Development of breeding values for susceptibility to virulent footrot in sheep: A strategy to accommodate variable disease progression at time of scoring.

Genetic evaluations utilising footrot scores from industry flocks in their essence, incorporate data from a wide range of challenge environments, resulting in potentially large differences in means, variances and distribution of scores across challenges. The date that commencement of infection occurs is generally unknown, and progression of the infection varies with the prevailing environmental and management conditions, virulence of the bacterium Dichelobacter nodosus, as well as the genetic potential and (permanent) environmental ability of animals to resist footrot. In practice, animals are unlikely to be repeatedly scored to identify the best time for comparison, or monitor development of disease progression. Furthermore, field challenges are limited by the need to treat animals before their welfare is compromised. Therefore, the duration and intensity of infection varies and this affects comparisons between animals for their susceptibility. Diseases such as footrot are characterised by multiple categorical scores reflecting clinical stages that describe the progression and relative impact of the disease. This provides the opportunity for the transformation of the data to a standardised prevalence. Scoring events from multiple footrot field challenges under a standardised protocol were used to establish a series of transition matrices to describe disease progression between scores over time. These transition matrices were used to standardise challenge events to the more severe scoring events, observed later in the challenge. The accuracy of the transition technique was tested by comparing the ranking of animals and sires against the observed scores. Transitioning the data from low disease prevalence to the higher prevalence at the subsequent scoring event improved the correlations between the scoring events, at the animal level, by upwards of 0.10 across challenges. The utilisation of a transition matrix to transform low prevalence disease challenges by taking into account the natural biological rate of progression through the clinical stages of the disease provides a more accurate technique to account for variation in disease prevalence. The transition technique increases the acceptable range of disease expression targeted by producers when scoring virulent footrot challenges reducing the need for repeat scoring and allowing earlier treatment and reducing the impact of the disease on the host animal.

Mitochondrial DNAs provide insight into trypanosome phylogeny and molecular evolution.

BACKGROUND: Trypanosomes are single-celled eukaryotic parasites characterised by the unique biology of their mitochondrial DNA. African livestock trypanosomes impose a major burden on agriculture across sub-Saharan Africa, but are poorly understood compared to those that cause sleeping sickness and Chagas disease in humans. Here we explore the potential of the maxicircle, a component of trypanosome mitochondrial DNA to study the evolutionary history of trypanosomes. RESULTS: We used long-read sequencing to completely assemble maxicircle mitochondrial DNA from four previously uncharacterized African trypanosomes, and leveraged these assemblies to scaffold and assemble a further 103 trypanosome maxicircle gene coding regions from published short-read data. While synteny was largely conserved, there were repeated, independent losses of Complex I genes. Comparison of pre-edited and non-edited genes revealed the impact of RNA editing on nucleotide composition, with non-edited genes approaching the limits of GC loss. African tsetse-transmitted trypanosomes showed high levels of RNA editing compared to other trypanosomes. The gene coding regions of maxicircle mitochondrial DNAs were used to construct time-resolved phylogenetic trees, revealing deep divergence events among isolates of the pathogens Trypanosoma brucei and T. congolense. CONCLUSIONS: Our data represents a new resource for experimental and evolutionary analyses of trypanosome phylogeny, molecular evolution and function. Molecular clock analyses yielded a timescale for trypanosome evolution congruent with major biogeographical events in Africa and revealed the recent emergence of Trypanosoma brucei gambiense and T. equiperdum, major human and animal pathogens.

Quantitative relations between transient BOLD responses, cortical energetics, and impulse firing in different cortical regions.

The blood oxygen level-dependent (BOLD) functional magnetic resonance imaging signal arises as a consequence of changes in blood flow (cerebral blood flow) and oxygen usage (cerebral metabolic rate of oxygen) that in turn are modulated by changes in neuronal activity. Much attention has been given to both theoretical and experimental aspects of the energetics but not to the neuronal activity. Here we use our previous theory relating the steady-state BOLD signal to neuronal activity and amalgamate it with the standard dynamic causal model (DCM, Friston) theory to produce a quantitative model relating the time-dependent BOLD signal to the underlying neuronal activity. Unlike existing treatments, this new theory incorporates a nonzero baseline activity in a completely consistent way and is thus able to account for both positive and negative BOLD signals. It can reproduce a wide variety of experimental BOLD signals reported in the literature solely by adjusting the neuronal input activity. In this way it provides support for the claim that the main features of the signals, including poststimulus undershoot and overshoot, are principally a result of changes in neuronal activity.NEW & NOTEWORTHY A previous model relating the steady-state blood oxygen level-dependent (BOLD) signal to neuronal activity, both above and below baseline, is extended to account for transient BOLD signals. This allows for a detailed investigation of the role neuronal activity can play in such signals and also encompasses poststimulus undershoot and overshoot. A wide variety of experimental BOLD signals are reproduced solely by adjusting the neuronal input activity, including recent results regarding the BOLD signal in patients with schizophrenia.

Visually induced analgesia in a deep tissue experimental pain model: A randomised crossover experiment.

BACKGROUND: Visualizing one's own painful body part appears to have an effect on reported pain intensity. Furthermore, it seems that manipulating the size of the viewed image can determine the direction and extent of this phenomenon. When visual distortion has been applied to clinical populations, the analgesic effects have been in opposition to those observed in some experimental pain models. To help resolve this problem, we explored the effect of visualisation and magnification of the visual image on reported pain using a delayed onset muscle soreness (DOMS) pain model. METHODS: We induced DOMS in the quadriceps of 20 healthy volunteers. Forty-eight hours later, participants performed a series of painful contractions of the DOMS-affected muscle under four randomised conditions: (1) Viewing the injured thigh; (2) Viewing the contralateral thigh; (3) Viewing a neutral object; and (4) Viewing the injured thigh through magnifying glasses. For each condition, participants rated their pain intensity during a series of painful contractions. RESULTS: We observed that direct visualisation of the injured thigh had no effect on pain intensity when compared to viewing the contralateral thigh or neutral object. However, magnification of the DOMS-affected leg during the performance of painful contractions caused participants to report more pain than when viewing the injured thigh normally. CONCLUSIONS: These results further demonstrate that the effect of visualisation varies between different pain conditions. These results may have implications for the integration of visual feedback into clinical practice. SIGNIFICANCE: We present delayed onset muscle soreness as a model for exploring visually induced analgesia. Our findings suggest that this phenomenon is expressed differently in exogenous and endogenous experimental pain models. Further exploration may offer a potential pathway for the integration of visual analgesia into the management of clinical pain.

International consensus (ICON) on treatment of Ménière's disease.

OBJECTIVE: To present the international consensus for recommendations for Ménière's disease (MD) treatment. METHODS: Based on a literature review and report of 4 experts from 4 continents, the recommendations have been presented during the 21st IFOS congress in Paris, in June 2017 and are presented in this work. RESULTS: The recommendation is to change the lifestyle, to use the vestibular rehabilitation in the intercritic period and to propose psychotherapy. As a conservative medical treatment of first line, the authors recommend to use diuretics and Betahistine or local pressure therapy. When medical treatment fails, the recommendation is to use a second line treatment, which consists in the intratympanic injection of steroids. Then as a third line treatment, depending on the hearing function, could be either the endolymphatic sac surgery (when hearing is worth being preserved) or the intratympanic injection of gentamicin (with higher risks of hearing loss). The very last option is the destructive surgical treatment labyrinthectomy, associated or not to cochlear implantation or vestibular nerve section (when hearing is worth being preserved), which is the most frequent option.

Quantitative relations between BOLD responses, cortical energetics, and impulse firing.

The blood oxygen level-dependent (BOLD) functional magnetic resonance imaging signal arises as a consequence of changes in blood flow and oxygen usage that in turn are modulated by changes in neural activity. Much attention has been given to both theoretical and experimental aspects of the energetics but not to the neural activity. Here we identify the best energetic theory for the steady-state BOLD signal on the basis of correct predictions of experimental observations. This theory is then used, together with the recently determined relationship between energetics and neural activity, to predict how the BOLD signal changes with activity. Unlike existing treatments, this new theory incorporates a nonzero baseline activity in a completely consistent way and is thus able to account for both sustained positive and negative BOLD signals. We also show that the increase in BOLD signal for a given increase in activity is significantly smaller the larger the baseline activity, as is experimentally observed. Furthermore, the decline of the positive BOLD signal arising from deeper cortical laminae in response to an increase in neural firing is shown to arise as a consequence of the larger baseline activity in deeper laminae. Finally, we provide quantitative relations integrating BOLD responses, energetics, and impulse firing, which among other predictions give the same results as existing theories when the baseline activity is zero. NEW & NOTEWORTHY We use a recently established relation between energetics and neural activity to give a quantitative account of BOLD dependence on neural activity. The incorporation of a nonzero baseline neural activity accounts for positive and negative BOLD signals, shows that changes in neural activity give BOLD changes that are smaller the larger the baseline, and provides a basis for the observed inverse relation between BOLD responses and the depth of cortical laminae giving rise to them.

A systematic review of genetic syndromes with obesity.

Syndromic monogenic obesity typically follows Mendelian patterns of inheritance and involves the co-presentation of other characteristics, such as mental retardation, dysmorphic features and organ-specific abnormalities. Previous reviews on obesity have reported 20 to 30 syndromes but no systematic review has yet been conducted on syndromic obesity. We searched seven databases using terms such as 'obesity', 'syndrome' and 'gene' to conduct a systematic review of literature on syndromic obesity. Our literature search identified 13,719 references. After abstract and full-text review, 119 relevant papers were eligible, and 42 papers were identified through additional searches. Our analysis of these 161 papers found that 79 obesity syndromes have been reported in literature. Of the 79 syndromes, 19 have been fully genetically elucidated, 11 have been partially elucidated, 27 have been mapped to a chromosomal region and for the remaining 22, neither the gene(s) nor the chromosomal location(s) have yet been identified. Interestingly, 54.4% of the syndromes have not been assigned a name, whereas 13.9% have more than one name. We report on organizational inconsistencies (e.g. naming discrepancies and syndrome classification) and provide suggestions for improvements. Overall, this review illustrates the need for increased clinical and genetic research on syndromes with obesity.

Sensitivity of the cochlear nerve to acoustic and electrical stimulation months after a vestibular labyrinthectomy in guinea pigs.

Single-sided deafness patients are now being considered candidates to receive a cochlear implant. With this, many people who have undergone a unilateral vestibular labyrinthectomy for the treatment of chronic vertigo are now being considered for cochlear implantation. There is still some concern regarding the potential efficacy of cochlear implants in these patients, where factors such as cochlear fibrosis or nerve degeneration following unilateral vestibular labyrinthectomy may preclude their use. Here, we have performed a unilateral vestibular labyrinthectomy in normally hearing guinea pigs, and allowed them to recover for either 6 weeks, or 10 months, before assessing morphological and functional changes related to cochlear implantation. Light sheet fluorescence microscopy was used to assess gross morphology throughout the entire ear. Whole nerve responses to acoustic, vibrational, or electrical stimuli were used as functional measures. Mild cellular infiltration was observed at 6 weeks, and to a lesser extent at 10 months after labyrinthectomy. Following labyrinthectomy, cochlear sensitivity to high-frequency acoustic tone-bursts was reduced by 16 ± 4 dB, vestibular sensitivity was almost entirely abolished, and electrical sensitivity was only mildly reduced. These results support recent clinical findings that patients who have received a vestibular labyrinthectomy may still benefit from a cochlear implant.

A novel microdeletion affecting the CETP gene raises HDL-associated cholesterol levels.

We describe a novel, inherited 16q13 microdeletion that removes cholesteryl ester transfer protein (CETP) and several nearby genes. The proband was originally referred for severe childhood-onset obesity and moderate developmental delay, but his fasting lipid profile revealed relatively high levels of high density lipoprotein cholesterol (HDL-C) and relatively low levels of low density lipoprotein cholesterol (LDL-C) for age, despite his obesity. Testing of first-degree relatives identified two other microdeletion carriers. Functional assays in affected individuals showed decreased CETP mRNA expression and enzymatic activity. This microdeletion may or may not be pathogenic for obesity and developmental delay, but based on the lipid profile, the functional studies, and the phenotype of other patients with loss-of-function mutations of CETP, we believe this microdeletion to be antipathogenic for cardiovascular disease.

Are older women more likely to receive surgical treatment for stress urinary incontinence since the introduction of the mid-urethral sling? An examination of Hospital Episode Statistics data.

OBJECTIVE: To examine the trends in surgical treatment of stress urinary incontinence (SUI) in older women since the introduction of the mid-urethral sling. DESIGN: Analysis of data from Hospital Episode Statistics (HES) between 2000 and 2012. SETTING AND POPULATION: All surgical procedures for SUI in the National Health Service (NHS) in England. METHODS: Retrospective cohort analysis of Hospital Episode Statistics for England from 2000 to 2012. MAIN OUTCOME MEASURES: Number of invasive, less invasive, and urethral bulking procedures performed in women in three age groups. RESULTS: There was a 90% fall in the number of invasive surgical treatments for SUI and a four-fold increase in the number of mid-urethral slings over this time. The total number of surgical procedures for SUI increased from 8458 to 13 219. However, the rise in the number of procedures in women aged over 75 was more modest-a three-fold increase from a low start of 187-and these women now make up a smaller proportion of all women receiving a mid-urethral sling (MUS). CONCLUSIONS: Despite the development and wide availability of a less invasive, safe and effective operation for stress urinary incontinence in older women, they do not appear to have benefitted. The reasons for this require prospective investigation.

A national benchmark for the initial assessment of men with LUTS: data from the 2010 Royal College of Physicians National Audit of Continence Care.

OBJECTIVE: To assess the degree of adherence to the current National Institute for Health and Clinical Excellence (NICE) guidelines on the management of urinary incontinence (UI) in men. DESIGN: Retrospective survey of male patients with UI in primary and acute hospital (AH) care as part of a national audit. SETTING: NHS AH and primary care (PC) trusts. SAMPLE: Twenty-five men <65 years old and 25 men ≥65 years old from each participating site. METHODS: All NHS trusts in England, Wales Northern Ireland and Channel Islands were eligible to participate. A web-based data collection form aligned to the NICE guidelines was constructed for the study. All data submitted to the audit were anonymous, and access to the web tool was password protected for confidentiality. RESULTS: Data were returned by 80 % (128/161) of acute trusts and 52 % (75/144) of PC trusts in England, and 71 % (10/14) of combined trusts from Northern Ireland, Wales and the Channel Islands including data on 559 men <65 and 1271 65+ from 141 sites within acute hospitals and 445 men <65 and 826 men 65+ in PC, a total of 3101 participants. CONCLUSION: The majority of men seen within the NHS with LUTS do not receive management according to evidence-informed NICE guidelines; in general, older men are less likely to receive care that meets guideline standards than younger men.

Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care.

An accurate diagnosis is an integral component of patient care for children with rare genetic disease. Recent advances in sequencing, in particular whole-exome sequencing (WES), are identifying the genetic basis of disease for 25-40% of patients. The diagnostic rate is probably influenced by when in the diagnostic process WES is used. The Finding Of Rare Disease GEnes (FORGE) Canada project was a nation-wide effort to identify mutations for childhood-onset disorders using WES. Most children enrolled in the FORGE project were toward the end of the diagnostic odyssey. The two primary outcomes of FORGE were novel gene discovery and the identification of mutations in genes known to cause disease. In the latter instance, WES identified mutations in known disease genes for 105 of 362 families studied (29%), thereby informing the impact of WES in the setting of the diagnostic odyssey. Our analysis of this dataset showed that these known disease genes were not identified prior to WES enrollment for two key reasons: genetic heterogeneity associated with a clinical diagnosis and atypical presentation of known, clinically recognized diseases. What is becoming increasingly clear is that WES will be paradigm altering for patients and families with rare genetic diseases.

Eccentric Fatigue Modulates Stretch-shortening Cycle Effectiveness--A Possible Role in Lower Limb Overuse Injuries.

The role of fatigue in injury development is an important consideration for clinicians. In particular, the role of eccentric fatigue in stretch-shortening cycle (SSC) activities may be linked to lower limb overuse conditions. The purpose of this study was to explore the influence of ankle plantarflexor eccentric fatigue on SSC effectiveness during a hopping task in healthy volunteers. 11 healthy volunteers (23.2±6.7 years) performed a sub-maximal hopping task on a custom-built sledge system. 3D motion capture and surface EMG were utilised to measure lower limb stiffness, temporal kinematic measures and muscle timing measures at baseline and immediately following an eccentric fatigue protocol. A linear mixed model was used to test whether measures differed between conditions. Compared to baseline, eccentric fatigue induced increased stiffness during the hopping task (+ 15.3%; P<0.001). Furthermore, ankle stretch amplitude decreased (- 9.1%; P<0.001), whilst all other ankle kinematic measures remained unchanged. These changes were accompanied by a temporal shift in onset of activity in soleus and tibialis anterior muscles (- 4.6 to - 8.5%; p<0.001). These findings indicate that eccentric fatigue alters SSC effectiveness in healthy volunteers. These findings may be applied to inform pathogenetic models of overuse injury development.

An epidemiological study to investigate the relationship between Meniere's disease and migraine.

OBJECTIVES: A relationship between Meniere's disease and migraine has been postulated previously. This study investigates this relationship further and determines the most influential factors for developing Meniere's disease. DESIGN: Epidemiological study. SETTING: Two tertiary referral Neuro-Otological centres in Sheffield and Sydney. PARTICIPANTS: Adult patients referred to the Neuro-Otology clinic between 2003 and 2010. MAIN OUTCOME MEASURES: Past history and family history of Meniere's disease and migraine. Logistic regression analysis to determine the most influential factors for Meniere's disease. RESULTS: One hundred and eighty-one patients were included in the study, 102 with Meniere's disease and 79 with other balance disorders. Three significant findings were demonstrated. Firstly, a family history of Meniere's disease (33.3% versus 6.3%) or migraine (21.6% versus 9%) is more common in the Meniere's disease group than in the other balance disorders group. Secondly, a history of migrainous headaches is more common in the Meniere's disease group than in the other balance disorders group (45.1% versus 9%). Thirdly, patients with a past history or a family history of Meniere's disease or migraine have a higher likelihood of suffering from Meniere's disease. CONCLUSIONS: There is an overall relationship between Meniere's disease and migraine. A family history of Meniere's disease or migraine is more common in Meniere's disease. A history of migrainous headache is more common in Meniere's disease. Patients with a past history or family history of Meniere's disease or migraine have a higher likelihood of suffering from Meniere's disease.

NSD1 mutations generate a genome-wide DNA methylation signature.

Sotos syndrome (SS) represents an important human model system for the study of epigenetic regulation; it is an overgrowth/intellectual disability syndrome caused by mutations in a histone methyltransferase, NSD1. As layered epigenetic modifications are often interdependent, we propose that pathogenic NSD1 mutations have a genome-wide impact on the most stable epigenetic mark, DNA methylation (DNAm). By interrogating DNAm in SS patients, we identify a genome-wide, highly significant NSD1(+/-)-specific signature that differentiates pathogenic NSD1 mutations from controls, benign NSD1 variants and the clinically overlapping Weaver syndrome. Validation studies of independent cohorts of SS and controls assigned 100% of these samples correctly. This highly specific and sensitive NSD1(+/-) signature encompasses genes that function in cellular morphogenesis and neuronal differentiation, reflecting cardinal features of the SS phenotype. The identification of SS-specific genome-wide DNAm alterations will facilitate both the elucidation of the molecular pathophysiology of SS and the development of improved diagnostic testing.

Important tips and numbers on using the cortical step and diameter difference sign in assessing femoral rotation--should we abandon the technique?

Rotational malalignment during femoral nailing is common despite having various intraoperative assessment methods. The cortical step sign and diameter difference sign (CSSDDS) is commonly used because of convenience, yet it lack proper scientific scrutiny and is thought to be error prone. Using a software algorithm, cross-sectional dimensions were obtained from CT scans of 22 intact adult femurs at the proximal, mid and distal diaphysis. With multiple simulated scenarios the sensitivity of CSSDDS was comprehensively determined at all possible C-arm positions. At rotation, cortical width changed most significantly around the thick linea aspera and femoral diameter changed most significantly at the sagittal plane. At 15 degrees of rotation and with the linea aspera in view, CSSDDS thresholds of 0.3mm, 0.6mm and 1mm had sensitivities of 98.8%, 93.1% and 73.8%. With the linea aspera masked behind the femur and out of view, the sensitivities significantly deteriorated to 96.4%, 77.1% and 44.1% respectively. CSSDDS is sufficiently sensitive only when strict rules are followed. It is imperative that the operator position the image intensifier in lateral view under proper magnification so that steps of less than 0.6mm around the linea aspera may be appreciated.