Multi-parametric classification of Alzheimer's disease and mild cognitive impairment: the impact of quantitative magnetization transfer MR imaging

Multi-parametric and quantitative magnetic resonance imaging (MRI) techniques have come into the focus of interest, both as a research and diagnostic modality for the evaluation of patients suffering from mild cognitive decline and overt dementia. In this study we address the question, if disease related quantitative magnetization transfer effects (qMT) within the intra- and extracellular matrices of the hippocampus may aid in the differentiation between clinically diagnosed patients with Alzheimer disease (AD), patients with mild cognitive impairment (MCI) and healthy controls. We evaluated 22 patients with AD (n=12) and MCI (n=10) and 22 healthy elderly (n=12) and younger (n=10) controls with multi-parametric MRI. Neuropsychological testing was performed in patients and elderly controls (n=34). In order to quantify the qMT effects, the absorption spectrum was sampled at relevant off-resonance frequencies. The qMT-parameters were calculated according to a two-pool spin-bath model including the T1- and T2 relaxation parameters of the free pool, determined in separate experiments. Histograms (fixed bin-size) of the normalized qMT-parameter values (z-scores) within the anterior and posterior hippocampus (hippocampal head and body) were subjected to a fuzzy-c-means classification algorithm with downstreamed PCA projection. The within-cluster sums of point-to-centroid distances were used to examine the effects of qMT- and diffusion anisotropy parameters on the discrimination of healthy volunteers, patients with Alzheimer and MCIs. The qMT-parameters T2(r) (T2 of the restricted pool) and F (fractional pool size) differentiated between the three groups (control, MCI and AD) in the anterior hippocampus. In our cohort, the MT ratio, as proposed in previous reports, did not differentiate between MCI and AD or healthy controls and MCI, but between healthy controls and AD.

Pancreatic carcinoma, pancreatitis, and healthy controls: metabolite models in a three-class diagnostic dilemma

Metabolomics as one of the most rapidly growing technologies in the "-omics" field denotes the comprehensive analysis of low molecular-weight compounds and their pathways. Cancer-specific alterations of the metabolome can be detected by high-throughput mass-spectrometric metabolite profiling and serve as a considerable source of new markers for the early differentiation of malignant diseases as well as their distinction from benign states. However, a comprehensive framework for the statistical evaluation of marker panels in a multi-class setting has not yet been established. We collected serum samples of 40 pancreatic carcinoma patients, 40 controls, and 23 pancreatitis patients according to standard protocols and generated amino acid profiles by routine mass-spectrometry. In an intrinsic three-class bioinformatic approach we compared these profiles, evaluated their selectivity and computed multi-marker panels combined with the conventional tumor marker CA 19-9. Additionally, we tested for non-inferiority and superiority to determine the diagnostic surplus value of our multi-metabolite marker panels. Compared to CA 19-9 alone, the combined amino acid-based metabolite panel had a superior selectivity for the discrimination of healthy controls, pancreatitis, and pancreatic carcinoma patients [Formula: see text] We combined highly standardized samples, a three-class study design, a high-throughput mass-spectrometric technique, and a comprehensive bioinformatic framework to identify metabolite panels selective for all three groups in a single approach. Our results suggest that metabolomic profiling necessitates appropriate evaluation strategies and-despite all its current limitations-can deliver marker panels with high selectivity even in multi-class settings.

Evaluation of texture features in hepatic tissue characterization from non-enhanced CT images

Aim of this paper is to evaluate the diagnostic contribution of various types of texture features in discrimination of hepatic tissue in abdominal non-enhanced Computed Tomography (CT) images. Regions of Interest (ROIs) corresponding to the classes: normal liver, cyst, hemangioma, and hepatocellular carcinoma were drawn by an experienced radiologist. For each ROI, five distinct sets of texture features are extracted using First Order Statistics (FOS), Spatial Gray Level Dependence Matrix (SGLDM), Gray Level Difference Method (GLDM), Laws' Texture Energy Measures (TEM), and Fractal Dimension Measurements (FDM). In order to evaluate the ability of the texture features to discriminate the various types of hepatic tissue, each set of texture features, or its reduced version after genetic algorithm based feature selection, was fed to a feed-forward Neural Network (NN) classifier. For each NN, the area under Receiver Operating Characteristic (ROC) curves (Az) was calculated for all one-vs-all discriminations of hepatic tissue. Additionally, the total Az for the multi-class discrimination task was estimated. The results show that features derived from FOS perform better than other texture features (total Az: 0.802+/-0.083) in the discrimination of hepatic tissue.

Avoiding misclassification bias with the traditional Charnley classification: rationale for a fourth Charnley class BB

Long-term follow up of patients with total hip arthroplasty (THA) revealed a marked deterioration of walking capacities in Charnley class B after postoperative year 4. We hypothesized that a specific group of patients, namely those with unilateral hip arthroplasty and an untreated but affected contralateral hip was responsible for this observation. Therefore, we conducted a study taking into consideration the two subclasses that make up Charnley class B: patients with unilateral THA and contralateral hip disease and patients with bilateral THA. A sample of 15,160 patients with 35,773 follow ups that were prospectively collected over 10 years was evaluated. The sample was categorized into four classes according to a new modified Charnley classification. Annual analyses of the proportion of patients with ambulation longer than 60 min were conducted. The traditionally labeled Charnley class B consists of two very different patient groups with respect to their walking capacities. Those with unilateral THA and contralateral hip disease have underaverage walking capacities and a deterioration of ambulation beginning 3 to 4 years after surgery. Those with bilateral THA have stable overaverage walking capacities similar to Charnley class A. An extension of the traditional Charnley classification is proposed, taking into account the two different patient groups in Charnley class B. The new fourth Charnley class consists of patients with bilateral THA and was labeled BB in order to express the presence of two artificial hip joints and to preserve the traditional classification A through C.

Phenotypes of childhood asthma: are they real?

It has been suggested that there are several distinct phenotypes of childhood asthma or childhood wheezing. Here, we review the research relating to these phenotypes, with a focus on the methods used to define and validate them. Childhood wheezing disorders manifest themselves in a range of observable (phenotypic) features such as lung function, bronchial responsiveness, atopy and a highly variable time course (prognosis). The underlying causes are not sufficiently understood to define disease entities based on aetiology. Nevertheless, there is a need for a classification that would (i) facilitate research into aetiology and pathophysiology, (ii) allow targeted treatment and preventive measures and (iii) improve the prediction of long-term outcome. Classical attempts to define phenotypes have been one-dimensional, relying on few or single features such as triggers (exclusive viral wheeze vs. multiple trigger wheeze) or time course (early transient wheeze, persistent and late onset wheeze). These definitions are simple but essentially subjective. Recently, a multi-dimensional approach has been adopted. This approach is based on a wide range of features and relies on multivariate methods such as cluster or latent class analysis. Phenotypes identified in this manner are more complex but arguably more objective. Although phenotypes have an undisputed standing in current research on childhood asthma and wheezing, there is confusion about the meaning of the term 'phenotype' causing much circular debate. If phenotypes are meant to represent 'real' underlying disease entities rather than superficial features, there is a need for validation and harmonization of definitions. The multi-dimensional approach allows validation by replication across different populations and may contribute to a more reliable classification of childhood wheezing disorders and to improved precision of research relying on phenotype recognition, particularly in genetics. Ultimately, the underlying pathophysiology and aetiology will need to be understood to properly characterize the diseases causing recurrent wheeze in children.

Identification of problems in functioning of people with sleep disorders in a clinical setting using the International Classification of Functioning Disability and Health (ICF) Checklist

We conducted an explorative, cross-sectional, multi-centre study in order to identify the most common problems of people with any kind of (primary) sleep disorder in a clinical setting using the International Classification of Functioning, Disability and Health (ICF) as a frame of reference. Data were collected from patients using a structured face-to-face interview of 45-60 min duration. A case record form for health professionals containing the extended ICF Checklist, sociodemographic variables and disease-specific variables was used. The study centres collected data of 99 individuals with sleep disorders. The identified categories include 48 (32%) for body functions, 13 (9%) body structures, 55 (37%) activities and participation and 32 (22%) for environmental factors. 'Sleep functions' (100%) and 'energy and drive functions', respectively, (85%) were the most severely impaired second-level categories of body functions followed by 'attention functions' (78%) and 'temperament and personality functions' (77%). With regard to the component activities and participation, patients felt most restricted in the categories of 'watching' (e.g. TV) (82%), 'recreation and leisure' (75%) and 'carrying out daily routine' (74%). Within the component environmental factors the categories 'support of immediate family', 'health services, systems and policies' and 'products or substances for personal consumption [medication]' were the most important facilitators; 'time-related changes', 'light' and 'climate' were the most important barriers. The study identified a large variety of functional problems reflecting the complexity of sleep disorders. The ICF has the potential to provide a comprehensive framework for the description of functional health in individuals with sleep disorders in a clinical setting.

Classification of suppressor additives based on synergistic and antagonistic ensemble effects

Three fundamental types of suppressor additives for copper electroplating could be identified by means of potential Transient measurements. These suppressor additives differ in their synergistic and antagonistic interplay with anions that are chemisorbed on the metallic copper surface during electrodeposition. In addition these suppressor chemistries reveal different barrier properties with respect to cupric ions and plating additives (Cl, SPS). While the type-I suppressor selectively forms efficient barriers for copper inter-diffusion on chloride-terminated electrode surfaces we identified a type-II suppressor that interacts non-selectively with any kind of anions chemisorbed on copper (chloride, sulfate, sulfonate). Type-I suppressors are vital for the superconformal copper growth mode in Damascene processing and show an antagonistic interaction with SPS (Bis-Sodium-Sulfopropyl-Disulfide) which involves the deactivation of this suppressor chemistry. This suppressor deactivation is rationalized in terms of compositional changes in the layer of the chemisorbed anions due to the competition of chloride and MPS (Mercaptopropane Sulfonic Acid) for adsorption sites on the metallic copper surface. MPS is the product of the dissociative SPS adsorption within the preexisting chloride matrix on the copper surface. The non-selectivity in the adsorption behavior of the type-II suppressor is rationalized in terms of anion/cation pairing effects of the poly-cationic suppressor and the anion-modified copper substrate. Atomic-scale insights into the competitive Cl/MPS adsorption are gained from in situ STM (Scanning Tunneling Microscopy) using single crystalline copper surfaces as model substrates. Type-III suppressors are a third class of suppressors. In case of type-land type-II suppressor chemistries the resulting steady-state deposition conditions are completely independent on the particular succession of additive adsorption. In contrast to that a strong dependence of the suppressing capabilities on the sequence of additive adsorption ("first comes, first serves" principle) is observed for the type-IIIsuppressor. This behavior:is explained by a suppressor barrier that impedes not only the copper inter-diffusion but also the transport of other additives (e.g. SPS) to the copper surface. (C) 2011 Elsevier Ltd. All rights reserved.

Interrelation of peri-operative morbidity and ASA class assignment in patients undergoing gynaecological surgery

OBJECTIVE: The aim of this study was to estimate intra- and post-operative risk using the American Society of Anaesthesiologists (ASA) classification which is an important predictor of an intervention and of the entire operating programme. STUDY DESIGN: In this retrospective study, 4435 consecutive patients undergoing elective and emergency surgery at the Gynaecological Clinic of the University Hospital of Zurich were included. The ASA classification for pre-operative risk assessment was determined by an anaesthesiologist after a thorough physical examination. We observed several pre-, intra- and post-operative parameters, such as age, body-mass-index, duration of anaesthesia, duration of surgery, blood loss, duration of post-operative stay, complicated post-operative course, morbidity and mortality. The investigation of different risk factors was achieved by a multiple linear regression model for log-transformed duration of hospitalisation. RESULTS: Age and obesity were responsible for a higher ASA classification. ASA grade correlates with the duration of anaesthesia and the duration of the surgery itself. There was a significant difference in blood loss between ASA grades I (113+/-195 ml) and III (222+/-470 ml) and between classes II (176+/-432 ml) and III. The duration of post-operative hospitalisation could also be correlated with ASA class. ASA class I=1.7+/-3.0 days, ASA class II=3.6+/-4.3 days, ASA class III=6.8+/-8.2 days, and ASA class IV=6.2+/-3.9 days. The mean post-operative in-hospital stay was 2.5+/-4.0 days without complications, and 8.7+/-6.7 days with post-operative complications. Multiple linear regression model showed that not only the ASA classification contained an important information for the duration of hospitalisation. Parameters such as age, class of diagnosis, post-operative complications, etc. also have an influence on the duration of hospitalisation. CONCLUSION: This study shows that the ASA classification can be used as a good and early available predictor for the planning of an intervention in gynaecological surgery. The ASA classification helps the surgeon to assess the peri-operative risk profile of which important information can be derived for the planning of the operation programme.

EEG microstate duration and syntax in acute, medication-naive, first-episode schizophrenia: a multi-center study

In young, first-episode, productive, medication-naive patients with schizophrenia, EEG microstates (building blocks of mentation) tend to be shortened. Koenig et al. [Koenig, T., Lehmann, D., Merlo, M., Kochi, K., Hell, D., Koukkou, M., 1999. A deviant EEG brain microstate in acute, neuroleptic-naïve schizophrenics at rest. European Archives of Psychiatry and Clinical Neuroscience 249, 205–211] suggested that shortening concerned specific microstate classes. Sequence rules (microstate concatenations, syntax) conceivably might also be affected. In 27 patients of the above type and 27 controls, from three centers, multichannel resting EEG was analyzed into microstates using k-means clustering of momentary potential topographies into four microstate classes (A–D). In patients, microstates were shortened in classes B and D (from 80 to 70 ms and from 94 to 82 ms, respectively), occurred more frequently in classes A and C, and covered more time in A and less in B. Topography differed only in class B where LORETA tomography predominantly showed stronger left and anterior activity in patients. Microstate concatenation (syntax) generally were disturbed in patients; specifically, the class sequence A→C→D→A predominated in controls, but was reversed in patients (A→D→C→A). In schizophrenia, information processing in certain classes of mental operations might deviate because of precocious termination. The intermittent occurrence might account for Bleuler's “double bookkeeping.” The disturbed microstate syntax opens a novel physiological comparison of mental operations between patients and controls.

Incremental Dynamic Updates with First-class Contexts

Highly available software systems occasionally need to be updated while avoiding downtime. Dynamic software updates reduce down-time, but still require the system to reach a quiescent state in which a global update can be performed. This can be difficult for multi-threaded systems. We present a novel approach to dynamic updates using first-class contexts, called Theseus. First-class contexts make global updates unnecessary: existing threads run to termination in an old context, while new threads start in a new, updated context; consistency between contexts is ensured with the help of bidirectional transformations. We show that for multi-threaded systems with coherent memory, first-class contexts offer a practical and flexible approach to dynamic updates, with acceptable overhead.

A Texture-based land cover classification for the delineation of a shifting cultivation landscape in the Lao PDR using landscape metrics

The delineation of shifting cultivation landscapes using remote sensing in mountainous regions is challenging. On the one hand, there are difficulties related to the distinction of forest and fallow forest classes as occurring in a shifting cultivation landscape in mountainous regions. On the other hand, the dynamic nature of the shifting cultivation system poses problems to the delineation of landscapes where shifting cultivation occurs. We present a two-step approach based on an object-oriented classification of Advanced Land Observing Satellite, Advanced Visible and Near-Infrared Spectrometer (ALOS AVNIR) and Panchromatic Remote-sensing Instrument for Stereo Mapping (ALOS PRISM) data and landscape metrics. When including texture measures in the object-oriented classification, the accuracy of forest and fallow forest classes could be increased substantially. Based on such a classification, landscape metrics in the form of land cover class ratios enabled the identification of crop-fallow rotation characteristics of the shifting cultivation land use practice. By classifying and combining these landscape metrics, shifting cultivation landscapes could be delineated using a single land cover dataset.

Oxygen and indicators of stress for marine life in multi-model global warming projections

Decadal-to-century scale trends for a range of marine environmental variables in the upper mesopelagic layer (UML, 100–600 m) are investigated using results from seven Earth System Models forced by a high greenhouse gas emission scenario. The models as a class represent the observation-based distribution of oxygen (O2) and carbon dioxide (CO2), albeit major mismatches between observation-based and simulated values remain for individual models. By year 2100 all models project an increase in SST between 2 °C and 3 °C, and a decrease in the pH and in the saturation state of water with respect to calcium carbonate minerals in the UML. A decrease in the total ocean inventory of dissolved oxygen by 2% to 4% is projected by the range of models. Projected O2 changes in the UML show a complex pattern with both increasing and decreasing trends reflecting the subtle balance of different competing factors such as circulation, production, remineralization, and temperature changes. Projected changes in the total volume of hypoxic and suboxic waters remain relatively small in all models. A widespread increase of CO2 in the UML is projected. The median of the CO2 distribution between 100 and 600m shifts from 0.1–0.2 mol m−3 in year 1990 to 0.2–0.4 mol m−3 in year 2100, primarily as a result of the invasion of anthropogenic carbon from the atmosphere. The co-occurrence of changes in a range of environmental variables indicates the need to further investigate their synergistic impacts on marine ecosystems and Earth System feedbacks.

Immunologic response to the survivin-derived multi-epitope vaccine EMD640744 in patients with advanced solid tumors

PURPOSE Survivin is a member of the inhibitor-of-apoptosis family. Essential for tumor cell survival and overexpressed in most cancers, survivin is a promising target for anti-cancer immunotherapy. Immunogenicity has been demonstrated in multiple cancers. Nonetheless, few clinical trials have demonstrated survivin-vaccine-induced immune responses. EXPERIMENTAL DESIGN This phase I trial was conducted to test whether vaccine EMD640744, a cocktail of five HLA class I-binding survivin peptides in Montanide(®) ISA 51 VG, promotes anti-survivin T-cell responses in patients with solid cancers. The primary objective was to compare immunologic efficacy of EMD640744 at doses of 30, 100, and 300 μg. Secondary objectives included safety, tolerability, and clinical efficacy. RESULTS In total, 49 patients who received ≥2 EMD640744 injections with available baseline- and ≥1 post-vaccination samples [immunologic-diagnostic (ID)-intention-to-treat] were analyzed by ELISpot- and peptide/MHC-multimer staining, revealing vaccine-activated peptide-specific T-cell responses in 31 patients (63 %). This cohort included the per study protocol relevant ID population for the primary objective, i.e., T-cell responses by ELISpot in 17 weeks following first vaccination, as well as subjects who discontinued the study before week 17 but showed responses to the treatment. No dose-dependent effects were observed. In the majority of patients (61 %), anti-survivin responses were detected only after vaccination, providing evidence for de novo induction. Best overall tumor response was stable disease (28 %). EMD640744 was well tolerated; local injection-site reactions constituted the most frequent adverse event. CONCLUSIONS Vaccination with EMD640744 elicited T-cell responses against survivin peptides in the majority of patients, demonstrating the immunologic efficacy of EMD640744.

A Multi-Breed Genome-Wide Association Analysis for Canine Hypothyroidism Identifies a Shared Major Risk Locus on CFA12.

Hypothyroidism is a complex clinical condition found in both humans and dogs, thought to be caused by a combination of genetic and environmental factors. In this study we present a multi-breed analysis of predisposing genetic risk factors for hypothyroidism in dogs using three high-risk breeds-the Gordon Setter, Hovawart and the Rhodesian Ridgeback. Using a genome-wide association approach and meta-analysis, we identified a major hypothyroidism risk locus shared by these breeds on chromosome 12 (p = 2.1x10-11). Further characterisation of the candidate region revealed a shared ~167 kb risk haplotype (4,915,018-5,081,823 bp), tagged by two SNPs in almost complete linkage disequilibrium. This breed-shared risk haplotype includes three genes (LHFPL5, SRPK1 and SLC26A8) and does not extend to the dog leukocyte antigen (DLA) class II gene cluster located in the vicinity. These three genes have not been identified as candidate genes for hypothyroid disease previously, but have functions that could potentially contribute to the development of the disease. Our results implicate the potential involvement of novel genes and pathways for the development of canine hypothyroidism, raising new possibilities for screening, breeding programmes and treatments in dogs. This study may also contribute to our understanding of the genetic etiology of human hypothyroid disease, which is one of the most common endocrine disorders in humans.