The oral glucose test predicts laminitis risk in ponies fed a diet high in nonstructural carbohydrates.

The aim of this study was to investigate the relationship between laminitis development in ponies and insulin/glucose concentrations in response to the oral glucose test (OGT) and a dietary challenge high in nonstructural carbohydrates (NSCs). After undergoing an OGT (1 g dextrose/kg BW in feed), 37 ponies with 2-h serum insulin concentrations ranging from 22 to 1,133 µIU/mL were subjected to a diet challenge period (DCP), consuming 12 g NSC/kg BW/d for up to 18 d. Insulin and glucose responses were measured on day 2 of the DCP. Clinical laminitis was diagnosed by blinded experts and confirmed radiographically. Basal ACTH levels and clinical signs were assessed to investigate concurrent putative pituitary pars intermedia dysfunction (PPID). The diet induced Obel grade 1 or 2 laminitis in 14 ponies (38%). The ponies that developed laminitis had higher maximum concentrations of blood glucose (P = 0.04) and serum insulin (P = 0.02) in response to the diet. The geometric mean (95% CI) blood glucose concentration for laminitis cases was 14.9 (12.9-17.2) mM, compared to 10.7 (9.2-12.5) mM for ponies who did not develop laminitis. Similarly, the geometric mean (95% CI) for serum insulin was 396 (301-520) µIU/mL for laminitis cases, compared to 216 (148-316) µIU/mL for ponies who did not develop laminitis. Laminitis incidence was likewise associated with insulin concentrations measured during the OGT. Laminitis occurred at frequencies of 0% (0/7) if postdextrose insulin (µIU/mL) was <50; 35% (8/23) if insulin was 50 to 195; and 86% (6/7) if insulin was >195 µIU/mL. Basal ACTH concentrations were above seasonally accepted reference ranges in 16/37 ponies, and 8 of these animals (50%) developed laminitis. This included all 5 ponies in the study that had clinical signs of PPID (100%). In contrast, hyperinsulinemia and laminitis occurred in only 3/11 ponies (27%) with elevated ACTH concentrations and no clinical signs of PPID (P = 0.009). Thus, laminitis occurrence was associated with higher glucose and insulin responses to both the OGT and challenge diet, and the frequency of laminitis can be predicted based on insulin and glucose hyperresponsiveness to these oral carbohydrate challenges.

Repeatability of Oral Sugar Test Results, Glucagon-Like Peptide-1 Measurements, and Serum High-Molecular-Weight Adiponectin Concentrations in Horses.

BACKGROUND: Repeatability of the oral sugar test (OST) has not been evaluated. OBJECTIVES: We hypothesized that OST glucose, insulin, active (aGLP-1) and total (tGLP-1) glucagon-like peptide 1, and high-molecular-weight (HMW) adiponectin results would be repeatable. ANIMALS: Fifty-three horses from a Tennessee research facility (n = 23) and private practice in Missouri (n = 30), including animals with medical histories of equine metabolic syndrome. METHODS: Two OSTs were performed 7-14 days apart and plasma glucose and insulin concentrations were measured at 0, 60, and 75 minutes; a positive result was defined as detection of an insulin concentration >45 µU/mL at 60 or 75 minutes. Plasma aGLP-1 and serum tGLP-1 concentrations at 75 minutes and serum HMW adiponectin concentrations at 0 minute were measured in the Missouri group. Bland-Altman analyses were performed. RESULTS: No adverse events were reported. Bland-Altman analysis indicated mean ± SD bias of 1.5 ± 14.8 µU/mL (95% confidence interval [CI], -27.6 to 30.5 µU/mL) and 1.2 ± 16.1 µU/mL (95% CI, -30.4 to 32.8 µU/mL) for insulin concentrations at 60 and 75 minutes, respectively. There was 91 and 83% agreement in test interpretation between test days for OST insulin results for all horses in the Tennessee and Missouri groups, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: Repeatability of the OST was acceptable when values obtained from Bland-Altman analyses were evaluated, and there was good agreement in binary (negative/positive) test interpretation for insulin concentrations. However, wide 95% CIs were detected for insulin concentrations.

Rapid assessment of cognitive function in down syndrome across intellectual level and dementia status.

BACKGROUND: Adults with Down syndrome (DS) are at risk of developing dementia and cognitive assessment is a fundamental part of the diagnostic process. Previously, we developed a Rapid Assessment for Developmental Disabilities (RADD), a brief, broadly focused direct test of cognition. In the current report, we assess whether the RADD is sensitive to dementia in DS and the degree to which it compares with other cognitive measures of dementia in this population. METHODS: In a sample of 114 individuals with DS, with dementia diagnosed in 62%, the RADD was compared with the Dementia Questionnaire for Mentally Retarded Persons (DMR), the Bristol Activities of Daily Living Scale, Severe Impairment Battery (SIB), and the Brief Praxis Test (BPT). RESULTS: The RADD showed predicted effects across intellectual disability (ID) levels and dementia status (p < 0.001). Six-month test-retest reliability for the subset of individuals without dementia was high (r(41) = 0.95, p < 0.001). Criterion-referenced validity was demonstrated by correlations between RADD scores and ID levels based upon prior intelligence testing and clinical diagnoses (rs (114) = 0.67, p = 0.001) and with other measures of cognitive skills, such as the BPT, SIB, and DMR-Sum of Cognitive scores (range 0.84 through 0.92). Using receiver operating characteristic curves for groups varying in pre-morbid severity of ID, the RADD exhibited high sensitivity (0.87) and specificity (0.81) in discriminating among individuals with and without dementia, although sensitivity was somewhat lower (0.73) for the subsample of dementia cases diagnosed no more than 2 years prior to their RADD assessment. CONCLUSION: Taken together, findings indicated that the RADD, a relatively brief, easy-to-administer test for cognitive function assessment across ID levels and dementia status, would be a useful component of cognitive assessments for adults with DS, including assessments explicitly focused on dementia.

Circadian dysregulation of clock genes: clues to rapid treatments in major depressive disorder.

Conventional antidepressants require 2-8 weeks for a full clinical response. In contrast, two rapidly acting antidepressant interventions, low-dose ketamine and sleep deprivation (SD) therapy, act within hours to robustly decrease depressive symptoms in a subgroup of major depressive disorder (MDD) patients. Evidence that MDD may be a circadian-related illness is based, in part, on a large set of clinical data showing that diurnal rhythmicity (sleep, temperature, mood and hormone secretion) is altered during depressive episodes. In a microarray study, we observed widespread changes in cyclic gene expression in six regions of postmortem brain tissue of depressed patients matched with controls for time-of-death (TOD). We screened 12 000 transcripts and observed that the core clock genes, essential for controlling virtually all rhythms in the body, showed robust 24-h sinusoidal expression patterns in six brain regions in control subjects. In MDD patients matched for TOD with controls, the expression patterns of the clock genes in brain were significantly dysregulated. Some of the most robust changes were seen in anterior cingulate (ACC). These findings suggest that in addition to structural abnormalities, lesion studies, and the large body of functional brain imaging studies reporting increased activation in the ACC of depressed patients who respond to a wide range of therapies, there may be a circadian dysregulation in clock gene expression in a subgroup of MDDs. Here, we review human, animal and neuronal cell culture data suggesting that both low-dose ketamine and SD can modulate circadian rhythms. We hypothesize that the rapid antidepressant actions of ketamine and SD may act, in part, to reset abnormal clock genes in MDD to restore and stabilize circadian rhythmicity. Conversely, clinical relapse may reflect a desynchronization of the clock, indicative of a reactivation of abnormal clock gene function. Future work could involve identifying specific small molecules capable of resetting and stabilizing clock genes to evaluate if they can rapidly relieve symptoms and sustain improvement.

Calcium and vitamin D intake maintained from preovariectomy independently affect calcium metabolism and bone properties in Sprague Dawley rats.

UNLABELLED: The interaction of habitual Ca and vitamin D intake from preovariectomy to 4 months postovariectomy on bone and Ca metabolism was assessed. Higher Ca intake suppressed net bone turnover, and both nutrients independently benefitted trabecular structure. Habitual intake of adequate Ca and ~50 nmol/L vitamin D status is most beneficial. INTRODUCTION: Dietary strategies to benefit bone are typically tested prior to or after menopause but not through menopause transition. We investigated the interaction of Ca and vitamin D status on Ca absorption, bone remodeling, Ca kinetics, and bone strength as rats transitioned through estrogen deficiency. METHODS: Sprague Dawley rats were randomized at 8 weeks to 0.2 or 1.0 % Ca and 50, 100, or 1,000 IU (1.25, 2.5, or 25 µg) vitamin D/kg diet (2 × 3 factorial design) and ovariectomized at 12 weeks. Urinary (45)Ca excretion from deep-labeled bone was used to assess net bone turnover weekly. Ca kinetics was performed between 25 and 28 weeks. Rats were killed at 29 weeks. Femoral and tibiae structure (by µCT), dynamic histomorphometry, and bone Ca content were assessed. RESULTS: Mean 25(OH)D for rats on the 50, 100, 1,000 IU vitamin D/kg diet were 32, 54, and 175 nmol/L, respectively. Higher Ca intake ameliorated net bone turnover, reduced fractional Ca absorption and bone resorption, and increased net Ca absorption. Tibial and femoral trabecular structures were enhanced independently by higher Ca and vitamin D intake. Tibial bone width and fracture resistance were enhanced by higher vitamin D intake. Dynamic histomorphometry in the tibia was not affected by either nutrient. A Ca × vitamin D interaction existed in femur length, tibial Ca content, and mass of the soft tissue/extracellular fluid compartment. CONCLUSIONS: Adequate Ca intake and serum 25(OH)D level of 50 nmol/L provided the most benefit for bone health, mostly through independent effects of Ca and vitamin D.

Transcutaneous electrical nerve stimulation and conditioned pain modulation influence the perception of pain in humans.

BACKGROUND: Research in animal models suggests that transcutaneous electrical nerve stimulation (TENS) and conditioned pain modulation (CPM) produce analgesia via two different supraspinal pathways. No known studies have examined whether TENS and CPM applied simultaneously in human subjects will enhance the analgesic effect of either treatment alone. The purpose of the current study was to investigate whether the simultaneous application of TENS and CPM will enhance the analgesic effect of that produced by either treatment alone. METHODS: Sixty healthy adults were randomly allocated into two groups: (1) CPM plus active TENS; (2) CPM plus placebo TENS. Pain threshold for heat (HPT) and pressure (PPT) were recorded from subject's left forearm at baseline, during CPM, during active or placebo TENS, and during CPM plus active or placebo TENS. CPM was induced by placing the subjects' contralateral arm in a hot water bath (46.5 °C) for 2 min. TENS (100 µs, 100 Hz) was applied to the forearm for 20 min at a strong but comfortable intensity. RESULTS: Active TENS alone increased PPT (but not HPT) more than placebo TENS alone (p = 0.011). Combining CPM and active TENS did not significantly increase PPT (p = 0.232) or HPT (p = 0.423) beyond CPM plus placebo TENS. There was a significant positive association between PPT during CPM and during active TENS (r(2) = 0.46; p = 0.003). CONCLUSIONS: TENS application increases PPT; however, combining CPM and TENS does not increase the CPM's hypoalgesic response. CPM effect on PPT is associated with the effects of TENS on PPT.

The feral horse foot. Part B: radiographic, gross visual and histopathological parameters of foot health in 100 Australian feral horses.

BACKGROUND: It has been proposed that the feral horse foot is a benchmark model for foot health in horses. However, the foot health of feral horses has not been formally investigated. OBJECTIVES: To investigate the foot health of Australian feral horses and determine if foot health is affected by environmental factors, such as substrate properties and distance travelled. METHODS: Twenty adult feral horses from five populations (n = 100) were investigated. Populations were selected on the basis of substrate hardness and the amount of travel typical for the population. Feet were radiographed and photographed, and digital images were surveyed by two experienced assessors blinded to each other's assessment and to the population origin. Lamellar samples from 15 feet from three populations were investigated histologically for evidence of laminitis. RESULTS: There was a total of 377 gross foot abnormalities identified in 100 left forefeet. There were no abnormalities detected in three of the feet surveyed. Each population had a comparable prevalence of foot abnormalities, although the type and severity of abnormality varied among populations. Of the three populations surveyed by histopathology, the prevalence of chronic laminitis ranged between 40% and 93%. CONCLUSIONS: Foot health appeared to be affected by the environment inhabited by the horses. The observed chronic laminitis may be attributable to either nutritional or traumatic causes. Given the overwhelming evidence of suboptimal foot health, it may not be appropriate for the feral horse foot to be the benchmark model for equine foot health.

Lipotropes (methyl nutrients) inhibit growth of feline lymphoma in vitro.

Feline lymphoma is one of the most frequently diagnosed tumors in cats. Lipotropes are dietary methyl donors that may modulate DNA methylation status and the expression of genes involved in growth and apoptosis of feline lymphoma cells. The specific objective of the study was to determine if lipotropes affect the growth of feline lymphoma cells, which entailed examining a correlation between lymphoma cell proliferation and apoptosis. F1B and FeLV-3281 cells were cultured and treated with 20 times the level of lipotropes contained in the basal culture medium. Cell growth and death and caspase 3 and tumor protein p53 activity were measured. Lipotropes were found to significantly reduce cell growth; increased cell death and caspase 3 and p53 activity was seen in F1B cells after 72 h, but the effect was minimal on FeLV-3281. These results could be useful in the development of dietary strategies for treating and preventing feline lymphoma.

A Novel ABCA12 Mutation in Two Families with Congenital Ichthyosis.

Autosomal recessive congenital ichthyosis (ARCI) is a rare genetically heterogeneous disorder characterized by hyperkeratosis in addition to dry, scaly skin. There are six genes currently known to be associated with the disease. Exome sequencing data for two affected individuals with ichthyosis from two apparently unrelated consanguineous Pakistani families was analysed. Potential candidate mutations were analysed in additional family members to determine if the putative mutation segregated with disease status. A novel mutation (c.G4676T, p.Gly1559Val) in ABCA12 occurred at a highly conserved residue, segregated with disease status in both families, and was not detected in 143 control chromosomes. Genotyping with microsatellite markers demonstrated a partial common haplotype in the two families, and a common founder mutation could not be excluded. Comparison to previously reported cases was consistent with the hypothesis that severe loss of function ABCA12 mutations are associated with Harlequin Ichthyosis and missense mutations are preferentially associated with milder phenotypes. In addition to identifying a possible founder mutation, this paper illustrates how advances in genome sequencing technologies could be utilised to rapidly elucidate the molecular basis of inherited skin diseases which can be caused by mutations in multiple disease genes.

Aberrant protein structure and diseases of the brain.

Extracellular fibrous amyloid deposits or intracellular inclusion bodies containing abnormal protein aggregates are pathological hallmarks of several neurodegenerative disorders and it has been hotly debated whether these aberrant protein structures merely occur as a consequence of disease or actually participate in a pathogenic cascade which culminates in neural dysfunction and death. Here, we review the role of aberrant protein structure in the two most common neurodegenerative disorders: Alzheimer's disease and Parkinson's disease and in two rare familial dementias, familial British dementia and familial Danish dementia. We also discuss possible mechanisms by which aberrant protein structures may mediate disease and the therapeutic opportunities this knowledge offers.

Seasonal variation in serum concentrations of selected metabolic hormones in horses.

BACKGROUND: Determination of adrenocorticotropic hormone (ACTH) concentration is a commonly used test in the evaluation of endocrine causes of equine laminitis, but the concentration in healthy horses can be high at certain times of year, which alters the specificity of the ACTH test. OBJECTIVE: To determine if circulating concentrations of ACTH, cortisol, glucose, insulin, and thyroxine vary month to month in healthy horses and in horses with equine metabolic syndrome (EMS). ANIMALS: Nine healthy adult horses were studied on their farm/stable over the course of 1 year. After the diagnosis of EMS, 10 laminitic horses residing at the same farm/stable were also studied. METHODS: Prospective study of healthy and laminitic horses. Plasma/serum samples were analyzed for concentrations of hormones and glucose. RESULTS: ACTH was the only analyte to show a discrete seasonal pattern, with concentrations in healthy and EMS horses frequently outside of the reference range (9-35 pg/mL) in August through October. Insulin was elevated (>40 microIU/mL) in EMS horses during most months and median serum glucose was generally higher in EMS horses (100 mg/dL, range, 76-163 mg/ dL) than in controls (94 mg/dL, range, 56-110 mg/dL), but no seasonal patterns for insulin or glucose were found. CONCLUSIONS AND CLINICAL IMPORTANCE: An increased ACTH concentration in horses in late summer or autumn should be interpreted with caution. In contrast, insulin concentration is maintained within the reference range throughout the year in healthy horses, thus an increased insulin concentration at any time of year should raise suspicions of EMS, ECD, or both.

Repeatability of subjective evaluation of lameness in horses.

REASONS FOR PERFORMING STUDY: Previous studies have suggested that agreement between equine veterinarians subjectively evaluating lameness in horses is low. These studies were limited to small numbers of horses, evaluating movement on the treadmill or to evaluating previously-recorded videotape. OBJECTIVES: To estimate agreement between equine practitioners performing lameness evaluations in horses in the live, over ground setting. METHODS: 131 mature horses were evaluated for lameness by 2-5 clinicians (mean 3.2) with a weighted-average of 18.7 years of experience. Clinicians graded each limb using the AAEP lameness scale by first watching the horse trot in a straight line only and then after full lameness evaluation. Agreement was estimated by calculation of Fleiss' (kappa). Evaluators agreed if they picked the same limb as lame or not lame regardless of the severity of perceived lameness. RESULTS: After only evaluating the horse trot in a straight line clinicians agreed whether a limb was lame or not 76.6% of the time (kappa= 0.44). After full lameness evaluation clinicians agreed whether a limb was lame or not 72.9% of the time (kappa= 0.45). Agreement on forelimb lameness was slightly higher than on hindlimb lameness. When the mean AAEP lameness score was >1.5 clinicians agreed whether or not a limb was lame 93.1% of the time (kappa= 0.86), but when the mean score was < or = 1.5 they agreed 61.9% (kappa= 0.23) of the time. When given the task of picking whether or not the horse was lame and picking the worst limb after full lameness evaluation, clinicians agreed 51.6% (kappa= 0.37) of the time. CONCLUSIONS: For horses with mild lameness subjective evaluation of lameness is not very reliable. POTENTIAL RELEVANCE: A search for and the development of more objective and reliable methods of lameness evaluation is justified and should be encouraged and supported.

Exercise and manual auricular acupuncture: a pilot assessor-blind randomised controlled trial. (The acupuncture and personalised exercise programme (APEP) trial).

BACKGROUND: Evidence supports the use of exercise for chronic low back pain (CLBP); however, adherence is often poor due to ongoing pain. Auricular acupuncture is a form of pain relief involving the stimulation of points on the outer ear corresponding with specific body parts. It may be a useful adjunct to exercise in managing CLBP; however, there is only limited evidence to support its use with this patient group. METHODS/DESIGN: This study was designed to test the feasibility of an assessor-blind randomised controlled trial which assess the effects on clinical outcomes and exercise adherence of adding manual auricular acupuncture to a personalised and supervised exercise programme (PEP) for CLBP. No sample size calculation has been carried out as this study aims to identify CLBP referral rates within the catchment area of the study site. The researchers aim to recruit four cohorts of n = 20 participants to facilitate a power analysis for a future randomised controlled trial. A computer generated random allocation sequence will be prepared centrally and used to allocate participants by cohort to one of the following interventions: 1) six weeks of PEP plus manual auricular acupuncture; 2) six weeks of PEP alone. Both groups will also complete a further six weeks of self-paced exercise with telephone follow-up support. In addition to a baseline and exit questionnaire at the beginning and end of the study, the following outcomes will be collected at baseline, and after 7, 13 and 25 weeks: pain frequency and bothersomeness, back-specific function, objective assessment and recall of physical activity, use of analgesia, perceived self-efficacy, fear avoidance beliefs, and beliefs about the consequences of back pain. Since this is a feasibility study, significance tests will not be presented, and treatment effects will be represented by point estimates and confidence intervals. For each outcome variable, analysis of covariance will be performed on the data, conditioning on the baseline value. DISCUSSION: The results of this study investigating the adjuvant effects of auricular acupuncture to exercise in managing CLBP will be used to inform the design of a future multi-centre randomised controlled trial. TRIAL REGISTRATION: Current Controlled Trials ISRCTN94142364.

The APP family of proteins: similarities and differences.

Overwhelming evidence indicates that the Abeta (amyloid beta-peptide) plays a critical role in the pathogenesis of Alzheimer's disease. Abeta is derived from the APP (amyloid precursor protein) by the action of two aspartyl proteases (beta- and gamma-secretases) that are leading candidates for therapeutic intervention. APP is a member of a multigene family that includes APLP1 (amyloid precursor-like protein 1) and APLP2. Both APLPs are processed in a manner analogous to APP, with all three proteins subject to ectodomain shedding and subsequent cleavage by gamma-secretase. Careful study of the APP family of proteins has already revealed important insights about APP. Here, we will review how knowledge of the similarities and differences between APP and the APLPs may prove useful for the development of novel disease-modifying therapeutics.

Rapid assessment of severe cognitive impairment in individuals with developmental disabilities.

BACKGROUND: Most standardized intelligence tests require more than 1 hour for administration, which is problematic when evaluating individuals with intellectual disabilities and developmental disabilities (IDDD), because a significant proportion of these individuals can not tolerate lengthy evaluations. Furthermore, most standardized intelligence tests are of limited usefulness for individuals with severe cognitive deficits because of floor effects. METHODS: A number of low-difficulty items were selected from standardized tests. A total of 271 participants with profound, severe, moderate and mild levels of cognitive impairment took part in this study. In the formative phase, 68 participants were evaluated with the selected items, and those items that differentiated between levels of cognitive impairment were retained in the battery. The instrument was then modified and standardized with an additional 203 participants. RESULTS: The instrument, referred to as the Rapid Assessment for Developmental Disabilities (RADD), required 10-25 min for administration. Internal reliability estimates from the RADD total score and from individual subtests satisfied conventional and rigorous statistical criteria (median alpha r = 0.93). The RADD total score was strongly correlated with the level of cognitive impairment (rho = 0.86). The RADD total score and individual subtests differentiated between all levels of cognitive impairment ( Wilks Lambda = 0.135, F(42,525.832) = 12.075, P < 0.001). Receiver operating characteristic curves indicated the instrument was particularly sensitive to the cognitive abilities of the most seriously impaired participants. CONCLUSIONS: The RADD, composed of low-difficulty items from published tests, is rapidly administered, assesses a wide range of cognitive skills and differentiates among all levels of cognitive impairment. The battery has clinical utility with populations exhibiting short attention spans because of its ability to quickly assess a wide range of cognitive abilities. The RADD also has research potential for the documentation of cognitive function in studies of individuals with IDDD.

Organisms as natural purposes: the contemporary evolutionary perspective.

Kant's conception of organisms as natural purposes raises a challenge to the adequacy of mechanistic explanation in biology. Certain features of organisms appear to be inexplicable by appeal to mechanical law alone. Some biological phenomena, it seems, can only be accounted for teleologically. Contemporary evolutionary biology has by and large ignored this challenge. It is widely held that Darwin's theory of natural selection gives us an adequate, wholly mechanical account of the nature of organisms. In contemporary biology, the category of the organism plays virtually no explanatory role. Contemporary evolutionary biology is a science of sub-organismal entities-replicators. I argue that recent advances in developmental biology demonstrate the inadequacy of sub-organismal mechanism. The category of the organism, construed as a 'natural purpose' should play an ineliminable role in explaining ontogenetic development and adaptive evolution. According to Kant the natural purposiveness of organisms cannot be demonstrated to be an objective principle in nature, nor can purposiveness figure in genuine explain. I attempt to argue, by appeal to recent work on self-organization, that the purposiveness of organisms is a natural phenomenon, and, by appeal to the apparatus of invariance explanation, that biological purposiveness provides genuine, ineliminable biological explanations.

Mitochondrial-related gene expression changes are sensitive to agonal-pH state: implications for brain disorders.

Mitochondrial defects in gene expression have been implicated in the pathophysiology of bipolar disorder and schizophrenia. We have now contrasted control brains with low pH versus high pH and showed that 28% of genes in mitochondrial-related pathways meet criteria for differential expression. A majority of genes in the mitochondrial, chaperone and proteasome pathways of nuclear DNA-encoded gene expression were decreased with decreased brain pH, whereas a majority of genes in the apoptotic and reactive oxygen stress pathways showed an increased gene expression with a decreased brain pH. There was a significant increase in mitochondrial DNA copy number and mitochondrial DNA gene expression with increased agonal duration. To minimize effects of agonal-pH state on mood disorder comparisons, two classic approaches were used, removing all subjects with low pH and agonal factors from analysis, or grouping low and high pH as a separate variable. Three groups of potential candidate genes emerged that may be mood disorder related: (a) genes that showed no sensitivity to pH but were differentially expressed in bipolar disorder or major depressive disorder; (b) genes that were altered by agonal-pH in one direction but altered in mood disorder in the opposite direction to agonal-pH and (c) genes with agonal-pH sensitivity that displayed the same direction of changes in mood disorder. Genes from these categories such as NR4A1 and HSPA2 were confirmed with Q-PCR. The interpretation of postmortem brain studies involving broad mitochondrial gene expression and related pathway alterations must be monitored against the strong effect of agonal-pH state. Genes with the least sensitivity to agonal-pH could present a starting point for candidate gene search in neuropsychiatric disorders.

Hammocking: the effect of cushion covers on interface pressure measurements.

PURPOSE: To investigate the effects of the cushion covers on interface pressure measurements using pressure mapping technology. METHODS: Sixty-one healthy participants were recruited for a laboratory-based study using a single group design. Participants were pressure mapped on a visco-elastic foam cushion and a foam and fluid pack cushion with their covers on and with their covers removed. An air-filled cushion was tested with two different types of covers, an incontinence cover and a 'Comfair' cover. Average and maximum pressures recorded at 6 mins by the Force Sensing Array pressure mapping system were used for statistical analysis. RESULTS: There were no significant differences in maximum pressures for the three cushions tested with their covers on or with their covers removed. The cushion with the foam base and fluid pack did not demonstrate any significant differences in average pressure with the cover on or with the cover removed. However, the visco-elastic foam cushion showed significantly lower average pressures with the cover on (p=0.019). The air-filled cushion showed lower average pressures with the incontinence cover on, when compared to the Comfair cover (p=0.029). CONCLUSION: Contrary to the belief that the process of hammocking may create surface tension within the cushion covers, which in turn may adversely affect the cushions ability to reduce interface pressure, the cushions tested in the current study did not show significantly lower interface pressure measurements with the covers removed. Therefore the covers did not adversely affect the cushion's ability to reduce interface pressure. The findings of this study require verification with disabled clients.

The role of cell-derived oligomers of Abeta in Alzheimer's disease and avenues for therapeutic intervention.

Burgeoning evidence suggests that soluble oligomers of Abeta (amyloid beta-protein) are the earliest effectors of synaptic compromise in Alzheimer's disease. Whereas most other investigators have employed synthetic Abeta peptides, we have taken advantage of a beta-amyloid precursor protein-overexpressing cell line (referred to as 7PA2) that secretes sub-nanomolar levels of low-n oligomers of Abeta. These are composed of heterogeneous Abeta peptides that migrate on SDS/PAGE as dimers, trimers and tetramers. When injected into the lateral ventricle of rats in vivo, these soluble oligomers inhibit hippocampal long-term potentiation and alter the memory of a complex learned behaviour. Biochemical manipulation of 7PA2 medium including immunodepletion with Abeta-specific antibodies and fractionation by size-exclusion chromatography allowed us to unambiguously attribute these effects to low-n oligomers. Using this paradigm we have tested compounds directed at three prominent amyloid-based therapeutic targets: inhibition of the secretases responsible for Abeta production, inhibition of Abeta aggregation and immunization against Abeta. In each case, compounds capable of reducing oligomer production or antibodies that avidly bind Abeta oligomers also ameliorate the synaptotoxic effects of these natural, cell-derived oligomers.

An investigation of the impact of the Force Sensing Array pressure mapping system on the clinical judgement of occupational therapists.

OBJECTIVES: To examine the impact of pressure mapping technology on the clinical decisions of occupational therapists and to examine the role of the Braden Scale in assisting with the selection of pressure-reducing cushions. DESIGN: Case studies. SETTING: Community. SUBJECTS: Forty clients. INTERVENTIONS: Clients were pressure mapped on their current seating surface and on four pre-selected cushions by the principal researcher. An occupational therapist completed the Braden Scale and a decision tree to assist in recommending a suitable pressure-reducing cushion. MAIN OUTCOME MEASURES: Interface pressure maps, Braden Scale, and the cushion recommended, using a decision tree to guide clinical judgement. RESULTS: Thirty per cent (12) of the 40 cushions recommended were changed when the pressure maps from the Force Sensing Array (FSA) system were viewed. In 70% (26) of cases, the maps supported the cushion recommended. In 25% (10) of the cases, the maps showed that the client's current seating surface was unsuitable. After viewing the pressure maps, a surface other than the client's current surface was recommended in 47% (19) of the cases. There was a lack of agreement between the risk level of the clients as identified by the Braden Scale score, and the risk level of the clients as identified by the occupational therapist using a decision tree and the FSA maps. CONCLUSION: Pressure mapping technology has a positive impact on clinical decisions regarding the provision of pressure-reducing cushions. Future research should examine the predictive validity of this technology. The Braden Scale may underpredict the risk level of the clients.