Novel biomarkers for the prediction of metastasis in colorectal cancer

INTRODUCTION In patients with metastatic colorectal cancers, multimodal management and the use of biological agents such as monoclonal antibodies have had major positive effects on survival. The ability to predict which patients may be at 'high risk' of distant metastasis could have major implications on patient management. Histomorphological, immunohistochemical or molecular biomarkers are currently being investigated in order to test their potential value as predictors of metastasis. AREAS COVERED Here, the author reviews the clinical and functional data supporting the investigation of three novel promising biomarkers for the prediction of metastasis in patients with colorectal cancer: tumor budding, Raf1 kinase inhibitor protein (RKIP) and metastasis-associated in colon cancer-1 (MACC1). EXPERT OPINION The lifespan of most potential biomarkers is short as evidenced by the rare cases that have successfully made their way into daily practice such as KRAS or microsatellite instability (MSI) status. Although the three biomarkers reviewed herein have the potential to become important predictive biomarkers of metastasis, they have similar hurdles to overcome before they can be implemented into clinical management: standardization and validation in prospective patient cohorts.

IMILAST: A community effort to intercompare extratropical cyclone detection and tracking algorithms: assessing method-related uncertainties

The variability of results from different automated methods of detection and tracking of extratropical cyclones is assessed in order to identify uncertainties related to the choice of method. Fifteen international teams applied their own algorithms to the same dataset - the period 1989-2009 of interim European Centre for Medium-Range Weather Forecasts (ECMWF) Re-Analysis (ERAInterim) data. This experiment is part of the community project Intercomparison of Mid Latitude Storm Diagnostics (IMILAST; see www.proclim.ch/imilast/index.html). The spread of results for cyclone frequency, intensity, life cycle, and track location is presented to illustrate the impact of using different methods. Globally, methods agree well for geographical distribution in large oceanic regions, interannual variability of cyclone numbers, geographical patterns of strong trends, and distribution shape for many life cycle characteristics. In contrast, the largest disparities exist for the total numbers of cyclones, the detection of weak cyclones, and distribution in some densely populated regions. Consistency between methods is better for strong cyclones than for shallow ones. Two case studies of relatively large, intense cyclones reveal that the identification of the most intense part of the life cycle of these events is robust between methods, but considerable differences exist during the development and the dissolution phases.

Secondary prevention in the clinical management of patients with cardiovascular diseases. Core components, standards and outcome measures for referral and delivery

Despite major improvements in diagnostics and interventional therapies, cardiovascular diseases remain a major health care and socio-economic burden both in western and developing countries, in which this burden is increasing in close correlation to economic growth. Health authorities and the general population have started to recognize that the fight against these diseases can only be won if their burden is faced by increasing our investment on interventions in lifestyle changes and prevention. There is an overwhelming evidence of the efficacy of secondary prevention initiatives including cardiac rehabilitation in terms of reduction in morbidity and mortality. However, secondary prevention is still too poorly implemented in clinical practice, often only on selected populations and over a limited period of time. The development of systematic and full comprehensive preventive programmes is warranted, integrated in the organization of national health systems. Furthermore, systematic monitoring of the process of delivery and outcomes is a necessity. Cardiology and secondary prevention, including cardiac rehabilitation, have evolved almost independently of each other and although each makes a unique contribution it is now time to join forces under the banner of preventive cardiology and create a comprehensive model that optimizes long term outcomes for patients and reduces the future burden on health care services. These are the aims that the Cardiac Rehabilitation Section of the European Association for Cardiovascular Prevention & Rehabilitation has foreseen to promote secondary preventive cardiology in clinical practice.

Fluktuierende Kopfschmerzen und Wesensveränderung bei einem 63-jährigen Patienten

We present a 63 year old man with new onset of fluctuating headache and behavioural changes showing marked inhibition and disorientation. After non invasive and invasive diagnostics an isolated cerebral vasculitis was found. Key results have been found in cerebral MRI and cerebral digital subtraction angiography with irregularities of vessel calibre of the intracerebral arteries. During treatment with high-dose corticosteroid therapy and Cyclophosphamid pulse therapy qualitative disorders and headache rapidly regressed. We discuss differential diagnosis of secondary headache, etiology of cerebral vasculitides, diagnostic challenge and therapy in isolated cerebral vasculitis.

Nanomaterials and the human lung: what is known and what must be deciphered to realise their potential advantages?

Due to the constant expansion within the nanotechnology industry in the last decade, nanomaterials are omnipresent in society today. Nanotechnology-based products have numerous different applications ranging from electronic (e.g., advanced memory chips) to industrial (e.g., coatings or composites) to biomedical (e.g., drug delivery systems, diagnostics). Although these new nanomaterials can be found in many "everyday" products, their effects on the human body have still to be investigated in order to identify not only their risk, but also their potential benefits towards human health. Since the lung is commonly thought to be the main portal of entry into the human body for nanomaterials released within the environment, this review will attempt to summarise the current knowledge and understanding of how nanomaterials interact with the respiratory tract. Furthermore, the advantages and disadvantages of different experimental model systems that are commonly used to study this exposure route to the human body will be discussed.

Clinical Significance of 3D Ultrasound Compared to MRI in Uterine Malformations

Purpose: Congenital uterine anomalies often remain asymptomatic until they cause problems, for example during pregnancy. We studied the diagnostic aspects of two- and three-dimensional ultrasound and MRI. Materials and Methods: 63 women referred for suspected uterine anomalies were studied: In the first group (until July 2008) with 2 D-US and MRI, in the second group (from August 2008) additionally with 3 D-US; these women also had diagnostic or therapeutic operative confirmation. In the third group, only 3D-US was used. Results: In all women 3D-US was possible and successful. The most common anomaly was a subseptate uterus, while a septate uterus was less frequent, and uterus bicornis (unicollis) and uterus didelphys (bicornis bicollis) were rare. The women in the first two groups all underwent at least diagnostic hysteroscopy, and some (subseptate or septate uterus) underwent operative hysteroscopy. After preoperative volume imaging, laparoscopies were required less often. 3D-US diagnoses as judged by intraoperative findings were correct in 100 % of cases, while the MRI diagnoses in the same group were correct in only 7/13 cases. Conclusion: Since the introduction of volume imaging (MRI, later 3 D-US), laparoscopy during hysteroscopic septum resection was not necessary in the majority of cases. 3D-US brings the diagnostics of uterine anomalies back into the hands of the gynecologist and can provide the gynecological surgeon with a higher subjective degree of certainty during operative hysteroscopy.

Annexin A5-Conjugated Polymeric Micelles For Dual SPECT and Optical Detection of Apoptosis

Apoptosis, a form of programmed cell death, is critical to homoeostasis, normal development, and physiology. Dysregulation of apoptosis can lead to the accumulation of unwanted cells, such as occurs in cancer, and the removal of needed cells or disorders of normal tissues, such as heart, neurodegenerative, and autoimmune diseases. Noninvasive detection of apoptosis may play an important role in the evaluation of disease states and response to therapeutic intervention for a variety of diseases. It is desirable to have an imaging method to accurately detect and monitor this process in patients. In this study, we developed annexin A5-conjugated polymeric micellar nanoparticles dual-labeled with a near-infrared fluorescence fluorophores (Cy7) and a radioisotope (111In), named as 111In-labeled annexin A5-CCPM. In vitro studies demonstrated that annexin A5-CCPM could strongly and specifically bind to apoptotic cells. In vivo studies showed that apoptotic tissues could be clearly visualized by both single photon emission computed tomography (SPECT) and fluorescence molecular tomography (FMT) after intravenous injection of 111In-labeled Annexin A5-CCPM in 6 different apoptosis models. In contrast, there was little signal in respective healthy tissues. All the biodistribution data confirmed imaging results. Moreover, histological analysis revealed that radioactivity count correlated with fluorescence signal from the nanoparticles, and both signals co-localized with the region of apoptosis. In sum, 111In-labeled annexin A5-CCPM allowed visualization of apoptosis by both nuclear and optical imaging techniques. The complementary information acquired with multiple imaging techniques should be advantageous in improving diagnostics and management of patients.

APPLICATIONS OF EPHB4 RECEPTOR SPECIFIC PEPTIDES IN TARGETED CANCER IMAGING AND THERAPY

EphB4 receptors, a member of the largest family of receptor tyrosine kinases, are found over-expressed in a variety of tumors cells including glioma cells as well as angiogenic blood vessels. Noninvasive imaging of EphB4 could potentially increase early detection rates, monitor response to therapy directed against EphB4, and improve patient outcomes. Targeted delivery of EphB4 receptor specific peptide conjugated hollow gold nanoshells (HAuNS) into tumors has great potential in cancer imaging and photothermal therapy. In this study, we developed an EphB4 specific peptide named TNYL-RAW and labeled with radioisotope 64Cu and Cy5.5 dye. We also conjugate this specific peptide with hollow gold nanoshells (HAuNS) to evaluate targeted photothermal therapy of cancers. In vitro, 64Cu-DOTA-TNYL- RAW specifically bind to CT26 and PC-3M cells but not to A549 cells. In vivo, Small-animal PET/CT clearly showed the significant uptake of 64Cu-DOTA-TNYL-RAW in CT26 and PC-3M tumors but not in A549 tumors. Furthermore, µPET/CT and near-infrared optical imaging clearly showed the uptake of the dual labeled TNYL-RAW peptide in both U251 and U87 tumors in the brains of nude mice. In U251 tumors, Cy5.5-labeled peptide can bind to EphB4-expressing tumor blood vessels and tumors cells. But in U87 models, dual labeled peptide only could bind to tumor associated blood vessels. Also, Irradiation of PC-3M and CT-26 cell treated with TNYL-PEG-HAuNS nanopatilces with near-infrared (NIR) laser resulted in selective destruction of these cells in vitro. EphB4 targeted TNYL-PEG-HAuNS showed more photothermal killing effect on CT26 tumor model than PEG-HAuNS did. In summary, tumors with overexpression of EphB4 receptors can be noninvasively visualized by micro PET/CT with 64Cu labeled or dual labeled TNYL-RAW peptide. Targeted delivery of TNYL-RAW conjugated HAuNS into tumors can greatly improve the treatment effect of photothermal therapy. The information acquired with this study should be advantageous in improving diagnostics and future applications in photothermal ablation therapy in clinical.

Nonviolent factors: Variables associated with ethnic violence, and factors which are associated with nonviolent response to grievances toward members of other ethnic groups

Ethnic violence appears to be the major source of violence in the world. Ethnic hostilities are potentially all-pervasive because most countries in the world are multi-ethnic. Public health's focus on violence documents its increasing role in this issue.^ The present study is based on a secondary analysis of a dataset of responses by 272 individuals from four ethnic groups (Anglo, African, Mexican, and Vietnamese Americans) who answered questions regarding variables related to ethnic violence from a general questionnaire which was distributed to ethnically diverse purposive, nonprobability, self-selected groups of individuals in Houston, Texas, in 1993.^ One goal was psychometric: learning about issues in analysis of datasets with modest numbers, comparison of two approaches to dealing with missing observations not missing at random (conducting analysis on two datasets), transformation analysis of continuous variables for logistic regression, and logistic regression diagnostics.^ Regarding the psychometric goal, it was concluded that measurement model analysis was not possible with a relatively small dataset with nonnormal variables, such as Likert-scaled variables; therefore, exploratory factor analysis was used. The two approaches to dealing with missing values resulted in comparable findings. Transformation analysis suggested that the continuous variables were in the correct scale, and diagnostics that the model fit was adequate.^ The substantive portion of the analysis included the testing of four hypotheses. Hypothesis One proposed that attitudes/efficacy regarding alternative approaches to resolving grievances from the general questionnaire represented underlying factors: nonpunitive social norms and strategies for addressing grievances--using the political system, organizing protests, using the system to punish offenders, and personal mediation. Evidence was found to support all but one factor, nonpunitive social norms.^ Hypothesis Two proposed that the factor variables and the other independent variables--jail, grievance, male, young, and membership in a particular ethnic group--were associated with (non)violence. Jail, grievance, and not using the political system to address grievances were associated with a greater likelihood of intergroup violence.^ No evidence was found to support Hypotheses Three and Four, which proposed that grievance and ethnic group membership would interact with other variables (i.e., age, gender, etc.) to produce variant levels of subgroup (non)violence.^ The generalizability of the results of this study are constrained by the purposive self-selected nature of the sample and small sample size (n = 272).^ Suggestions for future research include incorporating other possible variables or factors predictive of intergroup violence in models of the kind tested here, and the development and evaluation of interventions that promote electoral and nonelectoral political participation as means of reducing interethnic conflict. ^

Bouveret's syndrome: presentation of two cases with review of the literature and development of a surgical treatment strategy

BACKGROUND Bouveret's syndrome causes gastric outlet obstruction when a gallstone is impacted in the duodenum or stomach via a bilioenteric fistula. It is a rare condition that causes significant morbidity and mortality and often occurs in the elderly with significant comorbidities. Individual diagnostic and treatment strategies are required for optimal management and outcome. The purpose of this paper is to develop a surgical strategy for optimized individual treatment of Bouveret's syndrome based on the available literature and motivated by our own experience. CASE PRESENTATION Two cases of Bouveret's syndrome are presented with individual management and restrictive surgical approaches tailored to the condition of the patients and intraoperative findings. CONCLUSIONS Improved diagnostics and restrictive individual surgical approaches have shown to lower the mortality rates of Bouveret's syndrome. For optimized outcome of the individual patient: The medical and perioperative management and time of surgery are tailored to the condition of the patient. CT-scan is most often required to secure the diagnosis. The surgical approach includes enterolithotomy alone or in combination with simultaneous or subsequent cholecystectomy and fistula repair. Lower overall morbidity and mortality are in favor of restrictive surgical approaches. The surgical strategy is adapted to the intraoperative findings and to the risk for secondary complications vs. the age and comorbidities of the patient.

Identification of cryptic Anopheles mosquito species by molecular protein profiling.

Vector control is the mainstay of malaria control programmes. Successful vector control profoundly relies on accurate information on the target mosquito populations in order to choose the most appropriate intervention for a given mosquito species and to monitor its impact. An impediment to identify mosquito species is the existence of morphologically identical sibling species that play different roles in the transmission of pathogens and parasites. Currently PCR diagnostics are used to distinguish between sibling species. PCR based methods are, however, expensive, time-consuming and their development requires a priori DNA sequence information. Here, we evaluated an inexpensive molecular proteomics approach for Anopheles species: matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). MALDI-TOF MS is a well developed protein profiling tool for the identification of microorganisms but so far has received little attention as a diagnostic tool in entomology. We measured MS spectra from specimens of 32 laboratory colonies and 2 field populations representing 12 Anopheles species including the A. gambiae species complex. An important step in the study was the advancement and implementation of a bioinformatics approach improving the resolution over previously applied cluster analysis. Borrowing tools for linear discriminant analysis from genomics, MALDI-TOF MS accurately identified taxonomically closely related mosquito species, including the separation between the M and S molecular forms of A. gambiae sensu stricto. The approach also classifies specimens from different laboratory colonies; hence proving also very promising for its use in colony authentication as part of quality assurance in laboratory studies. While being exceptionally accurate and robust, MALDI-TOF MS has several advantages over other typing methods, including simple sample preparation and short processing time. As the method does not require DNA sequence information, data can also be reviewed at any later stage for diagnostic or functional patterns without the need for re-designing and re-processing biological material.

L’hépatite auto-immune

Autoimmune hepatitis is a systemic disease, difficult to diagnose due the high variability of the clinical presentation and some non specific histological features. The recent identification of additional autoantibodies used as serological markers, as well as simplified diagnostic criteria should help the primary care physician to advance with the diagnostic process. These progresses are crucial as undiagnosed and therefore untreated autoimmune hepatitis has a poor prognosis, whereas immunosuppressive therapy leads to remission in a majority of cases.

Tuning Molecular Recognition of RNA and DNA via Sugar Modification

This minireview highlights three aspects of our recent work in the area of sugar modified oligonucleotide analogues. It provides an overview over recent results on the conformationally constrained analogue tricyclo-DNA with special emphasis of its antisense properties, it summarizes results on triple-helix forming oligodeoxynucleotides containing pyrrolidino-nucleosides with respect to DNA recognition via the dual recognition mode, and it highlights the advantageous application of the orthogonal oligonucleotidic pairing system homo-DNA in molecular beacons for DNA diagnostics

The biomechanics of the hip joint using new diagnostic aspects in the field of hip joint dysplasia. Constructive criticism of hip dysplasia diagnosis and present marketable breeding methods with an outlook on future perspectives and possibilities. Part I

In absence of basic canine hip biomechanics, a specific, consequent three dimensional concept to evaluate the coxofemoral joint was developed for the dog. With the help of a new method to radiologically demonstrate the hip in a physiological standing position several new clinically relevant aspects could be further investigated. For example the breed specific anatomical differences in the hip, and dynamics and the background on "iatrogenic luxations" in HD diagnostics could be shown. The caudal luxation and the growth abnormalities of the hip and their consequences on the whole leg (antetorsion syndrome) as a consequence of inadequate breeding could be demonstrated.

The new bern PET cyclotron, its research beam line, and the development of an innovative beam monitor detector

The new Bern cyclotron laboratory aims at industrial radioisotope production for PET diagnostics and multidisciplinary research by means of a specifically conceived beam transfer line, terminated in a separate bunker. In this framework, an innovative beam monitor detector based on doped silica and optical fibres has been designed, constructed, and tested. Scintillation light produced by Ce and Sb doped silica fibres moving across the beam is measured, giving information on beam position, shape, and intensity. The doped fibres are coupled to commercial optical fibres, allowing the read-out of the signal far away from the radiation source. This general-purpose device can be easily adapted for any accelerator used in medical applications and is suitable either for low currents used in hadrontherapy or for currents up to a few μA for radioisotope production, as well as for both pulsed and continuous beams.