozen Tumour Tissue Bank (TuBaFrost) has responded to this need by the promotion of an integrated platform of tumour banks in Europe. The operational framework for TuBaFrost has drawn upon the best practice of standard workflows and operating procedures employed by members of the TuBaFrost project and key initiatives worldwide.

TuBaFrost 4: access rules and incentives for a European tumour bank.

When designing infrastructure for a networked virtual tumour bank (samples remain at the collector institutes and sample data are collected in a searchable central database), it is apparent that this can only function properly after developing an adequate set of rules for use and access. These rules must include sufficient incentives for the tissue sample collectors to remain active within the network and maintain sufficient sample levels in the local bank. These requirements resulted in a key TuBaFrost rule, stating that the custodianship of the samples remains under the authority of the local collector. As a consequence, the samples and the decision to issue the samples to a requestor are not transferred to a large organisation but instead remain with the collector, thus allowing autonomous negotiation between collector and requestor, potential co-authorship in publications or compensation for collection and processing costs. Furthermore, it realises a streamlined cost effective network, ensuring tissue visibility and accessibility thereby improving the availability of large amounts of samples of highly specific or rare tumour types as well as providing contact opportunities for collaboration between scientists with cutting edge technology and tissue collectors. With this general purpose in mind, the rules and responsibilities for collectors, requestors and central office were generated.

TuBaFrost 3: regulatory and ethical issues on the exchange of residual tissue for research across Europe.

The regulatory regimes for research with residual tissue and accompanying data differ widely between countries in the European Union (EU): from specific consent to opt-out or even no consent at all. This could greatly hamper research where the exchange of tissue and accompanying data has become the gold standard, like in TubaFrost. Instead of adhering to international guidelines, which have a democratic deficit, or an attempt for a new set of possible harmonising rules, TubaFrost chose to create a coordinating rule: if tissue may legitimately be used for a certain kind of research in the country where it was taken and under whose jurisdiction the patient falls, it may also be used for such research in the country where it is sent to in the context of a scientific program even if in that other country other regulations would apply for research with residual tissue taken from patients under their jurisdiction. This coordinating rule has a sound basis in EU law in general and will solve the problems related to diverging national regulatory regimes in the case of cross national research with residual tissue.

TuBaFrost 5: multifunctional central database application for a European tumor bank.

Developing a tissue bank database has become more than just logically arranging data in tables combined with a search engine. Current demand for high quality samples and data, and the ever-changing legal and ethical regulations mean that the application must reflect TuBaFrost rules and protocols for the collection, exchange and use of tissue. To ensure continuation and extension of the TuBaFrost European tissue bank, the custodianship of the samples, and hence the decision over whether to issue samples to requestors, remains with the local collecting centre. The database application described in this article has been developed to facilitate this open structure virtual tissue bank model serving a large group. It encompasses many key tasks, without the requirement for personnel, hence minimising operational costs. The Internet-accessible database application enables search, selection and request submission for requestors, whereas collectors can upload and edit their collection. Communication between requestor and involved collectors is started with automatically generated e-mails.

The podocyte: from bench to bedside.

The understanding of the molecular structure of the podocyte has increased considerabely in recent 5 years by genetic research in inherited glomerulopathies. Injury to the podocyte often leads to a reorganisation of the slit diaphragm and to foot process effacement, which can be noted in all forms of the nephrotic syndrome. Since the recent progress in our understanding of the molecular biology of the podocyte, it has become obvious that the podocyte is crucial in the pathogenesis of not only genetic but also of many acquired glomerulopathies such as focal segmental glomerulosclerosis, membranous glomerulopathy and diabetic nephropathy. In this review we provide a summary of the recent physiological and molecular insights into the podocyte and of its significance in different glomerulopathies.

Completion thyroidectomy after the unexpected diagnosis of thyroid cancer.

The optimal surgical management of well-differentiated thyroid cancer (DTC) remains a controversial topic. Preoperative and peroperative investigations quite frequently fail to detect thyroid cancer in cold nodules, and only postoperative histological examination reveals malignancy. In these cases many physicians perform a completion thyroidectomy. Others recommend a conservative approach with close follow-up because of the increased risk of complications after re-operation. In our department, routine management includes completion thyroidectomy once the histopathological report concludes that there is carcinoma, except in cases of papillary carcinoma measuring less than 1 cm. The aim of our study was to determine the incidence of contralateral malignancy and of complications after completion thyroidectomy. We reviewed the records of 29 patients--25 women and 4 men-- who all underwent completion thyroidectomy because of an unexpected diagnosis of DTC. Residual malignancy was found in 12 patients (41.4%) after completion thyroidectomy. In ten patients (34.5%) the malignancy was localised in the contralateral lobe and two patients (6.9%) had lymph node metastases. Postoperative transient hypocalcaemia (< 8.0 mg/dl) occurred in five patients (17.2%) and permanent hypocalcaemia (lasting longer than 6 months) was a feature in two patients. One patient suffered transient laryngeal nerve injury occurred in one patient and there were no permanent lesions. In conclusion, we found residual DTC in 41.4% of patients undergoing reintervention. Because of the rather low re-operation rate, we prefer to perform a completion thyroidectomy to remove potential occult malignancy and to allow for postoperative 131I-treatment in all patients with a diagnosis of malignancy in their thyroid lobectomy specimen, with the exception of papillary carcinoma < 1 cm.

A new methodology for teaching clinical reasoning skills: problem solving clinical seminars.

In the final year of the medical curriculum of the Faculty of Medicine of the Katholieke Universiteit Leuven (Belgium), a new methodology for teaching clinical skills was introduced: Problem Solving Clinical Seminars (PSCS). Two eight-week series of 70 seminars were offered. Students prepared for the seminars in groups of five students who worked on one or more clinical cases followed by half-open questions. Additional information was collected individually. At the clinical seminar the solutions were presented and discussed, guided by a clinical teacher. A questionnaire was administered to investigate whether students perceive the new type of clinical seminars as a powerful learning environment. Students were satisfied with the new methodology. The importance of the postulated educational aspects--preparation, clinical case and the seminar--was confirmed. The preparation phase (self-study and group work) and the clinical seminar were experienced as two separate and important learning events. The implementation of the problem solving clinical seminars is considered by students to be a powerful learning environment and therefore a broader applicability of the PSCS methodology is recommended.

Nodular regenerative hyperplasia, portal vein thrombosis, and avascular hip necrosis due to hyperhomocysteinaemia.

A male patient with portal hypertension, portal vein thrombosis, spontaneous splenorenal shunt formation, and encephalopathy, thought to have post-hepatitis B cirrhosis, is described. His condition deteriorated and necessitated liver transplantation. In the explant liver, nodular regenerative hyperplasia with pronounced vascular lesions both in portal venules and in arterioles was found instead of classical cirrhosis. Two years post-transplant he developed bilateral ischaemic femur head necrosis. The three disorders (portal vein thrombosis, nodular regenerative hyperplasia, and ischaemic hip necrosis) seemed to be due to a common vasculopathy induced by hyperhomocyteinaemia. Genetic studies showed that he carried a mutation in the gene encoding for formation of methylenetetrahydrofolate reductase. Treatment with folic acid combined with pyridoxine (vitamin B6) and cyanocobalamin (vitamin B12) normalised his serum homocysteine levels.