Functional symptoms in dermatology: Part 2.

Functional disorders within dermatology present as various constellations of skin symptoms, but without evidence of organic pathology. Examples can include mucocutaneous pain syndromes, functional pruritus, somatoform pain disorder and rarer entities, such as undifferentiated somatoform idiopathic anaphylaxis and multiple chemical sensitivity syndrome. These conditions can have a significant impact on a patient's quality of life, and can present challenges in communication, investigation and management. The aetiology of functional disorders is not fully understood, but with an effective collaborative approach, a psychological explanation for these symptoms is often found. A structured approach to assessment can lead to a confident diagnosis, and understanding a patient's belief system and the impact of symptoms on their functioning can give better grounding for successful management. Treatment is dependent on the level of the patient's engagement with healthcare professionals, and often takes a measured and rehabilitative approach. Psychological therapies have been shown to be effective, often alongside both psychopharmacological and topical medications.

Functional symptoms in dermatology: Part 1.

Functional - or somatoform - symptoms are those that arise with no proven organic pathology. Also known as 'medically unexplained' symptoms, they can present in any medical speciality, including dermatology. Mucocutaneous pain syndromes and functional pruritus are two examples of functional disorders encountered by dermatologists. Patients presenting with somatoform symptoms have paradoxically complex and often subjectively severe symptomatology, yet minimal abnormalities on clinical examination or investigation. Such disparity can be frustrating and distressing for patients and clinicians alike, and there are many pitfalls regarding overinvestigation and misleading communication. However, with an honest and open approach - sometimes requiring collaboration with psychological services - management of functional symptoms can be effective, and patients can be successfully rehabilitated.

Microarray analysis of primary epithelial and fibroblast cells in chronic rhinosinusitis without nasal polyps.

BACKGROUND: Chronic rhinosinusitis is an inflammatory condition with an as yet unknown pathophysiology. We aimed to detect clusters of differentially regulated genes in the epithelial and fibroblast cells of patients with Chronic Rhinosinusitis without nasal polyposis (CRSsNP) and healthy controls. METHODOLOGY: Carefully phenotyped CRSsNP and healthy control participants were recruited. Primary cultures of isolated epithelial and fibroblast cells were established. Whole transcriptome analysis of the cells was performed using microarrays and replicated with quantitative RT-PCR and immunohistochemistry. RESULTS: Fibroblast cells from CRSsNP patients showed a significant upregulation (more than 2x) of the transcription factor NFE2L3 when compared to healthy controls by microarray with multiple hypothesis testing correction, qRT-PCR and immunohistochemistry. CONCLUSIONS: Here we have utilized microarray analysis to search for differentially expressed genes in isolated patient derived epithelial and fibroblast cells. The transcription factor NFE2L3 has been shown to be upregulated in fibroblast cells consistent with increasing evidence that fibroblasts play a key role in tissue specific inflammation within the paranasal sinuses.

Prognostic models for identifying adults with intellectual disabilities and mealtime support needs who are at greatest risk of respiratory infection and emergency hospitalisation.

BACKGROUND: Among adults with intellectual disabilities (ID), problems with eating, drinking and swallowing (EDS), and an associated need for mealtime support, are common, with an estimated 15% of adults known to specialist ID services requiring mealtime support. We set out to identify which adults with ID who receive mealtime support are at an increased risk of respiratory infections and emergency hospitalisation related to EDS problems. METHOD: An exploratory, prospective cohort study was undertaken in the East of England. At baseline, structured interviews with the caregivers of 142 adults with ID and any type of mealtime support needs were used to gather information on health and support needs over the previous 12 months. These interviews were repeated at follow-up, 12 months later. The resulting dataset, covering a 24-month period, was analysed with logistic regression, using model averaging to perform sensitivity analysis, and backwards step-wise variable selection to identify the most important predictors. RESULTS: Individuals with a history of respiratory infections (in the first year of study), those who had epilepsy and those with caregiver-reported difficulty swallowing were most likely to have respiratory infections in the second year. Adults with increasing mealtime support needs, epilepsy and/or full mealtime support needs (fed mainly or entirely by a caregiver or enterally) were at increased risk of emergency hospitalisation for EDS-related problems. CONCLUSIONS: Our findings highlight the importance of carefully monitoring health issues experienced by adults with ID and EDS problems, as well as their eating, drinking and swallowing skills. However, the models developed in this exploratory research require validation through future studies addressing the EDS problems commonly experienced by adults with ID and their implications for health outcomes and quality of life. Further research into the relationship between epilepsy and EDS problems would provide much-needed insight into the complex relationship between the two areas.

The incidence of healthcare use, ill health and mortality in adults with intellectual disabilities and mealtime support needs.

BACKGROUND: Adults with intellectual disabilities (ID) experience a wide range of eating, drinking and/or swallowing (EDS) problems, for which they receive diverse mealtime support interventions. Previous research has estimated that dysphagia (difficulty swallowing) affects 8% of all adults with ID and that 15% require some form of mealtime support. People with ID (whether they require mealtime support or not) also experience a greater burden of ill health and die younger than their peers in the general population with no ID. METHODS: Using an exploratory, population-based cohort study design, we set out to examine health-related outcomes in adults with ID who receive mealtime support for any eating, drinking or swallowing problem, by establishing the annual incidence of healthcare use, EDS-related ill health, and all-cause mortality. This study was conducted in two counties in the East of England. RESULTS: In 2009, 142 adults with mild to profound ID and a need for any type of mealtime support were recruited for a baseline survey. At follow-up 1 year later, 127 individuals were alive, eight had died and seven could not be contacted. Almost all participants had one or more consultations with a general practitioner (GP) each year (85-95%) and, in the first year, 20% reportedly had one or more emergency hospitalizations. Although their annual number of GP visits was broadly comparable with that of the general population, one-fifth of this population's primary healthcare use was directly attributable to EDS-related ill health. Respiratory infections were the most common cause of morbidity, and the immediate cause of all eight deaths, while concerns about nutrition and dehydration were surprisingly minor. Our participants had a high annual incidence of death (5%) and, with a standardized mortality ratio of 267, their observed mortality was more than twice that expected in the general population of adults with ID (not selected because of mealtime support for EDS problems). CONCLUSIONS: All Annual Health Checks now offered to adults with ID should include questions about respiratory infections and EDS functioning, in order to focus attention on EDS problems in this population. This has the potential to reduce life-threatening illness.

The extent and nature of need for mealtime support among adults with intellectual disabilities.

BACKGROUND: For many adults with an intellectual disability (ID), mealtimes carry significant health risks. While research and allied clinical guidance has focused mainly on dysphagia, adults with a range of physical and behavioural difficulties require mealtime support to ensure safety and adequate nutrition. The extent of need for and nature of such support within the wider ID population has yet to be reported. METHODS: In this study, we have estimated the prevalence of need for mealtime support among people with ID in the UK, using a population of 2230 adults known to specialist ID services (in Cambridgeshire, UK, total population 586,900). In a sample (n = 69, aged 19 to 79 years, with mild to profound ID), we characterised the support provided, using a structured proforma to consult support workers and carers providing mealtime support, and health and social care records. RESULTS: Mealtime support was found to be required by a significant minority of people with ID for complex and varied reasons. Prevalence of need for such support was estimated at 15% of adults known to specialist ID services or 56 per 100,000 total population. Within a sample, support required was found to vary widely in nature (from texture modification or environmental adaptation to enteral feeding) and in overall level (from minimal to full support, dependent on functional skills). Needs had increased over time in almost half (n = 34, 49.3%). Reasons for support included difficulties getting food into the body (n = 56, 82.2%), risky eating and drinking behaviours (n = 31, 44.9%) and slow eating or food refusal (n = 30, 43.5%). These proportions translate into crude estimates of the prevalence of these difficulties within the known ID population of 11.9%, 6.6% and 6.4% respectively. Within the sample of those requiring mealtime support, need for support was reported to be contributed to by the presence of additional disability or illness (e.g. visual impairment, poor dentition and dementia; n = 45, 65.2%) and by psychological or behavioural issues (e.g. challenging behaviour, emotional disturbance; n = 36, 52.2%). CONCLUSIONS: These findings not only highlight the need for a multidisciplinary approach to mealtime interventions (paying particular attention to psychological and environmental as well as physical issues), but also signal the daily difficulties faced by carers and paid support workers providing such support and illustrate their potentially crucial role in managing the serious health risks associated with eating and drinking difficulties in this population.

Comparison of three strains of diabetic rats with respect to the rate at which retinopathy and tactile allodynia develop.

PURPOSE: We compared three rat strains to determine if different strains develop early-stage diabetic retinopathy or sensory neuropathy at different rates. METHODS: Sprague Dawley, Lewis, and Wistar rats were made diabetic with streptozotocin. Diabetic and nondiabetic animals had retinal vascular pathology measured at eight months of diabetes. The number of cells in the retinal ganglion cell layer (GCL), retinal function (using electroretinography [ERG]), and retinal levels of inducible nitric oxide synthase (iNOS), cyclooxygenase2 (COX2), and vascular endothelial growth factor (VEGF) were measured at four months of diabetes. Tactile allodynia was assessed in hind paws at two months of diabetes. RESULTS: Diabetes of eight months' duration resulted in a significant increase in retinal degenerate capillaries and pericyte ghosts in Lewis and Wistar rats, but not in Sprague Dawley rats. A significant loss of cells in the GCL occurred only in diabetic Lewis rats, whereas Wistar and Sprague Dawley rats showed little change. Diabetes-induced iNOS and VEGF were statistically significant in all strains. Cyclooxygenase 2 (COX2) was significantly elevated in the Sprague Dawley and Wistar strains. Lewis rats showed a similar trend, however, the results were not statistically significant. All strains tended to show diabetes-induced impairment of dark-adapted b-wave amplitude, but only Sprague Dawley and Lewis strains had a significant reduction in latency. All strains showed significant tactile allodynia in peripheral nerves. CONCLUSIONS: At the durations studied, Lewis rats showed accelerated loss of both retinal capillaries and ganglion cells in diabetes, whereas diabetic Wistar rats showed degeneration of the capillaries without significant neurodegeneration, and Sprague Dawley rats showed neither lesion. Identification of strains that develop retinal lesions at different rates should be of value in investigating the pathogenesis of retinopathy.

Theoretical exploration of the neural bases of behavioural disinhibition, apathy and executive dysfunction in preclinical Alzheimer's disease in people with Down's syndrome: potential involvement of multiple frontal-subcortical neuronal circuits.

BACKGROUND: Recent research has suggested a specific impairment in frontal-lobe functioning in the preclinical stages of Alzheimer's disease (AD) in people with Down's syndrome (DS), characterised by prominent changes in personality or behaviour. The aim of the current paper is to explore whether particular kinds of change (namely executive dysfunction (EDF), disinhibition and apathy), associated in the literature with disruption of different underlying frontal-subcortical circuits, are a) more or less frequently reported than others and b) related to poor performance on tasks involving different cognitive processes. METHOD: Seventy-eight participants (mean age 47 years, range 36-72) with DS and mild to moderate intellectual disability (based on ICD-10 criteria), without a diagnosis of dementia of Alzheimer's type (DAT) or other psychiatric disorders, were selected from a larger sample of older adults with DS (n = 122). Dementia diagnosis was based on the CAMDEX informant interview, conducted with each participant's main carer. Informant-reported changes in personality/behaviour and memory were recorded. Participants were scored based on symptoms falling into three behavioural domains and completed five executive function (EF) tasks, six memory tasks (two of which also had a strong executive component) and the BPVS (as a measure of general intellectual ability). Multiple regression analyses were conducted to determine the degree to which the behavioural variables of 'EDF', 'disinhibition' and 'apathy', along with informant-reported memory decline and antidepressant medication use, predicted performance on the cognitive tasks (whilst controlling for the effects of age and general intellectual ability). RESULTS: Strikingly, disinhibited behaviour was reported for 95.7% of participants with one or more behavioural change (n = 47) compared to 57.4% with reported apathy and 36.2% with reported EDF. 'Disinhibition' score significantly predicted performance on three EF tasks (designed to measure planning, response inhibition and working memory) and an object memory task, (also thought to place high demands on working memory), while 'apathy' score significantly predicted performance on two different tasks, those measuring spatial reversal and prospective memory (p < 0.05). Informant reported memory decline was associated only with performance on a delayed recall task while antidepressant medication use was associated with better performance on a working memory task (p < 0.05). CONCLUSION: Observed dissociation between performance on cognitive tasks associated with reported apathy and disinhibition is in keeping with proposed differences underlying neural circuitry and supports the involvement of multiple frontal-subcortical circuits in the early stages of DAT in DS. However, the prominence of disinhibition in the behavioural profile (which more closely resembles that of disinhibited subtype of DFT than that of AD in the general population) leads us to postulate that the serotonergically mediated orbitofrontal circuit may be disproportionately affected. A speculative theory is developed regarding the biological basis for observed changes and discussion is focused on how this understanding may aid us in the development of treatments directly targeting underlying abnormalities.

Noninvasive assessment of retinal function in rats using multifocal electroretinography.

PURPOSE: To assess the applicability of multifocal electroretinograms (mfERGs) for evaluation of function in this small-eyed animal with a rod-dominant retina that is often used to model retinal diseases. METHODS: Noninvasive monocular mfERGs were recorded in anesthetized albino (Sprague-Dawley) and pigmented (Long Evans) rats. Achromatic stimuli subtending a 49 degrees by 53 degrees field consisted of 61 hexagons that were generated and presented (at varying rates and luminances) using a Visual Evoked Response Imaging System (VERIS; EDI, San Mateo, CA). The VERIS also was used to calculate individual responses and for analysis. RESULTS: mfERGs were recorded from pigmented and albino rats by slowing the rate of stimulus presentation to allow for the slow recovery time of the rod system. In each rat strain, responses varied systematically with changes in stimulus parameters. Peak response amplitude increased as the rate of stimulation was slowed and as stimulus luminance was increased. Response latency decreased as stimulus intensity was increased. The local nature of the response was assessed by several independent measures. CONCLUSIONS: The present work demonstrated the feasibility and limitations of using mfERG to assess topographical changes in the rat retina. It showed that despite the problems of the unavoidable self-adapting nature of the stimulus, the small eye of the animal, and the high potential for light scatter within the retina, multifocal responses with a good signal-to-noise ratio can be obtained from the rat.

Successful cotransplantation of intact sheets of fetal retina with retinal pigment epithelium.

PURPOSE: Many retinal diseases, such as macular degeneration, affect both retinal pigment epithelium (RPE) and photoreceptors. Therefore, retinal repair may require transplantation of both tissues together as a cograft. METHODS: As recipients of retina-RPE cografts, 7- to 10-week-old albino Royal College of Surgeons rats that lose their photoreceptors because of a pigment epithelium defect were used. Freshly harvested intact sheets of RPE with neural retina from pigmented normal rat fetuses were gel embedded for protection and transplanted into the subretinal space. RESULTS: After 6 to 7 weeks, with the support of the cografted RPE sheet, transplanted photoreceptors developed fully in organized parallel layers in the subretinal space. Immunohistochemistry for rhodopsin, rod alpha-transducin, and S-antigen and peanut agglutinin labeling for cone interphotoreceptor matrix domains suggested that the photoreceptors in the graft were capable of normal function. CONCLUSIONS: Freshly harvested intact sheets of fetal RPE and retina, transplanted together into the subretinal space, can develop a normal morphology. Such transplants have the potential to benefit retinal diseases with dysfunctional RPE and photoreceptors.

Electroretinograms remain normal in mice lacking a synapse associated protein.

Integrin-associated protein (IAP) is normally localized to the synapse rich plexiform layers of the mammalian retina. In other neuronal systems, IAP and its ligand, P84, have been implicated in synaptic function. Previously, an abnormal distribution of P84 was noted in the IAP-null retina. To examine the potential role of IAP in the function of the retinal outer plexiform layer, we recorded electroretinograms (ERGs) from IAP-null mice and wild-type littermates. Under a wide range of stimulus conditions, there was no difference between the responses of these two groups, including ERG components that reflect post-receptoral activity. These results indicate that IAP and/or P84 may not be critical for the development and maintenance of the photoreceptor-to-bipolar cell synapse.

Photoreceptor function of retinal transplants implicated by light-dark shift of S-antigen and rod transducin.

The aim was to demonstrate functional properties of transplanted histologically normal photoreceptors. Subretinal intact-sheet transplants of fetal E17-E20 rat retinas to light-damaged albino rat eyes were fixed in light or dark, 2 to 42 weeks after transplantation, and stained immunohistochemically for certain phototransduction proteins. In light adapted transplants, transducin was predominantly found in inner segments of parallel-organized photoreceptors. Transducin shifted to the outer segments with dark-adaptation. S-antigen distribution was opposite to transducin. Rhodopsin distribution did not change. The shift of signal transduction proteins correlated to the light conditions indicates that normal phototransduction processes were established in photoreceptors of transplanted retinal sheets.

Effects of heavy ions on visual function and electrophysiology of rodents: the ALTEA-MICE project.

ALTEA-MICE will supplement the ALTEA project on astronauts and provide information on the functional visual impairment possibly induced by heavy ions during prolonged operations in microgravity. Goals of ALTEA-MICE are: (1) to investigate the effects of heavy ions on the visual system of normal and mutant mice with retinal defects; (2) to define reliable experimental conditions for space research; and (3) to develop animal models to study the physiological consequences of space travels on humans. Remotely controlled mouse setup, applied electrophysiological recording methods, remote particle monitoring, and experimental procedures were developed and tested. The project has proved feasible under laboratory-controlled conditions comparable in important aspects to those of astronauts' exposure to particle in space. Experiments are performed at the Brookhaven National Laboratories [BNL] (Upton, NY, USA) and the Gesellschaft für Schwerionenforschung mbH [GSI]/Biophysik (Darmstadt, FRG) to identify possible electrophysiological changes and/or activation of protective mechanisms in response to pulsed radiation. Offline data analyses are in progress and observations are still anecdotal. Electrophysiological changes after pulsed radiation are within the limits of spontaneous variability under anesthesia, with only indirect evidence of possible retinal/cortical responses. Immunostaining showed changes (e.g. increased expression of FGF2 protein in the outer nuclear layer) suggesting a retinal stress reaction to high-energy particles of potential relevance in space.

Device for filamentous fungi growth monitoring using the multimodal frequency response of cantilevers.

Filamentous fungi cause opportunistic infections in hospital patients. A fast assay to detect viable spores is of great interest. We present a device that is capable of monitoring fungi growth in real time via the dynamic operation of cantilevers in an array. The ability to detect minute frequency shifts for higher order flexural resonance modes is demonstrated using hydrogel functionalised cantilevers. The use of higher order resonance modes sees the sensor dependent mass responsivity enhanced by a factor of 13 in comparison to measurements utilizing the fundamental resonance mode only. As a proof of principle measurement, Aspergillus niger growth is monitored using the first two flexural resonance modes. The detection of single spore growth within 10 h is reported for the first time. The ability to detect and monitor the growth of single spores, within a small time frame, is advantageous in both clinical and industrial settings.

Pharyngeal angiosarcoma following multimodal treatment for oropharyngeal squamous cell carcinoma.

It is well established that angiosarcoma can develop following radiotherapy. We present an unusual case of angiosarcoma of the pharynx that developed three years after treatment with surgery and adjuvant chemoradiotherapy for a T2N2bM0 squamous cell carcinoma of the oropharynx. The patient was tumour free until developing dysphagia, which was found to be caused by an angiosarcoma. The patient underwent surgery of the pharyngeal angiosarcoma by laryngopharyngectomy, tongue base resection, selective neck dissection and radial forearm microvascular free flap reconstruction. Angiosarcoma following head and neck malignancy is rare but must be considered as part of the differential diagnosis in patients with new symptoms after radiotherapy.

Age-related changes in plasma dehydroepiandrosterone levels in adults with Down's syndrome and the risk of dementia.

People with Down's syndrome (DS) are at high risk of developing early onset dementia. Recent studies suggest a link between age-related decreases in dehydroepiandrosterone (DHEA) concentrations and dementia in the general population. The present study investigates the relationship between DHEA serum levels and age and the risk of dementia in adults with DS. The DHEA plasma concentrations of 67 adults with DS and 65 age-matched controls were determined. Participants with DS were assessed for the presence of dementia using the CAMDEX informant interview. The DHEA plasma concentrations decreased with age in subjects with DS as well as in controls. Age significantly predicted DHEA levels in both groups (B = -0.06, t = -4.536, P < 0.001 in the DS group and B = -0.04, t = -2.928, P < 0.005 in control participants). The mean ± SD DHEA level was 3.47 ± 1.41 µmol/l in controls and 2.79 ± 1.24 µmol/l in participants with DS. This difference was significant (t = -2.981, P < 0.01). Within the DS population, ancova revealed a significant relationship between DHEA concentrations and dementia (F(1,65) = 4.348, P < 0.05). We found that DHEA levels declined significantly with age in people with DS and controls and were lower, in comparison to age-matched controls, in people with DS across all ages studied. Those with DS and evidence of dementia have lower DHEA concentrations than those with DS (controlling for age) but without dementia.

Expression and immunolocalisation of antimicrobial peptides within human palatine tonsils.

BACKGROUND: Recurrent acute tonsillitis is one of the most frequent ENT referrals, yet its pathogenesis remains poorly understood, and tonsillectomy still costs the National Health Service more than pound 60,000000 annually. Antimicrobial cationic peptides are components of the innate immune system. They are generally small, highly positively charged peptides with broad spectrum antimicrobial activity which function as the body's 'natural antibiotics'. The role of antimicrobial cationic peptides in the susceptibility of patients to recurrent acute tonsillitis is unknown. AIMS: To characterise and compare antimicrobial cationic peptide expression and localisation in human palatine tonsils from control subjects and recurrent acute tonsillitis patients, and to assess the potential role of these peptides in the pathogenesis of tonsillitis. METHODS: Palatine tonsils were harvested with informed consent from 19 recurrent acute tonsillitis patients and from five control subjects undergoing tonsillectomy for sleep disorders. Total ribonucleic acid was isolated and antimicrobial cationic peptide expression was characterised using reverse transcription polymerase chain reaction. Fluorescent immunohistochemical techniques were used to localise antimicrobial cationic peptides within fresh frozen tonsil sections. RESULTS: Using molecular analyses, the palatine tonsils from control and recurrent acute tonsillitis subjects were confirmed as a site of expression of the antimicrobial cationic peptides human beta-defensin 1-3, LL-37 (cathelicidin) and Liver expressed antimicrobial peptide-1 (LEAP-1). We also demonstrated for the first time the expression of Liver expressed antimicrobial peptide-2 (LEAP-2). Our analyses indicated that all six antimicrobial cationic peptides were expressed in all 26 tonsil samples. Immunohistochemical staining indicated that the antimicrobial cationic peptides were localised to the tonsil surface and crypt epithelium. However, the surface epithelium of tonsils from recurrent acute tonsillitis patients showed reduced amounts of antimicrobial peptides human beta-defensins 1 and 3, and LL-37, compared with healthy controls. CONCLUSION: The tonsil epithelium synthesizes an array of antimicrobial cationic peptides which function as host defence. Preliminary immunohistochemical data suggest that the surface epithelium of tonsils from recurrent acute tonsillitis patients contains reduced amounts of such peptides, which may increase these patients' susceptibility to infection.