Myotonic dystrophy type 2 (DM2) : Diagnostic methods and molecular pathology

Myotonic dystrophies type 1 (DM1) and type 2 (DM2) are the most common forms of muscular dystrophy affecting adults. They are autosomal dominant diseases caused by microsatellite tri- or tetranucleotide repeat expansion mutations in transcribed but not translated gene regions. The mutant RNA accumulates in nuclei disturbing the expression of several genes. The more recently identified DM2 disease is less well known, yet more than 300 patients have been confirmed in Finland thus far, and the true number is believed to be much higher. DM1 and DM2 share some features in general clinical presentation and molecular pathology, yet they show distinctive differences, including disease severity and differential muscle and fiber type involvement. However, the molecular differences underlying DM1 and DM2 muscle pathology are not well understood. Although the primary tissue affected is muscle, both DMs show a multisystemic phenotype due to wide expression of the mutation-carrying genes. DM2 is particularly intriguing, as it shows an incredibly wide spectrum of clinical manifestations. For this reason, it constitutes a real diagnostic challenge. The core symptoms in DM2 include proximal muscle weakness, muscle pain, myotonia, cataracts, cardiac conduction defects and endocrinological disturbations; however, none of these is mandatory for the disease. Myalgic pains may be the most disabling symptom for decades, sometimes leading to incapacity for work. In addition, DM2 may cause major socio-economical consequences for the patient, if not diagnosed, due to misunderstanding and false stigmatization. In this thesis work, we have (I) improved DM2 differential diagnostics based on muscle biopsy, and (II) described abnormalities in mRNA and protein expression in DM1 and DM2 patient skeletal muscles, showing partial differences between the two diseases, which may contribute to muscle pathology in these diseases. This is the first description of histopathological differences between DM1 and DM2, which can be used in differential diagnostics. Two novel high-resolution applications of in situ -hybridization have been described, which can be used for direct visualization of the DM2 mutation in muscle biopsy sections, or mutation size determination on extended DNA-fibers. By measuring protein and mRNA expression in the samples, differential changes in expression patterns affecting contractile proteins, other structural proteins and calcium handling proteins in DM2 compared to DM1 were found. The dysregulation at mRNA level was caused by altered transciption and abnormal splicing. The findings reported here indicate that the extent of aberrant splicing is higher in DM2 compared to DM1. In addition, the described abnormalities to some extent correlate to the differences in fiber type involvement in the two disorders.

Occupational chronic solvent encephalopathy in Finland 1995 - 2007 : incidence and diagnostic methods

The occurrence of occupational chronic solvent encephalopathy (CSE) seems to decrease, but still every year reveals new cases. To prevent CSE and early retirement of solvent-exposed workers, actions should focus on early CSE detection and diagnosis. Identifying the work tasks and solvent exposure associated with high risk for CSE is crucial. Clinical and exposure data of all the 128 cases diagnosed with CSE as an occupational disease in Finland during 1995-2007 was collected from the patient records at the Finnish Institute of Occupational Health (FIOH) in Helsinki. The data on the number of exposed workers in Finland were gathered from the Finnish Job-exposure Matrix (FINJEM) and the number of employed from the national workforce survey. We analyzed the work tasks and solvent exposure of CSE patients and the findings in brain magnetic resonance imaging (MRI), quantitative electroencephalography (QEEG), and event-related potentials (ERP). The annual number of new cases diminished from 18 to 3, and the incidence of CSE decreased from 8.6 to 1.2 / million employed per year. The highest incidence of CSE was in workers with their main exposure to aromatic hydrocarbons; during 1995-2006 the incidence decreased from 1.2 to 0.3 / 1 000 exposed workers per year. The work tasks with the highest incidence of CSE were floor layers and lacquerers, wooden surface finishers, and industrial, metal, or car painters. Among 71 CSE patients, brain MRI revealed atrophy or white matter hyperintensities or both in 38% of the cases. Atrophy which was associated with duration of exposure was most frequently located in the cerebellum and in the frontal or parietal brain areas. QEEG in a group of 47 patients revealed increased power of the theta band in the frontal brain area. In a group of 86 patients, the P300 amplitude of auditory ERP was decreased, but at individual level, all the amplitude values were classified as normal. In 11 CSE patients and 13 age-matched controls, ERP elicited by a multimodal paradigm including an auditory, a visual detection, and a recognition memory task under single and dual-task conditions corroborated the decrease of auditory P300 amplitude in CSE patients in single-task condition. In dual-task conditions, the auditory P300 component was, more often in patients than in controls, unrecognizable. Due to the paucity and non-specificity of the findings, brain MRI serves mainly for differential diagnostics in CSE. QEEG and auditory P300 are insensitive at individual level and not useful in the clinical diagnostics of CSE. A multimodal ERP paradigm may, however, provide a more sensitive method to diagnose slight cognitive disturbances such as CSE.

Aperiodic Variability in the Cane-Zebiak Model: A Diagnostic Study

The finite predictability of the coupled ocean-atmosphere system is determined by its aperiodic variability. To gain insight regarding the predictability of such a system, a series of diagnostic studies has been carried out to investigate the role of convergence feedback in producing the aperiodic behavior of the standard version of the Cane-Zebiak model. In this model, an increase in sea surface temperature (SST) increases atmospheric heating by enhancing local evaporation (SST anomaly feedback) and low-level convergence (convergence feedback). The convergence feedback is a nonlinear function of the background mean convergence field. For the set of standard parameters used in the model, it is shown that the convergence feedback contributes importantly to the aperiodic behaviour of the model. As the strength of the convergence feedback is increased from zero to its standard value, the model variability goes from a periodic regime to an aperiodic regime through a broadening of the frequency spectrum around the basic periodicity of about 4 years. Examination of the forcing associated with the convergence feedback reveals that it is intermittent, with relatively large amplitude only during 2 or 3 months in the early part of the calendar year. This seasonality in the efficiency of the convergence feedback is related to the strong seasonality of the mean convergence over the eastern Pacific. It is shown that if the mean convergence field is fixed at its March value, aperiodic behavior is produced even in the absence of annual cycles in the other mean fields. On the, other hand, if the mean convergence field is fixed at its September value, the coupled model evolution remains close to periodic, even in the presence of the annual cycle in the other fields. The role of convergence feedback on the aperiodic variability of the model for other parameter regimes is also examined. It is shown that a range exists in the strength of the SST anomaly feedback for which the model variability is aperiodic even without the convergence feedback. It appears that in the absence of convergence feedback, enhancement of the strength of the air-sea coupling in the model through other physical processes also results in aperiodicity in the model.

Fault-Diagnostic System using Support Vector Machines for Power Transmission Systems

This paper presents an approach for identifying the faulted line section and fault location on transmission systems using support vector machines (SVMs) for diagnosis/post-fault analysis purpose. Power system disturbances are often caused by faults on transmission lines. When fault occurs on a transmission system, the protective relay detects the fault and initiates the tripping operation, which isolates the affected part from the rest of the power system. Based on the fault section identified, rapid and corrective restoration procedures can thus be taken to minimize the power interruption and limit the impact of outage on the system. The approach is particularly important for post-fault diagnosis of any mal-operation of relays following a disturbance in the neighboring line connected to the same substation. This may help in improving the fault monitoring/diagnosis process, thus assuring secure operation of the power systems. In this paper we compare SVMs with radial basis function neural networks (RBFNN) in data sets corresponding to different faults on a transmission system. Classification and regression accuracy is reported for both strategies. Studies on a practical 24-Bus equivalent EHV transmission system of the Indian Southern region is presented for indicating the improved generalization with the large margin classifiers in enhancing the efficacy of the chosen model.

Evaluation of Brugia malayi sheath protein (Shp-1) as a diagnostic antigen for human lymphatic filariasis

Lymphatic filariasis is the second leading cause of permanent long-term disability globally and control of this disease needs efficient diagnostic methods. In this study, abundantly expressing microfilarial sheath protein (Shp-1) from Brugia malayi was characterized as a filarial diagnostic candidate using samples from different clinical population. Monoclonal antibodies were developed against E. coil expressed recombinant Shp-1 in order to assess its efficiency in filarial antigen detection assay system. Endemic Normal (EN, n = 170), asymptomatic microfilaeremics (MF, n = 65), symptomatic chronic pathology (CP, n = 45) and non endemic normal (NEN, n = 10) sera were analyzed by antigen capture enzyme-linked immunosorbent assay. Of the 290 individuals, all MF individuals (both brugian and bancroftian) were positive in this assay followed by CP and EN. When compared with SXP-1 and Og4C3 antigen assays, all assays detected Wb MF correctly, Bm MF was detected by Shp-1 and SXP-1 assays, and only Shp-1 was able to detect EN (12%) and CP (29%). Results showed that this assay may be useful for monitoring prior to mass drug administration. (c) 2014 Elsevier Inc. All rights reserved.

A questioning based method to automatically acquire expert assembly diagnostic knowledge

In the domain of manual mechanical assembly, expert knowledge is an important means of supporting assembly planning that leads to fewer issues during actual assembly. Knowledge based systems can be used to provide assembly planners with expert knowledge as advice. However, acquisition of knowledge remains a difficult task to automate, while manual acquisition is tedious, time-consuming, and requires engagement of knowledge engineers with specialist knowledge to understand and translate expert knowledge. This paper describes the development, implementation and preliminary evaluation of a method that asks a series of questions to an expert, so as to automatically acquire necessary diagnostic and remedial knowledge as rules for use in a knowledge based system for advising assembly planners diagnose and resolve issues. The method, called a questioning procedure, organizes its questions around an assembly situation which it presents to the expert as the context, and adapts its questions based on the answers it receives from the expert. (C) 2014 Elsevier Ltd. All rights reserved.

Draft genome of a commonly misdiagnosed multidrug resistant pathogen Candida auris

Background: Candida auris is a multidrug resistant, emerging agent of fungemia in humans. Its actual global distribution remains obscure as the current commercial methods of clinical diagnosis misidentify it as C. haemulonii. Here we report the first draft genome of C. auris to explore the genomic basis of virulence and unique differences that could be employed for differential diagnosis. Results: More than 99.5 % of the C. auris genomic reads did not align to the current whole (or draft) genome sequences of Candida albicans, Candida lusitaniae, Candida glabrata and Saccharomyces cerevisiae; thereby indicating its divergence from the active Candida clade. The genome spans around 12.49 Mb with 8527 predicted genes. Functional annotation revealed that among the sequenced Candida species, it is closest to the hemiascomycete species Clavispora lusitaniae. Comparison with the well-studied species Candida albicans showed that it shares significant virulence attributes with other pathogenic Candida species such as oligopeptide transporters, mannosyl transfersases, secreted proteases and genes involved in biofilm formation. We also identified a plethora of transporters belonging to the ABC and major facilitator superfamily along with known MDR transcription factors which explained its high tolerance to antifungal drugs. Conclusions: Our study emphasizes an urgent need for accurate fungal screening methods such as PCR and electrophoretic karyotyping to ensure proper management of fungemia. Our work highlights the potential genetic mechanisms involved in virulence and pathogenicity of an important emerging human pathogen namely C. auris. Owing to its diversity at the genomic scale; we expect the genome sequence to be a useful resource to map species specific differences that will help develop accurate diagnostic markers and better drug targets.

A semi-automated, field-portable microscopy platform for clinical diagnostic applications

Clinical microscopy is a versatile diagnostic platform used for diagnosis of a multitude of diseases. In the recent past, many microfluidics based point-of-care diagnostic devices have been developed, which serve as alternatives to microscopy. However, these point-of-care devices are not as multi-functional and versatile as clinical microscopy. With the use of custom designed optics and microfluidics, we have developed a versatile microscopy-based cellular diagnostic platform, which can be used at the point of care. The microscopy platform presented here is capable of detecting infections of very low parasitemia level (in a very small quantity of sample), without the use of any additional computational hardware. Such a cost-effective and portable diagnostic device, would greatly impact the quality of health care available to people living in rural locations of the world. Apart from clinical diagnostics, it's applicability to field research in environmental microbiology has also been outlined. (C) 2015 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 Unported License.

Object attributes combine additively in visual search

We perceive objects as containing a variety of attributes: local features, relations between features, internal details, and global properties. But we know little about how they combine. Here, we report a remarkably simple additive rule that governs how these diverse object attributes combine in vision. The perceived dissimilarity between two objects was accurately explained as a sum of (a) spatially tuned local contour-matching processes modulated by part decomposition; (b) differences in internal details, such as texture; (c) differences in emergent attributes, such as symmetry; and (d) differences in global properties, such as orientation or overall configuration of parts. Our results elucidate an enduring question in object vision by showing that the whole object is not a sum of its parts but a sum of its many attributes.

Optical Diagnostic and Modeling Solution Growth Process of Sodium Chlorate Crystals

Both a real time optical interferometric experiment and a numerical simulation of two-dimension non-steady state model were employed to study the growth process of aqueous sodium chlorate crystals. The parameters such as solution concentration distribution, crystal dimensions, growth rate and velocity field were obtained by both experiment and numerical simulation. The influence of earth gravity during crystal growth process was analyzed. A reasonable theory model corresponding to the present experiment is advanced. The thickness of concentration boundary layer was investigated especially. The results from the experiment and numerical simulation match well.

A diagnostic system for the microgravity experiments on Marangoni drop migrations

An optical diagnostic system designed for the microgravity experiments on Marangoni drop migrations has been depicted in the presented paper. One part of the optical system was used to image and record the drops tracks; the other part was an equal-thick interferential system, it has the ability to observe the fine structures of the drop migrations. Some ground-based experiments had been performed and the results were simply discussed in the present paper.

Neighborhoods attributes as determinants of children's academic achievement

Resumen: Los estudios sobre los efectos del vecindario sobre los logros educativos han confirmado la existencia de estos efectos particularmente en la adolescencia. Una deficiencia común de la investigación empírica hasta la fecha, la falta de información en múltiples contextos, se aborda en este trabajo mediante el uso de encuestas escolares de datos para obtener una mayor comprensión sobre el efecto de la pobreza en los niños que cursan el nivel primario de enseñanza en los EE.UU. Este trabajo propone la utilización de un modelo jerárquico lineal de clasificación cruzada para tomar en cuenta en forma apropiada la estructura anidada de la información ya que los niños pertenecen simultáneamente a los dos grupos, el barrio y la escuela. Los resultados que se presentan, basados en la encuesta ECLS-K, una muestra de más de 20000 niños en aproximadamente 1.000 vecindarios y 1200 escuelas 1200, pone de manifiesto la asociación entre la composición socioeconómica del vecindario y los resultados académicos de los estudiantes. Este estudio proporciona evidencia a favor de las teorías de la socialización y epidémica. La presencia de adultos con buen nivel educativo en el vecindario así como la mediana de ingresos tienen impacto positivo en el logro del estudiante. De la misma forma, elevados niveles de pobreza tienen una influencia significativa, pero negativa en los resultados académicos. Sin embargo, el impacto se produce cuando se supera el umbral de 30% de hogares pobres en el vecindario. Los resultados agregados son invariantes a distintas especificaciones en términos de variables, esto no sucede cuando se analizan subgrupos clasificados según su origen étnico, género y estatus socio-económico.