High fat diet increases cognitive decline and neuroinflammation in a model of orexin loss.

Midlife obesity is a risk factor for cognitive decline and is associated with the earlier onset of Alzheimer's disease (AD). Diets high in saturated fat potentiate the onset of obesity, microglial activation, and neuroinflammation. Signaling deficiencies in the hypothalamic peptide orexin and/or orexin fiber loss are linked to neurodegeneration, cognitive impairment, and neuroinflammation. Prior studies show that orexin is neuroprotective, suppresses neuroinflammation, and that treatment with orexin improves cognitive processes in orexin/ataxin-3 (O/A3) mice, a transgenic mouse model of orexin neurodegeneration. Our overall hypothesis is that loss of orexin contributes to high fat diet (HFD)-induced hippocampal neuroinflammation and cognitive decline. To examine this, we tested male O/A3 mice (7-8 mo. of age) in a two-way active avoidance (TWAA) hippocampus-dependent memory task. We tested whether (1) orexin loss impaired cognitive function; (2) HFD worsened cognitive impairment; and (3) HFD increased microglial activation and neuroinflammation. O/A3 mice showed significant impairments in TWAA task learning vs. wild type (WT) mice (increased escapes p < 0.05, reduced avoidances p < 0.0001). Mice were then placed on HFD (45% total fat, 31.4% saturated fat) or remained on normal chow (NC; 4% total fat and 1% saturated fat), and TWAA was retested at 2 and 4 weeks. Learning impairment was evident at both 2 and 4 weeks in O/A3 mice fed HFD for following diet exposure vs. WT mice on normal chow or HFD (increased escapes, reduced avoidances p < 0.05). Additionally, O/A3 mice had increased gene expression of the microglial activation marker Iba-1 (measured via qRT-PCR, p < 0.001). Further characterization of the microglial immune response genes in hippocampal tissue revealed a significant increase in CX3 chemokine receptor 1 (CX3CR1), tumor necrosis factor-alpha (TNF-α) and the mitochondria-associated enzyme immune responsive gene-1 (Irg1). Collectively, our results indicate that orexin loss impairs memory, and that HFD accelerates hippocampus-dependent learning deficits and the onset of neuroinflammation.

Role of the non-opioid dynorphin peptide des-Tyr-dynorphin (DYN-A(2-17)) in food intake and physical activity, and its interaction with orexin-A.

Food intake and physical activity are regulated by multiple neuropeptides, including orexin and dynorphin (DYN). Orexin-A (OXA) is one of two orexin peptides with robust roles in regulation of food intake and spontaneous physical activity (SPA). DYN collectively refers to several peptides, some of which act through opioid receptors (opioid DYN) and some whose biological effects are not mediated by opioid receptors (non-opioid DYN). While opioid DYN is known to increase food intake, the effects of non-opioid DYN peptides on food intake and SPA are unknown. Neurons that co-express and release OXA and DYN are located within the lateral hypothalamus. Limited evidence suggests that OXA and opioid DYN peptides can interact to modulate some aspects of behaviors classically related to orexin peptide function. The paraventricular hypothalamic nucleus (PVN) is a brain area where OXA and DYN peptides might interact to modulate food intake and SPA. We demonstrate that injection of des-Tyr-dynorphin (DYN-A(2-17), a non opioid DYN peptide) into the PVN increases food intake and SPA in adult mice. Co-injection of DYN-A(2-17) and OXA in the PVN further increases food intake compared to DYN-A(2-17) or OXA alone. This is the first report describing the effects of non-opioid DYN-A(2-17) on food intake and SPA, and suggests that DYN-A(2-17) interacts with OXA in the PVN to modulate food intake. Our data suggest a novel function for non-opioid DYN-A(2-17) on food intake, supporting the concept that some behavioral effects of the orexin neurons result from combined actions of the orexin and DYN peptides.

Plantar pressures in children with congenital talipes equino varus--a comparison between surgical management and the Ponseti technique.

The Ponseti technique for treatment for Congenital Talipes Equinovarus (CTEV) was introduced in the authors' institution in 2001, substituting a more traditional orthopaedic approach which involved surgery. There is currently limited published information regarding the differences in clinical outcomes between these two techniques, particularly in relation to plantar pressure analysis. This study aims to determine differences in pedobarographic outcome in children with CTEV, treated with either a surgical or Ponseti approach. A high resolution pedobarograph was used to record plantar pressure distribution in 52 children with CTEV and 26 children with typical development. Data were imported into Matlab where a custom programme was developed for processing and analysing pedobarographic recordings. There were significant differences in both treatment groups compared to the typically developed group (p<0.05) for most measurements. The most salient differences between treatment groups were (i) at the hind-foot where the Ponseti group had significantly lower maximum peak pressures (p<0.05); (ii) at the lateral mid-foot where children treated by the Ponseti approach showed significantly larger peak force (p<0.001), average peak pressure (p<0.001) and maximum peak pressure (p<0.01); (iii) at the lateral fore-foot where the surgical group showed lower average peak pressure (p<0.05); and (iv) in the medial/lateral fore-foot ratio where the Ponseti group showed significantly lower values (p<0.05). Plantar pressure analysis is a complementary measurement for the assessment of gait in children with CTEV. Data presented in this study showed that while there were deviations in children with CTEV, the differences observed between treatment groups suggest children in the Ponseti group have some level of under correction or recurrence.

A scanning Kelvin probe study of charge trapping in zone-cast pentacene thin film transistors.

We have used scanning Kelvin probe microscopy (SKPM) as a local probe to study charge trapping in zone-cast pentacene field effect transistors on both SiO(2) and benzocyclobutene (BCB) substrates. Annealing at 130 degrees C was found to reduce the threshold voltage, susceptibility to negative gate bias stress and trapping of positive charges within single pentacene grains. We conclude that oxygen is able to penetrate and disassociatively incorporate into crystalline pentacene, chemically creating electrically active defect states. Screening of a positive gate bias caused by electron injection from Au into pentacene was directly observed with SKPM. The rate of screening was found to change significantly after annealing of the film and depended on the choice of gate dielectric.

Health-related quality of life in adolescents with juvenile idiopathic arthritis.

OBJECTIVE: To describe the health-related quality of life (HRQOL) of adolescents with juvenile idiopathic arthritis (JIA), and to examine the usefulness of the Juvenile Arthritis Quality of Life Questionnaire (JAQQ) in a UK context. It was hypothesized that HRQOL would decrease with worsening disease and disability. METHODS: Patients with JIA ages 11, 14, and 17 years were recruited from 10 major rheumatology centers. HRQOL was measured using the JAQQ. Other data were core outcome variables including the Childhood Health Assessment Questionnaire, demographic characteristics, arthritis-related knowledge, and satisfaction with health care. RESULTS: Questionnaires were completed by 308 adolescents. One-fifth had persistent oligoarthritis. Median disease duration was 5.7 years (range <1-16 years). The JAQQ was shown to have good psychometric properties when used in the UK, but was not without limitations. HRQOL of adolescents with JIA was less than optimal, particularly in the domains of gross motor and systemic functioning. Items most frequently rated as adolescents' biggest psychological problems were "felt frustrated" and "felt depressed," rated by 30.2% and 23.4%, respectively. These were particularly problematic for the 17-year-olds, with 39% reporting frustration as one of their biggest problems and 63.6% reporting depression. Variation in the adolescent JAQQ scores was explained by functional disability, pain, and disease activity. CONCLUSION: JIA can have a significant adverse effect on the HRQOL of adolescents. The JAQQ is a useful tool to assess the HRQOL of UK adolescents with JIA, but there is need for improved measures that incorporate developmentally appropriate issues.

Acute rheumatic fever and poststreptococcal reactive arthritis: diagnostic and treatment practices of pediatric subspecialists in Canada.

OBJECTIVE: We conducted a survey of pediatric specialists in rheumatology, cardiology, and infectious diseases to ascertain present Canadian clinical practice with respect to diagnosis and treatment of acute rheumatic fever (ARF) and poststreptococcal reactive arthritis (PSReA), and to determine what variables influence the decision for or against prophylaxis in these cases. METHODS: A questionnaire comprising 6 clinical case scenarios of acute arthritis occurring after recent streptococcal pharyngitis was sent to members of the Canadian Pediatric Rheumatology Association, and to heads of divisions of pediatric cardiology and pediatric infectious diseases at the 16 university affiliated centers across Canada. RESULTS: There is considerable variability with respect to diagnosis in cases of ReA following group A streptococcal (GAS) infection both within and across specialties. There is extensive variability regarding the decision to provide prophylaxis in cases designated as ARF or PSReA. Findings indicated that physicians are most comfortable prescribing antibiotic prophylaxis in the presence of clear cardiac risk and are less inclined to such intervention for patients diagnosed with PSReA. When prophylaxis was recommended for cases of PSReA, the majority of respondents prescribed longer term courses of antibiotics. CONCLUSION: The lack of observed consistency in diagnosis and treatment in cases of reactive arthritis post-GAS infection likely reflects the lack of universally accepted criteria for diagnosis of PSReA and insufficient longterm data regarding carditis risk within this population. There is a need for clear definitions and treatment guidelines to allow greater consistency in clinical practice across pediatric specialties.

Inflammatory arthritis in children with osteochondrodysplasias.

Osteochondrodysplasias are a heterogeneous group of genetic skeletal dysplasias. Patients with these diseases commonly develop an early degenerative arthritis or osteoarthritis. Occasional observations of inflammatory arthritis have been made in this population but such observations are based on clinical grounds alone without confirmatory imaging studies. Four patients followed up in a paediatric rheumatology clinic with three different skeletal dysplasias, who had both clinical and radiological evidence of an inflammatory arthritis and coexistent degenerative arthritis, are described.

The influence of ankle-foot orthoses on gait and energy expenditure in spina bifida.

We examined the effect of ankle-foot orthoses (AFOs) on gait and energy expenditure in children with spina bifida. Nine boys and three girls, 6 to 16 years of age, took part in the study. There were four children each with L4, L5, and sacral level lesions. Each child underwent gait analysis and energy consumption studies with and without AFOs. Walking speed was faster with AFOs (mean, 58 m/min) than without (mean, 50 m/min, p < 0.01). Stride length improved significantly (p < 0.001) from 0.89 m barefoot to 1.08 m with AFOs. Double support time was decreased from 0.32 seconds barefoot to 0.28 seconds with AFOs (p < 0.05). The oxygen cost of walking was significantly better with (0.33 mL/kg/m) than without AFOs (0.41 mL/kg/m, p < 0.001). Hip flexion at initial contact was increased. Ankle kinematics were unchanged, but ankle power generation showed a significant improvement; from 0.5 W/kg barefoot to 1.3 W/kg with AFOs. Increased ankle power generation results in improved hip flexion and stride length, which contributes to increased walking speed and reduced oxygen cost. The stability conferred by the AFOs is reflected in the reduced time spent in double support.

Head and neck manifestations of Kawasaki disease.

Kawasaki disease, also known as acute infantile febrile mucocutaneous lymph node syndrome, is a self-limited vasculitic disease of infants and young children. The cause of the disease remains uncertain. Within the constellation of signs and symptoms, there are numerous otolaryngologic manifestations. The following represents the largest series of patients in the otolaryngology literature, involving 155 confirmed cases of Kawasaki disease as treated at our institution during the last 10 years. The demographic data, clinical pictures of the typical and atypical forms of the illness, as well as the laboratory values, therapy and complications are discussed.

Sevoflurane and anesthesia for neurosurgery: a review.

This review assesses the extent to which sevoflurane fulfills the requirements of the ideal inhalational agent for use in neuroanesthetic practice. Sevoflurane's pharmacokinetic profile is outlined. Data from animal and human studies are used to discuss its effects on cerebral hemodynamics, central nervous system monitoring, and cardiovascular parameters. Where possible, sevoflurane is compared with isoflurane, currently considered the inhalational agent of choice in neuroanesthesia. Sevoflurane's potential for toxicity is reviewed.

Update on functional assessment tools.

In recent years, there has been a tremendous growth in the development of measurement instruments that evaluate health status, functional status, disability, and quality of life in adults with rheumatic diseases. In the past decade, similar measures have been developed for application in children with rheumatic diseases. These include the Childhood Arthritis Impact Measurement Scales (CHAIMS), the Childhood Health Assessment Questionnaire (CHAQ), the Juvenile Arthritis Functional Assessment Report (JAFAR), the Juvenile Arthritis Self-report Index (JASI), the Juvenile Arthritis Quality of Life Questionnaire (JAQQ), and the Childhood Arthritis Health Profile (CAHP). The latter 2 instruments assess health related quality of life (HRQOL) and they are discussed here. The need to adapt this kind of instrument for use in an international climate creates an interesting dilemma and this is discussed.

Botulinum toxin A in hamstring spasticity.

Hamstring injection of Botulinum toxin A (BtA) may have a role in the conservative management of flexed knee gait in cerebral palsy or in simulating the effect of surgery. Ten children who were likely to require future hamstring lengthening were injected. Short term outcome was assessed by clinical examination and 3-D gait analysis. Mean popliteal angle decreased by 16 degrees and maximum knee extension in stance increased by 8 degrees, the latter relapsing by 12 weeks. Mean pelvic tilt tended to increase suggesting that isolated hamstring weakening be approached with caution. Energy cost of walking was not significantly changed in six of the ten patients. A small increase in knee extension in stance was often associated with patient satisfaction. There are theoretical grounds for expecting an associated increased longitudinal muscle growth after BtA injection.

Rap1b association with the platelet cytoskeleton occurs in the absence of glycoproteins IIb/IIIa.

Platelet membrane glycoproteins (GP) IIb/IIa and rap1b, a 21 kDa GTP binding protein, associate with the triton-insoluble, activation-dependent platelet cytoskeleton with similar rates and divalent cation requirement. To examine the possibility that GPIIb/IIIa was required for rap1b association with the cytoskeleton, experiments were performed to determine if the two proteins were linked under various conditions. Chromatography of lysates from resting platelets on Sephacryl S-300 showed that GPIIb/IIIa and rap1b were well separated and distinct proteins. Immunoprecipitation of GPIIb/IIIa from lysates of resting platelets did not produce rap1b or other low molecular weight GTP binding proteins and immunoprecipitation of rap1b from lysates of resting platelets did not produce GPIIb/IIIa. Finally, rap1b was associated with the activation-dependent cytoskeleton of platelets from a patient with Glanzmann's thrombasthenia who lacks surface expressed glycoproteins IIb and IIIa. Based on these findings, we conclude that no association between GPIIb/IIIa and raplb is found in resting platelets and that rap1b association with the activation-dependent cytoskeleton is at least partly independent of GPIIb/IIIa.

Botulinum toxin A compared with stretching casts in the treatment of spastic equinus: a randomised prospective trial.

Conservative therapies for equinus in cerebral palsy may help to postpone calf surgery in younger children. This study reports a prospective randomised trial of intramuscular botulinum toxin A (BtA) as an alternative to serial casting in 20 children with a dynamic component to calf equinus. Outcome was assessed in the short term to show the effect of one treatment cycle. Assessments were by clinical examination, video gait analysis, and three-dimensional gait analysis. BtA was of efficacy similar to that of serial casting. Tone reduction in the BtA group allowed a more prolonged improvement in passive dorsiflexion, which may allow more opportunity for increase in muscle length. Gait analysis showed an improved mean ankle kinematic pattern in a subsection of both groups, which was maintained at 12 weeks in the BtA group, whereas the cast group relapsed. There were fewer side effects in the BtA group. Median time to reintervention was similar.

Systemic juvenile rheumatoid arthritis complicated by two different renal lesions.

Systemic-onset juvenile rheumatoid arthritis (JRA) is a complex disease which affects many organ systems. Associated renal lesions are unusual, with the possible exception of amyloidosis. We describe a girl with systemic-onset JRA who developed first membranous nephropathy and then, 3.5 years later, a severe crescentic glomerulonephritis. The membranous lesion followed therapy with intravenous immune globulin, and the possibility that this intervention caused the renal disease must be considered. It appears that both of these lesions should be added to the list of possible complications of systemic-onset JRA.

Assessment of a new ultrafiltration blood processing system.

PURPOSE: To report our clinical experience with a new blood processing device which uses ultrafiltration. We assessed safety and efficacy by evaluating: 1 ) the quality and the quantity of intraoperative shed blood processed and reinfused to the patient 2) homologous blood requirements 3) clinical status of the patient post-transfusion. METHODS: With Ethics Committee approval, the ultrafiltration device was used in six consenting patients undergoing major elective spinal surgery. Blood samples for haematology and biochemistry tests were collected from patients post-induction of anaesthesia (baseline), 1 hr and 24 hr post-autotransfusion. Volumes of blood collected and processed, and all autologous and homologous transfusions were recorded. Patients were assessed post-operatively for any adverse effects. RESULTS: Five patients had donated blood preoperatively. One patient required homologous blood products in addition to autologous blood. In two patients, the filtration cartridge became blocked and required changing midprocessing. No patient sustained device-related complications. One patient had postoperative haematuria which resolved spontaneously within two hours. CONCLUSION: The ultrafiltration device was safe and effective in reducing homologous blood requirements in six patients undergoing elective spinal surgery. Further evaluation of the ultrafiltration device will be necessary, especially in view of the blockage of the filtration cartridge.

Comparison of cerebral oximeter and evoked potential monitoring in carotid endarterectomy.

PURPOSE: To assess the cerebral oximeter, which measures regional oxygen saturation (rSO2) continuously and noninvasively, as a cerebral monitor during carotid endarterectomy (CEA). The rSO2 was compared with Somatosensory Evoked Potentials (SSEPs) as an indicator for shunting and as a predictor of postoperative neurological deficits. METHODS: Seventy-two consenting patients undergoing CEA with general anaesthesia were studied. Normocarbia, normothermia and normotension were maintained. Cerebral monitoring consisted of bilateral median nerve SSEPs and the INVOS 3100 cerebral oximeter with the sensor pad placed on the ipsilateral forehead. Decreases in SSEP amplitude of 50% and in rSO2 of 10% were considered clinically significant. Neurological assessment was performed at emergence from anaesthesia, 24 hr postoperatively and at discharge. The rSO2 changes were compared with SSEP changes and with neurological deficits. Statistical analysis was with chi square and analysis of variance P < 0.05 was considered significant. RESULTS: During carotid artery clamping, rSO2 decreased from 72 +/- 8% to 68 +/- 9% and mean arterial blood pressure increased from 92 +/- 14 mmHg to 98 +/- 14 mmHg. In four patients, the carotid artery was shunted because of SSEP changes after cross-clamping. Five patients had > or = 10% decreases in rSO2 following clamp application. Changes in both SSEP and rSO2 occurred in two patients. Three of the four shunted patients had transient postoperative neurological deficits. One patients had a transient deficit without changes in either monitor. There were no persistent postoperative deficits. Compared with SSEPs, rSO2 had a sensitivity of 50% and a specificity of 96%. CONCLUSION: Clinical experience with this evolving technology is ongoing. Its role in neurovascular procedures has yet to be established.

Health assessment in the rheumatic diseases of childhood.

Assessment of children and adults with rheumatic diseases, both in clinical practice and controlled clinical trials in rheumatology, has traditionally focused on the measurement of disease activity. More recently emphasis has been placed on the need to incorporate estimates of physical, social, and mental functioning into health assessment. Thus there has been a tremendous growth in the development of measurement instruments that evaluate health status, functional status, disability, and quality of life. This type of measurement has become essential, particularly for clinical trials in adults with rheumatic diseases, for which the AIMS (Arthritis Impact Measurement Scales), the HAQ (Health Assessment Questionnaire), and the MACTAR (McMaster-Toronto arthritis) patient preference questionnaire have been the most widely used. In the past few years, similar measures have been developed for application in children with rheumatic diseases. These include the CHAIMS (Childhood Arthritis Impact Measurement Scales), the CHAQ (Childhood Health Assessment Questionnaire), the JAFAR (Juvenile Arthritis Functional Assessment Report), the JASI (Juvenile Arthritis Self-report Index), the JAQQ (Juvenile Arthritis Quality of Life Questionnaire), and the CAHP (Childhood Arthritis Health Profile). In this review, the development and measurement properties of these childhood instruments are discussed, with particular emphasis on their potential roles as supported by recent literature.

The Juvenile Arthritis Quality of Life Questionnaire--development of a new responsive index for juvenile rheumatoid arthritis and juvenile spondyloarthritides.

OBJECTIVE: To develop a disease specific measure of quality of life for application in children with juvenile rheumatoid arthritis and juvenile spondyloarthritides-the Juvenile Arthritis Quality of Life Questionnaire (JAQQ). METHODS: Patients and their parents were interviewed by a trained interviewer using a questionnaire focusing on physical function, psychosocial function, and general symptoms to determine the most appropriate items to include in the JAQQ. Respondents volunteered items and scored them for frequency of occurrence and importance. Items so generated were scored by a panel of experts for potential responsiveness and categorized into dimensions. Item number was reduced using this scoring system. The product was then pretested to confirm its construct validity and responsiveness. Thereafter, it was distributed to clinical experts to establish face and content validity. RESULTS: 91 patients, mean age 10.35 years (range 1.25-18.0), mean disease duration 3.99 years, and their parents were included in the interview process. 220 items generated were ultimately reduced to 85. Pretesting this version of the instrument in a further 30 patients showed it to have construct validity and responsiveness and led to a further reduction in items to 74, distributed in 4 dimensions: gross motor function (17 items), fine motor function (16 items), psychosocial function (22 items), and general symptoms (19 items). Face and content validity were established in 20 clinicians. Scaling was by 7 point Likert scale to enhance responsiveness. English and French versions were developed. CONCLUSION: The JAQQ measures physical and psychosocial function and an array of general symptoms. Preliminary data suggest it is valid and responsive and thus might have potential in clinical trials.

The influence of flexed-knee gait on the energy cost of walking in children.

There is an understanding that walking with flexed knees contributes to the increased energy cost of walking found in children with neurological conditions. To determine the influence of flexed-knee gait on energy cost of walking in a group of children without neurological abnormality, the gait patterns of 10 normal children were studied using a Vicon system and standard marker set. A telemetric system (Cosmed K2) was then used to measure the oxygen cost of walking of the same children. The tests were repeated restricting the subjects' knee extension bilaterally, using hinged braces, set to 0, 15, 30, and 45 degrees of flexion. Although the braces themselves caused a significant increase in O2 cost (mL/kg/m) (P < 0.05), due to a decrease in walking speed, no further significant increase in oxygen cost was demonstrated regardless of the degree of knee flexion imposed, despite a significant increase in measured hip flexion and ankle dorsiflexion at the 45 degrees of knee flexion setting (P < 0.05). We propose that moderate flexed-knee gait does not of itself cause an increase in the energy cost of walking and that other factors present in the physically disabled child are likely to be implicated.