ß-catenin has potential effects on the expression, subcellular localization, and release of high mobility group box 1 during bovine herpesvirus 1 productive infection in MDBK cell culture.

High mobility group box 1 (HMGB1), a ubiquitous DNA-binding protein, can be released into extracellular space and function as a strong proinflammatory cytokine, which plays critical roles in the pathogenesis of various inflammatory diseases. Here, we showed that BoHV-1 productive infection in MDBK cells at later stage significantly increases HMGB1 mRNA expression and the protein release, but decreases the steady-state protein levels. Virus infection increases accumulation of HMGB1 protein in both nucleus and mitochondria, and relocalizes nuclear HMGB1 to assemble in highlighted foci via a confocal microscope assay. Interestingly, ß-catenin-specific inhibitor iCRT14 is able to increase HMGB1 transcription and the protein release, and subcellular translocation in virus-infected cells. HMGB1-specific inhibitor, glycyrrhizin, could differentially affect virus gene transcription such as, the viral regulatory protein bICP0, bICP4 and bICP22, as well as glycoprotein gD. In summary, our data provides a novel mechanism that ß-catenin signaling may regulate inflammatory response via affecting HMGB1 signaling.

Circadian disturbances in Alzheimer's disease progression: a prospective observational cohort study of community-based older adults.

BACKGROUND: Circadian disturbances are commonly seen in people with Alzheimer's disease and have been reported in individuals without symptoms of dementia but with Alzheimer's pathology. We aimed to assess the temporal relationship between circadian disturbances and Alzheimer's progression. METHODS: We did a prospective cohort study of 1401 healthy older adults (aged >59 years) enrolled in the Rush Memory and Aging Project (Rush University Medical Center, Chicago, IL, USA) who had been followed up for up to 15 years. Participants underwent annual assessments of cognition (with a battery of 21 cognitive performance tests) and motor activities (with actigraphy). Four measures were extracted from actigraphy to quantify daily and circadian rhythmicity, which were amplitude of 24-h activity rhythm, acrophase (representing peak activity time), interdaily stability of 24-h activity rhythm, and intradaily variability for hourly fragmentation of activity rhythm. We used Cox proportional hazards models and logistic regressions to assess whether circadian disturbances predict an increased risk of incident Alzheimer's dementia and conversion of mild cognitive impairment to Alzheimer's dementia. We used linear mixed-effects models to investigate how circadian rhythms changed longitudinally and how the change integrated to Alzheimer's progression. FINDINGS: Participants had a median age of 81·8 (IQR 76·3-85·7) years. Risk of developing Alzheimer's dementia was increased with lower amplitude (1 SD decrease, hazard ratio [HR] 1·39, 95% CI 1·19-1·62) and higher intradaily variability (1 SD increase, 1·22, 1·04-1·43). In participants with mild cognitive impairment, increased risk of Alzheimer's dementia was predicted by lower amplitude (1 SD decrease, HR 1·46, 95% CI 1·24-1·72), higher intradaily variability (1 SD increase, 1·36, 1·15-1·60), and lower interdaily stability (1 SD decrease, 1·21, 1·02-1·44). A faster transition to Alzheimer's dementia in participants with mild cognitive impairment was predicted by lower amplitude (1 SD decrease, odds ratio [OR] 2·08, 95% CI 1·53-2·93), increased intradaily variability (1 SD increase, 1·97, 1·43-2·79), and decreased interdaily stability (1 SD decrease, 1·35, 1·01-1·84). Circadian amplitude, acrophase, and interdaily stability progressively decreased over time, and intradaily variability progressively increased over time. Alzheimer's progression accelerated these aging effects by doubling or more than doubling the annual changes in these measures after the diagnosis of mild cognitive impairment, and further doubled them after the diagnosis of Alzheimer's dementia. The longitudinal change of global cognition positively correlated with the longitudinal changes in amplitude and interdaily stability and negatively correlated with the longitudinal change in intradaily variability. INTERPRETATION: Our results indicate a link between circadian dysregulation and Alzheimer's progression, implying either a bidirectional relation or shared common underlying pathophysiological mechanisms. FUNDING: National Institutes of Health, and the BrightFocus Foundation.

Photocatalytic reduction of CO2 with H2O: significant enhancement of the activity of Pt-TiO2 in CH4 formation by addition of MgO.

Photocatalytic activity in the reduction of CO(2) with H(2)O to CH(4) was significantly enhanced by simply adding MgO to TiO(2) loaded with Pt. A positive correlation between CH(4) formation activity and basicity was observed. The interface between TiO(2), Pt and MgO in the trinary nanocomposite played a crucial role in CO(2) photocatalytic reduction.

Semiconductor-based nanocomposites for photocatalytic H2 production and CO2 conversion.

Semiconductor-based photocatalysis has attracted much attention in recent years because of its potential for solving energy and environmental problems that we are now facing. Among many photocatalytic reactions, the splitting of H(2)O into H(2) and O(2) and the reduction of CO(2) with H(2)O into organic compounds such as CH(4) and CH(3)OH are two of the most important and challenging reactions. Many studies have been devoted to designing and preparing novel photocatalytic materials for these two reactions. This article highlights recent advances in developing semiconductor-based nanocomposite photocatalysts for the production of H(2) and the reduction of CO(2). The systems of semiconductor-cocatalyst, semiconductor-carbon (carbon nanotube or graphene) and semiconductor-semiconductor nanocomposites have mainly been described. It has been demonstrated that the design and preparation of nanocomposites with proper structures can facilitate charge separation/migration and decrease the charge recombination probability, thus promoting the photocatalytic activity. Keeping the reduction and oxidation processes in different regions in the nanocomposite may also enhance the photocatalytic efficiency and stability. The location and size of cocatalysts, the interfacial contact between semiconductor and carbon materials, and the heterojunctions between different semiconductors together with the suitable alignment of band edges of semiconductors are key factors determining the photocatalytic behaviours of the nanocomposite catalysts.

Jaw-opening dystonia: Quality of life after botulinum toxin injections.

The objective of this study was to investigate quality-of-life outcomes in patients with jaw-opening oromandibular dystonia who had received treatment with botulinum neurotoxin injections. The Glasgow Benefit Inventory (GBI) was used as a post-intervention questionnaire to measure patient benefit. Twenty-five questionnaires were sent to patients. Of the 12 patients who returned the form (48% response rate), the mean scores for the general GBI subscore (p = 0.001), the social support GBI subscore (p = 0.031), and the physical health GBI subscore (p = 0.002) demonstrated statistically significant benefit from the injections. No scores demonstrated a negative impact. Botulinum neurotoxin injections were demonstrated to benefit the quality of life in patients suffering from jaw-opening oromandibular dystonia.

Association between antipsychotics and body mass index when treating patients with tics.

OBJECTIVE: Treatment with antipsychotics can be associated with weight gain, and second-generation (atypical) antipsychotics (SGAs) can increase the risk for diabetes and dyslipidemia. These risks have not been assessed in patients with tics, who receive lower doses than those used to treat psychosis. The objective of this study is to investigate the relationship between antipsychotic use and weight in tic patients and compare the effects of SGAs to first-generation (typical) antipsychotics (FGAs). METHODS: We studied the association between antipsychotic use and body mass index (BMI) in consecutive patients with tics seen in a specialty Movement Disorders clinic. RESULTS: Height and weight were recorded on 198 patients, average age 19.9 years+/-14.0 years, 128 treated and 70 not treated with antipsychotics. Standardized measures of BMI were significantly higher in the antipsychotic-treated patients compared to the untreated patients (0.56+/-1.10) treated vs. untreated (-0.31+/-0.82). This difference remained significant after controlling for age, gender, stimulant medications, and co-morbidities such as attention-deficit/hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD). Concomitant medications did not independently influence weight, and there was no difference between FGAs and SGAs. Antipsychotic dose, expressed in chlorpromazine (CPZ) equivalents, and treatment duration did not influence weight. CONCLUSION: Patients with tics on either FGAs or SGAs have higher BMI values compared to patients on no antipsychotics. Better knowledge of this risk should guide physician decision making when treating patients with tics.

The Montreal Cognitive Assessment as a screening tool for cognitive dysfunction in Huntington's disease.

Cognitive dysfunction is one of the hallmarks of Huntington's disease (HD) and may precede the onset of motor symptoms. The Montreal Cognitive Assessment (MoCA), a brief cognitive screening instrument with high specificity and sensitivity for detecting early cognitive impairments, has not been studied in the HD population. In this study, we compare the MoCA with the mini-mental state examination (MMSE) as a screening tool for cognitive dysfunction among 53 patients with HD. The mean MMSE score was 26 +/- 2.4, and mean MoCA score was 21 +/- 4.4. Twenty-one patients (81%) of those who scored >or=26 on the MMSE had the MoCA score <26. Thirty-two patients (78%) of those who scored >or=24 on the MMSE had the MoCA score <24. The MoCA may be a more sensitive screening tool for cognitive impairments in HD relative to the MMSE.

Reducing dosing frequency of carbidopa/levodopa: double-blind crossover study comparing twice-daily bilayer formulation of carbidopa/levodopa (IPX054) versus 4 daily doses of standard carbidopa/levodopa in stable Parkinson disease patients.

OBJECTIVE: We compared IPX054, a bilayer tablet of immediate- and extended-release carbidopa/levodopa (CD/LD) given twice daily to standard CD/LD given 4 times daily in patients with stable Parkinson disease (PD). METHODS: Twelve PD patients with no or mild fluctuations on CD/LD 25/100 mg 4 times daily were randomized to a double-blind crossover comparison with IPX054 (50/200 mg) twice daily. At the end of each 2-week treatment, patients were video recorded while performing a modified Unified Parkinson's Disease Rating Scale motor examination and Rush Dyskinesia Rating Scale at 30-minute intervals over 8.5 hours. The primary outcome measure was the number of videotape epochs rated as "ON" without troublesome dyskinesia by a blinded observer (Wilcoxon signed rank tests). RESULTS: The 9 men and 3 women had a mean age of 69 years and mean PD duration of 6 years. IPX054 and CD/LD showed no significant differences in the primary outcome measure (mean number of video epochs rated as ON without troublesome dyskinesia; P = 0.14). The mean time to ON was improved with IPX054 (P = 0.014), and the mean modified Unified Parkinson's Disease Rating Scale scores slightly favored IPX054 (14.4 vs 16.9; P = 0.052). Mean Rush Dyskinesia Rating Scale scores were not significantly different between IPX054 and CD/LD (0.45 vs 0.69; P = 0.25). No patient developed troublesome dyskinesias. CONCLUSIONS: In stable PD patients, no difference was detected between twice-daily treatment with IPX054 and CD/LD given 4 times daily. In this group, substitution with IPX054 reduced dosing frequency while maintaining CD/LD efficacy. In clinical practice, this ease of administration may offer improved treatment compliance.

Daytime somnolence and nocturnal sleep disturbances in Huntington disease.

Sleep disorders and daytime somnolence have not been systematically studied in the Huntington disease (HD) population. In this study we have assessed nocturnal sleep and daytime somnolence in 30 patients recruited from a subspecialty HD clinic. Disturbed nocturnal sleep and excessive daytime somnolence were common in this cohort. Further studies employing objective measures of sleep/daytime somnolence in the HD population are needed.

HTR2A variation and sudden infant death syndrome: a case-control analysis.

AIM: The serotonergic (5-HT) system functions in central autonomic regulation with homeostatic roles in cardiorespiratory control, thermoregulation, arousal and sleep-wake cycling. Altered function and development of this system in cases of sudden infant death syndrome (SIDS) have been established, but the aetiology of these disturbances remains unclear. The serotonin receptor, HTR2A, functions within this system with roles in the homeostatic response to hypoxia including excitatory effects on respiration, gasping and rhythm generation, all functions potentially compromised in SIDS. The objective of this study was to examine the relationship between SIDS risk and HTR2A variation. METHODS: All coding regions, intron-exon boundaries and the promoter region of HTR2A were PCR amplified and analysed by standard sequencing in 96 SIDS cases and 96 matched controls. RESULTS: Twenty-one HTR2A variations were identified in this case-control cohort, including four novel variations (c.C-1185A, c.T-923C, c.T-17C and c.C50T). None of the variations identified showed a significant association with SIDS. CONCLUSION: This report provides evidence that despite known alterations of the 5-HT system in SIDS, and the logical role for the HTR2A receptor, genetic variation of HTR2A as studied in our cohort is not responsible for these alterations. These results represent a further step in the investigation of the aetiology of the altered serotonin system in SIDS cases.

Evaluating Parkinson's disease patients at home: utility of self-videotaping for objective motor, dyskinesia, and ON-OFF assessments.

The objective is to test feasibility and utility of home-based videos for assessing Parkinson's disease (PD) patients. As part of a clinical trial, patients opted between coming to the study sites or learning to videotape assessments at home. Those opting for at-home filming completed training on videotape techniques. Ten-minute films were taken at 30-minute intervals over 8.5 hours, 2 and 4 weeks after study entry using a protocol covering most items of the UDPRS motor examination and all Rush Dyskinesia Rating Scale items. After each filming, patients marked their ON/OFF status, based on prior training. We determined the number of patients who elected self-taping and the quality of video segments obtained. To assess ON/OFF patient accuracy, we compared the rater's and patient's assessment of ON/OFF at each time point. Of 12 participants, 10 elected self-videotaping and only 1 time point was missed (99.5% taping compliance). All self-recorded video segments were clear with all protocol elements included. With the exception of one missed ON/OFF rating, patient-based self-ratings occurred on time. Rating ON/OFF, UPDRS, and RDRS assessments for 8.5 hours required 170 minutes by the blinded rater. In spite of patient training, mean ON/OFF concordance between rater and patients was only 64%. At home video-based self-recordings are feasible and allow accurate rater-based ON/OFF assessments. In this group of patients with no or mild fluctuations, in spite of pretrial training, patients were inaccurate in separating ON vs. OFF status.

Antipsychotic medication treatment for mild hallucinations in Parkinson's disease: Positive impact on long-term worsening.

To test if antipsychotic medication treatment of Parkinson's disease (PD) patients with mild hallucinations and retained insight delays deterioration to delusions or hallucinations without insight. We identified subjects at the time they developed their first hallucination, based on documented progression in their UPDRS thought disorder (TD) score from <2 to 2 ("benign" hallucinations with insight retained). We registered TD scores at follow-up visits and their hallucination treatment: antipsychotic medication, PD medication reduction, or observation. The primary outcome measure was the time from the first TD = 2 until the TD score worsened to 3 (hallucinations with loss of insight) or 4 (delusions, psychosis). The effect of antipsychotic medication treatment on transition hazard rate was modeled by proportional hazards regression (Cox model) with antipsychotic medication use as a time-dependent covariate. Of 64 patients, 31 received antipsychotic medication during the study (mean group follow-up 31 months). Of the 38 subjects who reached endpoint, eight subjects had been treated with antipsychotic medication compared to 30/33 in those not treated with antipsychotic medication. Antipsychotic medication treatment reduced the risk of deterioration [hazard ratio = 0.156, CI = (0.067-0.363), P < 0.0001] compared to treatment without antipsychotic medications. The median time from the introduction of antipsychotic medication to the conversion from TD = 2 to TD > 2 was 39 months in subjects on antipsychotic medication compared to 12 months in patients treated otherwise. Until randomized treatment trials provide definitive information, early antipsychotic medication treatment for mild hallucinations should be considered with the combined goal of improving current hallucinations and reducing risks of later deterioration.

Visual hallucinations and symptoms of REM sleep behavior disorder in Parkinsonian tauopathies.

BACKGROUND: In Parkinsonism, visual hallucinations (VH) and REM sleep behavior disorder (RBD) have been thought to indicate underlying synucleinopathy. OBJECTIVES: We tested the validity of this hypothesis by searching for VH and RBD symptoms in Parkinsonism related to tauopathies. METHODS: Patients with progressive supranuclear palsy or corticobasal degeneration were identified via a clinical data bank. RESULTS: Of 53 patients who expressed study interest by telephone, 44 returned questionnaires. VH occurred in 16% of patients. Similarly, acting out of dreams occurred in 16% of patients. Neither VH nor RBD symptoms were linked to disease duration or dopaminergic medication and there was no mutual association. CONCLUSION: VH and RBD symptoms also occur in Parkinsonism related to tauopathies, thus refuting the initial hypothesis.

Sudden infant death syndrome: rare mutation in the serotonin system FEV gene.

Recent studies have identified abnormalities in the development and function of medullary serotonin (5-HT) pathways in postmortem brain from sudden infant death syndrome (SIDS) cases, suggesting 5-HT-mediated dysregulation of the autonomic nervous system (ANS) in SIDS. The human fifth Ewing variant (FEV) gene is specifically expressed in central 5-HT neurons in the brain, with a predicted role in specification and maintenance of serotonergic neuronal phenotype. We hypothesized that variations of FEV may underlie abnormalities of the 5-HT system in SIDS cases and thus may be associated with SIDS risk. To elucidate the relationship between variation in FEV and SIDS, DNA was prepared from 96 African American and Caucasian SIDS cases and 96 gender- and ethnicity-matched controls. Standard sequencing and analysis of FEV revealed a heterozygous insertion mutation (IVS-191_190insA) upstream of the 5' exon 3 splice site occurring more frequently in SIDS cases (6/96) compared with controls (0/96; p = 0.01) and in the overall African American group (6/98) compared with the Caucasian group (0/94; p = 0.03). Identification of a variation in a gene responsible for 5-HT neuronal development, exclusively in a subset of African American SIDS cases in this cohort, may help explain both the observed abnormalities of this system in some SIDS cases and the ethnic disparity observed in SIDS.

Association of daytime napping and Parkinsonian signs in Alzheimer's disease.

BACKGROUND AND PURPOSE: Excessive daytime sleepiness (EDS) is reported in Alzheimer's disease (AD), with unstable sleep-wake rhythms that worsen with advancing disease stage. EDS is also very common in Parkinson's disease (PD), regardless of disease severity. The purpose of this study was to determine whether more Parkinsonian motor signs exist in AD patients with more reported daytime napping compared to AD patients without daytime napping. PATIENTS AND METHODS: AD patients ((National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association) NINCDS/ADRDA criteria) were prospectively evaluated in a dementia clinic. Parkinsonian motor signs were assessed using a modified motor Unified Parkinson's Disease Rating Scale (mmUPDRS). AD patients were grouped according to daytime napping frequency: (1) minimal napping (AD-Naps), or (2) napping at least once a day (AD+Naps). Wilcoxon rank-sum tests and chi2-tests computed differences between groups for mmUPDRS, nighttime sleep disturbances, and the Mini Mental State Examination (MMSE). Statistical significance was set at P<0.05. RESULTS: AD patients were classified as AD-Naps (n=155) or AD+Naps (n=180). Compared with AD-Naps patients, AD+Naps patients had higher total mmUPDRS scores (P<0.001), higher rigidity scores (P<0.005), and more gait impairment (P<0.001). CONCLUSION: AD patients with more reported daytime napping had more Parkinsonian motor signs, suggesting that this subgroup may have an increased propensity for sleepiness resembling PD. Longitudinal studies with objective measures are needed to determine whether causal relationships exist between sleepiness and Parkinsonism in AD.

The malignant course of "benign hallucinations" in Parkinson disease.

OBJECTIVE: To monitor progression of "benign hallucinations" in Parkinson disease (PD). METHODS: We searched our data repository for subjects with PD with 3 sets of neuropsychological testing during 3 years and Unified Parkinson's Disease Rating Scale thought disorder scores taken at 4- to 12-month intervals during this period. We found 48 patients with benign hallucinations, defined as a thought disorder score of 2 (benign hallucinations, insight retained), receiving no treatment for hallucinations. We followed up thought disorder scores under best medical management for at least 3 years or until a thought disorder score of 3 (loss of insight) or 4 (delusions) occurred. In subjects whose thought disorder scores remained at 2, we assessed neuroleptic use and decreases in PD medications to abate hallucinations. RESULTS: Most subjects (81%) progressed to thought disorder scores of 3 or 4. In 7 (78%) of 9 subjects who retained a thought disorder score of 2, PD medications were reduced to treat hallucinations, and 3 subjects (33%) also received neuroleptics. If the composite end point (any of the criteria) was used, 96% of subjects progressed, with only 2 subjects continuing with stable, untreated benign hallucinations. CONCLUSIONS: Because hallucinations progress, the concept of benign hallucinations is prognostically misleading. Though hallucinations with retained insight may be "benign" for the moment, they portend serious consequences. The term benign hallucinations of PD should be considered generally unsound and dropped from operative vocabulary.