Can accelerometer ear tags identify behavioural changes in sheep associated with parturition?

On-animal sensor systems provide an opportunity to monitor ewes during parturition, potentially reducing ewe and lamb mortality risk. This study investigated the capacity of machine learning (ML) behaviour classification to monitor changes in sheep behaviour around the time of lambing using ear-borne accelerometers. Accelerometers were attached to 27 ewes grazing a 4.4 ha paddock. Data were then classified based on three different ethograms: (i) detection of grazing, lying, standing, walking; (ii) detection of active behaviour; and (iii) detection of body posture. Proportion of time devoted to performing each behaviour and activity was then calculated at a daily and hourly scale. Frequency of posture change was also calculated on an hourly scale. Assessment of each metric using a linear mixed-effects model was conducted for the 7 days (day scale) or 12 h (hour scale) before and after lambing. For all physical movements, regardless of the ethogram, there was a change in the days surrounding lambing. This involved either a decrease (grazing, lying, active behaviour) or peak (standing, walking) on the day of parturition, with most values returning to either pre-partum or near-pre-partum levels (all P < 0.001). Hourly changes also occurred for all behaviours (all P < 0.001), the most marked being increased walking behaviour and frequency of posture change. These findings indicate ewes were more restless around the time of parturition. Further application of this research should focus on development of algorithms that can be used to identify onset of lambing and/or time of parturition in pasture-based ewes.

DECO: decompose heterogeneous population cohorts for patient stratification and discovery of sample biomarkers using omic data profiling.

MOTIVATION: Patient and sample diversity is one of the main challenges when dealing with clinical cohorts in biomedical genomics studies. During last decade, several methods have been developed to identify biomarkers assigned to specific individuals or subtypes of samples. However, current methods still fail to discover markers in complex scenarios where heterogeneity or hidden phenotypical factors are present. Here, we propose a method to analyze and understand heterogeneous data avoiding classical normalization approaches of reducing or removing variation. RESULTS: DEcomposing heterogeneous Cohorts using Omic data profiling (DECO) is a method to find significant association among biological features (biomarkers) and samples (individuals) analyzing large-scale omic data. The method identifies and categorizes biomarkers of specific phenotypic conditions based on a recurrent differential analysis integrated with a non-symmetrical correspondence analysis. DECO integrates both omic data dispersion and predictor-response relationship from non-symmetrical correspondence analysis in a unique statistic (called h-statistic), allowing the identification of closely related sample categories within complex cohorts. The performance is demonstrated using simulated data and five experimental transcriptomic datasets, and comparing to seven other methods. We show DECO greatly enhances the discovery and subtle identification of biomarkers, making it especially suited for deep and accurate patient stratification. AVAILABILITY AND IMPLEMENTATION: DECO is freely available as an R package (including a practical vignette) at Bioconductor repository (http://bioconductor.org/packages/deco/). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Cochlear implantation for chronic electrical stimulation in the mouse.

The mouse is becoming an increasingly attractive model for auditory research due to the number of genetic deafness models available. These genetic models offer the researcher an array of congenital causes of hearing impairment, and are therefore of high clinical relevance. To date, the use of mice in cochlear implant research has not been possible due to the lack of an intracochlear electrode array and stimulator small enough for murine use, coupled with the difficulty of the surgery in this species. Here, we present a fully-implantable intracochlear electrode stimulator assembly designed for chronic implantation in the mouse. We describe the surgical approach for implantation, as well as presenting the first functional data obtained from intracochlear electrical stimulation in the mouse.

The effect of organelle discovery upon sub-cellular protein localisation.

Prediction of protein sub-cellular localisation by employing quantitative mass spectrometry experiments is an expanding field. Several methods have led to the assignment of proteins to specific subcellular localisations by partial separation of organelles across a fractionation scheme coupled with computational analysis. Methods developed to analyse organelle data have largely employed supervised machine learning algorithms to map unannotated abundance profiles to known protein-organelle associations. Such approaches are likely to make association errors if organelle-related groupings present in experimental output are not included in data used to create a protein-organelle classifier. Currently, there is no automated way to detect organelle-specific clusters within such datasets. In order to address the above issues we adapted a phenotype discovery algorithm, originally created to filter image-based output for RNAi screens, to identify putative subcellular groupings in organelle proteomics experiments. We were able to mine datasets to a deeper level and extract interesting phenotype clusters for more comprehensive evaluation in an unbiased fashion upon application of this approach. Organelle-related protein clusters were identified beyond those sufficiently annotated for use as training data. Furthermore, we propose avenues for the incorporation of observations made into general practice for the classification of protein-organelle membership from quantitative MS experiments. BIOLOGICAL SIGNIFICANCE: Protein sub-cellular localisation plays an important role in molecular interactions, signalling and transport mechanisms. The prediction of protein localisation by quantitative mass-spectrometry (MS) proteomics is a growing field and an important endeavour in improving protein annotation. Several such approaches use gradient-based separation of cellular organelle content to measure relative protein abundance across distinct gradient fractions. The distribution profiles are commonly mapped in silico to known protein-organelle associations via supervised machine learning algorithms, to create classifiers that associate unannotated proteins to specific organelles. These strategies are prone to error, however, if organelle-related groupings present in experimental output are not represented, for example owing to the lack of existing annotation, when creating the protein-organelle mapping. Here, the application of a phenotype discovery approach to LOPIT gradient-based MS data identifies candidate organelle phenotypes for further evaluation in an unbiased fashion. Software implementation and usage guidelines are provided for application to wider protein-organelle association experiments. In the wider context, semi-supervised organelle discovery is discussed as a paradigm with which to generate new protein annotations from MS-based organelle proteomics experiments.

Inhibition of activin/nodal signalling is necessary for pancreatic differentiation of human pluripotent stem cells.

AIMS/HYPOTHESIS: Human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hIPSCs) offer unique opportunities for regenerative medicine and for the study of mammalian development. However, developing methods to differentiate hESCs/hIPSCs into specific cell types following a natural pathway of development remains a major challenge. METHODS: We used defined culture media to identify signalling pathways controlling the differentiation of hESCs/hIPSCs into pancreatic or hepatic progenitors. This approach avoids the use of feeders, stroma cells or serum, all of which can interfere with experimental outcomes and could preclude future clinical applications. RESULTS: This study reveals, for the first time, that activin/TGF-ß signalling blocks pancreatic specification induced by retinoic acid while promoting hepatic specification in combination with bone morphogenetic protein and fibroblast growth factor. Using this knowledge, we developed culture systems to differentiate human pluripotent stem cells into near homogenous population of pancreatic and hepatic progenitors displaying functional characteristics specific to their natural counterparts. Finally, functional experiments showed that activin/TGF-ß signalling achieves this essential function by controlling the levels of transcription factors necessary for liver and pancreatic development, such as HEX and HLXB9. CONCLUSION/INTERPRETATION: Our methods of differentiation provide an advantageous system to model early human endoderm development in vitro, and also represent an important step towards the generation of pancreatic and hepatic cells for clinical applications.

Genome-wide expression profile of first trimester villous and extravillous human trophoblast cells.

We have examined the transcriptional changes associated with differentiation from villous to extravillous trophoblast using a whole genome microarray. Villous trophoblast (VT) is in contact with maternal blood and mediates nutrient exchange whereas extravillous trophoblast (EVT) invades the decidua and remodels uterine arteries. Using highly purified first trimester trophoblast we identified over 3000 transcripts that are differentially expressed. Many of these transcripts represent novel functions and pathways that show co-ordinated up-regulation in VT or EVT. In addition we identify new players in established functions such as migration, immune modulation and cytokine or angiogenic factor secretion by EVT. The transition from VT to EVT is also characterised by alterations in transcription factors such as STAT4 and IRF9, which may co-ordinate these changes. Transcripts encoding several members of the immunoglobulin-superfamily, which are normally expressed on leukocytes, were highly transcribed in EVT but not expressed as protein, indicating specific control of translation in EVT. Interactions of trophoblast with decidual leukocytes are involved in regulating EVT invasion. We show that decidual T-cells, macrophages and NK cells express the inhibitory collagen receptor LAIR-1 and that EVT secrete LAIR-2, which can block this interaction. This represents a new mechanism by which EVT can modulate leukocyte function in the decidua. Since LAIR-2 is detectable in the urine of pregnant, but not non-pregnant women, trophoblast-derived LAIR-2 may also have systemic effects during pregnancy.

Monitoring distances travelled by horses using GPS tracking collars.

OBJECTIVE: The aims of this work were to (1) develop a low-cost equine movement tracking collar based on readily available components, (2) conduct preliminary studies assessing the effects of both paddock size and internal fence design on the movements of domestic horses, with and without foals at foot, and (3) describe distances moved by mares and their foals. Additional monitoring of free-ranging feral horses was conducted to allow preliminary comparisons with the movement of confined domestic horses. PROCEDURES: A lightweight global positioning system (GPS) data logger modified from a personal/vehicle tracker and mounted on a collar was used to monitor the movement of domestic horses in a range of paddock sizes and internal fence designs for 6.5-day periods. RESULTS: In the paddocks used (0.8-16 ha), groups of domestic horses exhibited a logarithmic response in mean daily distance travelled as a function of increasing paddock size, tending asymptotically towards approximately 7.5 km/day. The distance moved by newborn foals was similar to their dams, with total distance travelled also dependent on paddock size. Without altering available paddock area, paddock design, with the exception of a spiral design, did not significantly affect mean daily distance travelled. Feral horses (17.9 km/day) travelled substantially greater mean daily distances than domestic horses (7.2 km/day in 16-ha paddock), even when allowing for larger paddock size. CONCLUSIONS: Horses kept in stables or small yards and paddocks are quite sedentary in comparison with their feral relatives. For a given paddock area, most designs did not significantly affect mean daily distance travelled.

Is there a role for flexible oesophagogastroscopy in upper aerodigestive tract squamous cell carcinoma?

INTRODUCTION: There is growing evidence to suggest that reflux (both laryngopharyngeal and gastroesophageal) has a role in the development of upper aerodigestive tract squamous cell carcinoma. This study discusses the role of identifying reflux in this patient group, and its prevalence. METHODS: Prospective review of patients with head and neck cancer undergoing flexible oesophagogastroscopy as part of their diagnostic investigation. RESULTS: Forty-five consecutive patients were identified. All patients were found to have evidence of oesophagitis, with 28 having oesophageal erosions and two Barrett's oesophagitis. CONCLUSION: Flexible oesophagogastroscopy is a useful test in patients with upper aerodigestive tract squamous cell carcinoma.

Classification of cochlear implant failures and explantation: the Melbourne experience, 1982-2006.

The definition and categorization of reasons for cochlear implant (CI) failure have recently been standardized following the publication of the European Consensus Statement on Cochlear Implant Failures and Explantation (ECSCIFE) (2005). The aim of this study was to review the Melbourne experience with cochlear implant failure and reimplantation, applying ECSCIFE guidelines for categorization and assessing hearing outcomes. A retrospective review was carried out of Melbourne CI clinic's records to identify all cases of implant failure and categorize them using ECSCIFE guidelines. Comparison was made of pre- and post-reimplantation hearing levels for those patients who had undergone ipsilateral reimplantation. Between September 1982 and October 2006 the Melbourne clinic conducted 1164 CIs with 62 implant failures and explantation (5.3%). Reasons included device failure, (ECSCIFE category C, n = 35, 3.0%), medical complication (ECSCIFE category D, n = 19), characteristics decrement (ECSCIFE category B1, n = 2) and performance decrement (ECSCIFE category B2 n = 6). Forty-nine patients underwent ipsilateral explantation/reimplantation. Auditory performance with the second implant was comparable to the first implant levels. The ECSCIFE provides an easy-to-use classification system for international reporting of CI device failures and explantations, however, detailed information of each implant failure may be lost in the final category, however. Cochlear explantation/reimplantation in Melbourne is a safe and effective procedure to restore patients to their pre-operative best auditory function levels.

Workload measurement in subspecialty dermatopathology.

AIM: To measure pathologist workload in subspecialty dermatopathology. METHODS: Three subspecialty dermatopathologists, working in a university-affiliated laboratory, participated in a time-motion study during which they reported 2891 consecutive skin cases received from community-based dermatologists. All pathology reports were retrospectively reviewed and workload measured using the Royal College of Pathologists (RCPath) guidelines and the level 4 equivalent (L4E) method. RESULTS: The majority of dermatopathology cases were scored as low (32%) or intermediate (52%) complexity using the RCPath matrix. Only 16% of cases were considered high or very high complexity. The mean RCPath score per case was 2.68 units. Using L4E complexity levels, 83% of specimens were level 3, 15% were level 4, and only 2% were higher complexity (levels 5 and 6). Mean values for specimens/case, blocks/case, and slides/case were 1.31, 1.52, and 2.92, respectively. Time-motion analysis demonstrated a mean workload per hour of 16.3 cases, 21.3 specimens, 45.1 slides, 43.0 RCPath units, and 12.2 L4E. All three dermatopathologists reported >35 RCPath units per hour. CONCLUSIONS: The RCPath histopathology workload guidelines underestimate the workload achievable by an experienced dermatopathologist, and thus are not directly applicable to subspecialty dermatopathology practice. Hourly work rates 3-4 times that recommended by the RCPath workload matrix are routinely achievable, but extrapolation to yearly workload estimates requires detailed knowledge of practice pattern and time required for non-clinical duties such as teaching, research and administration.

Bilateral facial nerve palsy associated with HIV seroconversion illness.

Bilateral facial nerve palsy is a rare but recognised manifestation of HIV seroconversion illness. The pathophysiology of this clinical presentation is thought to be associated with the immune response of the dissemination of virus throughout the body. We describe a case of bilateral facial nerve palsy, subsequently diagnosed with HIV. Related medical literature is also reviewed. The case highlights the vigilance required in unusual, atypical signs and symptoms if a diagnosis of HIV infection is not to be missed. Clinicians should be aware of the potential presentation of HIV seroconversion illness to provide opportunity for early diagnosis and intervention.

Hearing aids and tinnitus therapy: a 25-year experience.

OBJECTIVES: (1) To assess the subjective tinnitus perception of patients with audiologically proven hearing loss presenting to a tinnitus clinic, both before and after hearing aid provision; (2) to investigate subjective tinnitus perception in patients with unilateral and bilateral hearing loss; and (3) to assess the impact on tinnitus perception, if any, of a digital hearing aid programme in patients provided with hearing aids. DESIGN: Prospective data collection for patients attending a tinnitus clinic over a 25-year period (1980-2004). SETTING: University teaching hospital otolaryngology department. PARTICIPANTS: A total of 2153 consecutive patients attending a consultant-delivered specialist tinnitus clinic. MAIN OUTCOMES MEASURES: A visual analogue scale was used to assess the degree of tinnitus perception improvement, if any, comparing before versus after unilateral or bilateral aiding (in those with audiometrically proven hearing loss). A further assessment compared the effect of digital hearing aid programme introduction on symptomatic tinnitus perception in patients provided with unilateral or bilateral aids. RESULTS: A total of 1440 patients were given hearing aids (826 unilateral and 614 bilateral). There was little difference in tinnitus perception, comparing overall aiding results in unilaterally or bilaterally aided patients. Overall, 554 (67 per cent) of unilaterally aided patients and 424 (69 per cent) of bilaterally aided patients reported some improvement in their tinnitus perception following aiding. There was a statistically significant improvement in tinnitus perception, comparing analogue aids with digital hearing aids, following introduction of a digital hearing aid programme in 2000, in both unilaterally (p < 0.001) and bilaterally (p < 0.001) aided patients. CONCLUSIONS: Provision of hearing aids in patients with audiometrically demonstrable hearing loss can play a very important part in tinnitus control. The additional improvement in tinnitus control observed following introduction of programmable digital aids had a summative effect in the management of these patients.

Evidence that dysregulated DNA mismatch repair characterizes human nonmelanoma skin cancer.

BACKGROUND: In addition to an established role in the repair of postreplicative DNA errors, DNA mismatch repair (MMR) proteins also contribute to cellular responses to exogenous DNA damage. Previously, we have shown that Msh2-null mice display increased sensitivity to ultraviolet (UV) B-induced tumorigenesis, but squamous cell carcinomas (SCC) generated are microsatellite stable, suggesting a role for MMR other than postreplicative repair in UV-induced cutaneous tumour formation. OBJECTIVES: We questioned whether there was evidence of MMR dysfunction in human SCC, thus validating the mouse models of MMR-dependent UVB-induced skin cancer. METHODS: Using tissue microarrays we examined both nuclear and cytoplasmic levels of MMR proteins MSH2, MSH6, MSH3, MLH1 and PMS2 in more than 200 cases of cutaneous SCC and basal cell carcinoma (BCC). RESULTS: We found that subsets of these 10 MMR protein measures were increased in nonmelanoma skin cancer (NMSC) compared with normal epidermal samples; this was particularly true of SCC. In fact, based on post hoc tests and MMR protein distribution patterns, BCC was distinct from SCC. With the exception of nuclear MSH2, the BCC had lower levels of identified MMR protein measures than SCC. We believe this to be important because not only is SCC more aggressive than BCC, but evidence suggests that these two NMSC subtypes arise through different molecular pathways. CONCLUSIONS: In combination with previously established roles for MMR proteins in response to UVB-induced DNA damage, our data point towards an expanded perspective of the importance of MMR proteins in the suppression of UVB-induced tumorigenesis and, potentially, tumour behaviour.

Refractory Crohn's disease of the vulva treated with infliximab: a case report.

Crohn's disease (CD) is a chronic relapsing and remitting inflammatory disorder of the gastrointestinal tract. The common presentation includes abdominal pain, abdominal cramping and diarrhea. Many patients may exhibit systemic symptoms of fever and weight loss. Approximately 20% to 40% of patients will experience extraintestinal manifestations that involve the eyes, skin and joints. Women may experience a variety of gynecological manifestations, including vulvovaginal involvement, which is often not recognized and also difficult to treat. A case of refractory vulvovaginal CD is presented and the literature of gynecological manifestations of CD and its treatment are reviewed.

Follicular lymphoma presenting as mumps, with persistent cervical lymphadenopathy.

We report a case of follicular lymphoma in a healthy individual, which presented as saliva- and serum-proven mumps. The patient presented with a sore throat and parotid and submandibular lymphadenopathy. Fine needle aspiration, undertaken three weeks following presentation, revealed no malignant cells. An excision biopsy of a level two node was performed due to persistent lymphadenopathy, five weeks following presentation. As far as we are aware, this is the first reported case of follicular lymphoma presenting as mumps. This case highlights the importance of follow up in patients in whom lymphadenopathy is persistent despite the proven diagnosis of mumps.

Dysplastic naevi with moderate to severe histological dysplasia: a risk factor for melanoma.

BACKGROUND: The risk of malignant melanoma associated with histologically dysplastic naevi (HDN) has not been defined. While clinically atypical naevi appear to confer an independent risk of melanoma, no study has evaluated the extent to which HDN are predictive of melanoma. OBJECTIVES: To estimate the risk of melanoma associated with HDN. Secondarily, the risk associated with number of naevi and large naevi is estimated. METHODS: We enrolled 80 patients with newly diagnosed melanoma along with 80 spousal controls. After obtaining information on melanoma risk factors and performing a complete cutaneous examination, the most clinically atypical naevus was biopsied in both cases and controls. Histological dysplasia was then assessed independently by 13 dermatopathologists (0, no dysplasia; 1, mild dysplasia; 2, moderate dysplasia; 3, severe dysplasia). The dermatopathologists were blinded as to whether the naevi were from melanoma subjects or controls. Multivariate analyses were performed to determine if there was an independent association between the degree of histological dysplasia in naevi and a personal history of melanoma. RESULTS: In persons with naevi receiving an average score of > 1 (i.e. naevi considered to have greater than mild histological dysplasia), there was an increased risk of melanoma [odds ratio (OR) 2.60, 95% confidence interval (CI) 0.99-6.86] which persisted after adjustment for confounders (OR 3.99, 95% CI 1.02-15.71). Very few dermatopathologists reliably graded naevi of subjects with melanoma as being more dysplastic than naevi of control subjects. Among the entire group, the interobserver reliability associated with grading histological dysplasia in naevi was poor (weighted kappa 0.28). CONCLUSIONS: HDN do appear to confer an independent risk of melanoma. However, this result may add more to our biological understanding of melanoma risk than to clinical assessment of risk, because HDN assessed by a single pathologist generally cannot be used to assess risk of melanoma. Future studies should be directed at establishing reproducible, predictive criteria for grading naevi.

Leishmaniasis of the nasal cavity: a case report.

Establishing diagnosis of a granulomatous lesion of the nose is often difficult. Here we report a case of granulomatous lesion of the nose caused by Leishmania--an unlikely cause in the UK. The diagnosis and management of the case is discussed here.

Simple snoring: current practice.

Snoring is a significant problem with both social and medical manifestations. This article addresses the current management of the simple snorer from initial out-patient assessment to definitive treatment.

Thrombospondin-1 and cutaneous melanoma.

BACKGROUND: Thrombospondins (TSPs) are recognized as important glycoproteins that regulate a wide variety of cell functions and interactions. TSPs in malignant tumors can both enhance and inhibit tumor progression, invasion, and metastasis, depending on cell type, stromal interactions, and microenvironment. These proteins are potential targets for anticancer therapy. OBJECTIVE: The aim of our article is to review the role of thrombospondin-1 (TSP1) in cutaneous melanoma. CONCLUSIONS: TSP1 expression is variable in melanoma cell lines and tumors. Similar to findings in other human cancers, expression of TSP1 by melanoma cells usually inhibits tumor progression via the antiangiogenic effect of TSP1. Conversely, stromal TSP1 overexpression in melanoma is a poor prognostic factor associated with decreased survival. Understanding the interactions of TSP1 with other melanoma- and matrix-associated proteins should provide new prognostic indices and possible therapeutic targets for melanoma treatment.

Lactococcus lactis DPC5598, a plasmid-free derivative of a commercial starter, provides a valuable alternative host for culture improvement studies.

AIMS: To generate a plasmid-free derivative of an extensively used industrial starter strain Lactococcus lactis DPC4268, which could be used as a backbone strain for starter improvement programmes. METHODS AND RESULTS: DPC4268 containing four large plasmids was subjected to high temperature plasmid curing resulting in derivatives, each with a different plasmid complement of one, two or three different plasmids in addition to a plasmid-free derivative. Industrially relevant phenotypes were assigned to each plasmid on the basis of detailed phenotypic and genetic analyses and these were (a) proteinase activity (Prt, 60 kb) (b) lactose fermentation (Lac, 55 kb) (c) bacteriophage adsorption inhibition (Ads, 44 kb) and (d) type I restriction/modification (R/M, 40 kb). The plasmid-free variant of DPC4268 was shown to be transformable at frequencies comparable to the common laboratory strain L. lactis MG1614. Furthermore its genome was demonstrated to be significantly different from the laboratory strains L. lactis MG1614 and the recently sequenced L. lactis IL1403 genomes by pulsed-field gel electrophoresis. CONCLUSIONS: This study produced an easily transformable plasmid-free derivative which was genomically different from both MG1614 and IL1403. In addition, important plasmid-borne industrial traits, including two phage-resistance mechanisms, were identified in DPC4268. SIGNIFICANCE AND IMPACT OF THE STUDY: L. DPC4268 is a vitally important commercial strain used in the manufacture of Cheddar cheese. The generation of a plasmid-free derivative may provide an important backbone strain as a basis for future strain improvement purposes.