CineCT platform for in vivo and ex vivo measurement of 3D high resolution Lagrangian strains in the left ventricle following myocardial infarction and intramyocardial delivery of theranostic hydrogel.

Myocardial infarction (MI) produces acute changes in strain and stiffness within the infarct that can affect remote areas of the left ventricle (LV) and drive pathological remodeling. We hypothesized that intramyocardial delivery of a hydrogel within the MI region would lower wall stress and reduce adverse remodeling in Yorkshire pigs (n = 5). 99mTc-Tetrofosmin SPECT imaging defined the location and geometry of induced MI and border regions in pigs, and in vivo and ex vivo contrast cine computed tomography (cineCT) quantified deformations of the LV myocardium. Serial in vivo cineCT imaging provided data in hearts from control pigs (n = 3) and data from pigs (n = 5) under baseline conditions before MI induction, post-MI day 3, post-MI day 7, and one hour after intramyocardial delivery of a hyaluronic acid (HA)-based hydrogel with shear-thinning and self-healing properties to the central infarct area. Isolated, excised hearts underwent similar cineCT imaging using an ex vivo perfused heart preparation with cyclic LV pressurization. Deformations were evaluated using nonlinear image registration of cineCT volumes between end-diastole (ED) and end-systole (ES), and 3D Lagrangian strains were calculated from the displacement gradients. Post-MI day 3, radial, circumferential, maximum principal, and shear strains were reduced within the MI region (p < 0.04) but were unchanged in normal regions (p > 0.6), and LV end diastolic volume (LV EDV) increased (p = 0.004), while ejection fraction (EF) and stroke volume (SV) decreased (p < 0.02). Post-MI day 7, radial strains in MI border zones increased (p = 0.04) and dilation of LV EDV continued (p = 0.052). There was a significant negative linear correlation between regional radial and maximum principal/shear strains and percent infarcted tissue in all hearts (R2 > 0.47, p < 0.004), indicating that cineCT strain measures could predict MI location and degree of injury. Post-hydrogel day 7 post-MI, LV EDV was significantly reduced (p = 0.009), EF increased (p = 0.048), and radial (p = 0.021), maximum principal (p = 0.051), and shear strain (p = 0.047) increased within regions bordering the infarct. A smaller strain improvement within the infarct and normal regions was also noted on average along with an improvement in SV in 4 out of 5 hearts. CineCT provides a reliable method to assess regional changes in strains post-MI and the therapeutic effects of intramyocardial hydrogel delivery.

High-level association of bovine digital dermatitis Treponema spp. with contagious ovine digital dermatitis lesions and presence of Fusobacterium necrophorum and Dichelobacter nodosus.

Contagious ovine digital dermatitis (CODD) is an important foot disease in sheep, with significant animal welfare and economic implications. It is thought that CODD emerged from bovine digital dermatitis (BDD) via treponemal bacteria. With wildlife species such as elk now suffering a CODD-like disease, it is imperative to clarify these disease etiologies. A large investigation into treponemal association with CODD is warranted. CODD lesions (n = 58) and healthy sheep foot tissues (n = 56) were analyzed by PCR for the three BDD-associated Treponema phylogroups and two other lameness-associated bacteria, Dichelobacter nodosus and Fusobacterium necrophorum. Spirochete culture was also attempted on CODD lesions. "Treponema medium/Treponema vincentii-like," "Treponema phagedenis-like," and Treponema pedis spirochetes were identified in 39/58 (67%), 49/58 (85%), and 41/58 (71%) of CODD lesions, respectively. One or more BDD-associated Treponema phylogroups were detected in 100% of CODD lesions. Healthy foot tissues did not amplify BDD-associated Treponema phylogroup DNA. D. nodosus and F. necrophorum were present in 34/58 (59%) and 41/58 (71%) of CODD lesions and 22/56 (39%) and 5/56 (9%) of healthy foot tissues, respectively. Thirty-two spirochetes were isolated from CODD lesions, with representatives clustering with, and indistinguishable from, each of the three BDD-associated Treponema phylogroups based on 16S rRNA gene comparisons. This study for the first time demonstrates a high-level association for BDD treponeme phylogroups in CODD and their absence from healthy tissues, supporting the hypothesis that BDD treponemes play a primary causative role in CODD and confirming that the specific PCR assays are an effective differential diagnostic tool for CODD.

The gastrointestinal tract as a potential infection reservoir of digital dermatitis-associated treponemes in beef cattle and sheep.

Digital dermatitis (DD) is an important cause of lameness in dairy cattle worldwide. It has now been reported in beef cattle and also sheep (contagious ovine digital dermatitis [CODD]). Three Treponema phylogroups are consistently isolated from lesions, Treponema medium-like, Treponema phagedenis-like, and Treponema pedis. The gastrointestinal (GI) tract and feces are suggested sites of treponemal infection in dairy cattle; however, isolation of DD-associated treponemes from these areas has previously failed. This study surveyed gingival tissues, rectal tissues, and feces of beef cattle and sheep for the molecular presence (PCR) and isolation of the three cultivable DD-treponeme phylogroups. Of the sheep gingival (n = 40) and rectal (n = 40) tissues, 1/40 gingival tissues was positive for DD-associated treponemes (T. pedis), as were 3/40 rectal tissues (one containing T. medium-like and two containing T. pedis). No DD-associated treponeme DNA was amplified from beef cattle rectal tissues (n = 40); however, 4/40 beef gingival tissues were positive for DD-associated treponemes (all containing T. phagedenis-like). A T. phagedenis-like DD-associated treponeme was isolated from the rectal tissue of a CODD symptomatic sheep. Beef cattle (n = 41) and sheep (n = 79) feces failed to amplify DD-associated Treponema DNA. Twenty-two treponemes were isolated from sheep feces; however, upon phylogenetic analysis, these clustered with the considered nonpathogenic treponemes. This study detected DD-associated treponemes in the GI tract tissues of sheep and beef cattle and successfully isolated a DD-associated treponeme from ruminant rectal tissue. This gives evidence that the GI tract is an important infection reservoir of DD-associated treponemes in multiple DD-infected species.

Temporal lobe epilepsy and affective disorders: the role of the subgenual anterior cingulate cortex.

OBJECTIVE: Reduced deactivation within the default mode network (DMN) is common in individuals with primary affective disorders relative to healthy volunteers (HVs). It is unknown whether similar network abnormalities are present in temporal lobe epilepsy (TLE) patients with a history of affective psychopathology. METHODS: 17 TLE patients with a lifetime affective diagnosis, 31 TLE patients with no formal psychiatric history and 30 HVs were included. We used a visuo-spatial 'n-back' paradigm to compare working memory (WM) network activation between these groups. Post hoc analyses included voxel-based morphometry and diffusion tensor imaging. The Beck Depression Inventory-Fast Screen and Beck Anxiety Inventory were completed on the day of scanning. FINDINGS: Each group activated the fronto-parietal WM networks and deactivated the typical DMN in response to increasing task demands. Group comparison revealed that TLE patients with lifetime affective morbidity showed significantly greater deactivation in subgenual anterior cingulate cortex (sACC) than either the TLE-only or the HVs (p<0.001). This effect persisted after covarying for current psychotropic medication and severity of current depressive/anxiety symptoms (all p<0.001). Correlational analysis revealed that this finding was not driven by differences in task performance. There were no significant differences in grey matter volume or structural connectivity between the TLE groups. CONCLUSIONS: Our results provide novel evidence suggesting that affective psychopathology in TLE has a neurobiological correlate, and in this context the sACC performs differently compared with network activity in primary affective disorders.

NMDA receptor binding in focal epilepsies.

OBJECTIVE: To demonstrate altered N-methyl-d-aspartate (NMDA) receptor availability in patients with focal epilepsies using positron emission tomography (PET) and [(18)F]GE-179, a ligand that selectively binds to the open NMDA receptor ion channel, which is thought to be overactive in epilepsy. METHODS: Eleven patients (median age 33 years, 6 males) with known frequent interictal epileptiform discharges had an [(18)F]GE-179 PET scan, in a cross-sectional study. MRI showed a focal lesion but discordant EEG changes in two, was non-localising with multifocal EEG abnormalities in two, and was normal in the remaining seven patients who all had multifocal EEG changes. Individual patient [(18)F]GE-179 volume-of-distribution (VT) images were compared between individual patients and a group of 10 healthy controls (47 years, 7 males) using Statistical Parametric Mapping. RESULTS: Individual analyses revealed a single cluster of focal VT increase in four patients; one with a single and one with multifocal MRI lesions, and two with normal MRIs. Post hoc analysis revealed that, relative to controls, patients not taking antidepressants had globally increased [(18)F]GE-179 VT (+28%; p<0.002), and the three patients taking an antidepressant drug had globally reduced [(18)F]GE-179 VT (-29%; p<0.002). There were no focal abnormalities common to the epilepsy group. CONCLUSIONS: In patients with focal epilepsies, we detected primarily global increases of [(18)F]GE-179 VT consistent with increased NMDA channel activation, but reduced availability in those taking antidepressant drugs, consistent with a possible mode of action of this class of drugs. [(18)F]GE-179 PET showed focal accentuations of NMDA binding in 4 out of 11 patients, with difficult to localise and treat focal epilepsy.

Temporal and farm-management-associated variation in faecal-pat prevalence of Campylobacter fetus in sheep and cattle.

SUMMARY: The faecal-pat prevalence (as estimated by culture) of Campylobacter fetus from cattle and sheep on 19 farms in rural Lancashire was investigated using standard Campylobacter culture techniques and PCR during a 2-year longitudinal study. C. fetus was isolated from 9·48% [95% confidence interval (CI) 8·48-10·48] of cattle faecal pats and 7·29% (95% CI 6·21-9·62) of sheep faecal pats. There was evidence of significant differences in shedding prevalence between geographical regions; cows in geographical zone 3 had an increased risk of shedding C. fetus compared to cows in geographical zones 1 and 2 (OR 6·64, 95% CI 1·67-26·5, P = 0·007), as did cows at pasture (OR 1·66, 95% CI 1·01-2·73, P = 0·046) compared to when housed. Multiple logistic regression modelling demonstrated underlying seasonal periodicity in both species.

Multilocus sequence typing of pathogenic treponemes isolated from contagious ovine digital dermatitis stage five lesions: Implications for disease transmission dynamics.

Contagious ovine digital dermatitis (CODD) causes a severe, infectious foot disease and lameness of sheep, is common within the UK and is now also emerging in other countries. As well as causing severe animal welfare issues, huge economic losses emerge from the disease due to weight loss/lack of weight gain, and veterinary treatments. CODD lesion progress is measured, with a scoring system from 1 (early lesions) to 5 (healed). Here, using samples from an experimental flock infected by natural means, samples were taken from CODD stage 5 lesions, post treatment, and subjected to bacterial isolation and MLST using previously published methods. Sequences were compared to others from the same flock, and those from previous studies. All CODD 5 lesions produced viable Treponema spp. bacteria. High levels of variation of bacteria were seen, with 12 sequence types (STs) for T. medium phylogroup (11 new), 15 STs for T. phagedenis phylogroup (9 new) and six T. pedis STs, of which two were new. This study shows that CODD stage 5 lesions still contain viable bacteria, representing all three known pathogenic Treponema spp. phylogroups, and these may thus play a role in disease transmission and epidemiology despite appearing healed after treatment. The high level CODD treponeme variability within an infected flock where sheep were bought from different sources, as might occur in common agricultural practice, may suggest reasons as to why the bacterial disease is difficult to treat, control and eradicate, and adds further complexity to the polybacterial pathogenesis of these lesions.

Specific pathway abundances in the neonatal calf faecal microbiome are associated with susceptibility to Cryptosporidium parvum infection: a metagenomic analysis.

BACKGROUND: Cryptosporidium parvum is the main cause of calf scour worldwide. With limited therapeutic options and research compared to other Apicomplexa, it is important to understand the parasites' biology and interactions with the host and microbiome in order to develop novel strategies against this infection. The age-dependent nature of symptomatic cryptosporidiosis suggests a link to the undeveloped immune response, the immature intestinal epithelium, and its associated microbiota. This led us to hypothesise that specific features of the early life microbiome could predict calf susceptibility to C. parvum infection. RESULTS: In this study, a single faecal swab sample was collected from each calf within the first week of life in a cohort of 346 animals. All 346 calves were subsequently monitored for clinical signs of cryptosporidiosis, and calves that developed diarrhoea were tested for Rotavirus, Coronavirus, E. coli F5 (K99) and C. parvum by lateral flow test (LFT). A retrospective case-control approach was taken whereby a subset of healthy calves (Control group; n = 33) and calves that went on to develop clinical signs of infectious diarrhoea and test positive for C. parvum infection via LFT (Cryptosporidium-positive group; n = 32) were selected from this cohort, five of which were excluded due to low DNA quality. A metagenomic analysis was conducted on the faecal microbiomes of the control group (n = 30) and the Cryptosporidium-positive group (n = 30) prior to infection, to determine features predictive of cryptosporidiosis. Taxonomic analysis showed no significant differences in alpha diversity, beta diversity, and taxa relative abundance between controls and Cryptosporidium-positive groups. Analysis of functional potential showed pathways related to isoprenoid precursor, haem and purine biosynthesis were significantly higher in abundance in calves that later tested positive for C. parvum (q ≤ 0.25). These pathways are either absent or streamlined in the C. parvum parasites. Though the de novo production of isoprenoid precursors, haem and purines are absent, C. parvum has been shown to encode enzymes that catalyse the downstream reactions of these pathway metabolites, indicating that C. parvum may scavenge those products from an external source. CONCLUSIONS: The host has previously been put forward as the source of essential metabolites, but our study suggests that C. parvum may also be able to harness specific metabolic pathways of the microbiota in order to survive and replicate. This finding is important as components of these microbial pathways could be exploited as potential therapeutic targets for the prevention or mitigation of cryptosporidiosis in bovine neonates.

Improving the sensitivity of EEG-fMRI studies of epileptic activity by modelling eye blinks, swallowing and other video-EEG detected physiological confounds.

RATIONALE: To improve the sensitivity and specificity of simultaneous electroencephalography and functional magnetic resonance imaging (EEG-fMRI) it is prudent to devise modelling strategies explaining the residual variance. The purpose of this study is to investigate the potential value of including additional regressors for physiological activities, derived from video-EEG, in the modelling of haemodynamic patterns linked to interictal epileptiform discharges (IEDs) using simultaneously recorded video-EEG-fMRI. METHODS: Ten patients with IED (focal epilepsy: 6, idiopathic generalized epilepsy (IGE):4) were studied. BOLD-sensitive fMRI images were acquired on a 3T MRI scanner. 64-channel EEG was recorded using MR-compatible system. A custom made, dual-video-camera system synchronised with EEG was used to record video simultaneously. IEDs and physiological activities were identified and labelled on video-EEG using Brain Analyzer2. fMRI time-series data were pre-processed and analysed using SPM5 software. Two general linear models (GLM) were created; GLM1: IEDs were convolved with the canonical haemodynamic response function and its derivatives. Realignment parameters and pulse regressors were included in the design matrix as confounds, GLM2: GLM1 and additional regressors identified on video-EEG including: eye blinks, hand or foot movement, chewing and swallowing were also included in the design matrix. SPM [F] maps (p<0.05, corrected for family wise error and p<0.001, uncorrected) were generated for both models. We compared the resulting blood oxygen level dependent (BOLD) maps for cluster size, statistical significance and degree of concordance with the irritative zone. RESULTS: BOLD changes relating to physiological activities were generally seen in expected brain areas. In patients with focal epilepsy, the extent and Z-score of the IED-related global maximum BOLD clusters increased in 4/6 patients and additional IED-related BOLD clusters were observed in 3/6 patients for GLM2. Also, the degree of concordance of IED-related maps with irritative zone improved for one patient for GLM2 and was unchanged for the other cases. In patients with IGE, the size and statistical significance for global maximum and other BOLD clusters increased in 2/4 patients. We conclude that the inclusion of additional regressors, derived from video based information, in the design matrix explains a greater amount of variance and can reveal additional IED-related BOLD clusters which may be part of the epileptic networks.

Neural correlates of working memory in Temporal Lobe Epilepsy--an fMRI study.

It has traditionally been held that the hippocampus is not part of the neural substrate of working memory (WM), and that WM is preserved in Temporal Lobe Epilepsy (TLE). Recent imaging and neuropsychological data suggest this view may need revision. The aim of this study was to investigate the neural correlates of WM in TLE using functional MRI (fMRI). We used a visuo-spatial 'n-back' paradigm to compare WM network activity in 38 unilateral hippocampal sclerosis (HS) patients (19 left) and 15 healthy controls. WM performance was impaired in both left and right HS groups compared to controls. The TLE groups showed reduced right superior parietal lobe activity during single- and multiple-item WM. No significant hippocampal activation was found during the active task in any group, but the hippocampi progressively deactivated as the task demand increased. This effect was bilateral for controls, whereas the TLE patients showed progressive unilateral deactivation only contralateral to the side of the hippocampal sclerosis and seizure focus. Progressive deactivation of the posterior medial temporal lobe was associated with better performance in all groups. Our results suggest that WM is impaired in unilateral HS and the underlying neural correlates of WM are disrupted. Our findings suggest that hippocampal activity is progressively suppressed as the WM load increases, with maintenance of good performance. Implications for understanding the role of the hippocampus in WM are discussed.

Leanness in postnatally nutritionally programmed rats is associated with increased sensitivity to leptin and a melanocortin receptor agonist and decreased sensitivity to neuropeptide Y.

BACKGROUND: Pups of normally nourished dams that are cross-fostered after birth to dams fed a low-protein (8% by weight) diet (postnatal low protein (PLP)) grow slower during the suckling period and remain small and lean throughout adulthood. At weaning, they have increased expression in the arcuate nucleus (ARC) of the hypothalamus of the orexigenic neuropeptide Y (NPY) and decreased expression of pro-opiomelanocortin, the precursor of anorexigenic melanocortins. OBJECTIVES AND METHODS: We investigated, using third ventricle administration, whether 3-month-old male PLP rats display altered sensitivity to leptin with respect to food intake, NPY and the melanocortin 3/4-receptor agonist MTII, and using in situ hybridization or laser capture microdissection of the ARC followed by RT-PCR, whether the differences observed were associated with changes in the hypothalamic expression of NPY or the leptin receptor, NPY receptors and melanocortin receptors. RESULTS: PLP rats were smaller and had reduced percentage body fat content and plasma leptin concentration compared with control rats. Leptin (5 µg) reduced food intake over 0-48 h more in PLP than control rats (P<0.05). Submaximal doses of NPY increased the food intake less in PLP rats than in controls, whereas submaximal doses of MTII reduced the food intake more in PLP rats. Maximal responses did not differ between PLP and control rats. Leptin and melanocortin-3 receptor (MC3R) expression were increased in both ARC and ventromedial hypothalamic nuclei in PLP animals compared with the controls. MC4R, NPY Y1R, Y5R and NPY expression were unchanged. CONCLUSION: Postnatal undernourishment results in food intake in adult rats being more sensitive to reduction by leptin and melanocortins, and less sensitive to stimulation by NPY. We propose that this contributes to increased leptin sensitivity and resistance to obesity. Increased expression of ObRb and MC3R may partly explain these findings but other downstream mechanisms must also be involved.

Three-dimensional reconstructions from optical sections of thick mouse inner ears using confocal microscopy.

Three-dimensional (3D) reconstructions of the vertebrate inner ear have provided novel insights into the development of this complex organ. 3D reconstructions enable superior analysis of phenotypic differences between wild type and mutant ears but can result in laborious work when reconstructed from physically sectioned material. Although nondestructive optical sectioning light sheet microscopy may ultimately prove the ideal solution, these technologies are not yet commercially available, or in many instances are not monetarily feasible. Here we introduce a simple technique to image a fluorescently labelled ear at different stages throughout development at high resolution enabling 3D reconstruction of any component of the inner ear using confocal microscopy. We provide a step-by-step manual from tissue preparation to imaging to 3D reconstruction and analysis including a rationale and troubleshooting guide at each step for researchers with different equipment, protocols, and access to resources to successfully incorporate the principles of this method and customize them to their laboratory settings.

Clinical language fMRI with real-time monitoring in temporal lobe epilepsy: online processing methods.

The increasing demand for clinical fMRI data has resulted in a need to translate research methods to clinical use. Referrals for language lateralization prior to epilepsy surgery are becoming more common, but time constraints make this unachievable in many busy neuroimaging departments. This study examines whether a single covert verbal fluency paradigm with real-time monitoring and online processing (BrainWave) could replace conventional offline processing (SPM) for the purpose of establishing expressive language dominance prior to epilepsy surgery. We analyzed language fMRI results of 30 patients (17 female; 24 right-handed; median age: 30.5) with temporal lobe epilepsy. Concordance between visual assessment of SPM and BrainWave was 92.8%. Lateralization indices correlated closely with visual assessments of lateralization with a concordance of 85.7%. BrainWave provided a real-time, fast and accurate display of language lateralization easily applied in a clinical setting using only online image processing.

Late-life terminal seizure freedom in drug-resistant epilepsy: "Burned-out epilepsy".

The course of established epilepsy in late life is not fully known. One key question is whether the resolution of an epileptic diathesis is a natural outcome in some people with long-standing epilepsy. We investigated this with a view to generating a hypothesis. We retrospectively explored whether terminal seizure-freedom occurs in older people with previous drug-resistant epilepsy at the Chalfont Centre for Epilepsy over twenty years. Of the 226 people followed for a median period of 52 years, 39 (17%) achieved late-life terminal seizure-freedom of at least two years before death, which occurred at a median age of 68 years with a median duration of 7 years. Multivariate analysis suggests that a high initial seizure frequency was a negative predictor (p < 0.0005). Our findings indicate that the 'natural' course of long-standing epilepsy in some people is one of terminal seizure freedom. We also consider the concept of "remission" in epilepsy, its definition challenges, and the evolving terminology used to describe the state of seizure freedom. The intersection of ageing and seizure freedom is an essential avenue of future investigation, especially in light of current demographic trends. Gaining mechanistic insights into this phenomenon may help broaden our understanding of the neurobiology of epilepsy and potentially provide targets for therapeutic intervention.

Computer Assisted Planning for Curved Laser Interstitial Thermal Therapy.

Laser interstitial thermal therapy (LiTT) isa minimally invasive alternative to conventional open surgery for drug-resistant focal mesial temporal lobe epilepsy (MTLE). Recent studies suggest that higher seizure freedom rates are correlated with maximal ablation of the mesialhippocampal head, whilst sparing of the parahippocampal gyrus (PHG) may reduce neuropsychological sequelae. Current commercially available laser catheters are inserted following manually planned straight-line trajectories, which cannot conform to curved brain structures, such as the hippocampus, without causing collateral damage or requiring multiple insertions. OBJECTIVES: The clinical feasibility and potential of curved LiTT trajectories through steerable needles has yet to be investigated. This is the focus of our work. METHODS: We propose a GPU-accelerated computer-assisted planning (CAP) algorithm for steerable needle insertions that generates optimized curved 3D trajectories with maximal ablation of the amygdalohippocampal complex and minimal collateral damage to nearby structures, while accounting for a variable ablation diameter ( 5-15 mm). RESULTS: Simulated trajectories and ablations were performed on 5 patients with mesial temporal sclerosis (MTS), which were identified from a prospectively managed database. The algorithm generated obstacle-free paths with significantly greater target area ablation coverage and lower PHG ablation variance compared to straight line trajectories. CONCLUSIONS: The presented CAP algorithm returns increased ablation of the amygdalohippocampal complex, with lower patient risk scores compared to straight-line trajectories. SIGNIFICANCE: This is the first clinical application of preoperative planning for steerable needle based LiTT. This study suggests that steerableneedles have the potential to improve LiTT procedure efficacy whilst improving the safety and should thus be investigated further.

The dysbiosis of ovine foot microbiome during the development and treatment of contagious ovine digital dermatitis.

BACKGROUND: Contagious Ovine Digital Dermatitis (CODD) is an emerging and common infectious foot disease of sheep which causes severe welfare and economic problems for the sheep industry. The aetiology of the disease is not fully understood and control of the disease is problematic. The aim of this study was to investigate the polybacterial aetiopathogenesis of CODD and the effects of antibiotic treatment, in a longitudinal study of an experimentally induced disease outbreak using a 16S rRNA gene amplicon sequencing approach. RESULTS: CODD was induced in 15/30 experimental sheep. During the development of CODD three distinct phenotypic lesion stages were observed. These were an initial interdigital dermatitis (ID) lesion, followed by a footrot (FR) lesion, then finally a CODD lesion. Distinct microbiota were observed for each lesion in terms of microbial diversity, clustering and composition. Porphyromonadaceae, Family XI, Veillonellaceae and Fusobacteriaceae were significantly associated with the diseased feet. Veillonellaceae and Fusobacteriaceae were most associated with the earlier stages of ID and footrot rather than CODD. Following antibiotic treatment of the sheep, the foot microbiota showed a strong tendency to return to the composition of the healthy state. The microbiota composition of CODD lesions collected by swab and biopsy methods were different. In particular, the Spirochaetaceae family were more abundant in samples collected by the biopsy method, suggesting that these bacteria are present in deeper tissues of the diseased foot. CONCLUSION: In this study, CODD presented as part of a spectrum of poly-bacterial foot disease strongly associated with bacterial families Porphyromonadaceae, Family XI (a family in Clostridiales also known as Clostridium cluster XI), Veillonellaceae and Fusobacteriaceae which are predominately Gram-negative anaerobes. Following antibiotic treatment, the microbiome showed a strong tendency to return to the composition of the healthy state. The composition of the healthy foot microbiome does not influence susceptibility to CODD. Based on the data presented here and that CODD appears to be the severest end stage of sheep infectious foot disease lesions, better control of the initial ID and FR lesions would enable better control of CODD and enable better animal welfare.

Continuous EEG source imaging enhances analysis of EEG-fMRI in focal epilepsy.

INTRODUCTION: EEG-correlated fMRI (EEG-fMRI) studies can reveal haemodynamic changes associated with Interictal Epileptic Discharges (IED). Methodological improvements are needed to increase sensitivity and specificity for localising the epileptogenic zone. We investigated whether the estimated EEG source activity improved models of the BOLD changes in EEG-fMRI data, compared to conventional << event-related >> designs based solely on the visual identification of IED. METHODS: Ten patients with pharmaco-resistant focal epilepsy underwent EEG-fMRI. EEG Source Imaging (ESI) was performed on intra-fMRI averaged IED to identify the irritative zone. The continuous activity of this estimated IED source (cESI) over the entire recording was used for fMRI analysis (cESI model). The maps of BOLD signal changes explained by cESI were compared to results of the conventional IED-related model. RESULTS: ESI was concordant with non-invasive data in 13/15 different types of IED. The cESI model explained significant additional BOLD variance in regions concordant with video-EEG, structural MRI or, when available, intracranial EEG in 10/15 IED. The cESI model allowed better detection of the BOLD cluster, concordant with intracranial EEG in 4/7 IED, compared to the IED model. In 4 IED types, cESI-related BOLD signal changes were diffuse with a pattern suggestive of contamination of the source signal by artefacts, notably incompletely corrected motion and pulse artefact. In one IED type, there was no significant BOLD change with either model. CONCLUSION: Continuous EEG source imaging can improve the modelling of BOLD changes related to interictal epileptic activity and this may enhance the localisation of the irritative zone.

Imaging haemodynamic changes related to seizures: comparison of EEG-based general linear model, independent component analysis of fMRI and intracranial EEG.

BACKGROUND: Simultaneous EEG-fMRI can reveal haemodynamic changes associated with epileptic activity which may contribute to understanding seizure onset and propagation. METHODS: Nine of 83 patients with focal epilepsy undergoing pre-surgical evaluation had seizures during EEG-fMRI and analysed using three approaches, two based on the general linear model (GLM) and one using independent component analysis (ICA): The results were compared with intracranial EEG. RESULTS: The canonical GLM analysis revealed significant BOLD signal changes associated with seizures on EEG in 7/9 patients, concordant with the seizure onset zone in 4/7. The Fourier GLM analysis revealed changes in BOLD signal corresponding with the results of the canonical analysis in two patients. ICA revealed components spatially concordant with the seizure onset zone in all patients (8/9 confirmed by intracranial EEG). CONCLUSION: Ictal EEG-fMRI visualises plausible seizure related haemodynamic changes. The GLM approach to analysing EEG-fMRI data reveals localised BOLD changes concordant with the ictal onset zone when scalp EEG reflects seizure onset. ICA provides additional information when scalp EEG does not accurately reflect seizures and may give insight into ictal haemodynamics.

Premature mortality in refractory partial epilepsy: does surgical treatment make a difference?

BACKGROUND: Epilepsy carries an increased risk of premature death. For some people with intractable focal epilepsy, surgery offers hope for a seizure-free life. The authors aimed to see whether epilepsy surgery influenced mortality in people with intractable epilepsy. METHODS: The authors audited survival status in two cohorts (those who had surgery and those who had presurgical assessment but did not have surgery). RESULTS: There were 40 known deaths in the non-surgical group (3365 person years of follow-up) and 19 in the surgical group (3905 person-years of follow-up). Non-operated patients were 2.4 times (95% CI 1.4 to 4.2) as likely to die as those who had surgery. They were 4.5 times (95% CI 1.9 to 10.9) as likely to die a probable epilepsy-related death. In the surgical group, those with ongoing seizures 1 year after surgery were 4.0 (95% CI 1.2 to 13.7) times as likely to die as those who were seizure-free or who had only simple partial seizures. Time-dependent Cox analysis showed that the yearly outcome group did not significantly affect mortality (HR 1.3, 95% CI 0.9 to 1.8). CONCLUSION: Successful epilepsy surgery was associated with a reduced risk of premature mortality, compared with those with refractory focal epilepsy who did not have surgical treatment. To some extent, the reduced mortality is likely to be conferred by inducing freedom from seizures. It is not certain whether better survival is attributable only to surgery, as treatment decisions were not randomised, and there may be inherent differences between the groups.

Defining Meyer's loop-temporal lobe resections, visual field deficits and diffusion tensor tractography.

Anterior temporal lobe resection is often complicated by superior quadrantic visual field deficits (VFDs). In some cases this can be severe enough to prohibit driving, even if a patient is free of seizures. These deficits are caused by damage to Meyer's loop of the optic radiation, which shows considerable heterogeneity in its anterior extent. This structure cannot be distinguished using clinical magnetic resonance imaging sequences. Diffusion tensor tractography is an advanced magnetic resonance imaging technique that enables the parcellation of white matter. Using seed voxels antero-lateral to the lateral geniculate nucleus, we applied this technique to 20 control subjects, and 21 postoperative patients. All patients had visual fields assessed with Goldmann perimetry at least three months after surgery. We measured the distance from the tip of Meyer's loop to the temporal pole and horn in all subjects. In addition, we measured the size of temporal lobe resection using postoperative T(1)-weighted images, and quantified VFDs. Nine patients suffered VFDs ranging from 22% to 87% of the contralateral superior quadrant. In patients, the range of distance from the tip of Meyer's loop to the temporal pole was 24-43 mm (mean 34 mm), and the range of distance from the tip of Meyer's loop to the temporal horn was -15 to +9 mm (mean 0 mm). In controls the range of distance from the tip of Meyer's loop to the temporal pole was 24-47 mm (mean 35 mm), and the range of distance from the tip of Meyer's loop to the temporal horn was -11 to +9 mm (mean 0 mm). Both quantitative and qualitative results were in accord with recent dissections of cadaveric brains, and analysis of postoperative VFDs and resection volumes. By applying a linear regression analysis we showed that both distance from the tip of Meyer's loop to the temporal pole and the size of resection were significant predictors of the postoperative VFDs. We conclude that there is considerable variation in the anterior extent of Meyer's loop. In view of this, diffusion tensor tractography of the optic radiation is a potentially useful method to assess an individual patient's risk of postoperative VFDs following anterior temporal lobe resection.