Late-onset swallowing outcomes post-treatment for head and neck cancer in a UK-based population.

BACKGROUND: Adverse swallowing outcomes following head and neck squamous cell carcinoma treatment in the context of late-onset post-radiotherapy changes can occur more than five years post-treatment. METHODS: A retrospective study was conducted utilising patient records from March 2013 to April 2015. Patients were categorised into 'swallow dysfunction' and 'normal swallow' groups. Quality of life was investigated using the MD Anderson Dysphagia Inventory and EuroQol questionnaires. RESULTS: Swallow dysfunction was seen in 77 (51 per cent) of 152 patients. Twenty-eight patients (36 per cent) in the swallow dysfunction group reported symptoms in year five. Swallow dysfunction was associated with stage IV head and neck squamous cell carcinoma (p < 0.001) and radiotherapy (p < 0.001). MD Anderson Dysphagia Inventory global scores showed significant differences between swallow dysfunction and normal swallow groups (p = 0.01), and radiotherapy and surgery groups (p = 0.03), but there were no significant differences between these groups in terms of MD Anderson Dysphagia Inventory composite or EuroQol five-dimensions instrument scores. CONCLUSION: One-third of head and neck squamous cell carcinoma survivors with swallow dysfunction still show symptoms at more than five years post-surgery, a point at which they are typically discharged.

Viscerosensory input drives angiotensin II type 1A receptor-expressing neurons in the solitary tract nucleus.

Homeostatic regulation of visceral organ function requires integrated processing of neural and neurohormonal sensory signals. The nucleus of the solitary tract (NTS) is the primary sensory nucleus for cranial visceral sensory afferents. Angiotensin II (ANG II) is known to modulate peripheral visceral reflexes, in part, by activating ANG II type 1A receptors (AT1AR) in the NTS. AT1AR-expressing NTS neurons occur throughout the NTS with a defined subnuclear distribution, and most of these neurons are depolarized by ANG II. In this study we determined whether AT1AR-expressing NTS neurons receive direct visceral sensory input, and whether this input is modulated by ANG II. Using AT1AR-GFP mice to make targeted whole cell recordings from AT1AR-expressing NTS neurons, we demonstrate that two-thirds (37 of 56) of AT1AR-expressing neurons receive direct excitatory, visceral sensory input. In half of the neurons tested (4 of 8) the excitatory visceral sensory input was significantly reduced by application of the transient receptor potential vallinoid type 1 receptor agonist, capsaicin, indicating AT1AR-expressing neurons can receive either C- or A-fiber-mediated input. Application of ANG II to a subset of second-order AT1AR-expressing neurons did not affect spontaneous, evoked, or asynchronous glutamate release from visceral sensory afferents. Thus it is unlikely that AT1AR-expressing viscerosensory neurons terminate on AT1AR-expressing NTS neurons. Our data suggest that ANG II is likely to modulate multiple visceral sensory modalities by altering the excitability of second-order AT1AR-expressing NTS neurons.

Frailty Exists in Younger Adults Admitted as Surgical Emergency Leading to Adverse Outcomes.

BACKGROUND: Frailty is prevalent in the older adult population (≥65 years of age) and results in adverse outcomes in the emergency general surgical population. OBJECTIVE: To determine whether frailty exists in the younger adult emergency surgical population (<65 years) and what influence frailty may have on patient related outcomes. DESIGN: Prospective observational cohort study. SETTING: Emergency general surgical admissions. PARTICIPANTS: All patients ≥40 years divided into 2 groups: younger adults (40-64.9 years) and older adult comparative group (≥65). MEASUREMENTS: Over a 6-month time frame the following data was collected: demographics; Scottish Index of Multiple Deprivation (SIMD); blood markers; multi-morbidities, polypharmacy and cognition. Frailty was assessed by completion of the Canadian Study of Health and Ageing (CSHA). Each patient was followed up for 90 days to allow determination of length of stay, re-admission and mortality. RESULTS: 82 young adults were included and the prevalence of frailty was 16% (versus older adults 38%; p=0.001) and associated with: multi-morbidity; poly-pharmacy; cognitive impairment; and deprivation. Frailty in older adults was only significantly associated with increasing age. CONCLUSIONS: This novel study has found that frailty exists in 16% of younger adults admitted to emergency general surgical units, potentially leading to adverse short and long-term outcomes. Strategies need to be developed that identify and treat frailty in this vulnerable younger adult population.

Neonatal basal ganglia and thalamic volumes: very preterm birth and 7-year neurodevelopmental outcomes.

BackgroundThis study aims to (i) compare volumes of individual basal ganglia nuclei (caudate nucleus, pallidum, and putamen) and the thalamus between very preterm (VP) and term-born infants at term-equivalent age; (ii) explore neonatal basal ganglia and thalamic volume relationships with 7-year neurodevelopmental outcomes, and whether these relationships differed between VP and term-born children.Methods210 VP (<30 weeks' gestational age) and 39 term-born (≥37 weeks' gestational age) infants underwent brain magnetic resonance imaging at term-equivalent age, and deep gray matter volumes of interest were automatically generated. 186 VP and 37 term-born children were assessed for a range of neurodevelopmental measures at age 7 years.ResultsAll deep gray matter structures examined were smaller in VP infants compared with controls at term-equivalent age; ranging from (percentage mean difference (95% confidence intervals) -6.2% (-10.2%, -2.2%) for the putamen, to -9.5% (-13.9%, -5.1%) for the caudate nucleus. Neonatal basal ganglia and thalamic volumes were positively related to motor, intelligence quotient, and academic outcomes at age 7 years, with mostly similar relationships in the VP and control groups.ConclusionVP birth results in smaller basal ganglia and thalamic volumes at term-equivalent age, and these smaller volumes are related to a range of 7-year neurodevelopmental deficits in VP children.

Functional and neurochemical characterization of angiotensin type 1A receptor-expressing neurons in the nucleus of the solitary tract of the mouse.

Angiotensin II acts via two main receptors within the central nervous system, with the type 1A receptor (AT1AR) most widely expressed in adult neurons. Activation of the AT1R in the nucleus of the solitary tract (NTS), the principal nucleus receiving central synapses of viscerosensory afferents, modulates cardiovascular reflexes. Expression of the AT1R occurs in high density within the NTS of most mammals, including humans, but the fundamental electrophysiological and neurochemical characteristics of the AT1AR-expressing NTS neurons are not known. To address this, we have used a transgenic mouse, in which the AT1AR promoter drives expression of green fluorescent protein (GFP). Approximately one-third of AT1AR-expressing neurons express the catecholamine-synthetic enzyme tyrosine hydroxylase (TH), and a subpopulation of these stained for the transcription factor paired-like homeobox 2b (Phox2b). A third group, comprising approximately two-thirds of the AT1AR-expressing NTS neurons, showed Phox2b immunoreactivity alone. A fourth group in the ventral subnucleus expressed neither TH nor Phox2b. In whole cell recordings from slices in vitro, AT1AR-GFP neurons exhibited voltage-activated potassium currents, including the transient outward current and the M-type potassium current. In two different mouse strains, both AT1AR-GFP neurons and TH-GFP neurons showed similar AT1AR-mediated depolarizing responses to superfusion with angiotensin II. These data provide a comprehensive description of AT1AR-expressing neurons in the NTS and increase our understanding of the complex actions of this neuropeptide in the modulation of viscerosensory processing.

Modifiable lifestyle factors are associated with lower pain levels in adults with knee osteoarthritis.

BACKGROUND: With no cure or effective treatments for osteoarthritis (OA), the need to identify modifiable factors to decrease pain and increase physical function is well recognized. OBJECTIVE: To examine factors that characterize OA patients at different levels of pain, and to investigate the relationships among these factors and pain. METHODS: Details of OA characteristics and lifestyle factors were collected from interviews with healthy adults with knee OA (n=197). The Western Ontario and McMaster Universities Osteoarthritis Index was used to assess pain. Factors were summarized across three pain score categories, and χ(2) and Kruskal-Wallis tests were used to examine differences. Multiple linear regression analysis using a stepwise selection procedure was used to examine associations between lifestyle factors and pain. RESULTS: Multiple linear regression analysis indicated that pain was significantly higher with the use of OA medications and higher body mass index category, and significantly lower with the use of supplements and meeting physical activity guidelines (≥ 150 min/week). Stiffness and physical function scores, bilateral knee OA, body mass index category and OA medication use were significantly higher with increasing pain, whereas self-reported health, servings of fruit, supplement use and meeting physical activity guidelines significantly lower. No significant differences across pain categories were found for sex, age, number of diseases, duration of OA, ever smoked, alcoholic drinks/week, over-the-counter pain medication use, OA supplement use, physical therapy use, servings of vegetables or minutes walked/week. CONCLUSIONS: Healthy weight maintenance, exercise for at least 150 min/week and appropriate use of medications and supplements represent important modifiable factors related to lower knee OA pain.

High-rosmarinic acid spearmint tea in the management of knee osteoarthritis symptoms.

UNLABELLED: Individuals with medically diagnosed knee osteoarthritis (OA) participated in a randomized, double-blind study to investigate the effects of a high-rosmarinic acid (rosA) spearmint tea. Sixty-two participants were randomized by sex and screening pain score to consume tea brewed from a high-rosA spearmint variety or a commercially available spearmint twice daily for 16 weeks. Pain, quality of life (QoL), and physical function at baseline and week 16 were assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Short-Form 36-item Health Survey (SF-36), 6-minute walk test (6MWT), and stair climb test (SCT). Data from 46 participants (mean age=60.7; BMI=32.9 kg/m(2)) were analyzed. Pain score significantly decreased from week 0 to 16 for the high-rosA group but not for the control group and scores for stiffness and physical disability significantly decreased from week 0 to 16 for both groups. Increased QoL score on the bodily pain index in the SF-36 was observed at week 16 within the high-rosA group only, although no significant differences were observed between the groups. A nonsignificant improvement was observed in the 6MWT at week 16 in the high-rosA group only. There were no changes in the SCT for either group. Therefore, 16-week daily consumption of the high-rosA and commercial spearmint teas significantly improved stiffness and physical disability scores in adults with knee OA, but only the high-rosA tea significantly decreased pain. Consumption of high-rosA tea warrants further consideration as a potential complementary therapy to reduce pain in OA. CLINICAL TRIAL REGISTRATION NUMBER: NCT01380015.

Post-liver transplant leptin results in resolution of severe recurrence of lipodystrophy-associated nonalcoholic steatohepatitis.

We describe the first case of a patient undergoing orthoptic liver transplantation for acquired generalized lipodystrophy-related nonalcoholic steatohepatitis who developed severe recurrence of nonalcoholic fatty liver disease in the first few months posttransplant but responded rapidly to the administration of exogenous leptin. The beneficial effects of therapy were supported by histology along with magnetic resonance spectroscopy studies, which demonstrated that leptin therapy greatly reduced fat deposition in the liver. Leptin therapy may have a role to play in preventing patients with lipodystrophy developing end-stage liver disease or in rescuing such patients who develop disease recurrence postliver transplantation.

Endophenotypes of FOXP2: dysfunction within the human articulatory network.

The identification of the first gene involved in a speech-language disorder was made possible through the study of a British multi-generational family (the "KE family") in whom half the members have an inherited speech-language disorder caused by a FOXP2 mutation. Neuroimaging investigations in the affected members of the KE family have revealed structural and functional abnormalities in a wide cortical-subcortical network. Functional imaging studies have confirmed dysfunction of this network by revealing abnormal activation in several areas including Broca's area and the putamen during language-related tasks, such as word repetition and generation. Repeating nonsense words is particularly challenging for the affected members of the family, as well as in other individuals suffering from idiopathic developmental specific language impairments; yet, thus far the neural correlates of the nonword repetition task have not been examined in individuals with developmental speech and language disorders. Here, four affected members of the KE family and four unrelated age-matched healthy participants repeated nonsense words aloud during functional MRI scanning. Relative to control participants, repetition in the affected members was severely impaired, and brain activation was significantly reduced in the premotor, supplementary and primary motor cortices, as well as in the cerebellum and basal ganglia. We suggest that nonword repetition is the optimal endophenotype for FOXP2 disruption in humans because this task recruits brain regions involved in the imitation and vocal learning of novel sequences of speech sounds.

Developmental changes in cerebral grey and white matter volume from infancy to adulthood.

In order to quantify human brain development in vivo, high resolution magnetic resonance images of 158 normal subjects from infancy to young adulthood were studied (age range 3 months-30 years, 71 males, 87 females). Data were analysed using algorithms based on voxel-based morphometry (VBM) (an objective whole brain processing technique) to generate global volume measures of whole brain, grey matter (GM) and white matter (GM). Gender-specific development of WM and GM volumes is characterised using a piecewise polynomial growth curve model to account for the non-linear nature of human brain development, implemented using Markov chain Monte Carlo simulation. The statistical method employed in this study proved to be successful and robust in the characterisation of brain development. The resulting growth curve parameter estimates lead to the following observations: total brain volume is demonstrated to undergo an initial rapid spurt. The total GM volume peaks during childhood and decreases thereafter, whereas total WM volume increases up to young adulthood. Relative to brain size, GM decreases and WM increases markedly over this age range in a non-linear manner, resulting in an increasing WM-to-GM ratio over much of the observed age range. In addition, significant gender differences are found. In general, brain volume and total white and grey matter volume are larger in males than in females, with a time-dependent difference over the age range studied. Over part of the observed age range females tend to have more GM volume relative to brain size and lower WM-to-GM ratio than males. The presented findings should be taken into account when investigating physiological and pathological changes during brain development.

Management of dysphonia in children.

BACKGROUND: Dysphonia is common in children, but practice varies considerably regarding what, if any, investigations are performed and how the condition is managed. Although childhood dysphonia is mostly due to non-serious causes such as voice misuse, very serious pathology such as papillomatosis or malignancy needs occasionally to be excluded, and treatable congenital anomalies such as webs and cysts can be missed. Voice clinics and voice therapy services are now well established in most adult health services in the developed world, but equivalent services for children are less common, at least in the UK. METHODS: We retrospectively reviewed the records of all children presenting to our large children's hospital with a primary complaint of dysphonia between January 2001 and October 2007, in order to determine their management, investigations and final diagnosis. RESULTS: We identified 142 children. Case records were found for 137 (97 per cent). Eight-three children were male (61 per cent) and 54 female (39 per cent). Ages ranged from two months to 15 years (median 5.3 years). In 10 children (7 per cent), hoarseness was congenital, presenting as a hoarse, weak cry at birth. In 15 children (11 per cent), onset of hoarseness was related to a specific surgical procedure. The larynx was visualised by mirror alone in 23 children (17 per cent), by awake fibre-optic laryngoscopy in 27 (20 per cent) and by microlaryngoscopy-bronchoscopy under anaesthesia in 42 (31 per cent). Forty children (29 per cent) did not undergo laryngeal visualisation at any time and were diagnosed based on history alone. A further five (4 per cent) were scheduled for direct laryngoscopy but this was not performed due to resolution of symptoms. Voice abuse accounted for 62 (45 per cent) of all diagnoses. CONCLUSIONS: Childhood dysphonia accounts for a large number of referrals. There is considerable variation in how these children are managed. A more structured approach to diagnosis and investigation would be beneficial, perhaps within the setting of a dedicated paediatric voice clinic.

Minimising the effects of bolus dispersion in bolus-tracking MRI.

Bolus-tracking perfusion measurements in patients with vascular abnormalities are often unreliable, because delay and/or dispersion of the bolus within the vessels distorts the measured arterial input function (AIF). Erroneous measurements of perfusion can be identified by examining the measured response function, the shape of which is determined by both the tissue and arterial retention. In this work, an accurate response function is extracted by combining maximum-likelihood expectation-maximisation deconvolution, regularised using an oscillation index, with subsequent wavelet thresholding. Simulations show that this method recovers both the smooth-dispersed and the sharp-delayed response functions. This enables regions where the bolus is delayed and/or dispersed to be identified when the methodology is applied to data from patients with vascular abnormalities. Simulations also demonstrate robust and accurate perfusion estimates when there is no bolus delay and/or dispersion. The presence of delay and/or dispersion in the response function suggests that the perfusion measurements are erroneous, and that the global AIF is an inaccurate approximation to the true AIF in these regions. Perfusion measurements are corrected within the affected regions by defining a regional AIF from the independent component analysis of the dynamic susceptibility contrast MRI data. The regional AIF is shown to remove the delay and dispersion, improving the accuracy of the perfusion maps.

Human CIA30 is involved in the early assembly of mitochondrial complex I and mutations in its gene cause disease.

In humans, complex I of the respiratory chain is composed of seven mitochondrial DNA (mtDNA)-encoded and 38 nuclear-encoded subunits that assemble together in a process that is poorly defined. To date, only two complex I assembly factors have been identified and how each functions is not clear. Here, we show that the human complex I assembly factor CIA30 (complex I intermediate associated protein) associates with newly translated mtDNA-encoded complex I subunits at early stages in their assembly before dissociating at a later stage. Using antibodies we identified a CIA30-deficient patient who presented with cardioencephalomyopathy and reduced levels and activity of complex I. Genetic analysis revealed the patient had mutations in both alleles of the NDUFAF1 gene that encodes CIA30. Complex I assembly in patient cells was defective at early stages with subunits being degraded. Complementing the deficiency in patient fibroblasts with normal CIA30 using a novel lentiviral system restored steady-state complex I levels. Our results indicate that CIA30 is a crucial component in the early assembly of complex I and mutations in its gene can cause mitochondrial disease.

Quantification of the shape of fiber tracts.

The fiber tracts generated using diffusion MRI are usually simply displayed and assessed visually for a specific clinical or medical research purpose. This paper proposes computational techniques that can be used to study the shape of the tracts and make interindividual comparisons. These methods make use of fundamental geometric invariants, such as curvatures and torsions, or Fourier descriptors, together with the link of a pair of curves. Intersubject comparisons only require that the starting and ending points of the tracts can be defined and do not require point-by-point correspondences such as obtained using image registration. Principal component analysis-based shape analysis is also investigated. The invariants are tested on simulations and in vivo datasets, and the scale dependence and noise sensitivity of the measures are assessed. The potential for these techniques to be used in neuroscience research and clinical applications is demonstrated.

The role of the medial temporal lobe in autistic spectrum disorders.

The neural basis of autistic spectrum disorders (ASDs) is poorly understood. Studies of mnemonic function in ASD suggest a profile of impaired episodic memory with relative preservation of semantic memory (at least in high-functioning individuals). Such a pattern is consistent with developmental hippocampal abnormality. However, imaging evidence for abnormality of the hippocampal formation in ASD is inconsistent. These inconsistencies led us to examine the memory profile of children with ASD and the relationship to structural abnormalities. A cohort of high-functioning individuals with ASD and matched controls completed a comprehensive neuropsychological memory battery and underwent magnetic resonance imaging for the purpose of voxel-based morphometric analyses. Correlations between cognitive/behavioural test scores and quantified results of brain scans were also carried out to further examine the role of the medial temporal lobe in ASD. A selective deficit in episodic memory with relative preservation of semantic memory was found. Voxel-based morphometry revealed bilateral abnormalities in several areas implicated in ASD including the hippocampal formation. A significant correlation was found between parental ratings reflecting autistic symptomatology and the measure of grey matter density in the junction area involving the amygdala, hippocampus and entorhinal cortex. The data reveal a pattern of impaired and relatively preserved mnemonic function that is consistent with a hippocampal abnormality of developmental origin. The structural imaging data highlight abnormalities in several brain regions previously implicated in ASD, including the medial temporal lobes.

A rigorous framework for diffusion tensor calculus.

In biological tissue, all eigenvalues of the diffusion tensor are assumed to be positive. Calculations in diffusion tensor MRI generally do not take into account this positive definiteness property of the tensor. Here, the space of positive definite tensors is used to construct a framework for diffusion tensor analysis. The method defines a distance function between a pair of tensors and the associated shortest path (geodesic) joining them. From this distance a method for computing tensor means, a new measure of anisotropy, and a method for tensor interpolation are derived. The method is illustrated using simulated and in vivo data.

Language reorganization in children with early-onset lesions of the left hemisphere: an fMRI study.

It is widely assumed that following extensive damage to the left hemisphere sustained in early childhood, language functions are likely to reorganize and develop in the right hemisphere, especially if the lesion affects the classical Broca's or Wernicke's language areas. In the present study, functional MRI (fMRI) was used to examine language lateralization in 10 children and adolescents with intractable epilepsy who sustained an early lesion in the left hemisphere. Lesions were adjacent to or within anterior language cortex in five patients, while they were remote from both Broca's and Wernicke's areas in the remainder. A lateralization index was calculated on the basis of the number of voxels activated in the left and right inferior frontal gyri when performing a covert verb generation task. Only two patients were right-handed, suggesting a high incidence of functional reorganization for motor control in the remaining patients. Five out of 10 showed bilateral or right language lateralization, but lateralization could not be inferred from the proximity of lesions to classical language areas on an individual basis. Lesions in or near Broca's area were not associated with inter-hemispheric language reorganization in four out of five cases, but with perilesional activation within the damaged left hemisphere. Paradoxically, lesions remote from the classical language areas were associated with non-left language lateralization in four out of five cases. Finally, handedness, age at onset of chronic seizures, and site of EEG abnormality also showed no obvious association with language lateralization. In conclusion, it is difficult to infer intra- versus inter-hemispheric language reorganization on the basis of clinical observations in the presence of early pathology to the left hemisphere.

Anisotropic noise propagation in diffusion tensor MRI sampling schemes.

The subject of this study is the controversial choice of directions in diffusion tensor MRI (DT-MRI); specifically, the numerical algebra related to this choice. In DT-MRI, apparent diffusivities are sampled in six or more directions and a least-squares equation is solved to reconstruct the diffusion tensor. Numerical characteristics of the system are considered, in particular the condition number and normal matrix, and are shown to be dependent on the relative orientation of the tensor with respect to the laboratory frame. As a consequence, noise propagation can be anisotropic. However, the class of icosahedral direction schemes is an exception, and icosahedral directions have the same condition number and normal matrix for direction encoding as the ideal scheme with an infinite number of directions. This normal matrix and its condition number are rotationally invariant. Numerical simulations show that for icosahedral schemes with 30 directions the standard deviation of the fractional anisotropy is both low and nearly independent of fiber orientation. The recommended choice of directions for a DT-MRI experiment is therefore the icosahedral set of directions with the highest number of directions achievable in the available time.

The precision of anatomical normalization in the medial temporal lobe using spatial basis functions.

We investigated the accuracy of spatial basis function normalization using anatomical landmarks to determine how precisely homologous regions are colocalized. We examined precision in terms of: (1) the number of nonlinear basis functions used by the normalization procedure; (2) the degree of (Bayesian) regularization; and (3) the effect of substituting different templates and how this interacted with the number of basis functions. The face validity of spatial normalization was assessed as a function of these parameters, using the colocalization of homologous landmarks in a test sample of 20 normally developing children and 5 children with bilateral hippocampal pathology. Our results suggest that when optimal normalization parameters are used, anatomical landmarks in the medial temporal lobes are colocalized to within a standard deviation of about 1 mm. When suboptimal parameters are used this standard deviation can increase up to 3 mm. Interestingly the optimal parameters are those that provide a rather constrained normalization as opposed to those that optimize intensity matching at the expense of rendering the warps "unlikely." The implications of our results, for users of voxel-based morphometry, are discussed.

A direct test for lateralization of language activation using fMRI: comparison with invasive assessments in children with epilepsy.

This study introduces a direct method of assessing cerebral lateralization for language based on fMRI activation. The method, derived from a voxel-based morphometry study by C. H. Salmond et al. (2000, Hum. Brain Mapping 11, 223-232), bases lateralization on the direct statistical comparison of the magnitude of task-induced activation in homotopic regions of the two hemispheres. Lateralization results obtained with this direct method were compared to those obtained with a widely used method which involves the calculation of a laterality index (LI) based on the number of significantly activated voxels in the inferior frontal gyrus of each hemisphere. In order to compare the validity of the two methods, a covert verb-generation task was performed by eight children with epilepsy whose language lateralization was examined using invasive techniques. Lateralization results derived from fMRI activation showed that the calculation of a LI presented some limitations. Importantly, the LI value was dependent on the activation threshold chosen to calculate that LI. As a consequence, the correlation between the LI and the invasive methods could vary with the chosen threshold. By contrast, the proposed direct method gave some indication of the reliability of the lateralization and provided results that, in all eight children, were consistent with those obtained using invasive techniques. It is suggested that the direct method could be used in future fMRI studies to establish hemispheric lateralization for cognitive functions.