TDP-43-immunoreactive pathology in frontotemporal lobar degeneration with TDP proteinopathy (FTLD-TDP) with and without associated motor neuron disease (MND)

A proportion of patients with motor neuron disease (MND) exhibit frontotemporal dementia (FTD) and some patients with FTD develop the clinical features of MND. Frontotemporal lobar degeneration (FTLD) is the pathological substrate of FTD and some forms of this disease (referred to as FTLD-U) share with MND the common feature of ubiquitin-immunoreactive, tau-negative cellular inclusions in the cerebral cortex and hippocampus. Recently, the transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) has been found to be a major protein of the inclusions of FTLD-U with or without MND and these cases are referred to as FTLD with TDP-43 proteinopathy (FTLD-TDP). To clarify the relationship between MND and FTLD-TDP, TDP-43 pathology was studied in nine cases of FTLD-MND and compared with cases of familial and sporadic FTLD-TDP without associated MND. A principal components analysis (PCA) of the nine FTLD-MND cases suggested that variations in the density of surviving neurons in the frontal cortex and neuronal cytoplasmic inclusions (NCI) in the dentate gyrus (DG) were the major histological differences between cases. The density of surviving neurons in FTLD-MND was significantly less than in FTLD-TDP cases without MND, and there were greater densities of NCI but fewer neuronal intranuclear inclusions (NII) in some brain regions in FTLD-MND. A PCA of all FTLD-TDP cases, based on TDP-43 pathology alone, suggested that neuropathological heterogeneity was essentially continuously distributed. The FTLD-MND cases exhibited consistently high loadings on PC2 and overlapped with subtypes 2 and 3 of FTLD-TDP. The data suggest: (1) FTLD-MND cases have a consistent pathology, variations in the density of NCI in the DG being the major TDP-43-immunoreactive difference between cases, (2) there are considerable similarities in the neuropathology of FTLD-TDP with and without MND, but with greater neuronal loss in FTLD-MND, and (3) FTLD-MND cases are part of the FTLD-TDP 'continuum' overlapping with FTLD-TDP disease subtypes 2 and 3. © 2012 Nova Science Publishers, Inc. All rights reserved.

Clinical characteristics and benefit of cataract intervention amongst UK domiciliary eye care recipients

Purpose: Given the ageing UK population and the high prevalence of activity-limiting illness and disability in the over 65s, the demand for domiciliary eye care services is set to grow significantly. Over 400,000 NHS domiciliary eye examinations are conducted each year, yet minimal research attention has been directed to this mode of practice or patient needs amongst this group. The study aimed to compare clinical characteristics and benefits of cataract surgery between conventional in-practice patients and domiciliary service users. Methods: Clinical characteristics were compared between patients in North-West England receiving NHS domiciliary eye care services (n = 197; median age 76.5 years), and an age-matched group of conventional in-practice patients (n = 107; median age 74.6 years). Data including reason for visit; logMAR uncorrected and best corrected distance (UDVA and CDVA) and near acuities (UNVA and CNVA); presence of ocular pathology and examination outcome were documented retrospectively. To compare the benefit of cataract surgery in terms of functional capacity between the patient groups, individuals undergoing routine referral for first-eye surgery completed the VF-14 questionnaire pre-operatively, and at 6 weeks post-operatively. Results: UDVA was similar between the two groups (median 0.48 and 0.50 logMAR in the domiciliary and practice groups, P = 0.916); CDVA was significantly worse in the domiciliary group (median 0.18 vs 0.08 logMAR, P<0.001), who were more likely to have clinically-significant cataract. Both groups showed similar improvements in VF-14 scores following cataract surgery (mean gains 24.4 ± 11.7, and 31.5 ± 14.7 points in the in-practice and domiciliary groups, respectively. P = 0.312). Conclusions: Patients receiving domiciliary eye care services are more likely to have poorer corrected vision than in-practice patients of a similar age, partly due to a higher prevalence of significant cataract. Despite limitations in their activities due to illness and disability, domiciliary patients experience similar gains in self-reported functional capacity following cataract surgery

Validation of Coded Aperture Coherent Scatter Spectral Imaging for Differentiation of Normal and Neoplastic Breast Tissues via Surgical Pathology

This study intends to validate the sensitivity and specificity of coded aperture coherent scatter spectral imaging (CACSSI) by comparison to clinical histological preparation and pathologic analysis methods currently used for the differentiation of normal and neoplastic breast tissues. A composite overlay of the CACSSI rendered image and pathologist interpreted, stained sections validate the ability of coherent scatter imaging to differentiate cancerous tissues from normal, healthy breast structures ex-vivo. Via comparison to the pathologist annotated slides, the CACSSI system may be further optimized to maximized sensitivity and specificity for differentiation of breast carcinomas.

Machine learning classification of surgical pathology reports and chunk recognition for information extraction noise reduction

Background and aims: Machine learning techniques for the text mining of cancer-related clinical documents have not been sufficiently explored. Here some techniques are presented for the pre-processing of free-text breast cancer pathology reports, with the aim of facilitating the extraction of information relevant to cancer staging.

Materials and methods: The first technique was implemented using the freely available software RapidMiner to classify the reports according to their general layout: ‘semi-structured’ and ‘unstructured’. The second technique was developed using the open source language engineering framework GATE and aimed at the prediction of chunks of the report text containing information pertaining to the cancer morphology, the tumour size, its hormone receptor status and the number of positive nodes. The classifiers were trained and tested respectively on sets of 635 and 163 manually classified or annotated reports, from the Northern Ireland Cancer Registry.

Results: The best result of 99.4% accuracy – which included only one semi-structured report predicted as unstructured – was produced by the layout classifier with the k nearest algorithm, using the binary term occurrence word vector type with stopword filter and pruning. For chunk recognition, the best results were found using the PAUM algorithm with the same parameters for all cases, except for the prediction of chunks containing cancer morphology. For semi-structured reports the performance ranged from 0.97 to 0.94 and from 0.92 to 0.83 in precision and recall, while for unstructured reports performance ranged from 0.91 to 0.64 and from 0.68 to 0.41 in precision and recall. Poor results were found when the classifier was trained on semi-structured reports but tested on unstructured.

Conclusions: These results show that it is possible and beneficial to predict the layout of reports and that the accuracy of prediction of which segments of a report may contain certain information is sensitive to the report layout and the type of information sought.

Clinical implications of recent findings in schistosome proteomics

Schistosomiasis is a neglected tropical disease of clinical significance that, despite years of research, still requires an effective vaccine and improved diagnostics for surveillance, control and potential elimination. Furthermore, the causes of host pathology during schistosomiasis are still not completely understood. The recent sequencing of the genomes of the three key schistosome species has enabled the discovery of many new possible vaccine and drug targets, as well as diagnostic biomarkers, using high-throughput and sensitive proteomics methods. This review focuses on the literature of the last 5 years that has reported on the use of proteomics to both better understand the biology of the schistosome parasites and the disease they cause in definitive mammalian hosts.

Building a 'Repository of Science': the importance of integrating Biobanks within molecular pathology programmes

Repositories containing high quality human biospecimens linked with robust and relevant clinical and pathological information are required for the discovery and validation of biomarkers for disease diagnosis, progression and response to treatment. Current molecular based discovery projects using either low or high throughput technologies rely heavily on ready access to such sample collections. It is imperative that modern biobanks align with molecular diagnostic pathology practices not only to provide the type of samples needed for discovery projects but also to ensure requirements for ongoing sample collections and the future needs of researchers are adequately addressed. Biobanks within comprehensive molecular pathology programmes are perfectly positioned to offer more than just tumour derived biospecimens; for example, they have the ability to facilitate researchers gaining access to sample metadata such as digitised scans of tissue samples annotated prior to macrodissection for molecular diagnostics or pseudoanonymised clinical outcome data or research results retrieved from other users utilising the same or overlapping cohorts of samples. Furthermore, biobanks can work with molecular diagnostic laboratories to develop standardized methodologies for the acquisition and storage of samples required for new approaches to research such as ‘liquid biopsies’ which will ultimately feed into the test validations required in large prospective clinical studies in order to implement liquid biopsy approaches for routine clinical practice. We draw on our experience in Northern Ireland to discuss how this harmonised approach of biobanks working synergistically with molecular pathology programmes is key for the future success of precision medicine.

Clinical approach of atresia coli in a calf

Atresia coli is a congenital defect with disruption of the intestinal flow. Its etiopathogenesis is still unknown and the prognosis is reserved. This paper describes the case of a one week old Holstein Friesian calf that was referred to the HCVC, and was diagnosed with atresia coli. This confirmation was made by contrast radiography and the lesion was detected in dorsal portion of the spiral colon. A cecostomy was performed followed by a marsupialization of the intestinal cecum to the abdominal wall. After 36 hours of surgery, calf’s state worsens dramatically and for reasons of welfare, it was proceeded to sacrifice. The post-operative recovery is possible, even though the mortality rate is high. As in this case, this mortality rate increases when early diagnosis of atresia coli does not take place and there is peritonitis.

Clinical utility of amyloid PET imaging in the differential diagnosis of atypical dementias and its impact on caregivers

La maladie d’Alzheimer (MA) se caractérise pathologiquement par l’accumulation de plaques amyloïde dans le cerveau. La tomographie par émission de positrons (TEP) permet d’imager les plaques amyloïde in vivo. Le but de ce projet est d’évaluer le rôle de la TEP amyloïde dans le processus diagnostique de la MA dans des cas de démences atypiques. Le deuxième but de ce projet est de déterminer l’impact de la révélation d’un diagnostic plus certain chez les proches aidants. 28 patients sans diagnostic malgré une investigation exhaustive ont été sélectionnées et imagées avec le traceur amyloïde 18F-NAV4694 (âge 59,3 ans, é-t. 5,8; MMSE 21.4, é-t 6.0). Les neurologues référents documentaient par la suite tout changement de niveau de certitude, de diagnostic, de traitement et/ou de prise en charge. Les proches aidants consentants ont été rencontrés subséquemment, et un questionnaire avec une échelle de Likert a été utilisé afin de documenter l’impact de l’imagerie leur perception de la maladie. Notre cohorte a été également divisée entre amyloïde positifs (14/28) et négatifs (14/28). Un changement de diagnostic a lieu dans 9/28 cas (32,1% :17.8% ont changé de MA à non-MA, 14,3% de non-MA à MA). Il y avait une augmentation significative (p<0,05) de 44% dans la certitude du neurologue suite à cet examen. Un changement de prise en charge a été obtenu dans 20/28 (71,4%) des cas. Bien que non significatifs statistiquement, un impact favorable sur les proches-aidants a été noté. Cette étude suggère que l’imagerie amyloïde a un rôle bénéfique dans les cas de démences atypiques n’ayant pu être élucidés avec les techniques d’investigations actuellement recommandées. De plus, le processus a été perçu positivement par les proches aidants, notamment en encourageant du temps de qualité avec leurs personnes chères. Ceci illustre un rôle prometteur des biomarqueurs, qui sont de plus en plus explorés.

Oncology research and clinical decisions based on immunohistochemistry: the importance of the technical aspects that support a complex method

Immunohistochemistry (IHC) is the group of techniques that use antibodies as specific reagents to identify and demonstrate several cell and tissue components that are antigens. This linking allows locating and identifying the in situ presence of various substances by means of color that is associated with the formed antigen-antibody complexes. The practical value of this biotechnology area, widely used in Pathology and Oncology, in diagnostic, prognostic, theranostic and research context, results from the possibility of combining a colour marker with an antibody without causing any damage to specific binding established between antibody and antigen. This provides the microscopic observation of the target locations where the antibody and hence the antigen are present. IHC is presented as a powerful means for identification of several cellular and tissue structures that can be associated with pathologies, and of the consequences, at functional and morphological level, of these same elements action.

eLearning in the context of a one-year postgraduate course in macroscopy in pathology: benefits of a multifaceted and pluripotent concept

Performing Macroscopy in Pathology implies to plan and implement methods of selection, description and collection of biological material from human organs and tissues, actively contributing to the clinical pathology analysis by preparing macroscopic report and the collection and identification of fragments, according to the standardized protocols and recognizing the criteria internationally established for determining the prognosis. The Macroscopy in Pathology course is a full year program with theoretical and pratical components taught by Pathologists. It is divided by organ/system surgical pathology into weekly modules and includes a practical "hands-on" component in Pathology Departments. The students are 50 biomedical scientists aged from 22 to 50 years old from all across the country that want to acquire competences in macroscopy. A blended learning strategy was used in order to: give students the opportunity to attend from distance; support the contents, lessons and the interaction with colleagues and teachers; facilitate the formative/summative assessment.

Pathologically confirmed breast cancer in Malawi: a descriptive study: Clinical profile of breast cancer

Background Breast cancer is the most common female cancer in Africa, yet no published studies have investigated breast cancer in Malawi. Understanding the clinical profile of breast cancer is important to develop early diagnosis efforts. Aim To describe clinical and pathological characteristics of breast specimens from a pathology laboratory at a national teaching hospital. Methods Secondary analysis of pathology reports from July 2011 to September 2013. Results Among 85 breast cancer cases, 55% were < 50 years. Median tumor size was 4 cm and 49% were grade 3. Median symptom duration was eight months. Conclusions Malawian women with breast cancer commonly have long symptom durations prior to diagnosis, young age, and poorly differentiated tumors. Improved clinical and pathological characterization, including hormone receptor status, are urgently needed to better understand this disease in Malawi.

Clinical education reflective ecological model for health science majors

The clinical education is an integral part of the Health Science majors’ curriculum programs of the University of Aveiro’s School of Health (i.e., Nursing, Physical Therapy, Radiology, Radiotherapy and Speech-Language Pathology) and aims to develop clinical competences in order to generate excellent health care professionals. The organization was based on the Ecological Model of Clinical-Reflective Training, which was characterized by inter-institutional interaction and student’s reflection on actions on a professional setting. This study encompassed two moments of clinical internships in the Nursing, Physical Therapy, Radiology and Radiotherapy majors. The Clinical Internship I provided the 123 students with a global view of the health care professional activities. The Clinical Internship II, with 119 students, developed competences of each health professional. Questionnaires with categorical scales from 1 to 5 evaluated the organization and efficiency of the two internships. The results revealed averages over 3 in all items. In conclusion, the Ecological Model of Clinical-Reflective Training was well accepted by students and clinical supervisors. Applications in the health care area were demonstrated.

Clinical characteristics and selection of treatment modality for patients with vitreomacular traction:real-world implementation of NICE guidance (TA297)

Aim: To investigate the qualitative aspects in patient selection and the quantitative impact of disease burden in real world treatment of vitreomacular traction (VMT) and implementation of the National Institute for Health and Care Excellence (NICE) guidance (TA297). Methods: A monocentric, retrospective review of consecutive patients undergoing optical coherence tomography (OCT) imaging over a 3 month period. Patients with VMT in at least one eye were identified for further data collection on laterality, visual acuity, symptoms, presence of epiretinal membrane, macular hole and treatment selection. Results: A total of 3472 patients underwent OCT imaging with a total of 6878 eyes scanned. Out of 87 patients, 74 patients had unilateral VMT (38 right, 36 left) and 13 patients had bilateral VMT. Eighteen patients with unilateral VMT satisfied NICE criteria of severe sight problems in the affected eye. Eight were managed for a coexisting pathology, one refused treatment, one patient did not attend, two closed spontaneously, and one received ocriplasmin prior to the study start date. Only two patients with unilateral VMT received ocriplasmin and three underwent vitrectomy. Those failing to meet NICE criteria for unilateral VMT were predominantly asymptomatic (n=49) or had coexisting ERM (n=5) or both (n=2). Conclusion: Ocriplasmin provides an alternative treatment for patients with symptomatic VMT. Our data shows that the majority of patients with VMT do not meet NICE TA297 primarily due to lack of symptoms. Those meeting NICE criteria, but not treated, tended to have coexisting macular pathology. Variation in patient selection due to subjective factors not outlined in NICE guidance suggests that real world outcomes of ocriplasmin therapy should be interpreted with caution.

Quantitative susceptibility mapping as biomarker of neurodegeneration: methodological models and clinical applications

Quantitative Susceptibility Mapping (QSM) is an advanced magnetic resonance technique that can quantify in vivo biomarkers of pathology, such as alteration in iron and myelin concentration. It allows for the comparison of magnetic susceptibility properties within and between different subject groups. In this thesis, QSM acquisition and processing pipeline are discussed, together with clinical and methodological applications of QSM to neurodegeneration. In designing the studies, significant emphasis was placed on results reproducibility and interpretability. The first project focuses on the investigation of cortical regions in amyotrophic lateral sclerosis. By examining various histogram susceptibility properties, a pattern of increased iron content was revealed in patients with amyotrophic lateral sclerosis compared to controls and other neurodegenerative disorders. Moreover, there was a correlation between susceptibility and upper motor neuron impairment, particularly in patients experiencing rapid disease progression. Similarly, in the second application, QSM was used to examine cortical and sub-cortical areas in individuals with myotonic dystrophy type 1. The thalamus and brainstem were identified as structures of interest, with relevant correlations with clinical and laboratory data such as neurological evaluation and sleep records. In the third project, a robust pipeline for assessing radiomic susceptibility-based features reliability was implemented within a cohort of patients with multiple sclerosis and healthy controls. Lastly, a deep learning super-resolution model was applied to QSM images of healthy controls. The employed model demonstrated excellent generalization abilities and outperformed traditional up-sampling methods, without requiring a customized re-training. Across the three disorders investigated, it was evident that QSM is capable of distinguishing between patient groups and healthy controls while establishing correlations between imaging measurements and clinical data. These studies lay the foundation for future research, with the ultimate goal of achieving earlier and less invasive diagnoses of neurodegenerative disorders within the context of personalized medicine.

An Efficient Protocol For The Generation Of Monocyte Derived Dendritic Cells Using Serum-free Media For Clinical Applications In Post Remission Aml Patients.

Protocols for the generation of dendritic cells (DCs) using serum as a supplementation of culture media leads to reactions due to animal proteins and disease transmissions. Several types of serum-free media (SFM), based on good manufacture practices (GMP), have recently been used and seem to be a viable option. The aim of this study was to evaluate the results of the differentiation, maturation, and function of DCs from Acute Myeloid Leukemia patients (AML), generated in SFM and medium supplemented with autologous serum (AS). DCs were analyzed by phenotype characteristics, viability, and functionality. The results showed the possibility of generating viable DCs in all the conditions tested. In patients, the X-VIVO 15 medium was more efficient than the other media tested in the generation of DCs producing IL-12p70 (p=0.05). Moreover, the presence of AS led to a significant increase of IL-10 by DCs as compared with CellGro (p=0.05) and X-Vivo15 (p=0.05) media, both in patients and donors. We concluded that SFM was efficient in the production of DCs for immunotherapy in AML patients. However, the use of AS appears to interfere with the functional capacity of the generated DCs.