Enriching preschool classrooms and home visits with evidence-based programming: sustained benefits for low-income children.
Growing up in poverty undermines healthy development, producing disparities in the cognitive and social-emotional skills that support early learning and mental health. Preschool and home-visiting interventions for low-income children have the potential to build early cognitive and social-emotional skills, reducing the disparities in school readiness that perpetuate the cycle of poverty. However, longitudinal research suggests that the gains low-income children make during preschool interventions often fade at school entry and disappear by early elementary school. In an effort to improve the benefits for low-income children, the REDI program enriched Head Start preschool classrooms (study one) and home visits (study two) with evidence-based programming, documenting positive intervention effects in two randomized trials. In this study, REDI participants were followed longitudinally, to evaluate the sustained impact of the classroom and home-visiting enrichments 3 years later, when children were in second grade. The combined sample included 556 children (55% European American, 25% African American, 19% Latino; 49% male): 288 children received the classroom intervention, 105 children received the classroom intervention plus the home-visiting intervention, and 173 children received usual practice Head Start. The classroom intervention led to sustained benefits in social-emotional skills, improving second grade classroom participation, student-teacher relationships, social competence, and peer relations. The coordinated home-visiting intervention produced additional benefits in child mental health (perceived social competence and peer relations) and cognitive skills (reading skills, academic performance). Significant effects ranged from 25% to 48% of a standard deviation, representing important effects of small to moderate magnitude relative to usual practice Head Start. Preschool classroom and home-visiting programs for low-income children can be improved with the use of evidence-based programming, reducing disparities and promoting complementary benefits that sustain in elementary school.


Transcriptomic analyses of neurotoxic effects in mouse brain after intermittent neonatal administration of thimerosal.
Thimerosal is a vaccine antimicrobial preservative which has long been suspected an iatrogenic factor possibly contributing to neurodevelopmental disorders including autism. The association between infant vaccine thimerosal exposure and autism remains an open question. Although thimerosal has been removed from mandatory childhood vaccines in the United States, thimerosal-preserved vaccines are still widely used outside of the United States especially in developing countries. Notably, thimerosal-containing vaccines are being given to the newborns within the first 12-24 h after birth in some countries. To examine the possible neurotoxic effects of early neonatal exposure to a higher level of thimerosal, FVB mice were subcutaneously injected with thimerosal-mercury at a dose which is 20× higher than that used for regular Chinese infant immunization during the first 4 months of life. Thimerosal-treated mice exhibited neural development delay, social interaction deficiency, and inclination of depression. Apparent neuropathological changes were also observed in adult mice neonatally treated with thimerosal. High-throughput RNA sequencing of autistic-behaved mice brains revealed the alternation of a number of canonical pathways involving neuronal development, neuronal synaptic function, and the dysregulation of endocrine system. Intriguingly, the elevation of anterior pituitary secreting hormones occurred exclusively in male but not in female thimerosal-treated mice, demonstrating for the first time the gender bias of thimerosal-mercury toxicity with regard to endocrine system. Our results indicate that higher dose of neonatal thimerosal-mercury (20× higher than that used in human) is capable of inducing long-lasting substantial dysregulation of neurodevelopment, synaptic function, and endocrine system, which could be the causal involvements of autistic-like behavior in mice.


Improvement of recorded holographic fringes by feedback control.
A feedback control system has been designed to stabilize the position of interference fringes, particularly those which occur in holography. The result of closed loop operation of the system is that rather severe phase perturbations may occur in either of the beams, and yet be compensated for such that the fringes in the holographic recording medium are essentially stabilized. This paper discusses the design and analysis of an experimental model and its performance for phase perturbations due to acoustic and mechanical vibration, thermal drift, large perturbations, warm air turbulence, and small doppler shifts. The authors then speculate that more advanced designs may stabilize interference fringes even with larger phase perturbations such as large doppler shifts, optical frequency differences, motion of the scene, and holographic interferometry.


Auxotrophic interactions: a stabilizing attribute of aquatic microbial communities?
Auxotrophy, or an organism's requirement for an exogenous source of an organic molecule, is widespread throughout species and ecosystems. Auxotrophy can result in obligate interactions between organisms, influencing ecosystem structure and community composition. We explore how auxotrophy-induced interactions between aquatic microorganisms affect microbial community structure and stability. While some studies have documented auxotrophy in aquatic microorganisms, these studies are not widespread, and we therefore do not know the full extent of auxotrophic interactions in aquatic environments. Current theoretical and experimental work suggests that auxotrophy links microbial community members through a complex web of metabolic dependencies. We discuss the proposed ways in which auxotrophy may enhance or undermine the stability of aquatic microbial communities, highlighting areas where our limited understanding of these interactions prevents us from being able to predict the ecological implications of auxotrophy. Finally, we examine an example of auxotrophy in harmful algal blooms to place this often theoretical discussion in a field context where auxotrophy may have implications for the development and robustness of algal bloom communities. We seek to draw attention to the relationship between auxotrophy and community stability in an effort to encourage further field and theoretical work that explores the underlying principles of microbial interactions.


Complementary interplay between matrix metalloproteinase-9, vascular endothelial growth factor and osteoclast function drives endochondral bone formation.
Long bone development depends on endochondral bone formation, a complex process requiring exquisite balance between hypertrophic cartilage (HC) formation and its ossification. Dysregulation of this process may result in skeletal dysplasias and heterotopic ossification. Endochondral ossification requires the precise orchestration of HC vascularization, extracellular matrix remodeling, and the recruitment of osteoclasts and osteoblasts. Matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF) and osteoclasts have all been shown to regulate endochondral ossification, but how their function interrelates is not known. We have investigated the functional relationship among these regulators of endochondral ossification, demonstrating that they have complementary but non-overlapping functions. MMP-9, VEGF and osteoclast deficiency all cause impaired growth plate ossification resulting in the accumulation of HC. VEGF mRNA and protein expression are increased at the MMP-9-/- growth plate, and VEGF activity contributes to endochondral ossification since sequestration of VEGF by soluble receptors results in further inhibition of growth plate vascularization and ossification. However, VEGF bioavailability is still limited in MMP-9 deficiency, as exogenous VEGF is able to rescue the MMP-9-/- phenotype, demonstrating that MMP-9 may partially, but not fully, regulate VEGF bioavailability. The organization of the HC extracellular matrix at the MMP-9-/- growth plate is altered, supporting a role for MMP-9 in HC remodeling. Inhibition of VEGF impairs osteoclast recruitment, whereas MMP-9 deficiency leads to an accumulation of osteoclasts at the chondro-osseous junction. Growth plate ossification in osteoclast-deficient mice is impaired in the presence of normal MMP-9 expression, indicating that other osteoclastic functions are also necessary. Our data delineate the complementary interplay between MMP-9, VEGF and osteoclast function that is necessary for normal endochondral bone formation and provide a molecular framework for investigating the molecular defects contributing to disorders of endochondral bone formation.


Combined phacoemulsification and removal of gas following macular hole surgery.
We describe a technique for combined fluid-gas exchange and phacoemulsification 2 weeks after macular hole surgery to achieve rapid visual rehabilitation. The procedure uses a standard cataract set and requires minimal vitreoretinal expertise. We encountered no significant complications and obtained long-term outcomes comparable to those with conventional management.


Epidemiology and sociodemographics of systemic lupus erythematosus and lupus nephritis among US adults with Medicaid coverage, 2000-2004.
Systemic lupus erythematosus (SLE) and lupus nephritis (LN) disproportionately affect individuals who are members of racial/ethnic minority groups and individuals of lower socioeconomic status (SES). This study was undertaken to investigate the epidemiology and sociodemographics of SLE and LN in the low-income US Medicaid population. We utilized Medicaid Analytic eXtract data, with billing claims from 47 states and Washington, DC, for 23.9 million individuals ages 18-65 years who were enrolled in Medicaid for >3 months in 2000-2004. Individuals with SLE (≥3 visits >30 days apart with an International Classification of Diseases, Ninth Revision [ICD-9] code of 710.0) and with LN (≥2 visits with an ICD-9 code for glomerulonephritis, proteinuria, or renal failure) were identified. We calculated SLE and LN prevalence and incidence, stratified by sociodemographic category, and adjusted for number of American College of Rheumatology (ACR) member rheumatologists in the state and SES using a validated composite of US Census variables. We identified 34,339 individuals with SLE (prevalence 143.7 per 100,000) and 7,388 (21.5%) with LN (prevalence 30.9 per 100,000). SLE prevalence was 6 times higher among women, nearly double in African American compared to white women, and highest in the US South. LN prevalence was higher among all racial/ethnic minority groups compared to whites. The areas with lowest SES had the highest prevalence; areas with the fewest ACR rheumatologists had the lowest prevalence. SLE incidence was 23.2 per 100,000 person-years and LN incidence was 6.9 per 100,000 person-years, with similar sociodemographic trends. In this nationwide Medicaid population, there was sociodemographic variation in SLE and LN prevalence and incidence. Understanding the increased burden of SLE and its complications in this low-income population has implications for resource allocation and access to subspecialty care.


Doctors' learning habits: CME activities among Norwegian physicians over the last decade.
Coping with the increasing body of medical knowledge is a main challenge to all doctors. The aim of this study was to investigate self reported reading and learning habits among Norwegian doctors and their subjective ability to keep professionally updated. A cross sectional survey among a randomised sample of Norwegian doctors was undertaken in 2004 (n = 1005, response rate 71%). A similar study with many identical questions was done in 1993 (n = 1041, response rate 71%) and a comparison of the results was made. Attending courses/congresses and reading medical literature were reported to be the most important sources of professional information in 2004, just like in 1993. Less time was spent on courses/congresses in 2004 than in 1993, and more time was spent on medical reading. The internet was regarded as useful for their professional life for three out of five, mostly among the younger and least among GPs. Two out of three doctors felt that they could obtain sufficient information for keeping updated in 2004, the same proportion as in 1993. A correlation was found between subjective coping with the information and a high level of continuing medical education (CME)-activities. The information copers had a higher level of job satisfaction than non-copers. Over the last decade Norwegian doctors spend less time on attending courses/congresses and more time on medical reading, while the level of self perceived coping with information has been unchanged. The changing pattern of professional updating may reflect a more general individualistic trend in society. The consistent finding of a correlation between reading and attending courses, subjective coping and job satisfaction gives good reasons for recommending a high level of CME-activities among doctors.


A four-marker signature of TNF-RII, TGF-α, TIMP-1 and CRP is prognostic of worse survival in high-risk surgically resected melanoma.
E1694 tested GM2-KLH-QS21 vaccine versus high-dose interferon-α2b (HDI) as adjuvant therapy for operable stage IIB-III melanoma. We tested banked serum specimens from patients in the vaccine arm of E1694 for prognostic biomarkers. Aushon Multiplex Platform was used to quantitate baseline serum levels of 115 analytes from 40 patients. Least absolute shrinkage and selection operator proportional hazard regression (Lasso PH) was used to select markers that are most informative for relapse-free survival (RFS) and overall survival (OS). Regular Cox PH models were then fit with the markers selected by the Lasso PH. Survival receiver operating characteristic (ROC) analysis was used to evaluate the ability of the models to predict 1-year RFS and 5-year OS. Four markers that include Tumor Necrosis Factor alpha Receptor II (TNF-RII), Transforming Growth Factor alpha (TGF-α), Tissue Inhibitor of Metalloproteinases 1 (TIMP-1), and C-reactive protein (CRP) were found to be most informative for the prediction of OS (high levels correlate with worse prognosis). The dichotomized risk score based on the four markers could significantly separate the OS curves (p = 0.0005). When using the four-marker PH model to predict 5-year OS, we achieved an area under the curve (AUC) of 89% (cross validated AUC = 72%). High baseline TNF-RII was also significantly associated with worse RFS. The RFS with high (above median) TNF-RII was significantly lower than low TNF-RII (p = 0.01). The biomarker signature consisting of TNFR-II, TGF-α, TIMP-1 and CRP is significantly prognostic of survival in patients with high-risk melanoma and warrants further investigation.


Interpreting comparative died of wounds rates as a quality benchmark of combat casualty care.
The died of wounds (DOW) rate is cited as a measure of combat casualty care effectiveness without the context of injury severity or insight into lethality of the battlefield. The objective of this study was to characterize injury severity and other factors related to variations in the DOW rate. The highest monthly DOW (HDOW) and lowest monthly DOW (LDOW) rates from 2004 to 2008 were identified from analysis and casualty report databases and used to direct a search of the Joint Theater Trauma Registry. Casualties from the HDOW and LDOW were combined into cohorts, and injury data were analyzed and compared. The HDOW rates were 13.4%, 11.6%, and 12.8% (mean, 12.6%), and the LDOW rates were 1.3%, 2.0%, and 2.7% (mean, 2.0%) (p < 0.0001). The HDOW (n = 541) and LDOW (n = 349) groups sustained a total of 1,154 wounds. Injury Severity Score was greater in the HDOW than the LDOW group (mean [SD], 11.1 [0.53] vs. 9.4 [0.58]; p = 0.03) as was the percentage of patients with Injury Severity Score of more than 25 (HDOW, 12% vs. LDOW, 7.7%; p = 0.04). Excluding minor injuries (Abbreviated Injury Scale score of 1), there was a greater percentage of chest injuries in the HDOW compared with the LDOW group (16.5% vs. 11.2%, p = 0.03). Explosive mechanisms were more commonly the cause of injury in the HDOW group (58.7% vs. 49.7%; p = 0.007), which also had a higher percentage of Marine Corps personnel (p = 0.02). This study provides novel data demonstrating that the died of wounds rate ranges significantly throughout the course of combat. Discernible differences in injury severity, wounding patterns, and even service affiliation exist within this variation. For accuracy, the died of wounds rate should be cited only in the context of associated injury patterns, injury severity, and mechanisms of injury. Without this context, DOW should not be used as a comparative medical metric.


MyriMatch: highly accurate tandem mass spectral peptide identification by multivariate hypergeometric analysis.
Shotgun proteomics experiments are dependent upon database search engines to identify peptides from tandem mass spectra. Many of these algorithms score potential identifications by evaluating the number of fragment ions matched between each peptide sequence and an observed spectrum. These systems, however, generally do not distinguish between matching an intense peak and matching a minor peak. We have developed a statistical model to score peptide matches that is based upon the multivariate hypergeometric distribution. This scorer, part of the "MyriMatch" database search engine, places greater emphasis on matching intense peaks. The probability that the best match for each spectrum has occurred by random chance can be employed to separate correct matches from random ones. We evaluated this software on data sets from three different laboratories employing three different ion trap instruments. Employing a novel system for testing discrimination, we demonstrate that stratifying peaks into multiple intensity classes improves the discrimination of scoring. We compare MyriMatch results to those of Sequest and X!Tandem, revealing that it is capable of higher discrimination than either of these algorithms. When minimal peak filtering is employed, performance plummets for a scoring model that does not stratify matched peaks by intensity. On the other hand, we find that MyriMatch discrimination improves as more peaks are retained in each spectrum. MyriMatch also scales well to tandem mass spectra from high-resolution mass analyzers. These findings may indicate limitations for existing database search scorers that count matched peaks without differentiating them by intensity. This software and source code is available under Mozilla Public License at this URL: http://www.mc.vanderbilt.edu/msrc/bioinformatics/.


PairProSVM: protein subcellular localization based on local pairwise profile alignment and SVM.
The subcellular locations of proteins are important functional annotations. An effective and reliable subcellular localization method is necessary for proteomics research. This paper introduces a new method---PairProSVM---to automatically predict the subcellular locations of proteins. The profiles of all protein sequences in the training set are constructed by PSI-BLAST and the pairwise profile-alignment scores are used to form feature vectors for training a support vector machine (SVM) classifier. It was found that PairProSVM outperforms the methods that are based on sequence alignment and amino-acid compositions even if most of the homologous sequences have been removed. This paper also demonstrates that the performance of PairProSVM is sensitive (and somewhat proportional) to the degree of its kernel matrix meeting the Mercer's condition. PairProSVM was evaluated on Reinhardt and Hubbard's, Huang and Li's, and Gardy et al.'s protein datasets. The overall accuracies on these three datasets reach 99.3\\%, 76.5\\%, and 91.9\\%, respectively, which are higher than or comparable to those obtained by sequence alignment and by the methods compared in this paper.


Evaluation of antidepressant activity of vanillin in mice.
The main objective of this study was to evaluate antidepressant activity of vanillin in mice models of depression. Animals were divided into five groups, consisting six mice in each group. Out of these, three groups served as control (distilled water, imipramine,and fluoxetine) and the remaining two groups received test drug in two different doses (10 mg/kg and 100 mg/kg). All the drugs were administered orally one hour before the test procedure for acute study and daily for ten days for chronic study. Mice were subjected to forced swim (FST) and tail suspension tests (TST). Both the doses of vanillin reduced the immobility duration in TST as well as in FST. In TST, there was a statistically significant decrease in the immobility in all the groups when compared to the control (distilled water) group. But the reduction of immobility in FST did not show statistically significant reduction in immobility in the groups treated with vanillin when compared with control. In the chronic study group that received vanillin at a dose of 100 mg/kg, the immobility reduction was significantly lower when compared to the group receiving fluoxetine. Vanillin at the dosage of 100 mg/kg has demonstrated antidepressant activity in mice, which is comparable with fluoxetine.


Association of blood cotinine level with cognitive and physical performance in non-smoking older adults.
Background Studies show that active smoking may be associated with cognitive decline. However, the consequence of secondhand smoke on cognitive and physical performance remains unclear. The purpose of this study was to assess the association of secondhand smoke with cognitive performance and physical function using a population-based sample. Data of 2,542 non-smoking participants from the 1999-2002 National Health and Nutrition Examination Survey were analyzed. Secondhand smoke exposure level was estimated using blood cotinine concentrations. Cognitive performance was assessed with the Digit Symbol Substitution Test and self-reported confusion/memory problems. Physical performance was analyzed using visual gait speed (m/s) and self-reported physical function. Multivariate linear and logistic regression models were used to assess the association. In never smokers, cognitive performance score decreased by 2.03 points (95% confidence interval (CI): -3.00, -1.05) per one unit increase in log-transformed blood cotinine level. After adjusting for potential confounders, including diabetes, hypertension, body mass index, alcohol, and blood lead level, change in cognitive performance score was still statistically significant (-1.17 95% CI: -2.32, -0.02). Similar trends were observed in former smokers. Gait speed decreased by 0.02m/s for one unit increase in log-transformed blood cotinine level. This was evident in both never and former smokers. The relationship remained significant after adjusting for potential confounders in former smokers. Our study suggests that secondhand smoke may contribute to cognitive decline in never and former smokers. Considering the cross-sectional design and the limitations of this study, the relationship warrants further assessment.


Influence of HIV and other risk factors on tuberculosis.
Tuberculosis (TB) notification in South Africa has increased six-fold over the past two decades, mainly because of the HIV epidemic. To describe the sociodemographic and outcome characteristics of TB patients, and to identify risk factors associated with TB treatment outcomes stratified by HIV status. A cross-sectional study was used to analyse data from the Cape Town Metro East geographical service area (GSA) electronic TB register (ETR.Net), including adult patients aged ≥15 years who initiated TB treatment between 1 July 2011 and 30 June 2012. TB case notification in the GSA was 922 per 100 000 population. Of the 12 672 TB patients registered, 50.5% were co-infected with HIV. The death rate in co-infected patients was 5.4% v. 2.8% in HIV-negative patients, the rate of treatment success 66.6% v. 73.5%, and the rate of unfavourable treatment outcome 28.1% v. 23.7%. The Khayelitsha subdistrict had the highest proportion of TB burden (37.0%) and co-infection (47.6%). Fourteen percent of patients had extrapulmonary TB, 65.9% of whom were co-infected with HIV. In the multivariate analysis, HIV infection (relative risk (RR) 1.2), retreatment (RR 1.4) and sputum smear microscopy not done (RR 1.4) were significantly associated with unfavourable treatment outcome. The Eastern (RR 0.9) and Northern (RR 0.7) subdistricts were less likely to have unfavourable outcomes compared with Khayelitsha. In the stratified analysis, retreatment and smear not done were significant risk factors for an unfavourable treatment outcome in both co-infected and HIV-negative patients. The burdens of both TB and co-infection were high in this community, although HIV prevalence varied. Mortality was higher and treatment completion lower in co-infected patients than in those who were HIV-negative. Co-infection, previous TB treatment and smear not done were significant risk factors for an unfavourable outcome in all patients.


Dye Sensitized Solar Cells for Economically Viable Photovoltaic Systems.
TiO2 nanoparticle-based dye sensitized solar cells (DSSCs) have attracted a significant level of scientific and technological interest for their potential as economically viable photovoltaic devices. While DSSCs have multiple benefits such as material abundance, a short energy payback period, constant power output, and compatibility with flexible applications, there are still several challenges that hold back large scale commercialization. Critical factors determining the future of DSSCs involve energy conversion efficiency, long-term stability, and production cost. Continuous advancement of their long-term stability suggests that state-of-the-art DSSCs will operate for over 20 years without a significant decrease in performance. Nevertheless, key questions remain in regards to energy conversion efficiency improvements and material cost reduction. In this Perspective, the present state of the field and the ongoing efforts to address the requirements of DSSCs are summarized with views on the future of DSSCs.


Differential inhibition of Arabidopsis superoxide dismutases by peroxynitrite-mediated tyrosine nitration.
Despite the importance of superoxide dismutases (SODs) in the plant antioxidant defence system little is known about their regulation by post-translational modifications. Here, we investigated the in vitro effects of nitric oxide derivatives on the seven SOD isoforms of Arabidopsis thaliana. S-nitrosoglutathione, which causes S-nitrosylation of cysteine residues, did not influence SOD activities. By contrast, peroxynitrite inhibited the mitochondrial manganese SOD1 (MSD1), peroxisomal copper/zinc SOD3 (CSD3), and chloroplastic iron SOD3 (FSD3), but no other SODs. MSD1 was inhibited by up to 90% but CSD3 and FSD3 only by a maximum of 30%. Down-regulation of these SOD isoforms correlated with tyrosine (Tyr) nitration and both could be prevented by the peroxynitrite scavenger urate. Site-directed mutagenesis revealed that-amongst the 10 Tyr residues present in MSD1-Tyr63 was the main target responsible for nitration and inactivation of the enzyme. Tyr63 is located nearby the active centre at a distance of only 5.26 Å indicating that nitration could affect accessibility of the substrate binding pocket. The corresponding Tyr34 of human manganese SOD is also nitrated, suggesting that this might be an evolutionarily conserved mechanism for regulation of manganese SODs.


Risk of invasive breast cancer and ductal carcinoma in situ in women with atypical papillary lesions of the breast.
Benign papillary lesions of the breast include papilloma and papillomatosis. A retrospective analysis of patients with a papillary breast lesion diagnosed between October 1992 and December 2009 was performed. Patients were excluded if they had a previous or concurrent diagnosis of invasive or in situ cancer or less than 6 months of follow-up. The Kaplan-Meier method was used to determine the risk of developing subsequent malignancy. The log rank test was used to compare groups of patients. Median follow-up for the 167 patients included in the study was 4.6 years. Fifty-one patients had a papillary lesion with atypia and 116 patients had a papillary lesion without atypia. Patients with a papillary lesion with atypia were more likely to develop invasive or in situ breast cancer with a 5 year risk of 13.0% versus 4.6% in patients with no atypia (p = 0.03).


Exploring the use of the 'Adapted Miracle Question' in the assessment of low back pain.
Low back pain is a complex condition, often recurring or chronic, which has proved difficult to characterise. To explore an alternative approach to assessing low back pain, an expert panel adapted the 'Miracle Question' from Solution-Focused Brief Therapy. This asks about a forward scenario of waking without the problems that the client had presented with. The question was adapted to: What would you do if you did not have back pain? To explore the use of the Adapted Miracle Question (AMQ) within an interview study of patients with low back pain. The AMQ was used in an interview study of 34 participants recruited from the UK Back Skills Training (BeST) trial, assessing the effectiveness of a cognitive behavioural approach intervention for the management of low back pain. Responses to the AMQ were analysed thematically and then case by case. Interviewees talked about details of their activities and ability to function that would be different, and about change to their quality of life. Some talked about work. Five interviewees said that it would make no difference to them. When considered overall, the responses could be categorised as: no change; some change in activity/function; a return to their pre-back pain state; and life would be transformed. The AMQ was straightforward to ask and prompted a breadth of responses which may be useful in tailoring treatment. This question warrants further evaluation in the clinical setting.


Performance and preference for ACE stimulation rates obtained with nucleus RP 8 and freedom system.
Cochlear recently released the Nucleus Freedom System which has been based on the Nucleus Research Platform 8. Both systems make use of the same implant, the CI24RE, which includes expanded total stimulation rates up to 32 kHz. In this study the performance of the ACE strategy at 500, 1200 and 3500 pps/channel was investigated using an ABC-CBA design. At the end of each period speech tests were performed. In the CBA phase the patients completed a comparative questionnaire to determine the subjective rate preference. Preliminary results in 13 recipients indicate no differences in for the ACE strategy at rates ranging from 500 pps to 3500 pps/channel.


Concerning the mechanism of iodine(iii)-mediated oxidative dearomatization of phenols.
The iodine(iii)-mediated oxidative dearomatization of phenols has proven to be a general method for the preparation of cyclohexadienones. While this is a widely used reaction, there is still a great deal of uncertainty regarding the mechanistic pathway followed by these reactions. In part, this is due to the highly unstable nature of many of the key intermediates, which makes their direct detection extremely difficult. In order to gain some insight into these mechanistic questions, DFT calculations [M06-2X/6-31+G(d) for C, H, and O and LANL2DZdp for iodine] were used to evaluate the two most commonly proposed reaction mechanisms. These results show that unimolecular fragmentation of an oxygen-bound intermediate to give a phenoxenium ion (TS1) is preferred over direct addition of the nucleophile to the aromatic ring of the activated phenol (TS3). In addition, results are presented that suggest protonation and/or hydrogen bonding may play a key role in lowering the energy of the unimolecular fragmentation pathway.


Community-acquired infections and their association with myeloid malignancies.
Antigenic stimulation is a proposed aetiologic mechanism for many haematological malignancies. Limited evidence suggests that community-acquired infections may increase the risk of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). However, associations with other myeloid malignancies including chronic myeloid leukaemia (CML) and myeloproliferative neoplasms (MPNs) are unknown. Using the Surveillance, Epidemiology and End Result (SEER)-Medicare database, fourteen community-acquired infections were compared between myeloid malignancy patients [AML (n=8489), CML (n=3626) diagnosed 1992-2005; MDS (n=3072) and MPNs (n=2001) diagnosed 2001-2005; and controls (200,000 for AML/CML and 97,681 for MDS/MPN]. Odds ratios (ORs) and 95% confidence intervals were adjusted for gender, age and year of selection excluding infections diagnosed in the 13-month period prior to selection to reduce reverse causality. Risk of AML and MDS respectively, were significantly associated with respiratory tract infections, bronchitis (ORs 1.20 [95% CI: 1.14-1.26], 1.25 [95% CI: 1.16-1.36]), influenza (ORs 1.16 [95% CI: 1.07-1.25], 1.29 [95% CI: 1.16-1.44]), pharyngitis (ORs 1.13 [95% CI: 1.06-1.21], 1.22 [95% CI: 1.11-1.35]), pneumonia (ORs 1.28 [95% CI: 1.21-1.36], 1.52 [95% CI: 1.40-1.66]), sinusitis (ORs 1.23 [95% CI: 1.16-1.30], 1.25 [95% CI: 1.15-1.36]) as was cystitis (ORs 1.13 [95% CI: 1.07-1.18], 1.26 [95% CI: 1.17-1.36]). Cellulitis (OR 1.51 [95% CI: 1.39-1.64]), herpes zoster (OR 1.31 [95% CI: 1.14-1.50]) and gastroenteritis (OR 1.38 [95% CI: 1.17-1.64]) were more common in MDS patients than controls. For CML, associations were limited to bronchitis (OR 1.21 [95% CI: 1.12-1.31]), pneumonia (OR 1.49 [95% CI: 1.37-1.62]), sinusitis (OR 1.19 [95% CI: 1.09-1.29]) and cellulitis (OR 1.43 [95% CI: 1.32-1.55]) following Bonferroni correction. Only cellulitis (OR 1.34 [95% CI: 1.21-1.49]) remained significant in MPN patients. Many infections remained elevated when more than 6 years of preceding claims data were excluded. Common community-acquired infections may be important in the malignant transformation of the myeloid lineage. Differences in the aetiology of classic MPNs and other myeloid malignancies require further exploration.


Separating the influences of prereading skills on early word and nonword reading.
The essential first step for a beginning reader is to learn to match printed forms to phonological representations. For a new word, this is an effortful process where each grapheme must be translated individually (serial decoding). The role of phonological awareness in developing a decoding strategy is well known. We examined whether beginning readers recruit different skills depending on the nature of the words being read (familiar words vs. nonwords). Print knowledge, phoneme and rhyme awareness, rapid automatized naming (RAN), phonological short-term memory (STM), nonverbal reasoning, vocabulary, auditory skills, and visual attention were measured in 392 prereaders 4 and 5 years of age. Word and nonword reading were measured 9 months later. We used structural equation modeling to examine the skills-reading relationship and modeled correlations between our two reading outcomes and among all prereading skills. We found that a broad range of skills were associated with reading outcomes: early print knowledge, phonological STM, phoneme awareness and RAN. Whereas all of these skills were directly predictive of nonword reading, early print knowledge was the only direct predictor of word reading. Our findings suggest that beginning readers draw most heavily on their existing print knowledge to read familiar words.


Antibiotic-induced D-lactic acidosis.
To describe a case of oral antibiotic-induced D-lactic acidosis in a patient with enteric overgrowth of Lactobacillus acidophilus. Single case study. University-affiliated community hospital. Oral carbohydrate challenge test with 4000 kcal/d. A patient had several episodes of D-lactic acidosis after receiving oral antibiotics. Stool cultures yielded Lactobacillus acidophilus resistant to the implicated agents. Provocative challenge with dietary carbohydrate alone, in the absence of antibiotics, failed to reproduce the syndrome. Oral antibiotics may induce D-lactic acidosis in patients with the short-bowel syndrome by promoting the overgrowth of resistant D-lactate-producing organisms. Interactions between carbohydrate intake and antibiotic use are likely determinants in the development of this syndrome. Periodic use of stool cultures with antimicrobial susceptibility testing may assist in the management of these patients by optimizing the selection of antimicrobial agents.


Strain Identity of the Ectomycorrhizal Fungus Laccaria bicolor Is More Important than Richness in Regulating Plant and Fungal Performance under Nutrient Rich Conditions.
Effects of biodiversity on productivity are more likely to be expressed when there is greater potential for niche complementarity. In soil, chemically complex pools of nutrient resources should provide more opportunities for niche complementarity than chemically simple pools. Ectomycorrhizal (ECM) fungal genotypes can exhibit substantial variation in nutrient acquisition traits and are key components of soil biodiversity. Here, we tested the hypothesis that increasing the chemical complexity and forms of soil nutrients would enhance the effects of intraspecific ECM diversity on host plant and fungal productivity. In pure culture, we found substantial variation in growth of strains of the ECM fungus Laccaria bicolor on a range of inorganic and organic forms of nutrients. Subsequent experiments examined the effects of intraspecific identity and richness using Scots pine (Pinus sylvestris) seedlings colonized with different strains of L. bicolor growing on substrates supplemented with either inorganic or organic forms of nitrogen and phosphorus. Intraspecific identity effects on plant productivity were only found under the inorganic nutrient amendment, whereas intraspecific identity affected fungal productivity to a similar extent under both nutrient treatments. Overall, there were no significant effects of intraspecific richness on plant and fungal productivity. Our findings suggest soil nutrient composition does not interact strongly with ECM intraspecific richness, at least under experimental conditions where mineral nutrients were not limiting. Under these conditions, intraspecific identity of ECM fungi becomes more important than richness in modulating plant and fungal performance.


The selective inhibition of chenodeoxycholate synthesis by cholate metabolites in man.
1. Seven normal volunteers took 0-28--0-42 mmol (100--150 mg) of deoxycholate by mouth. This resulted in a reduced proportion of chenodeoxycholate in bile and an increased proportion of deoxycholate. Cholate was unchanged. 2. Cholate and chenodeoxycholate pools and rats of synthesis were determined in four of the subjects by simultaneously labelling each pool with 14C-labelled bile acids. The chenodeoxycholate pool and rate of synthesis decreased after deoxycholate administration. Cholate synthesis and pool size did not change appreciably. 3. The proportion of deoxycholate in bile samples of sixty-two subjects with intact enterohepatic circulation was found to be inversely related to the proportion of chenodeoxycholate in bile, but not to the cholate. 4. It is suggested that inhibition of chenodeoxycholate synthesis by deoxycholate, the principal bacterial product of cholate, regulates the size of the chenodeoxycholate pool independently of the total amount of bile salt.


"Time with Babe": Seeing Fetal Remains after Pregnancy Termination for Impairment.
Some North American hospitals now offer parents the opportunity to see, hold, and photograph fetal remains after pregnancy loss. I explore the social, material, and interpretive strategies mobilized to create this fetal visibility after second trimester-induced abortion for fetal anomaly. My analysis examines both the discursive framing of fetal remains in practice guidelines on pregnancy loss and the responses of a group of Canadian women to being offered "time with babe." I show that while guidelines tend to frame contact with fetal remains as a response to women's desires to see their baby and to feel like mothers, women's experiences of this contact were shaped by more diverse wishes and concerns as well as by specific abortion practices and practitioner comments and actions.


[Goldenrod--a classical exponent in the urological phytotherapy].
Herbal remedies based on goldenrod (Solidago virgaurea L.) have been well-tried for centuries in the treatment of urinary tract diseases. Investigations in molecular pharmacology could show new mechanisms responsible for the biological effect of natural product from goldenrod extracts. The use of such herbal preparations with a rather complex action spectrum (anti-inflammatory, antimicrobial, diuretic, antispasmodic, analgesic) is especially recommended for treatment of infections and inflammations, to prevent formation of kidney stones and to help remove urinary gravel. This therapy is safe at a reasonable price and does not show drug-related side-effects.


Moderate and heavy metabolic stress interval training improve arterial stiffness and heart rate dynamics in humans.
Traditional continuous aerobic exercise training attenuates age-related increases of arterial stiffness, however, training studies have not determined whether metabolic stress impacts these favourable effects. Twenty untrained healthy participants (n = 11 heavy metabolic stress interval training, n = 9 moderate metabolic stress interval training) completed 6 weeks of moderate or heavy intensity interval training matched for total work and exercise duration. Carotid artery stiffness, blood pressure contour analysis, and linear and non-linear heart rate variability were assessed before and following training. Overall, carotid arterial stiffness was reduced (p < 0.01), but metabolic stress-specific alterations were not apparent. There was a trend for increased absolute high-frequency (HF) power (p = 0.10) whereas both absolute low-frequency (LF) power (p = 0.05) and overall power (p = 0.02) were increased to a similar degree following both training programmes. Non-linear heart rate dynamics such as detrended fluctuation analysis [Formula: see text] also improved (p > 0.05). This study demonstrates the effectiveness of interval training at improving arterial stiffness and autonomic function, however, the metabolic stress was not a mediator of this effect. In addition, these changes were also independent of improvements in aerobic capacity, which were only induced by training that involved a high metabolic stress.


Mechanisms for the reduction of caffeine consumption: What, how and why.
Anecdotal evidence suggests consumers of caffeine self-administer strategies to reduce consumption, but little is known of what these strategies are or how they are implemented. This study aimed to understand the lived experience of reducing caffeine consumption including specific techniques (what) and implementation strategies (how), harm and withdrawal symptoms (why). We developed a classification system through an inductive and deductive approach and applied it to a large dataset derived from online sources. A total of 112 internet sources were identified, containing 2,682 different strategies. The classification system identified 22 categories of Behaviour Change Techniques (BCT): 10 categories were directly aligned with a BCT, one was split into two categories (substance and behavioural substitution), six represented a cluster of BCT's (e.g., withdrawal management and maintaining momentum) and four appeared to uniquely represent a consumer perspective (e.g., realisation of a problem). The most common techniques were substance substitution, seek knowledge and information, avoidance of caffeine and identify prompts for change. The most frequently perceived benefit was the stimulating effects of caffeine and a feeling of mental alertness. The most frequently cited harms were sleep problems including insomnia and concerns about dependence (or addiction) to caffeine. We found 16 categories of withdrawal symptoms. The most frequently endorsed symptom was headaches, followed by fatigue, exhaustion and low energy. Consumers use a wide range of techniques when attempting to reduce caffeine consumption. Treatment approaches are focused on fading, but the current study found consumers most frequently focus on substance and behavioural substitution.


Improved accuracy of low affinity protein-ligand equilibrium dissociation constants directly determined by electrospray ionization mass spectrometry.
There is continued interest in the determination by ESI-MS of equilibrium dissociation constants (K(D)) that accurately reflect the affinity of a protein-ligand complex in solution. Issues in the measurement of K(D) are compounded in the case of low affinity complexes. Here we present a K(D) measurement method and corresponding mathematical model dealing with both gas-phase dissociation (GPD) and aggregation. To this end, a rational mathematical correction of GPD (f(sat)) is combined with the development of an experimental protocol to deal with gas-phase aggregation. A guide to apply the method to noncovalent protein-ligand systems according to their kinetic behavior is provided. The approach is validated by comparing the K(D) values determined by this method with in-solution K(D) literature values. The influence of the type of molecular interactions and instrumental setup on f(sat) is examined as a first step towards a fine dissection of factors affecting GPD. The method can be reliably applied to a wide array of low affinity systems without the need for a reference ligand or protein.


Evolutionary force in confamiliar marine vertebrates of different temperature realms: adaptive trends in zoarcid fish transcriptomes.
Studies of temperature-induced adaptation on the basis of genomic sequence data were mainly done in extremophiles. Although the general hypothesis of an increased molecular flexibility in the cold is widely accepted, the results of thermal adaptation are still difficult to detect at proteomic down to the genomic sequence level. Approaches towards a more detailed picture emerge with the advent of new sequencing technologies. Only small changes in primary protein structure have been shown to modify kinetic and thermal properties of enzymes, but likewise for interspecies comparisons a high genetic identity is still essential to specify common principles. The present study uses comprehensive transcriptomic sequence information to uncover general patterns of thermal adaptation on the RNA as well as protein primary structure. By comparing orthologous sequences of two closely related zoarcid fish inhabiting different latitudinal zones (Antarctica: Pachycara brachycephalum, temperate zone: Zoarces viviparus) we were able to detect significant differences in the codon usage. In the cold-adapted species a lower GC content in the wobble position prevailed for preserved amino acids. We were able to estimate 40-60% coverage of the functions represented within the two compared zoarcid cDNA-libraries on the basis of a reference genome of the phylogenetically closely related fish Gasterosteus aculeatus. A distinct pattern of amino acid substitutions could be identified for the non-synonymous codon exchanges, with a remarkable surplus of serine and reduction of glutamic acid and asparagine for the Antarctic species. Based on the differences between orthologous sequences from confamiliar species, distinguished mainly by the temperature regimes of their habitats, we hypothesize that temperature leaves a signature on the composition of biological macromolecules (RNA, proteins) with implications for the transcription and translation level. As the observed pattern of amino acid substitutions only partly support the flexibility hypothesis further evolutionary forces may be effective at the global transcriptome level.


In situ metabolism in halite endolithic microbial communities of the hyperarid Atacama Desert.
The Atacama Desert of northern Chile is one of the driest regions on Earth, with areas that exclude plants and where soils have extremely low microbial biomass. However, in the driest parts of the desert there are microorganisms that colonize the interior of halite nodules in fossil continental evaporites, where they are sustained by condensation of atmospheric water triggered by the salt substrate. Using a combination of in situ observations of variable chlorophyll fluorescence and controlled laboratory experiments, we show that this endolithic community is capable of carbon fixation both through oxygenic photosynthesis and potentially ammonia oxidation. We also present evidence that photosynthetic activity is finely tuned to moisture availability and solar insolation and can be sustained for days, and perhaps longer, after a wetting event. This is the first demonstration of in situ active metabolism in the hyperarid core of the Atacama Desert, and it provides the basis for proposing a self-contained, endolithic community that relies exclusively on non-rainfall sources of water. Our results contribute to an increasing body of evidence that even in hyperarid environments active metabolism, adaptation, and growth can occur in highly specialized microhabitats.


Systematic estimation of insertion dates of endogenous bornavirus-like elements in vesper bats.
Endogenous bornavirus-like elements (EBLs) are sequences derived from bornaviruses (the family Bornaviridae) that are integrated into animal genomes. They are formed through germline insertions of segments of bornaviral transcripts into animal genomes. Because EBLs are molecular fossils of bornaviruses, they serve as precious sources of information to understand the evolutionary history of bornaviruses. Previous studies revealed the presence of many EBLs in bat genomes, especially in vesper bats, and suggested the long-term association between bats and bornaviruses. However, insertion dates of EBLs are largely unknown because of the limitations of available bat genome sequences in the public database. In this study, through a combination of database searches, PCR, and sequencing approaches, we systematically determined the gene orthologies of 13 lineages of EBLs in bats of the genus Myotis and Eptesicus and family Vespertilionidae. Using the above data, we estimated their insertion dates: the EBLs in vesper bats were inserted approximately 14.2 to 53 million years ago. These results suggest that vesper bats have been repeatedly infected by bornaviruses at different points in time during evolution. This study provides novel insights into the evolutionary history of bornaviruses and demonstrates the robustness of combining database searches, PCR, and sequencing approaches to estimate insertion dates of bornaviruses.


Disturbance and strategies for reactivation of the circadian rhythm system in aging and Alzheimer's disease.
Circadian rhythm disturbances, such as sleep disorders, are frequently seen in aging and are even more pronounced in Alzheimer's disease (AD). Alterations in the biological clock, the suprachiasmatic nucleus (SCN), and the pineal gland during aging and AD are considered to be the biological basis for these circadian rhythm disturbances. Recently, our group found that pineal melatonin secretion and pineal clock gene oscillation were disrupted in AD patients, and surprisingly even in non-demented controls with the earliest signs of AD neuropathology (neuropathological Braak stages I-II), in contrast to non-demented controls without AD neuropathology. Furthermore, a functional disruption of the SCN was observed from the earliest AD stages onwards, as shown by decreased vasopressin mRNA, a clock-controlled major output of the SCN. The observed functional disconnection between the SCN and the pineal from the earliest AD stage onwards seems to account for the pineal clock gene and melatonin changes and underlies circadian rhythm disturbances in AD. This paper further discusses potential therapeutic strategies for reactivation of the circadian timing system, including melatonin and bright light therapy. As the presence of melatonin MT1 receptor in the SCN is extremely decreased in late AD patients, supplementary melatonin in the late AD stages may not lead to clear effects on circadian rhythm disorders.


Drug administration frequency and provider office visit patterns for oncology patients during treatment with erythropoietic agents: an analysis of four observational studies.
Several drug administration regimens of epoetin alfa (EPO) and darbepoetin alfa (DARB) are used for the management of anemia in cancer patients in the clinical practice setting. The purpose of the present analysis was to assess whether drug administration regimens were associated with differences in the number of provider office visits and hemoglobin assessments during treatment with these agents. Data from 4 observational studies that examined treatment patterns of EPO and DARE and health care resource utilization were analyzed. These studies, selected based on the availability of office visit and/or hemoglobin determination data during the course of treatment, included a retrospective chart review, 2 retrospective claims analyses, and an ongoing prospective patient registry. The treatment patterns and oncology-related provider visits and/or the frequency of hemoglobin evaluations among the studies were reported. Data from 15,845 cancer patients were included in the analysis. The patient demographic and baseline characteristics were similar across all 4 studies; patients were predominantly women (62%-71%) with a mean age range of 56 to 63 years. Mean treatment duration ranged from 7.1 to 8.4 weeks without significant differences between EPO and DARE in any study. Weekly and extended (at least every 2 weeks [> or =Q2W]) drug administration frequencies were observed in both treatment groups. The most frequent drug administration schedule for EPO was once weekly (53%-75% of patients), and for DARE Q2W (67%-73%). Despite the difference in erythropoietic agent administration frequency, no significant differences were observed between EPO and DARB for either the number of oncology-related provider visits or the number of hemoglobin assessments. The frequency of oncology-related provider visits and hemoglobin assessments appears to be independent of the EPO and DARB administration frequency. These findings might provide useful information for health care providers and oncology patients in understanding patterns of care during treatment with erythropoietic agents.


Obesity: a move from traditional to more patient-oriented management.
Family physicians have been encouraged to be aggressive in their treatment of obesity in their overweight patients. This article examines our traditional management of obesity and presents a management approach that is relatively safe, healthy, and patient-oriented. A review of the literature on obesity and its treatment was performed by searching MEDLINE, PsychINFO, ERIC, and SOCA data bases from 1980 to 1993. Additional references were accessed by cross-referencing the bibliographies of the articles obtained through this search. Both physicians and society in general tend to be biased against obese individuals, and this bias has negative consequences in that it reinforces patients' negative stereotypes about their fatness and could contribute to their avoidance of physicians. To circumvent this tendency, physicians should make a conscious effort to treat their obese patients with understanding and respect and to offer treatment that optimizes their risk-benefit profile. Regardless of weight, all patients should be asked about their diet and exercise history, and a brief mental status evaluation should be performed to screen for eating disorders and other psychosocial disorders. In addition, all patients should be encouraged to follow a healthy lifestyle, which includes regular, moderate exercise and a balanced, low-fat diet. Repeated dieting should be avoided, because it can produce more harm than benefit by contributing to binge eating, loss of self-esteem, and increased risk of sudden death and cardiovascular disease. Thus, only obese patients who have never attempted comprehensive weight reduction programs should be encouraged to try such a program. Patients who have severe obesity that interferes with their lives or who have moderate obesity and a comorbid condition can be offered a gastroplasty or gastric bypass procedure, coupled with an explanation and discussion of the success and failure rates involved. Regardless of whether patients are able to lose weight, the family physician can still provide long-term support and care and encourage a healthy lifestyle in these patients.


Visual Predictions Operate on Different Timescales.
Humans live in a volatile environment, subject to changes occurring at different timescales. The ability to adjust internal predictions accordingly is critical for perception and action. We studied this ability with two EEG experiments in which participants were presented with sequences of four Gabor patches, simulating a rotation, and instructed to respond to the last stimulus (target) to indicate whether or not it continued the direction of the first three stimuli. Each experiment included a short-term learning phase in which the probabilities of these two options were very different (p = .2 vs. p = .8, Rules A and B, respectively), followed by a neutral test phase in which both probabilities were equal. In addition, in one of the experiments, prior to the short-term phase, participants performed a much longer long-term learning phase where the relative probabilities of the rules predicting targets were opposite to those of the short-term phase. Analyses of the RTs and P3 amplitudes showed that, in the neutral test phase, participants initially predicted targets according to the probabilities learned in the short-term phase. However, whereas participants not pre-exposed to the long-term learning phase gradually adjusted their predictions to the neutral probabilities, for those who performed the long-term phase, the short-term associations were spontaneously replaced by those learned in that phase. This indicates that the long-term associations remained intact whereas the short-term associations were learned, transiently used, and abandoned when the context changed. The spontaneous recovery suggests independent storage and control of long-term and short-term associations.


The effects of tetanus toxin-induced limbic epilepsy on the exploratory response to novelty in the rat.
To investigate the exploratory response to novelty in rats that have recovered from experimental limbic epilepsy. Epilepsy was induced in 12 male rats by injecting a minute amount of tetanus toxin into the ventral hippocampus (and buffer vehicle was injected into 12 controls). Eight weeks after the injection, when the animals appeared behaviourally normal (and previous work would indicate that their electroencephalograms also would have returned to normal), they were tested on the playground maze. In this, their exploratory response to a novel object introduced in the context of seven familiar objects is measured. Simultaneously, their locomotion and investigation of familiar objects is measured. Whereas the control animals showed a significant response to the novel object on both test days, in the toxin-injected rats the novelty response was not present. There was no difference between the groups on the locomotion measure, but the toxin rats explored the familiar as well as the novel objects less. The exploratory response to a novel object was abolished in the previously epileptic rats.


In vitro and in vivo modulation of testosterone mediated alterations in apoptosis related proteins by [6]-gingerol.
Ginger (Zingiber officinale, Zingiberaceae) has been widely used as a dietary spice, and as a traditional oriental medicine. The rhizome of ginger contains pungent vanillyl ketones, including [6]-gingerol and [6]-paradol, and have been credited with therapeutic and preventive health benefits, including anti-cancer activity. Prostate cancer is an attractive target for chemoprevention because of its ubiquity, treatment-related morbidity, long latency between premalignant lesions and clinically evident cancer, and defined molecular pathogenesis. Here we are reporting the modulatory effects of [6]-gingerol on testosterone-induced alterations on apoptosis related proteins in both in vitro, androgen sensitive LNCaP cells and in vivo, ventral prostate of Swiss albino mice. [6]-gingerol treatment resulted apoptosis in LNCaP cells, as indicated by depolarization of mitochondrial membrane potential, increase in sub G1 cell population by flow cytometry and the appearance of DNA laddering pattern in agarose gel electrophoresis. Results of western blot analysis showed that [6]-gingerol upregulated the testosterone depleted levels of p53 in mouse prostate and upregulated its downstream regulator Bax and further activated Caspase-9 and Caspase-3 in both LNCaP cells and in mouse prostate. We also found downregulation of testosterone induced antiapoptotic proteins, Bcl-2 and Survivin expression by [6]-gingerol in both LNCaP cells and in mouse ventral prostate. Thus, [6]-gingerol shows its protective effects in both in vivo and in vitro prostate cancer models by modulation of proteins involved in apoptosis pathway.


A multimodal micro-optrode combining field and single unit recording, multispectral detection and photolabeling capabilities.
Microelectrodes have been very instrumental and minimally invasive for in vivo functional studies from deep brain structures. However they are limited in the amount of information they provide. Here, we describe a, aluminum-coated, fibre optic-based glass microprobe with multiple electrical and optical detection capabilities while retaining tip dimensions that enable single cell measurements (diameter ≤10 µm). The probe enables optical separation from individual cells in transgenic mice expressing multiple fluorescent proteins in distinct populations of neurons within the same deep brain nucleus. It also enables color conversion of photoswitchable fluorescent proteins, which can be used for post-hoc identification of the recorded cells. While metal coating did not significantly improve the optical separation capabilities of the microprobe, the combination of metal on the outside of the probe and of a hollow core within the fiber yields a microelectrode enabling simultaneous single unit and population field potential recordings. The extended range of functionalities provided by the same microprobe thus opens several avenues for multidimensional structural and functional interrogation of single cells and their surrounding deep within the intact nervous system.


Cannabinoids: influence on neurotransmitter uptake in rat brain synaptosomes.
We have examined the effect of Delta1-tetrahydrocannabinol (delat1-THC) and 12 of its derivatives on the uptake of 3H-labeled norepinephrine (NE), dopamine (DA), serotonin (5-HT) gamma-aminobutyric acid (GABA) into synaptosomes in homogenates of various regions of rat brain. Delta1-THC inhibits the accumulation of NE and 5-HT into hypothalamic preparations and DA into the corpus striatum with Ki values of about 12 to 25 muM while GABA uptake into cerebral cortical preparations is inhibited less (Ki = 140 muM). The affinities of delta6-THC, 7-hydroxy-delta1-THC, 7-hydroxy-delta6-THC and cannabidiol for 5-HT, NE and GABA transports are similar to values for delta1-THC, while cannabigerol, cannabinol and delta6-THC-7-oic acid have substantially less affinity. Thus, hydroxylation of C-7 in delta6-THC does not alter inhibitory potency, but its oxidation to an acid and aromatization of ring A greatly reduce affinity. The hydroxyl at C-3(1) of ring C is critical for inhibition of NE, 5-HT and GABA uptake, since its acetylation or methylation abolishes activity. Inhibition of NE, DA, 5-HT and GABA uptake by all cannabinoids examined is noncompetitive. Only about 1% of delta1-THC and delta6-THC and 5% of cannabidiol are fully soluble under our experimental conditions.


Effects of intracoronary melatonin on ischemia-reperfusion injury in ST-elevation myocardial infarction.
Acute coronary occlusion is effectively treated by primary percutaneous coronary intervention. However, myocardial ischemia-reperfusion injury is at the moment an unavoidable consequence of the procedure. Oxidative stress is central in the development of ischemia-reperfusion injury. Melatonin, an endogenous hormone, acts through antioxidant mechanisms and could potentially minimize the myocardial injury. The aim of the experimental study was to examine the cardioprotective effects of melatonin in a porcine closed-chest reperfused infarction model. A total of 20 landrace pigs were randomized to a dosage of 200 mg (0.4 mg/mL) melatonin or placebo (saline). The intervention was administered intracoronary and intravenous. Infarct size, area at risk and microvascular obstruction were determined ex vivo by cardiovascular magnetic resonance imaging. Myocardial salvage index was calculated. The plasma levels of high-sensitive troponin T were assessed repeatedly. The experimenters were blinded with regard to treatment regimen. Melatonin did not significantly increase myocardial salvage index compared with placebo [melatonin 21.8% (16.1; 24.8) vs. placebo 20.2% (16.9; 27.0), p = 1.00]. The extent of microvascular obstruction was similar between the groups [melatonin 3.8% (2.7; 7.1) vs. placebo 3.7% (1.3; 7.7), p = 0.96]. The area under the curve for high-sensitive troponin T release was insignificantly reduced by 32% in the melatonin group [AUC melatonin 12,343.9 (6,889.2; 20,147.4) ng h/L vs. AUC placebo 18,285.3 (5,180.4; 23,716.8) ng h/L, p = 0.82]. Combined intracoronary and intravenous treatment with melatonin did not reduce myocardial reperfusion injury. The lack of a positive effect could be due to an ineffective dose of melatonin, a type II error or the timing of administration.


Spontaneous activity of ventral root axons following peripheral nerve injury.
In 18 Sprague-Dawley rats, the left sciatic nerve was divided at the mid-femur level. Seven to 9 days later, microfilament recordings were made from the ipsilateral L-5 ventral root. Spontaneous activity in the ventral root, ranging from 0.1 to 6.1 Hz, was recorded in 12 of the 18 animals. Conduction velocity determinations showed this activity to be in A-beta and A-delta fibers. Recordings in 10 normal L-5 ventral roots from five control rats showed no spontaneous activity. In the rats with sciatic nerve division, the ongoing discharge appeared to originate in the cut end of the nerve since mechanical stimulation of the neuroma produced synchronous ventral root activity. Furthermore, cooling of the neuroma inhibited the spontaneous discharge, whereas with rewarming it returned. Spontaneous ventral root activity was also increased by systemic application of epinephrine. This activity was qualitatively similar to spontaneous activity that has been recorded in dorsal root microfilaments after peripheral nerve injury. The observation of an ongoing discharge in potentially nociceptive ventral root axons subsequent to nerve injury may be relevant to the mechanism of chronic pain of peripheral origin.


Calcium ion concentrations and DNA fragmentation in target cell destruction by murine cloned cytotoxic T lymphocytes.
To investigate the destruction of target cells by murine CTLs, we examined intracellular Ca2+ concentrations ([Ca2+]i) and DNA fragmentation in target cells. Changes in [Ca2+]i were followed by flow cytometry by loading the cells with indo-1, a Ca2+-binding fluorescent dye, and determining the ration of fluorescence intensities at 405 nm (emission maximum for Ca2+-bound dye) over 480 nm (emission maximum for the free dye). Within minutes after interacting with the cytolytic granule fraction that had been isolated from CTLs, [Ca2+]i in target cells was strikingly increased. A pronounced increase in [Ca2+]i was also observed in target cells when they were specifically recognized by intact CTLs. Since ionomycin, a Ca2+ ionophore, caused a similar increase in [Ca2+]i and lysed cells (provided that extracellular Ca2+ was present), it appears that a sustained high level of [Ca2+]i is cytolytic. In contrast with other cells, CTLs, which have been shown to be refractory to granule-mediated lysis and to be poor targets for other CTLs, did not manifest an elevation in [Ca2+]i when they were similarly loaded with indo-1 and treated with isolated granules. The characteristic cleavage of target cell DNA into nucleosome-sized fragments was also induced by isolated granules as well as by valinomycin, a K+ ionophore, but not by ionomycin. The results support the view that lysis of most target cells by cloned CTLs is due primarily to target cell membrane changes that are fundamentally equivalent to the formation of nonspecific ion channels. The resulting large increase in [Ca2+]i is probably responsible for target cell lysis; and changes in intracellular ion concentrations also appear to be responsible for DNA fragmentation, probably by activating endogenous target cell endonucleases.


The multifunctional role of EKLF/KLF1 during erythropoiesis.
The cellular events that lead to terminal erythroid differentiation rely on the controlled interplay of extra- and intracellular regulatory factors. Their downstream effects are highly coordinated and result in the structural/morphologic and metabolic changes that uniquely characterize a maturing red blood cell. Erythroid Krüppel-like factor (EKLF/KLF1) is one of a very small number of intrinsic transcription factors that play a major role in regulating these events. This review covers 3 major aspects of erythropoiesis in which EKLF plays crucial functions: (1) at the megakaryocyte-erythroid progenitor stage, where it is involved in erythroid lineage commitment; (2) during the global expansion of erythroid gene expression in primitive and definitive lineages, where it plays a direct role in globin switching; and (3) during the terminal maturation of red cells, where it helps control exit from the cell cycle. We conclude by describing recent studies of mammalian EKLF/KLF1 mutations that lead to altered red cell phenotypes and disease.


Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia.
The most common human leukemia is B cell chronic lymphocytic leukemia (CLL), a malignancy of mature B cells with a characteristic clinical presentation but a variable clinical course. The rearranged immunoglobulin (Ig) genes of CLL cells may be either germ-line in sequence or somatically mutated. Lack of Ig mutations defined a distinctly worse prognostic group of CLL patients raising the possibility that CLL comprises two distinct diseases. Using genomic-scale gene expression profiling, we show that CLL is characterized by a common gene expression "signature," irrespective of Ig mutational status, suggesting that CLL cases share a common mechanism of transformation and/or cell of origin. Nonetheless, the expression of hundreds of other genes correlated with the Ig mutational status, including many genes that are modulated in expression during mitogenic B cell receptor signaling. These genes were used to build a CLL subtype predictor that may help in the clinical classification of patients with this disease.


Spatial coincidence modulates the Colavita visual dominance effect.
The Colavita visual dominance effect refers to the phenomenon whereby participants presented with auditory, visual, or audiovisual stimuli in a speeded response task sometimes fail to respond to the auditory component of the bimodal targets. We conducted an experiment on the Colavita effect in which the auditory and visual components of the bimodal targets were presented from either the same or different positions (sides) at one of two eccentricities (13 degrees or 26 degrees ). Participants were presented with auditory, visual, and bimodal stimuli to which they had to respond by pressing an auditory response key, a visual response key, or both response keys, respectively. On bimodal trials, participants failed to respond to the auditory stimulus significantly more often than they failed to respond to the visual stimulus, resulting in a significant Colavita visual dominance effect. The Colavita effect was significantly larger when the stimuli were presented from the same position than when they were presented from different positions. These results provide the first empirical evidence that the Colavita effect is modulated by the spatial coincidence of the auditory and visual stimuli.


Maintenance chemotherapy in children with ALL exerts metronomic-like thrombospondin-1 associated anti-endothelial effect.
Maintenance chemotherapy is an important part of the treatment of ALL in children. It relies on the long-term oral administration of daily low-dose mercaptopurin and weekly low-dose methotrexate. Although it has been used in the clinic for decades, its mechanisms of action remain unclear. Here, we investigated different angiogenic and immune biomarkers to gain insights into the mechanisms of action of maintenance therapy in children with ALL. We thus monitored circulating endothelial cells (CEC), endothelial progenitor cells (EPC) and endothelial microparticles (EMP), pro-angiogenic factors (VEGF, VEGFR-1 and Ang-2), anti-angiogenic factor thrombospondin-1 (THBS1) and regulatory T lymphocytes (Treg) in 47 children with ALL during the maintenance phase of their treatment (at treatment initiation and after 6, 12 and 18 months). We observed a statistically significant decrease in EPC and EMP counts throughout the maintenance phase associated with a significant increase in THBS1 levels. No significant change was detected in other angiogenic markers or in Treg numbers.The results presented here indicate that maintenance therapy in children with ALL exerts its antitumor activity at least in part through anti-angiogenic effects, similar to those induced by metronomic chemotherapy. Larger studies are now warranted to validate these findings and determine their clinical implications.


Obstetric complications and age at onset in schizophrenia: an international collaborative meta-analysis of individual patient data.
An excess of obstetric complications in the histories of schizophrenic patients is a well-replicated finding, but less consistent results have been found concerning the relationships between obstetric complications and family history of schizophrenia, age at onset of schizophrenia, and gender. Small sample size limited the power of previous studies that attempted to assess such relationships. The aim of this study was to use data on individual patients from all available studies to examine the links between a history of obstetric complications and family history of schizophrenia, age at onset, and gender. Raw data from 854 schizophrenic patients concerning history of obstetric complications rated according to the Lewis and Murray scale were obtained from 11 different research groups. Weighted average estimates were calculated with the use of regression techniques. A significant association was found between age at onset of schizophrenia and obstetric complications: the earlier the age at onset, the more likely the history of obstetric complications. Subjects with onset of schizophrenia before age 22 were 2.7 times more likely than those with onset at a later age to have had a history of abnormal presentation at birth and 10 times more likely to have had a history of complicated Cesarean birth. No association was found between obstetric complications and family history of schizophrenia or gender. The association between obstetric complications and early age at onset of schizophrenia indicates that the pathophysiology of early-onset schizophrenia involves neurodevelopmental impairment.


A new soft x-ray pulse height analysis array in the HL-2A tokamak.
A new soft x-ray pulse height analysis (PHA) array including nine independent subsystems, on basis of a nonconventional software multichannel analysis system and a silicon drift detector (SDD) linear array consisting of nine high performance SDD detectors, has been developed in the HL-2A tokamak. The use of SDD has greatly improved the measurement accuracy and the spatiotemporal resolutions of the soft x-ray PHA system. Since the ratio of peak to background counts obtained from the SDD PHA system is very high, p/b > or = 3000, the soft x-ray spectra measured by the SDD PHA system can approximatively be regarded as electron velocity distribution. The electron velocity distribution can be well derived in the pure ohmic and auxiliary heating discharges. The performance of the new soft x-ray PHA array and the first experimental results with some discussions are presented.


Preventing the reintroduction of malaria in Mauritius: a programmatic and financial assessment.
Sustaining elimination of malaria in areas with high receptivity and vulnerability will require effective strategies to prevent reestablishment of local transmission, yet there is a dearth of evidence about this phase. Mauritius offers a uniquely informative history, with elimination of local transmission in 1969, re-emergence in 1975, and second elimination in 1998. Towards this end, Mauritius's elimination and prevention of reintroduction (POR) programs were analyzed via a comprehensive review of literature and government documents, supplemented by program observation and interviews with policy makers and program personnel. The impact of the country's most costly intervention, a passenger screening program, was assessed quantitatively using simulation modeling.On average, Mauritius spent $4.43 per capita per year (pcpy) during its second elimination campaign from 1982 to 1988. The country currently spends $2.06 pcpy on its POR program that includes robust surveillance, routine vector control, and prompt and effective treatment and response. Thirty-five percent of POR costs are for a passenger screening program. Modeling suggests that the estimated 14% of imported malaria infections identified by this program reduces the annual risk of indigenous transmission by approximately 2%. Of cases missed by the initial passenger screening program, 49% were estimated to be identified by passive or reactive case detection, leaving an estimated 3.1 unidentified imported infections per 100,000 inhabitants per year.The Mauritius experience indicates that ongoing intervention, strong leadership, and substantial predictable funding are critical to consistently prevent the reestablishment of malaria. Sustained vigilance is critical considering Mauritius's enabling conditions. Although the cost of POR is below that of elimination, annual per capita spending remains at levels that are likely infeasible for countries with lower overall health spending. Countries currently embarking on elimination should quantify and plan for potentially similar POR operations and costs.


The risk of malaria in travelers to India.
Several countries have reported a decline in malaria cases imported by travelers returning from India. We collected data on imported malaria for the period 1992 to 2005 from nine countries. Traveler statistics denominator data were obtained from the Indian Ministry of Tourism. The malaria case numbers declined from 93 cases per 100,000 travelers in 1992 to 19 cases per 100,000 travelers in 2005. The proportion of Plasmodium falciparum decreased steadily throughout the years. The proportion of Plasmodium vivax accounts for more than 80% of all cases of malaria in travelers to India. Deaths due to malaria were rare; only the UK and the United States reported deaths, a total of 16, between 1992 and 2005. The high-risk areas for malaria in India can be clearly identified using endemic malaria data. High-risk states are Chhattisgarh, Orissa, Jharkhand, West Bengal, Goa (mainly P vivax), and the states east of Bangladesh. The decreasing incidence of malaria in travelers to India and the high proportion of P vivax support the current change in guidelines in some European countries advocating the use of the standby emergency self-treatment strategy or bite precautions plus awareness of risk instead of chemoprophylaxis. Otherwise in high-risk states, chemoprophylaxis should still be considered particularly in high-transmission seasons.


A STUDY OF THE PATHOLOGICAL ANATOMY OF THE PANCREAS IN NINETY CASES OF DIABETES MELLITUS.
1. Anatomical lesions of the pancreas occur in more than seven-eighths of all cases of diabetes mellitus. 2. In diabetes associated with lesions of the pancreas, the islands of Langerhans constantly show pathological changes (sclerosis, hyaline degeneration, infiltration with leucocytes and hypertrophy). 3. In some cases of pancreatic diabetes (twelve of ninety cases) the lesion of the pancreas is limited to the islands of Langerhans. 4. In sixteen cases of diabetes associated with hyaline degeneration of the islands of Langerhans the average duration of the disease has been three and a half years; in forty-six cases with sclerosis of these bodies, three years and eleven months. In six cases of diabetes associated with an infiltration of leucocytes about the islands of Langerhans the average duration has been eleven months. 5. Destructive lesions of the islands of Langerhans may be associated with compensatory hypertrophy of other interacinar islands. 6. Peculiar adenoma-like hypertrophy of the islands of Langerhans occurs in a small proportion of cases (seven of ninety) and may be associated with adenomata of the thyroid gland (two cases) and of the pituitary body (one case). 7. Diabetes mellitus occurring in association with haemochromatosis (bronzed diabetes) is referable to pigmentation and destruction of the islands of Langerhans. 8. The pancreas is found to exhibit no pathological changes in twelve per cent. of cases. In approximately one-half of these cases it has been noted that the size of the gland or the number of islands is much less than normal. 9. Fifty per cent. of cases of diabetes mellitus occurring before the age of thirty years are associated with lesions of the pancreas; seventy-five per cent. of all cases of diabetes in which the pancreas is normal occur before the age of thirty years. Ninety-seven per cent. of cases of diabetes occurring after the age of thirty years are associated with lesions of the pancreas; and eighty-six per cent. occur in association with chronic interacinar pancreatitis accompanying arteriosclerosis. 10. Interacinar pancreatitis which occurs in seventy-three per cent. of all cases of diabetes is almost constantly associated with arteriosclerosis: gangrene of the extremities, which occurs with one-fourth of all cases of interacinar pancreatitis, is doubtless referable to the same cause. 11. Chronic interlobular pancreatitis, when associated with diabetes, is accompanied by sclerosis or hyaline degeneration of the islands of Langerhans. 12. Diabetes in association with myxoedema or with exophthalmic goiter may be referable to a lesion of the pancreas, namely, chronic interacinar inflammation with sclerosis of the islands of Langerhans; diabetes in association with acromegaly may be referable to a lesion of the islands of Langerhans, namely, sclerosis and hyaline degeneration with adenoma-like hypertrophy.


Transplantation of embryonal spinal cord nerve cells cultured on biodegradable microcarriers followed by low power laser irradiation for the treatment of traumatic paraplegia in rats.
This pilot study examined the effects of composite implants of cultured embryonal nerve cells and laser irradiation on the regeneration and repair of the completely transected spinal cord. Embryonal spinal cord nerve cells dissociated from rat fetuses and cultured on biodegradable microcarriers and embedded in hyaluronic acid were implanted in the completely transected spinal cords of 24 adult rats. For 14 consecutive post-operative days, 15 rats underwent low power laser irradiation (780 nm, 250 mW), 30 min daily. Eleven of the 15 (73%) showed different degrees of active leg movements and gait performance, compared to 4 (44%) of the 9 rats with implantation alone. In a controlgroup of seven rats with spinal cord transection and no transplantation or laser, six (86%) remained completely paralyzed. Three months after transection, implantation and laser irradiation, SSEPs were elicited in 69% of rats (p = 0.0237) compared to 37.5% in the nonirradiated group. The control group had no SSEPs response. Intensive axonal sprouting occurred in the group with implantation and laser. In the control group, the transected area contained proliferating fibroblasts and blood capillaries only. This suggests: 1. These in vitro composite implants are a regenerative and reparative source for reconstructing the transected spinal cord. 2. Post-operative low power laser irradiation enhances axonal sprouting and spinal cord repair.


Effect of the core/shell interface on auger recombination evaluated by single-quantum-dot spectroscopy.
Previous single-particle spectroscopic studies of colloidal quantum dots have indicated a significant spread in biexciton lifetimes across an ensemble of nominally identical nanocrystals. It has been speculated that in addition to dot-to-dot variation in physical dimensions, this spread is contributed to by variations in the structure of the quantum dot interface, which controls the shape of the confinement potential. Here, we directly evaluate the effect of the composition of the core-shell interface on single- and multiexciton dynamics via side-by-side measurements of individual core-shell CdSe/CdS nanocrystals with a sharp versus smooth (graded) interface. To realize the latter type of structures we incorporate a CdSexS1-x alloy layer of controlled composition and thickness between the CdSe core and the CdS shell. We observe that while having essentially no effect on single-exciton decay, the interfacial alloy layer leads to a systematic increase in biexciton lifetimes, which correlates with the increase in the biexciton emission efficiency, as inferred from two-photon correlation measurements. These observations provide direct experimental evidence that in addition to the size of the quantum dot, its interfacial properties also significantly affect the rate of Auger recombination, which governs biexciton decay. These findings help rationalize previous observations of a significant heterogeneity in the biexciton lifetimes across similarly sized quantum dots and should facilitate the development of "Auger-recombination-free" colloidal nanostructures for a range of applications from lasers and light-emitting diodes to photodetectors and solar cells.


Synthesis of Zinc Oxide Nanorods via the Formation of Sea Urchin Structures and Their Photoluminescence after Heat Treatment.
A protocol for the aqueous synthesis of ca. 1-μm-long zinc oxide (ZnO) nanorods and their growth at intermediate reaction progression is presented, together with photoluminescence (PL) characteristics after heat treatment at temperatures of up to 1000 °C. The existence of solitary rods after the complete reaction (60 min) was traced back to the development of sea urchin structures during the first 5 s of the precipitation. The rods primarily formed in later stages during the reaction due to fracture, which was supported by the frequently observed broken rod ends with sharp edges in the final material, in addition to tapered uniform rod ends consistent with their natural growth direction. The more dominant rod growth in the c direction (extending the length of the rods), together with the appearance of faceted surfaces on the sides of the rods, occurred at longer reaction times (>5 min) and generated zinc-terminated particles that were more resistant to alkaline dissolution. A heat treatment for 1 h at 600 or 800 °C resulted in a smoothing of the rod surfaces, and PL measurements displayed a decreased defect emission at ca. 600 nm, which was related to the disappearance of lattice imperfections formed during the synthesis. A heat treatment at 1000 °C resulted in significant crystal growth reflected as an increase in luminescence at shorter wavelengths (ca. 510 nm). Electron microscopy revealed that the faceted rod structure was lost for ZnO rods exposed to temperatures above 600 °C, whereas even higher temperatures resulted in particle sintering and/or mass redistribution along the initially long and slender ZnO rods. The synthesized ZnO rods were a more stable Wurtzite crystal structure than previously reported ball-shaped ZnO consisting of merging sheets, which was supported by the shifts in PL spectra occurring at ca. 200 °C higher annealing temperature, in combination with a smaller thermogravimetric mass loss occurring upon heating the rods to 800 °C.


Adjuvant potential of low dose all-trans retinoic acid during oral typhoid vaccination in Zambian men.
There is an urgent need to identify ways of enhancing the mucosal immune response to oral vaccines. Rotavirus vaccine protection is much lower in Africa and Asia than in industrialized countries, and no oral vaccine has efficacy approaching the best systemic vaccines. All-trans retinoic acid (ATRA) up-regulates expression of α4β7 integrin and CCR9 on lymphocytes in laboratory animals, increasing their gut tropism. The aim of this study was to establish the feasibility of using ATRA as an oral adjuvant for oral typhoid vaccination. In order to establish that standard doses of oral ATRA can achieve serum concentrations greater than 10 nmol/l, we measured ATRA, 9-cis and 13-cis retinoic acid in serum of 14 male volunteers before and 3 h after 10 mg ATRA. We then evaluated the effect of 10 mg ATRA given 1 h before, and for 7 days following, oral typhoid vaccine in eight men, and in 24 men given various control interventions. We measured immunoglobulin (Ig)A directed against lipopolysaccharide (LPS)and protein preparations of vaccine antigens in whole gut lavage fluid (WGLF) and both IgA and IgG in serum, 1 day prior to vaccination and on day 14. Median [interquartile range (IQR)] C(max) was 26·2 (11·7-39·5) nmol/l, with no evidence of cumulation over 8 days. No adverse events were observed. Specific IgA responses to LPS (P = 0·02) and protein (P = 0·04) were enhanced in WGLF, but no effect was seen on IgA or IgG in serum. ATRA was well absorbed, well tolerated and may be a promising candidate oral adjuvant.


Dynamical mechanism for subcellular alternans in cardiac myocytes.
Cardiac repolarization alternans is an arrhythmogenic rhythm disturbance, manifested in individual myocytes as a beat-to-beat alternation of action potential durations and intracellular calcium transient magnitudes. Recent experimental studies have reported "subcellular alternans," in which distinct regions of an individual cell are seen to have counterphase calcium alternations, but the mechanism by which this occurs is not well understood. Although previous theoretical work has proposed a possible dynamical mechanism for subcellular alternans formation, no direct evidence for this mechanism has been reported in vitro. Rather, experimental studies have generally invoked fixed subcellular heterogeneities in calcium-cycling characteristics as the mechanism of subcellular alternans formation. In this study, we have generalized the previously proposed dynamical mechanism to predict a simple pacing algorithm by which subcellular alternans can be induced in isolated cardiac myocytes in the presence or absence of fixed subcellular heterogeneity. We aimed to verify this hypothesis using computational modeling and to confirm it experimentally in isolated cardiac myocytes. Furthermore, we hypothesized that this dynamical mechanism may account for previous reports of subcellular alternans seen in statically paced, intact tissue. Using a physiologically realistic computational model of a cardiac myocyte, we show that our predicted pacing algorithm induces subcellular alternans in a manner consistent with theoretical predictions. We then use a combination of real-time electrophysiology and fluorescent calcium imaging to implement this protocol experimentally and show that it robustly induces subcellular alternans in isolated guinea pig ventricular myocytes. Finally, we use computational modeling to demonstrate that subcellular alternans can indeed be dynamically induced during static pacing of 1D fibers of myocytes during tissue-level spatially discordant alternans. Here we provide the first direct experimental evidence that subcellular alternans can be dynamically induced in cardiac myocytes. This proposed mechanism may contribute to subcellular alternans formation in the intact heart.


Chloroviruses encode a bifunctional dCMP-dCTP deaminase that produces two key intermediates in dTTP formation.
The chlorovirus PBCV-1, like many large double-stranded DNA-containing viruses, contains several genes that encode putative proteins involved in nucleotide biosynthesis. This report describes the characterization of the PBCV-1 dCMP deaminase, which produces dUMP, a key intermediate in the synthesis of dTTP. As predicted, the recombinant protein has dCMP deaminase activity that is activated by dCTP and inhibited by dTTP. Unexpectedly, however, the viral enzyme also has dCTP deaminase activity, producing dUTP. Typically, these two reactions are catalyzed by proteins in separate enzyme classes; to our knowledge, this is the first example of a protein having both deaminase activities. Kinetic experiments established that (i) the PBCV-1 enzyme has a higher affinity for dCTP than for dCMP, (ii) dCTP serves as a positive heterotropic effector for the dCMP deaminase activity and a positive homotropic effector for the dCTP deaminase activity, and (iii) the enzymatic efficiency of the dCMP deaminase activity is about four times higher than that of the dCTP deaminase activity. Inhibitor studies suggest that the same active site is involved in both dCMP and dCTP deaminations. The discovery that the PBCV-1 dCMP deaminase has two activities, together with a previous report that the virus also encodes a functional dUTP triphosphatase (Y. Zhang, H. Moriyama, K. Homma, and J. L. Van Etten, J. Virol. 79:9945-9953, 2005), means that PBCV-1 is the first virus to encode enzymes involved in all three known pathways to form dUMP.


Holter monitoring in the diagnosis of stroke mechanism.
Atrial fibrillation (AF), an important and treatable cause of ischaemic stroke, can occur as a sustained or a paroxysmal arrhythmia. Continuous cardiac rhythm monitoring (Holter monitoring) is often performed in stroke patients to identify paroxysmal AF, which is an indication for warfarin anti-coagulation in this patient population. The aim of this study was to assess the clinical utility of Holter monitoring in detecting occult AF in patients with possible cardioembolic stroke. The medical records of ischaemic stroke patients consecutively hospitalized at a single academic centre during a one-year period were reviewed. Data regarding patient demographics, stroke characteristics, electrocardiography and echocardiography results and duration and findings of Holter monitoring were abstracted. The primary outcome was yield of newly diagnosed AF on Holter monitoring. Of 465 consecutive patients admitted with a diagnosis of new ischaemic stroke, 210 underwent Holter monitoring. The mean duration of monitoring was 22.8 +/- 4.0 h. Previously undiscovered AF was -identified in five cases (2.4%), all of which represented non-rheumatic AF. In three cases, the Holter test was negative despite AF documented on an admission electro-cardiogram. Holter monitoring can identify occult paroxysmal AF, assisting targeted secondary prevention in patients with new ischaemic stroke. However, the standard 24-h duration of monitoring probably under-estimates the prevalence of paroxysmal AF in this population. Prospective studies are indicated to evaluate the value of longer monitoring periods in stroke populations.


A checkpoint that monitors cytokinesis in Schizosaccharomyces pombe.
Cell division in Schizosaccharomyces pombe is achieved through the use of a medially positioned actomyosin ring. A division septum is formed centripetally, concomitant with actomyosin ring constriction. Genetic screens have identified mutations in a number of genes that affect actomyosin ring or septum assembly. These cytokinesis-defective mutants, however, undergo multiple S and M phases and die as elongated cells with multiple nuclei. Recently, we have shown that a mutant allele of the S. pombe drc1(+)/cps1(+) gene, which encodes a 1,3-(beta)-glucan synthase subunit, is defective in cytokinesis but displays a novel phenotype. drc1-191/cps1-191 cells are capable of assembling actomyosin rings and completing mitosis, but are incapable of assembling the division septum, causing them to arrest as binucleate cells with a stable actomyosin ring. Each nucleus in arrested cps1-191 cells is able to undergo S phase but these G(2) nuclei are significantly delayed for entry into the M phase. In this study we have investigated the mechanism that causes cps1-191 to block with two G(2) nuclei. We show that the inability of cps1-191 mutants to proceed through multiple mitotic cycles is not related to a defect in cell growth. Rather, the failure to complete some aspect of cytokinesis may prevent the G(2)/M transition of the two interphase-G(2) nuclei. The G(2)/M transition defect of cps1-191 mutants is suppressed by a mutation in the wee1 gene and also by the dominant cdc2 allele cdc2-1w, but not the cdc2-3w allele. Transient depolymerization of all F-actin structures also allowed a significant proportion of the cps1-191 cells to undergo a second round of mitosis. We conclude that an F-actin and Wee1p dependent checkpoint blocks G(2)/M transition until previous cytokinesis is completed.