Contrahelicase activity of the mitochondrial transcription termination factor mtDBP

The sea urchin mitochondrial D-loop binding protein (mtDBP) is a transcription termination factor that is able to arrest bidirectionally mitochondrial RNA chain elongation. The observation that the mtDBP binding site in the main non-coding region is located in correspondence of the 3′ end of the triplex structure, where the synthesis of heavy strand mitochondrial (mt) DNA is either prematurely terminated or allowed to continue, raised the question whether mtDBP could also regulate mtDNA replication. By using a helicase assay in the presence of the replicative helicase of SV40, we show that mtDBP is able to inhibit the enzyme thus acting as a contrahelicase. The impairing activity of mtDBP is bidirectional as it is independent of the orientation of the protein binding site. The inhibition is increased by the presence of the guanosine-rich sequence that flanks mtDBP binding site. Finally, a mechanism of abrogation of mtDBP contrahelicase activity is suggested that is based on the dissociation of mtDBP from DNA caused by the passage of the RNA polymerase through the protein–DNA complex. All these findings favour the view that mtDBP, besides serving as transcription termination factor, could also act as a negative regulator of mtDNA synthesis at the level of D-loop expansion

Differences in Inflammatory Markers between Nulliparous Women Admitted to Hospitals in Preactive vs Active Labor

Objective To determine whether labor-associated inflammatory markers differ between low-risk, nulliparous women in preactive vs active labor at hospital admission and over time. Study Design Prospective comparative study of low-risk, nulliparous women with spontaneous labor onset at term (n = 118) sampled from 2 large Midwestern hospitals. Circulating concentrations of inflammatory markers were measured at admission and again 2 and 4 hours later: namely, neutrophil, and monocyte counts; and serum inflammatory cytokines (interleukin -1β, interleukin-6, tumor necrosis factor-α, interleukin-10) and chemokines (interleukin-8). Biomarker concentrations and their patterns of change over time were compared between preactive (n = 63) and active (n = 55) labor admission groups using Mann-Whitney U tests. Results Concentrations of interleukin-6 and interleukin-10 in the active labor admission group were significantly higher than concentrations in the preactive labor admission group at all 3 time points. Neutrophil levels were significantly higher in the active group at 2 and 4 hours after admission. The rate of increase in neutrophils and interleukin-10 between admission and 2 hours later was faster in the active group (P \u3c .001 and P = .003, respectively). Conclusion Circulating concentrations of several inflammatory biomarkers are higher and their rate of change over time since admission is faster among low-risk, nulliparous women admitted to hospitals in active labor, as compared with those admitted in preactive labor. More research is needed to determine if progressive changes in inflammatory biomarkers might be a useful adjunct to improving the assessment of labor progression and determining the optimal timing of labor admission

Predictors of progression of cognitive decline in Alzheimer’s disease: the role of vascular and sociodemographic factors

Rates of disease progression differ among patients with Alzheimer’s disease, but little is known about prognostic predictors. The aim of the study was to assess whether sociodemographic factors, disease severity and duration, and vascular factors are prognostic predictors of cognitive decline in Alzheimer’s disease progression. We conducted a longitudinal clinical study in a specialized clinical unit for the diagnosis and treatment of dementia in Rome, Italy. A total of 154 persons with mild to moderate Alzheimer’s disease consecutively admitted to the dementia unit were included. All patients underwent extensive clinical examination by a physician at admittance and all follow-ups. We evaluated the time-dependent probability of a worsening in cognitive performance corresponding to a 5-point decrease in Mini-Mental State Examination (MMSE) score. Survival analysis was used to analyze risk of faster disease progression in relation to age, education, severity and duration of the disease, family history of dementia, hypertension, hypercholesterolemia, and type 2 diabetes. Younger and more educated persons were more likely to have faster Alzheimer’s disease progression. Vascular factors such as hypertension and hypercholesterolemia were not found to be significantly associated with disease progression. However, patients with diabetes had a 65% reduced risk of fast cognitive decline compared to Alzheimer patients without diabetes. Sociodemographic factors and diabetes predict disease progression in Alzheimer’s disease. Our findings suggest a slower disease progression in Alzheimer’s patients with diabetes. If confirmed, this result will contribute new insights into Alzheimer’s disease pathogenesis and lead to relevant suggestions for disease treatment

Heterogeneous Bond Percolation on Multitype Networks with an Application to Epidemic Dynamics

Considerable attention has been paid, in recent years, to the use of networks in modeling complex real-world systems. Among the many dynamical processes involving networks, propagation processes -- in which final state can be obtained by studying the underlying network percolation properties -- have raised formidable interest. In this paper, we present a bond percolation model of multitype networks with an arbitrary joint degree distribution that allows heterogeneity in the edge occupation probability. As previously demonstrated, the multitype approach allows many non-trivial mixing patterns such as assortativity and clustering between nodes. We derive a number of useful statistical properties of multitype networks as well as a general phase transition criterion. We also demonstrate that a number of previous models based on probability generating functions are special cases of the proposed formalism. We further show that the multitype approach, by naturally allowing heterogeneity in the bond occupation probability, overcomes some of the correlation issues encountered by previous models. We illustrate this point in the context of contact network epidemiology.Comment: 10 pages, 5 figures. Minor modifications were made in figures 3, 4 and 5 and in the text. Explanations and references were adde

Can an EASYcare based dementia training programme improve diagnostic assessment and management of dementia by general practitioners and primary care nurses? The design of a randomised controlled trial

Contains fulltext : 70099.pdf ( ) (Open Access)BACKGROUND: Early diagnosis of dementia benefits both patient and caregiver. Nevertheless, dementia in primary care is currently under-diagnosed. Some educational interventions developed to improve dementia diagnosis and management were successful in increasing the number of dementia diagnoses and in changing attitudes and knowledge of health care staff. However, none of these interventions focussed on collaboration between GPs and nurses in dementia care. We developed an EASYcare-based Dementia Training Program (DTP) aimed at stimulating collaboration in dementia primary care. We expect this program to increase the number of cognitive assessments and dementia diagnoses and to improve attitudes and knowledge of GPs and nurses. METHODS: The DTP is a complex educational intervention that consists of two workshops, a coaching program, access to an internet forum, and a Computerized Clinical Decision Support System on dementia diagnostics. One hundred duos of GPs and nurses will be recruited, from which 2/3 will be allocated to the intervention group and 1/3 to the control group. The effects of implementation of the DTP will be studied in a cluster-randomised controlled trial. Primary outcomes will be the number of cognitive assessments and dementia diagnoses in a period of 9 months following workshop participation. Secondary outcomes are measured on GP and nurse level: adherence to national guidelines for dementia, attitude, confidence and knowledge regarding dementia diagnosis and management; on patient level: number of emergency calls, visits and consultations and patient satisfaction; and on caregiver level: informal caregiver burden and satisfaction. Data will be collected from GPs' electronic medical records, self-registration forms and questionnaires. Statistical analysis will be performed using the MANOVA-method. Also, exploratory analyses will be performed, in order to gain insight into barriers and facilitators for implementation and the possible causal relations between the rate of success of the intervention components and the outcomes. DISCUSSION: We developed multifaceted dementia training programme. Novelties in this programme are the training in fixed collaborative duos and the inclusion of an individual coaching program. The intervention is designed according to international guidelines and educational standards. Exploratory analysis will reveal its successful elements. Selection bias and contamination may be threats to the reliability of future results of this trial. Nevertheless, the results of this trial may provide useful information for policy makers and developers of continuing medical education. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT00459784

Clinical Risk Factors Associated with Anti-Epileptic Drug Responsiveness in Canine Epilepsy

The nature and occurrence of remission, and conversely, pharmacoresistance following epilepsy treatment is still not fully understood in human or veterinary medicine. As such, predicting which patients will have good or poor treatment outcomes is imprecise, impeding patient management. In the present study, we use a naturally occurring animal model of pharmacoresistant epilepsy to investigate clinical risk factors associated with treatment outcome. Dogs with idiopathic epilepsy, for which no underlying cause was identified, were treated at a canine epilepsy clinic and monitored following discharge from a small animal referral hospital. Clinical data was gained via standardised owner questionnaires and longitudinal follow up data was gained via telephone interview with the dogs’ owners. At follow up, 14% of treated dogs were in seizure-free remission. Dogs that did not achieve remission were more likely to be male, and to have previously experienced cluster seizures. Seizure frequency or the total number of seizures prior to treatment were not significant predictors of pharmacoresistance, demonstrating that seizure density, that is, the temporal pattern of seizure activity, is a more influential predictor of pharmacoresistance. These results are in line with clinical studies of human epilepsy, and experimental rodent models of epilepsy, that patients experiencing episodes of high seizure density (cluster seizures), not just a high seizure frequency pre-treatment, are at an increased risk of drug-refractoriness. These data provide further evidence that the dog could be a useful naturally occurring epilepsy model in the study of pharmacoresistant epilepsy

Change in Ratio of Observed-to-Expected Deaths in Pediatric Patients after Implementing a Closed Policy in an Adult ICU That Admits Children

Backgrounds. We examined the effect on the prognosis of critically ill pediatric patients after a closed ICU policy was implemented into an adult ICU that admitted children. Materials and Methods. We assessed the Pediatric Index of Mortality 2 (PIM2) score of pediatric patients (≤15 y.o.) admitted to the ICU from 2001 to 2009. In our teaching hospital, the department for intensive care was established in January 2004. Since then, for critical care patients, we have followed a closed ICU policy with full-time intensivists. We subsequently compared PIM2 scores and the ratio of observed-to-expected deaths (O/E ratio) for three three-year periods: 2001–2003 (before closed policy), 2004–2006, and 2007–2009. Results. Data was collected from 532 pediatric patients. While the PIM2 score statistically significantly increased from 0.066 ± 0.130 for 2001–2003 to 0.114 ± 0.239 for 2004–2006 and 0.086 ± 0.147 for 2007–2009, the O/E ratio decreased from 1.49 for 2001–2003 to 0.82 for 2004–2006 and remained at 0.82 for 2007–2009. Conclusion. The O/E ratio for critically ill pediatric patients improved after the establishment of a closed policy in an adult ICU that admitted children

Role of right posterior parietal cortex in maintaining attention to spatial locations over time

Recent models of human posterior parietal cortex (PPC) have variously emphasized its role in spatial perception, visuomotor control or directing attention. However, neuroimaging and lesion studies also suggest that the right PPC might play a special role in maintaining an alert state. Previously, assessments of right-hemisphere patients with hemispatial neglect have revealed significant overall deficits on vigilance tasks, but to date there has been no demonstration of a deterioration of performance over time--a vigilance decrement--considered by some to be a key index of a deficit in maintaining attention. Moreover, sustained attention deficits in neglect have not specifically been related to PPC lesions, and it remains unclear whether they interact with spatial impairments in this syndrome. Here we examined the ability of right-hemisphere patients with neglect to maintain attention, comparing them to stroke controls and healthy individuals. We found evidence of an overall deficit in sustaining attention associated with PPC lesions, even for a simple detection task with stimuli presented centrally. In a second experiment, we demonstrated a vigilance decrement in neglect patients specifically only when they were required to maintain attention to spatial locations, but not verbal material. Lesioned voxels in the right PPC spanning a region between the intraparietal sulcus and inferior parietal lobe were significantly associated with this deficit. Finally, we compared performance on a task that required attention to be maintained either to visual patterns or spatial locations, matched for task difficulty. Again, we found a vigilance decrement but only when attention had to be maintained on spatial information. We conclude that sustaining attention to spatial locations is a critical function of the human right PPC which needs to be incorporated into models of normal parietal function as well as those of the clinical syndrome of hemispatial neglect

Studying a hospital distribution network with a stochastic end-uses demand model

The schematization of a hospital water network through a probabilistic model of end-uses is the focus of this study. The idea is to realize a model to evaluate the water demand related to the use of individual water-demanding devices to define a strategy for the prevention and control of legionella risk. The modelling of hospital network has been carried out through EPANET 2.0 software [1], in which the hot and cold water networks can be implemented separately. The suggested probabilistic model has already been applied to several case studies [2], [3], [4] and [5], but never to a hospital network