Elevated expression of artemis in human fibroblast cells is associated with cellular radiosensitivity and increased apoptosis

Copyright @ 2012 Nature Publishing GroupThis article has been made available through the Brunel Open Access Publishing Fund.Background: The objective of this study was to determine the molecular mechanism(s) responsible for cellular radiosensitivity in two human fibroblast cell lines 84BR and 175BR derived from two cancer patients. Methods: Clonogenic assays were performed following exposure to increasing doses of gamma radiation to confirm radiosensitivity. γ-H2AX foci assays were used to determine the efficiency of DNA double strand break (DSB) repair in cells. Quantitative-PCR (Q-PCR) established the expression levels of key DNA DSB repair proteins. Imaging flow cytometry using Annexin V-FITC was used to compare artemis expression and apoptosis in cells. Results: Clonogenic cellular hypersensitivity in the 84BR and 175BR cell lines was associated with a defect in DNA DSB repair measured by the γ-H2AX foci assay. Q-PCR analysis and imaging flow cytometry revealed a two-fold overexpression of the artemis DNA repair gene which was associated with an increased level of apoptosis in the cells before and after radiation exposure. Over-expression of normal artemis protein in a normal immortalised fibroblast cell line NB1-Tert resulted in increased radiosensitivity and apoptosis. Conclusion: We conclude elevated expression of artemis is associated with higher levels of DNA DSB, radiosensitivity and elevated apoptosis in two radio-hypersensitive cell lines. These data reveal a potentially novel mechanism responsible for radiosensitivity and show that increased artemis expression in cells can result in either radiation resistance or enhanced sensitivity.This work was supported in part by The Vidal Sassoon Foundation USA. This article is made available through the Brunel Open Access Publishing Fund

The dynamics and neural correlates of audio-visual integration capacity as determined by temporal unpredictability, proactive interference, and SOA

Over 5 experiments, we challenge the idea that the capacity of audio-visual integration need be fixed at 1 item. We observe that the conditions under which audio-visual integration is most likely to exceed 1 occur when stimulus change operates at a slow rather than fast rate of presentation and when the task is of intermediate difficulty such as when low levels of proactive interference (3 rather than 8 interfering visual presentations) are combined with the temporal unpredictability of the critical frame (Experiment 2), or, high levels of proactive interference are combined with the temporal predictability of the critical frame (Experiment 4). Neural data suggest that capacity might also be determined by the quality of perceptual information entering working memory. Experiment 5 supported the proposition that audio-visual integration was at play during the previous experiments. The data are consistent with the dynamic nature usually associated with cross-modal binding, and while audio-visual integration capacity likely cannot exceed uni-modal capacity estimates, performance may be better than being able to associate only one visual stimulus with one auditory stimulus

No rapid audiovisual recalibration in adults on the autism spectrum

Autism spectrum disorders (ASD) are characterized by difficulties in social cognition, but are also associated with atypicalities in sensory and perceptual processing. Several groups have reported that autistic individuals show reduced integration of socially relevant audiovisual signals, which may contribute to the higher-order social and cognitive difficulties observed in autism. Here we use a newly devised technique to study instantaneous adaptation to audiovisual asynchrony in autism. Autistic and typical participants were presented with sequences of brief visual and auditory stimuli, varying in asynchrony over a wide range, from 512 ms auditory-lead to 512 ms auditory-lag, and judged whether they seemed to be synchronous. Typical adults showed strong adaptation effects, with trials proceeded by an auditory-lead needing more auditory-lead to seem simultaneous, and vice versa. However, autistic observers showed little or no adaptation, although their simultaneity curves were as narrow as the typical adults. This result supports recent Bayesian models that predict reduced adaptation effects in autism. As rapid audiovisual recalibration may be fundamental for the optimisation of speech comprehension, recalibration problems could render language processing more difficult in autistic individuals, hindering social communication

What do clinicians want? Interest in integrative health services at a North Carolina academic medical center

BACKGROUND: Use of complementary medicine is common, consumer driven and usually outpatient focused. We wished to determine interest among the medical staff at a North Carolina academic medical center in integrating diverse therapies and services into comprehensive care. METHODS: We conducted a cross sectional on-line survey of physicians, nurse practitioners and physician assistants at a tertiary care medical center in 2006. The survey contained questions on referrals and recommendations in the past year and interest in therapies or services if they were to be provided at the medical center in the future. RESULTS: Responses were received from 173 clinicians in 26 different departments, programs and centers. There was strong interest in offering several specific therapies: therapeutic exercise (77%), expert consultation about herbs and dietary supplements (69%), and massage (66%); there was even stronger interest in offering comprehensive treatment programs such as multidisciplinary pain management (84%), comprehensive nutritional assessment and advice (84%), obesity/healthy lifestyle promotion (80%), fit for life (exercise and lifestyle program, 76%), diabetes healthy lifestyle promotion (73%); and comprehensive psychological services for stress management, including hypnosis and biofeedback (73%). CONCLUSION: There is strong interest among medical staff at an academic health center in comprehensive, integrated services for pain, obesity, and diabetes and in specific services in fitness, nutrition and stress management. Future studies will need to assess the cost-effectiveness of such services, as well as their financial sustainability and impact on patient satisfaction, health and quality of life

On-chip Single Nanoparticle Detection and Sizing by Mode Splitting in an Ultra-high-Q Microresonator

The ability to detect and size individual nanoparticles with high resolution is crucial to understanding behaviours of single particles and effectively using their strong size-dependent properties to develop innovative products. We report real-time, in-situ detection and sizing of single nanoparticles, down to 30 nm in radius, using mode-splitting in a monolithic ultra-high-Q whispering-gallery-mode (WGM) microtoroid resonator. Particle binding splits a WGM into two spectrally shifted resonance modes, forming a self-referenced detection scheme. This technique provides superior noise suppression and enables extracting accurate size information in a single-shot measurement. Our method requires neither labelling of the particles nor apriori information on their presence in the medium, providing an effective platform to study nanoparticles at single particle resolution.Comment: 23 pages, 8 figure

Delirium risk screening and haloperidol prophylaxis program in hip fracture patients is a helpful tool in identifying high-risk patients, but does not reduce the incidence of delirium

Background: Delirium in patients with hip fractures lead to higher morbidity and mortality. Prevention in high-risk patients by prescribing low dose haloperidol is currently under investigation. Methods. This prospective cohort surveillance assessed hip fracture patients for risk of developing a delirium with the Risk Model for Delirium (RD) score. High-risk patients (score ≥5 points) were treated with a prophylactic low-dose of haloperidol according to hospital protocol. Primary outcome was delirium incidence. Secondary outcomes were differences between high- and low-risk patients in delirium, length of stay (LOS), return to pre-fracture living situation and mortality. Logistic regression analysis was performed with age, ASA-classification, known dementia, having a partner, type of fracture, institutional residence and psychotropic drug use as possible confounders. Results: 445 hip fracture patients aged 65 years and older were admitted from January 2008 to December 2009. The RD-score was completed in 378 patients, 173 (45.8%) high-risk patients were treated with prophylactic medication. Sensitivity was 71.6%, specificity 63.8% and the negative predictive value (NPV) of a score < 5 was 85.9%. Delirium incidence (27.0%) was not significantly different compared to 2007 (27.8%) 2006 (23.9%) and 2005 (29.0%) prior to implementation of the RD- protocol. Logistic regression analysis showed that high-risk patients did have a significant higher delirium incidence (42.2% vs. 14.1%, OR 4.1, CI 2.43-7.02). They were more likely to be residing at an alternative living situation after 3 months (62.3% vs. 17.0%, OR 6.57, CI 3.23-13.37) and less likely to be discharged from hospital before 10 days (34.9% vs. 55.9%, OR 1.63, CI 1.03-2.59). Significant independent risk factors for a delirium were a RD-score 5 (OR 4.13, CI 2.43-7.02), male gender (OR 1.93, CI 0.99-1.07) and age (OR 1.03, CI 0.99-1.07). Conclusions: Introducing the delirium prevention protocol did not reduce delirium incidence. The RD-score did identify patients with a high risk to develop a delirium. This high-risk group had a longer LOS and returned to pre-fracture living situation less often. The NPV of a score < 5 was high, as it should be for a screening instrument. Concluding, the RD-score is a useful tool to identify patients with poorer outcome

High prevalence of ACE DD genotype among north Indian end stage renal disease patients

BACKGROUND: The Renin-Angiotensin system (RAS) is a key regulator of both blood pressure and kidney functions and their interaction. In such a situation, genetic variability in the genes of different components of RAS is likely to contribute for its heterogeneous association in the renal disease patients. Angiotensin converting enzyme-1 (ACE-1) is an important component of RAS which determines the vasoactive peptide Angiotensin-II. METHODS: In the present study, we have investigated 127 ESRD patients and 150 normal healthy controls from north India to deduce the association between ACE gene polymorphism and ESRD. The inclusion criteria for patients included a constantly elevated serum creatinine level above normal range (ranging from 3.4 to 15.8) and further the patients were recommended for renal transplantation. A total of 150 normal healthy controls were also genotyped for ACE I/D polymorphism. The criterion of defining control sample as normal was totally based on the absence of any kidney disease determined from the serum creatinin level. Genotyping of ACE I/D were assayed by polymerase chain reaction (PCR) based DNA amplification using specific flanking primers Based on the method described elsewhere. RESULTS: The difference of DD and II genotypes was found highly significant among the two groups (p = 0.025; OR = 3.524; 95%CI = 1.54-8.07). The combined genotype DD v/s ID+II comparison validated that DD genotype is a high risk genotype for ESRD (p = 0.001; OR = 5.74; 95%CI limit = 3.4-8.5). However, no correlation was obtained for different biochemical parameters of lipid profile and renal function among DD and non DD genotype. Interestingly, ~87% of the DD ESRD patients were found hypertensive in comparison to the 65% patients of non DD genotype CONCLUSION: Based on these observations we conclude that ACE DD genotype implicate a strong possible role in the hypertensive state and in renal damage among north Indians. The study will help in predetermining the timing, type and doses of anti-hypertensive therapy for ESRD patients

Perturbing Dynamin Reveals Potent Effects on the Drosophila Circadian Clock

BACKGROUND: Transcriptional feedback loops are central to circadian clock function. However, the role of neural activity and membrane events in molecular rhythms in the fruit fly Drosophila is unclear. To address this question, we expressed a temperature-sensitive, dominant negative allele of the fly homolog of dynamin called shibire(ts1) (shi(ts1)), an active component in membrane vesicle scission. PRINCIPAL FINDINGS: Broad expression in clock cells resulted in unexpectedly long, robust periods (>28 hours) comparable to perturbation of core clock components, suggesting an unappreciated role of membrane dynamics in setting period. Expression in the pacemaker lateral ventral neurons (LNv) was necessary and sufficient for this effect. Manipulation of other endocytic components exacerbated shi(ts1)'s behavioral effects, suggesting its mechanism is specific to endocytic regulation. PKA overexpression rescued period effects suggesting shi(ts1) may downregulate PKA pathways. Levels of the clock component PERIOD were reduced in the shi(ts1)-expressing pacemaker small LNv of flies held at a fully restrictive temperature (29 degrees C). Less restrictive conditions (25 degrees C) delayed cycling proportional to observed behavioral changes. Levels of the neuropeptide PIGMENT-DISPERSING FACTOR (PDF), the only known LNv neurotransmitter, were also reduced, but PERIOD cycling was still delayed in flies lacking PDF, implicating a PDF-independent process. Further, shi(ts1) expression in the eye also results in reduced PER protein and per and vri transcript levels, suggesting that shibire-dependent signaling extends to peripheral clocks. The level of nuclear CLK, transcriptional activator of many core clock genes, is also reduced in shi(ts1) flies, and Clk overexpression suppresses the period-altering effects of shi(ts1). CONCLUSIONS: We propose that membrane protein turnover through endocytic regulation of PKA pathways modulates the core clock by altering CLK levels and/or activity. These results suggest an important role for membrane scission in setting circadian period

Elderly with Autism: Executive Functions and Memory

Cognitive autism research is mainly focusing on children and young adults even though we know that autism is a life-long disorder and that healthy aging already has a strong impact on cognitive functioning. We compared the neuropsychological profile of 23 individuals with autism and 23 healthy controls (age range 51–83 years). Deficits were observed in attention, working memory, and fluency. Aging had a smaller impact on fluency in the high functioning autism (HFA) group than in the control group, while aging had a more profound effect on visual memory performance in the HFA group. Hence, we provide novel evidence that elderly with HFA have subtle neuropsychological deficits and that the developmental trajectories differ between elderly with and without HFA in particular cognitive domains