Coenzyme Q10 administration increases antibody titer in hepatitis B vaccinated volunteers--a single blind placebo-controlled and randomized clinical study.
Persons involved in the study, 21 per treatment arm, were consuming ubiquinone (Q10), 90 mg/day, 180 mg/day or placebo, for two weeks prior to hepatitis B vaccination. After 30 days this vaccination was repeated. Q10 was given as soft gelatin capsules containing 30 mg each. The consumption was continued throughout the study conducted for 90 days. Clinical observations and laboratory tests were performed throughout the study and no adverse effects were observed in any of the groups. Already after 30 days the two groups receiving Q10 showed a slightly titer of antibodies to hepatitis B surface antigen then the placebo group. This difference escalated and the immunopotentiating effect of Q10 was even more clear-cut in the residual part of the study. In addition, a dose response did also seem to be present when comparing the 90 mg group with the 180 mg group. Statistics revealed that Q10 in the dose 180 mg/day is able to increase antibody response in vivo in humans vaccinated against hepatitis B with up to 57% (p = 0.011).


Adenovirus preterminal protein binds to the CAD enzyme at active sites of viral DNA replication on the nuclear matrix.
Adenovirus (Ad) replicative complexes form at discrete sites on the nuclear matrix (NM) via an interaction mediated by the precursor of the terminal protein (pTP). The identities of cellular proteins involved in these complexes have remained obscure. We present evidence that pTP binds to a multifunctional pyrimidine biosynthesis enzyme found at replication domains on the NM. Far-Western blotting identified proteins of 150 and 240 kDa that had pTP binding activity. Amino acid sequencing of the 150-kDa band revealed sequence identity to carbamyl phosphate synthetase I (CPS I) and a high degree of homology to the related trifunctional enzyme known as CAD (for carbamyl phosphate synthetase, aspartate transcarbamylase, and dihydroorotase). Western blotting with an antibody directed against CAD detected a 240-kDa band that comigrated with that detected by pTP far-Western blotting. Binding experiments showed that a pTP-CAD complex was immunoprecipitable from cell extracts in which pTP was expressed by a vaccinia virus recombinant. Additionally, in vitro-translated epitope-tagged pTP and CAD were immunoprecipitable as a complex, indicating the occurrence of a protein-protein interaction. Confocal fluorescence microscopy of Ad-infected NM showed that pTP and CAD colocalized in nuclear foci. Both pTP and CAD were confirmed to colocalize with active sites of replication detected by bromodeoxyuridine incorporation. These data support the concept that the pTP-CAD interaction may allow anchorage of Ad replication complexes in the proximity of required cellular factors and may help to segregate replicated and unreplicated viral DNA.


[Soft tissue tumors in neonates].
Soft tissue tumors account for approximately 25% of neonatal tumors and are most often benign (more than 2/3 of cases). Vascular tumors are the most frequent benign tumors and infantile hemangioma accounts for 32% of these tumors, affecting 1 out of 200 children at birth. Kaposiform hemangioendothelioma (KH) is a rare vascular tumor with locally aggressive behavior. More than 50% of KH are associated with the Kasabach-Merritt phenomenon, a condition characterized by thrombocytopenia and consumptive coagulopathy. Malignant soft tissue tumors are, after neuroblastoma, the second cause of cancer in neonates. Infantile fibrosarcoma (IF) is a rare tumor that most often affects the extremities of children aged 4 years or younger. A recurrent t(12;15) (p13;q25) rearrangement fusing the ETV6 gene with the NTRK3 neurotrophin-3 receptor gene has been identified in IF. Complete conservative surgical resection is usually curative. Chemotherapy is indicated when initial surgical removal cannot be accomplished without unacceptable morbidity. Prognosis of IF is excellent, with reported overall survival rates ranging from 80 to 100%. Neonatal rhabdomyosarcoma (RMS) is a rare tumor (0.5-1% of RMS). The primary tumor predominantly involves the limbs and the genitourinary tract. Treatment is based on age-adapted chemotherapy and surgery. Prognosis of RMS in children less than 1 year old appears to be comparable with that of older children.


Prospective, multicenter study of ventricular assist device infections.
Ventricular assist devices (VADs) improve survival and quality of life in patients with advanced heart failure, but their use is frequently complicated by infection. There are limited data on the microbiology and epidemiology of these infections. One hundred fifty patients scheduled for VAD implantation were enrolled (2006-2008) at 11 US cardiac centers and followed prospectively until transplantation, explantation for recovery, death, or for 1 year. Eighty-six patients (57%) received HeartMate II devices. Data were collected on potential preoperative, intraoperative, and postoperative risk factors for infection. Clinical, laboratory, and microbiological data were collected for suspected infections and evaluated by an infectious diseases specialist. Thirty-three patients (22%) developed 34 VAD-related infections with an incidence rate of 0.10 per 100 person-days (95% confidence interval, 0.073-0.142). The median time to infection was 68 days. The driveline was the most commonly infected site (n=28); 18 (64%) were associated with invasive disease. Staphylococci were the most common pathogen (47%), but pseudomonas or other Gram-negative bacteria caused 32% of infections. A history of depression and elevated baseline serum creatinine were independent predictors of VAD infection (adjusted hazard ratio=2.8 [P=0.007] and 1.7 [P=0.023], respectively). The HeartMate II was not associated with a decreased risk of infection. VAD infection increased 1-year mortality (adjusted hazard ratio=5.6; P<0.0001). This prospective, multicenter study demonstrates that infection frequently complicates VAD placement and is a continuing problem despite the use of newer, smaller devices. Depression and renal dysfunction may increase the risk of VAD infection. VAD infection is a serious consequence because it adversely affects patient survival. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01471795.


Cell permeability, sodium transport, and the hypertensive process in the rat.
The tail artery of the spontaneously hypertensive rat (SHR) (Carworth Farms), excised rapidly and immersed immediately in cold (2 degrees C) Li-substituted physiologic salt solution (LiPSS), continues to exchange cell Na+ and K+ for Li+, this exchange is negligible to the control (Carworth Farms normotensive) CFN). In the incubated artery at 37 degrees C, when the vascular smooth muscle cell is slack, the leakiness of the cell membrane in the SHR is more than offset by increased Na+ pumping activity, so that cell Na+ is subnormal. A high precision technique with ion-specific electrodes was developed to follow the passive downhill and active uphill phases of Na+-K+ exchange in the perfused artery exposed to K+-free physiologic salt solution (K+-free PSS) followed by physiological salt solution (PSS). The exchange was found to be fully reversible and sufficiently equimolar to be definable in terms of movements of K+ alone. The rates of ionic movement across the vascular smooth muscle cell were found to be about 6 times faster for the vessel perfused at low pressure (less than 3 mm Hg) than for the slack incubated artery. The rate of passive downhill movement was significantly accelerated in the mature SHR compared with CFN, and the net active transport activity much enhanced. Similar changes were seen as early as 3 weeks after treatment with DOCA and were pronounced at 8 weeks. It is proposed that conditions favoring a sustained accumulation of Na+ in the vascular smooth muscle cell are countered by an enhanced synthesis of transport protein, of contractile protein, and of paracellular matrix protein which progressively restructure the wall.


Son preference and sterilisation use among young married women in two slums in Bengaluru city, India.
This paper explores the ways in which women's sterilisation decisions are influenced by the combination of a preference for male children and a desire for smaller family size among young married women in two urban slums in Bengaluru, India. While both son preference and an emphasis on sterilisation are well-known demographic characteristics of most South Asian countries, relatively little research has been conducted that links the two. We take advantage of a longitudinal survey of 416 unsterilised married women aged 16-25 to explore how having sons and the number of children influence a woman's sterilisation decision. Discrete-time event history techniques are used to estimate two models: the first examines the effect of having sons and number of children separately, and the second examines them in combination in the form of an interaction. The results suggest sterilisation is motivated by son preference mainly at lower parities (three or fewer children) and by concerns about family size at higher parities. Understanding how sterilisation and other reproductive behaviours are influenced by the interaction of family size and sex preferences will help policy-makers and programmers to meet the needs of women while continuing to address discriminatory behaviour against females.


Gene and protein expression pilot profiling and biomarkers in an experimental mouse model of hypertensive glaucoma.
Glaucoma is a group of genetically heterogeneous neurodegenerative disorders causing the degeneration of the ganglion neurons of the retina. Increased intraocular pressure (IOP) is a hallmark risk factor promoting the death of ganglion neurons of the retina in glaucoma. Yet, the molecular processes underlying the degeneration of these neurons by increased IOP are not understood. To gain insight into the early molecular events and discover biomarkers induced by IOP, we performed gene and protein expression profiling to compare retinas of eyes with and without high IOP in a rodent model of experimental glaucoma. This pilot study found that the IOP-mediated changes in the transcription levels of a restricted set of genes implicated in peroxisomal and mitochondrial function, modulation of neuron survival and inflammatory processes, were also accompanied by changes in the levels of proteins encoded by the same genes. With the exception of the inflammatory markers, serum amyloid-A1 (SAA1) and serum amyloid-A2 (SAA2), the IOP-induced changes in protein expression were restricted to ganglion neurons of the retina and they were detected also in the vitreous, thus suggesting an early IOP-mediated loss of ganglion cell integrity. Interestingly, SAA1 and SAA2 were induced in retinal microglia cells, whereas they were reduced in sera of IOP-responsive mice. Hence, this study defines novel IOP-induced molecular processes, biomarkers and sources thereof, and it further validates the extension of the analyses herein reported to other genes modulated by IOP.


The Current State of Fat Grafting: A Review of Harvesting, Processing, and Injection Techniques.
Interest in and acceptance of autologous fat grafting for use in contour abnormalities, breast reconstruction, and cosmetic procedures have increased. However, there are many procedural variations that alter the effectiveness of the procedure and may account for the unpredictable resorption rates observed. The authors highlighted studies investigating the effects of harvesting procedures, processing techniques, and reinjection methods on the survival of fat grafts. This review focused on the impact different techniques have on outcomes observed in the following: in vitro analyses, in vivo animal experiments, and human studies. This systemic review revealed the current state of the literature. There was no significant difference in the outcomes of grafted fat obtained from different donor sites, different donor-site preparations, harvest technique, fat harvesting cannula size, or centrifugation speed, when tumescent solution was used. Gauze rolling was found to enhance the volume of grafted fat, and no significant difference in retention was observed following centrifugation, filtration, or sedimentation in animal experiments. In contrast, clinical studies in patients found more favorable outcomes with fat processed by centrifugation compared with sedimentation. In addition, higher retention was observed with slower reinjection speed and when introduced into less mobile areas. There has been a substantial increase in research interest to identify methodologies for optimizing fat graft survival. Despite some differences in harvest and implantation technique in the laboratory, these findings have not translated into a universal protocol for fat grafting. Therefore, additional human studies are necessary to aid in the development of a universal protocol for clinical practice.


Prevention of infection caused by immunosuppressive drugs in gastroenterology.
Immunosuppressive therapy is frequently used to treat gastrointestinal diseases such as inflammatory bowel disease, autoimmune hepatitis, IgG4-related disease (autoimmune pancreatitis and sclerosing cholangitis) and in the post-transplantation setting. These drugs interfere with the immune system. The main safety concern with their use is the risk of infections. Certain infections can be prevented or their impact minimized. Physicians must adopt preventative strategies and should have a high degree of suspicion to recognize infections early and treat appropriately. This article reviews the risk factors for infections, the mechanism of action of immunosuppressive therapy and proposes preventive strategies.


Developing compassionate communities in Australia through collective caregiving: a qualitative study exploring network-centred care and the role of the end of life sector.
The new public health palliative care movement calls for a move away from an individualised model of caregiving to a whole of community approach which will increase expectations on community carers. In order to avoid carer isolation, exploitation and potential burnout there is then a very real need to understand environments and relationships which support collective community caregiving. In this research we explored in-home caring networks to understand if and how network centred care supports carers of the dying while developing a whole of community approach. Over a 6-year period the research team spoke to 301 caregivers, service providers and community members via interviews and focus groups in regional, rural and urban Australia. People are already caring for their dying at home and doing it well provided they are comprehensively supported by networks of care. Being part of a caring network provided people with a sense of achievement and developed their death literacy which flowed into a myriad of other community activities. While caring networks are essential they are not widely supported by service providers. At worst, services are obstructive of peoples stated preferences for place of death and caring and often adopt a paternalistic approach. Place of care, in this case the home, was supportive of maintaining networks and peoples' wellbeing. Operationalising public health approaches to palliative care requires moving to a place-based network centred model of care comprising formal and informal carers. Service systems need re-orienting to place caring networks as central to the caregiving process. This can be achieved by putting systems in place which initiate and maintain such networks and enable service providers to work with informal networks as equal and respectful partners.


Presence of 1,25-dihydroxyvitamin D3 receptors in established human cancer cell lines in culture.
Receptors for 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] have been described in several human breast cancer cell lines and more recently in human melanoma. The presence of 1,25-(OH)2D3 receptor (1,25-DR) in two cultured breast cancer cell lines was associated with receptors for calcitonin, another hormone thought to have effects on calcium handling. Therefore, it seemed important to examine a range of established human cancer cell lines for the presence of receptors for 1,25-(OH)2D3 and calcitonin. Thirty-three cancer cell lines were examined. 1,25-DR was found to be present in 23 lines, while calcitonin receptors were not detected in any of them. The 1,25-DR from several cell lines sedimented at about 3.5S in sucrose density gradients, had the appropriate specificity for vitamin D metabolites, had Kds of 0.8 to 2.2 x 10(-11) M, and had receptor concentrations of 12 to 99 fmol/mg protein. Ten malignant melanoma and nine colonic carcinoma lines constituted the largest groups of carcinoma cell lines, and seven and eight, respectively, of these were 1,25-DR positive. The high frequency of 1,25-DR positivity in the cultured colonic carcinoma cells is quite different from the low frequency of 1,25-DR in primary colonic carcinomas. It was also interesting that both of two cell lines derived from patients who had had both bone metastases and malignant hypercalcemia were 1,25-DR positive. These various cell lines may provide useful models for the examination of 1,25-(OH)2D3 action in vitro.


Characterization of time-resolved laser differential phase using 3D complementary cumulative distribution functions.
An experimental method for characterizing the time-resolved phase noise of a fast switching tunable laser is discussed. The method experimentally determines a complementary cumulative distribution function of the laser's differential phase as a function of time after a switching event. A time resolved bit error rate of differential quadrature phase shift keying formatted data, calculated using the phase noise measurements, was fitted to an experimental time-resolved bit error rate measurement using a field programmable gate array, finding a good agreement between the time-resolved bit error rates.


Mortality of coho salmon (Oncorhynchus kisutch) associated with burdens of multiple parasite species.
Multiple analytical techniques were used to evaluate the impact of multiple parasite species on the mortality of threatened juvenile coho salmon (Oncorhynchus kisutch) from the West Fork Smith River, Oregon, USA. We also proposed a novel parsimonious mathematical representation of macroparasite distribution, congestion rate, which (i) is easier to use than traditional models, and (ii) is based on Malthusian parameters rather than probability theory. Heavy infections of Myxobolus insidiosus (Myxozoa) and metacercariae of Nanophyetus salmincola and Apophallus sp. occurred in parr (subyearlings) from the lower mainstem of this river collected in 2007 and 2008. Smolts (yearlings) collected in 2007-2010 always harboured fewer Apophallus sp. with host mortality recognised as a function of intensity for this parasite. Mean intensity of Apophallus sp. in lower mainstem parr was 753 per fish in 2007 and 856 per fish in 2008, while parr from the tributaries had a mean of only 37 or 13 parasites per fish, respectively. Mean intensity of this parasite in smolts ranged between 47 and 251 parasites per fish. Over-dispersion (variance to mean ratios) of Apophallus sp. was always lower in smolts compared with all parr combined or lower mainstem parr. Retrospective analysis based on smolt data using both the traditional negative binomial truncation technique and our proposed congestion rate model showed identical results. The estimated threshold level for mortality involving Apophallus sp. was at 400-500 parasites per fish using both analytical methods. Unique to this study, we documented the actual existence of these heavy infections prior to the predicted mortality. Most of the lower mainstem parr (approximately 75%) had infections above this level. Heavy infections of Apophallus sp. metacercariae may be an important contributing factor to the high over-wintering mortality previously reported for these fish that grow and develop in this section of the river. Analyses using the same methods for M.insidiosus and N. salmincola generally pointed to minimal parasite-associated mortality.


Administration of a substituted adamantyl urea inhibitor of soluble epoxide hydrolase protects the kidney from damage in hypertensive Goto-Kakizaki rats.
Hypertension and Type 2 diabetes are co-morbid diseases that lead to the development of nephropathy. sEH (soluble epoxide hydrolase) inhibitors are reported to provide protection from renal injury. We hypothesized that the sEH inhibitor AUDA [12-(3-adamantan-1-yl-ureido)-dodecanoic acid] protects the kidney from the development of nephropathy associated with hypertension and Type 2 diabetes. Hypertension was induced in spontaneously diabetic GK (Goto-Kakizaki) rats using AngII (angiotensin II) and a high-salt diet. Hypertensive GK rats were treated for 2 weeks with either AUDA or its vehicle added to drinking water. MAP (mean arterial pressure) increased from 118+/-2 mmHg to 182+/-20 and 187+/-6 mmHg for vehicle and AUDA-treated hypertensive GK rats respectively. AUDA treatment did not alter blood glucose. Hypertension in GK rats resulted in a 17-fold increase in urinary albumin excretion, which was decreased with AUDA treatment. Renal histological evaluation determined that AUDA treatment decreased glomerular and tubular damage. In addition, AUDA treatment attenuated macrophage infiltration and inhibited urinary excretion of MCP-1 (monocyte chemoattractant protein-1) and kidney cortex MCP-1 gene expression. Taken together, these results provide evidence that sEH inhibition with AUDA attenuates the progression of renal damage associated with hypertension and Type 2 diabetes.


An Activity Index for Raw Accelerometry Data and Its Comparison with Other Activity Metrics.
Accelerometers have been widely deployed in public health studies in recent years. While they collect high-resolution acceleration signals (e.g., 10-100 Hz), research has mainly focused on summarized metrics provided by accelerometers manufactures, such as the activity count (AC) by ActiGraph or Actical. Such measures do not have a publicly available formula, lack a straightforward interpretation, and can vary by software implementation or hardware type. To address these problems, we propose the physical activity index (AI), a new metric for summarizing raw tri-axial accelerometry data. We compared this metric with the AC and another recently proposed metric for raw data, Euclidean Norm Minus One (ENMO), against energy expenditure. The comparison was conducted using data from the Objective Physical Activity and Cardiovascular Health Study, in which 194 women 60-91 years performed 9 lifestyle activities in the laboratory, wearing a tri-axial accelerometer (ActiGraph GT3X+) on the hip set to 30 Hz and an Oxycon portable calorimeter, to record both tri-axial acceleration time series (converted into AI, AC, and ENMO) and oxygen uptake during each activity (converted into metabolic equivalents (METs)) at the same time. Receiver operating characteristic analyses indicated that both AI and ENMO were more sensitive to moderate and vigorous physical activities than AC, while AI was more sensitive to sedentary and light activities than ENMO. AI had the highest coefficients of determination for METs (0.72) and was a better classifier of physical activity intensity than both AC (for all intensity levels) and ENMO (for sedentary and light intensity). The proposed AI provides a novel and transparent way to summarize densely sampled raw accelerometry data, and may serve as an alternative to AC. The AI's largely improved sensitivity on sedentary and light activities over AC and ENMO further demonstrate its advantage in studies with older adults.


Differential activation of temporal cortex during sentence completion in schizophrenic patients with and without formal thought disorder.
The neural correlates of processing linguistic context in schizophrenic patients with formal thought disorder (FTD) were examined. Six right-handed male patients with prominent 'positive' FTD were compared with six schizophrenic patients without FTD and seven volunteers, matched for cognitive and demographic variables. Functional magnetic resonance imaging (IMRI) was used to measure cerebral activation while subjects read and completed sentence stems out loud. During a GENERATION condition, subjects were required to generate a word which completed the sentence stem appropriately. During a DECISION condition, subjects selected and articulated one of two presented terminal words. A READING condition served as baseline. The three conditions were compared with each other. Regions activated were identified in each group, and between-group differences were detected using an ANCOVA. When GENERATION was compared with READING, FTD patients showed less activation in the right superior temporal gyrus than patients without FTD or controls, but greater activation in the left inferior frontal, inferior temporal and fusiform gyri. FTD patients also showed an attenuated right temporal response when GENERATION was compared with DECISION. This differential engagement of the right temporal cortex was independent of differences in the speed or accuracy of responses, whereas the left fronto-temporal differences in activation were not evident after covarying for task errors. The attenuated engagement of right temporal cortex, which is implicated in language comprehension at the discourse level, is consistent with neuropsychological evidence linking thought disorder with deficits in processing linguistic context.


How accurate are WorldPop-Global-Unconstrained gridded population data at the cell-level?: A simulation analysis in urban Namibia.
Disaggregated population counts are needed to calculate health, economic, and development indicators in Low- and Middle-Income Countries (LMICs), especially in settings of rapid urbanisation. Censuses are often outdated and inaccurate in LMIC settings, and rarely disaggregated at fine geographic scale. Modelled gridded population datasets derived from census data have become widely used by development researchers and practitioners; however, accuracy in these datasets are evaluated at the spatial scale of model input data which is generally courser than the neighbourhood or cell-level scale of many applications. We simulate a realistic synthetic 2016 population in Khomas, Namibia, a majority urban region, and introduce several realistic levels of outdatedness (over 15 years) and inaccuracy in slum, non-slum, and rural areas. We aggregate the synthetic populations by census and administrative boundaries (to mimic census data), resulting in 32 gridded population datasets that are typical of LMIC settings using the WorldPop-Global-Unconstrained gridded population approach. We evaluate the cell-level accuracy of these gridded population datasets using the original synthetic population as a reference. In our simulation, we found large cell-level errors, particularly in slum cells. These were driven by the averaging of population densities in large areal units before model training. Age, accuracy, and aggregation of the input data also played a role in these errors. We suggest incorporating finer-scale training data into gridded population models generally, and WorldPop-Global-Unconstrained in particular (e.g., from routine household surveys or slum community population counts), and use of new building footprint datasets as a covariate to improve cell-level accuracy (as done in some new WorldPop-Global-Constrained datasets). It is important to measure accuracy of gridded population datasets at spatial scales more consistent with how the data are being applied, especially if they are to be used for monitoring key development indicators at neighbourhood scales within cities.


Effect of Platform Shift/Switch and Concave Abutments on Crestal Bone Levels and Mucosal Profile following Flap and Flapless Implant Surgery.
Crestal remodeling/bone loss appears to be a common sequel to dental implant placement. Several hypotheses/clinical strategies have been proposed to explain/avert crestal remodeling; however, causative mechanisms remain unclear and the efficacy of these clinical approaches uncertain. The objective of the present study was to provide a histological account of crestal bone levels and mucosal profile at platform shift/switch and concave abutments following flapless and conventional flap surgery and subcrestal implant placement using a dog model. Four dental implants each were placed in the left/right mandibular posterior jaw quadrants in five adult male Hound/Labrador mongrel dogs using flap surgery with a 1 × 5 mm gap defect or using a flapless approach, both involving placement 2 mm subcrestally and platform shift/switch versus concave abutments. Block biopsies for histological/histometric analysis were collected at 8 weeks. No significant differences were observed regarding crestal bone levels, with all groups showing mean bone levels above the implant platform. Similarly, crestal bone-implant contact was not significantly different among groups. Moreover, peri-implant mucosal profiles were not statistically different among groups for buccal sites; average mucosal height reached 4.1 to 4.9 mm above the implant platform. Comparison between buccal and lingual sites showed a nonsignificant tendency toward greater crestal resorption at buccal sites, adjusting for other factors. Mean crestal bone-implant contact level approximated the implant platform for lingual sites while consistently remaining below the platform at the buccal sites. Peri-implant mucosal height was significantly higher at buccal than at lingual sites, with the epithelial attachment located a significant distance away from the implant platform at buccal sites. The surgical approaches (subcrestal implant placement by flap surgery or a flapless approach) and abutment designs (platform shift/switch or concave) used in this study seem to have a limited impact on crestal remodeling, associated bone loss, and mucosal profile. Bioclinical strategies should be developed to circumvent the limitations of current clinical protocol.


A general strategy for tailoring upconversion luminescence in lanthanide-doped inorganic nanocrystals through local structure engineering.
A local structure around lanthanide (Ln3+) emitters in Ln3+-doped upconversion nanocrystals (UCNCs) is of fundamental importance in tailoring their upconversion luminescence (UCL) features. However, a general strategy responsible for the local-structure-dependent UCL in Ln3+-doped UCNCs has not been conclusively established to date. Herein, we report a new class of alkaline zirconium fluoride-based Yb3+/Er3+ co-doped UCNCs featuring a diversity of crystallographic structures for Ln3+ ion doping, which thereby allow us to thoroughly understand the origin underlying the local-structure-dependent UCL of the Er3+ ion for the first time. We reveal that the high-symmetry crystal lattice of Yb3+/Er3+ co-doped UCNCs may incur the large UCL red-to-green intensity ratio of Er3+ regardless of their identical elemental compositions. In combination with the first-principles calculations, we show that such local-structure-dependent UCL of Er3+ is primarily due to the varied electronic band structures induced by the Yb3+/Er3+ doping in different crystallographic structures of alkaline zirconium fluorides. These findings may open up a new avenue for constructing high-quality UCNCs with a tailored UCL profile and lifetime for diverse applications.


Inhibition of acetylcholinesterase modulates NMDA receptor antagonist mediated alterations in the developing brain.
Exposure to N-methyl-d-aspartate (NMDA) receptor antagonists has been demonstrated to induce neurodegeneration in newborn rats. However, in clinical practice the use of NMDA receptor antagonists as anesthetics and sedatives cannot always be avoided. The present study investigated the effect of the indirect cholinergic agonist physostigmine on neurotrophin expression and the extracellular matrix during NMDA receptor antagonist induced injury to the immature rat brain. The aim was to investigate matrix metalloproteinase (MMP)-2 activity, as well as expression of tissue inhibitor of metalloproteinase (TIMP)-2 and brain-derived neurotrophic factor (BDNF) after co-administration of the non-competitive NMDA receptor antagonist MK801 (dizocilpine) and the acetylcholinesterase (AChE) inhibitor physostigmine. The AChE inhibitor physostigmine ameliorated the MK801-induced reduction of BDNF mRNA and protein levels, reduced MK801-triggered MMP-2 activity and prevented decreased TIMP-2 mRNA expression. Our results indicate that AChE inhibition may prevent newborn rats from MK801-mediated brain damage by enhancing neurotrophin-associated signaling pathways and by modulating the extracellular matrix.


Education for children with a poor prognosis: reflections on parental wishes and on an appropriate curriculum.
This paper examines the wishes expressed by parents in relation to the education of their children who are in the advanced stages of a life-threatening condition. They hope that through participating in education, their children will achieve success or fulfill their potential, experience peer friendship or, at least, companionship, have interests and activities which may distract them from the unpleasant aspects of their condition, leave behind a marker of their existence and above all, experience some aspects of a normal life. The curricular models available upon which education programmes for these children may be based are examined critically in relation to all children's entitlement to an 'appropriate curriculum'. Factors which may impede teachers' willingness and ability to address the educational and other needs of their dying pupils are explored and some positive ways forward are suggested.


MnO2-gated Nanoplatforms with Targeted Controlled Drug Release and Contrast-Enhanced MRI Properties: from 2D Cell Culture to 3D Biomimetic Hydrogels.
Multifunctional nanomaterials combining diagnosis and therapeutic properties have attracted a considerable attention in cancer research. Yet some important challenges are still to be faced, including an optimal coupling between these two types of properties that would be effective within complex biological tissues. To address these points, we have prepared novel nanoplatforms associating controlled drug delivery of doxorubicin and Magnetic Resonance Imaging (MRI) contrast-enhancement that exhibit high specificity towards cancer cells compared to normal cells and evaluated them both in 2D cultures and within 3D tissue-like biomimetic matrices. Nanoplatforms were prepared from hollow silica nanoparticles coated with MnO2 nanosheets and conjugated with the AS1411 aptamer as a targeting agent. They were fully characterized from a chemical and structural point of view as well as for drug release and MRI signal enhancement. Standard two-dimensional monolayer cultures were performed using HeLa and Normal Human Dermal Fibroblasts (NHDF) cells to testify targeting and cytotoxicity. Cellularized type I collagen-based hydrogels were also used to study nanoparticles behavior in 3D biomimetic environments. The as-established nanoplatforms can enter HeLa cells, leading to the dissociation of the MnO2 nanosheets into Mn2+ that enhanced T1 magnetic resonance signals and concomitantly release doxorubicin, both effects being markedly more significant than in the presence of NHDFs. Moreover, particles functionality and specificity were preserved when the cells were immobilized within type I collagen-based fibrillar hydrogels. The use of MnO2 nanosheets as glutathione-sensitive coatings of drug loaded nanoparticles together with surface conjugation with a targeting aptamer offers an effective strategy to obtain efficient and specific nanotheranostic systems for cancer research, both in 2D and 3D. The here-described tissue-like models should be easy to implement and could constitute an interesting intermediate validation step for newly-developed theranostic nanoparticles before in vivo evaluation.


ATM regulates a RASSF1A-dependent DNA damage response.
Hypermethylation of CpG islands in the RASSF1 promoter is one of the most frequent events identified in human cancer. The epigenetic-driven loss of RASSF1A protein expression is observed more often in tumors of higher grade and correlates with a decreased responsiveness to DNA-damaging therapy. Ras association domain-containing family 1A (RASSF1A) promotes apoptosis by signaling through the MST2 and LATS1 kinases, leading to stabilization of the YAP1/p73 transcriptional complex. Here we provide evidence for a new pathway linking DNA damage signaling to RASSF1A via the main sensor of double-strand breaks in cells, ataxia telangiectasia mutated (ATM). We show that, upon DNA damage, RASSF1A is phosphorylated by ATM on Ser131 and is involved in the activation of both MST2 and LATS1, leading to the stabilization of p73. Furthermore, lung and ovarian tumor cell lines that retain RASSF1A expression commonly harbor polymorphisms in the region of Ser131, and our analysis shows that the S131F polymorphism conveys resistance to DNA-damaging agents. Thus, we present a novel DNA damage pathway emanating from ATM that is frequently disabled in tumors via epigenetic silencing of RASSF1 or mutation of an ATM phosphorylation site.


Ancrod for the treatment of acute ischemic brain infarction. The Ancrod Stroke Study Investigators.
There is no acute therapy proven to be of benefit for ischemic stroke. Ancrod is a potentially effective therapy because of the advantageous consequences of fibrinogen lowering. We studied the safety and efficacy of ancrod in patients with acute ischemic stroke administered within 6 hours of stroke onset. In a double-blind, randomized, placebo-controlled trial 64 patients received intravenous ancrod and 68 received placebo for 7 days. Neurological outcome, disability, and brain infarct volume were measured. There was no significant difference in overall mean scores on the Scandinavian Stroke Scale. No increase in bleeding occurred in the ancrod-treated patients. The target reduction of plasma fibrinogen levels of less than 100 mg/dL was achieved in only 15 (23%) of 64 ancrod-treated patients. Those patients with ancrod-induced 6-hour fibrinogen levels 130 mg/dL or less had a marginally significantly better neurological outcome on the Scandinavian Stroke Scale, mortality, and Barthel Index than ancrod-treated patients with higher fibrinogen levels. Ancrod appears safe and potentially effective when administered to patients within 6 hours of onset of ischemic stroke.


Niacin action in the atherogenic mixed dyslipidemia of metabolic syndrome: Insights from metabolic biomarker profiling and network analysis.
Niacin as an adjunct to statin treatment to reduce cardiovascular risk is questioned. To evaluate interrelationships between the effects of niacin on mixed dyslipidemia and a spectrum of metabolic and inflammatory biomarkers. Obese, nondiabetic, hypertriglyceridemic males (n = 19) with low high-density lipoprotein-cholesterol levels received extended-release nicotinic acid for 8 weeks. Multiple biomarkers were measured using enzyme-linked immunosorbent assay, enzymatic/absorptiometric, or multiplex biochip assays. Treatment effects were determined for each variable and a differential correlation network created on the basis of univariate correlations between baseline and response to niacin treatment for all pairs of variables. Extended-release niacin treatment favoured normalization of plasma lipid and apolipoprotein profile. Plasma markers of inflammation, hepatic function, cellular adhesion and proliferation, and macrophage phenotype were attenuated; however, insulin resistance increased. Differential network analysis revealed that changes in triglycerides and high-density lipoprotein-cholesterol were closely linked; equally, niacin mediated reductions in total cholesterol, apolipoprotein B, low-density lipoprotein-cholesterol and lipoprotein(a) clustered together, as did homeostatic model assessment of insulin resistance, insulin, and interleukin-6 levels. Two clusters of inflammatory markers were identified, involving (1) intercellular adhesion molecule 1 and high-sensitive C-reactive protein and (2) soluble tumor necrosis factor receptors; and novel clusters involving matrix metallopeptidase 9 and apolipoprotein E, and adiponectin and cystatin C, respectively, were equally revealed. At lower stringency, lipid and insulin resistance clusters were linked; a C-reactive protein-centered cluster linked reduction in apolipoprotein CIII to intercellular adhesion molecule 1, gamma-glutamyltransferase, soluble tumor necrosis factor receptors, and E-selectin. A niacin-mediated trend to normalize atherogenic mixed dyslipidemia was intimately linked to attenuation of biomarkers of inflammation, cell adhesion, hepatic dysfunction and cell proliferation, but to enhanced insulin resistance and plasma homocysteine elevation.


Geochemistry and mercury contamination in receiving environments of artisanal mining wastes and identified concerns for food safety.
Artisanal small-scale gold mining (ASGM) using mercury (Hg) amalgamation has been occurring on Buru Island, Indonesia since early 2012, and has caused rapid accumulation of high Hg concentrations in river, estuary and marine sediments. In this study, sediment samples were collected from several sites downstream of the Mount Botak ASGM site, as well as in the vicinity of the more recently established site at Gogrea where no sampling had previously been completed. All sediment samples had total Hg (THg) concentrations exceeding Indonesian sediment quality guidelines and were up to 82 times this limit at one estuary site. The geochemistry of sediments in receiving environments indicates the potential for Hg-methylation to form highly bioavailable Hg species. To assess the current contamination threat from consumption of local seafood, samples of fish, molluscs and crustaceans were collected from the Namlea fish market and analysed for THg concentrations. The majority of edible tissue samples had elevated THg concentrations, which raises concerns for food safety. This study shows that river, estuary and marine ecosystems downstream of ASGM operations on Buru Island are exposed to dangerously high Hg concentrations, which are impacting aquatic food chains, and fisheries resources. Considering the high dietary dependence on marine protein in the associated community and across the Mollucas Province, and the short time period since ASGM operations commenced in this region, the results warrant urgent further investigation, risk mitigation, and community education.


Neutrophil extracellular traps promote deep vein thrombosis in mice.
Upon activation, neutrophils can release nuclear material known as neutrophil extracellular traps (NETs), which were initially described as a part of antimicrobial defense. Extracellular chromatin was recently reported to be prothrombotic in vitro and to accumulate in plasma and thrombi of baboons with experimental deep vein thrombosis (DVT). To explore the source and role of extracellular chromatin in DVT. We used an established murine model of DVT induced by flow restriction (stenosis) in the inferior vena cava (IVC). We demonstrate that the levels of extracellular DNA increase in plasma after 6 h IVC stenosis, compared with sham-operated mice. Immunohistochemical staining revealed the presence of Gr-1-positive neutrophils in both red (RBC-rich) and white (platelet-rich) parts of thrombi. Citrullinated histone H3 (CitH3), an element of NETs' structure, was present only in the red part of thrombi and was frequently associated with the Gr-1 antigen. Immunofluorescent staining of thrombi showed proximity of extracellular CitH3 and von Willebrand factor (VWF), a platelet adhesion molecule crucial for thrombus development in this model. Infusion of Deoxyribonuclease 1 (DNase 1) protected mice from DVT after 6 h and also 48 h IVC stenosis. Infusion of an unfractionated mixture of calf thymus histones increased plasma VWF and promoted DVT early after stenosis application. Extracellular chromatin, likely originating from neutrophils, is a structural part of a venous thrombus and both the DNA scaffold and histones appear to contribute to the pathogenesis of DVT in mice. NETs may provide new targets for DVT drug development.


Dynamics of coherent and incoherent emission from an artificial atom in a 1D space.
We study dynamics of a two-level superconducting quantum system, analogous to a natural atom in an open space, by measuring the evolution of its coherent and incoherent emission. The emitted waves containing full information about the states of the artificial atom are efficiently collected due to strong atom-transmission-line coupling. This allows us to do simultaneous measurements of all the quantum state projections and perform a full characterization of the system. We derive coherence times and extract the two-time correlation function from the dynamics of the coherent emission.


Determinants of the assembly and function of antibody variable domains.
The antibody Fv module which binds antigen consists of the variable domains VL and VH. These exhibit a conserved ß-sheet structure and comprise highly variable loops (CDRs). Little is known about the contributions of the framework residues and CDRs to their association. We exchanged conserved interface residues as well as CDR loops and tested the effects on two Fvs interacting with moderate affinities (KDs of ~2.5 µM and ~6 µM). While for the rather instable domains, almost all mutations had a negative effect, the more stable domains tolerated a number of mutations of conserved interface residues. Of particular importance for Fv association are VLP44 and VHL45. In general, the exchange of conserved residues in the VL/VH interface did not have uniform effects on domain stability. Furthermore, the effects on association and antigen binding do not strictly correlate. In addition to the interface, the CDRs modulate the variable domain framework to a significant extent as shown by swap experiments. Our study reveals a complex interplay of domain stability, association and antigen binding including an unexpected strong mutual influence of the domain framework and the CDRs on stability/association on the one side and antigen binding on the other side.


Pediatric research priorities in healthcare-associated infections and antimicrobial stewardship.
To develop a pediatric research agenda focused on pediatric healthcare-associated infections and antimicrobial stewardship topics that will yield the highest impact on child health. The study included 26 geographically diverse adult and pediatric infectious diseases clinicians with expertise in healthcare-associated infection prevention and/or antimicrobial stewardship (topic identification and ranking of priorities), as well as members of the Division of Healthcare Quality and Promotion at the Centers for Disease Control and Prevention (topic identification). Using a modified Delphi approach, expert recommendations were generated through an iterative process for identifying pediatric research priorities in healthcare associated infection prevention and antimicrobial stewardship. The multistep, 7-month process included a literature review, interactive teleconferences, web-based surveys, and 2 in-person meetings. A final list of 12 high-priority research topics were generated in the 2 domains. High-priority healthcare-associated infection topics included judicious testing for Clostridioides difficile infection, chlorhexidine (CHG) bathing, measuring and preventing hospital-onset bloodstream infection rates, surgical site infection prevention, surveillance and prevention of multidrug resistant gram-negative rod infections. Antimicrobial stewardship topics included β-lactam allergy de-labeling, judicious use of perioperative antibiotics, intravenous to oral conversion of antimicrobial therapy, developing a patient-level "harm index" for antibiotic exposure, and benchmarking and or peer comparison of antibiotic use for common inpatient conditions. We identified 6 healthcare-associated infection topics and 6 antimicrobial stewardship topics as potentially high-impact targets for pediatric research.


OX40-mediated differentiation to effector function requires IL-2 receptor signaling but not CD28, CD40, IL-12Rbeta2, or T-bet.
Ag-specific CD4 T cells transferred into unirradiated Ag-bearing recipients proliferate, but survival and accumulation of proliferating cells is not extensive and the donor cells do not acquire effector functions. We previously showed that a single costimulatory signal delivered by an agonist Ab to OX40 (CD134) promotes accumulation of proliferating cells and promotes differentiation to effector CD4 T cells capable of secreting IFN-gamma. In this study, we determined whether OX40 costimulation requires supporting costimulatory or differentiation signals to drive acquisition of effector T cell function. We report that OX40 engagement drives effector T cell differentiation in the absence of CD28 and CD40 signals. Two important regulators of Th1 differentiation, IL-12R and T-bet, also are not required for acquisition of effector function in CD4 T cells responsive to OX40 stimulation. Finally, we show that CD25-deficient CD4 T cells produce little IFN-gamma in the presence of OX40 costimulation compared with wild type, suggesting that IL-2R signaling is required for efficient OX40-mediated differentiation to IFN-gamma secretion.


Model Based Targeting of IL-6-Induced Inflammatory Responses in Cultured Primary Hepatocytes to Improve Application of the JAK Inhibitor Ruxolitinib.
IL-6 is a central mediator of the immediate induction of hepatic acute phase proteins (APP) in the liver during infection and after injury, but increased IL-6 activity has been associated with multiple pathological conditions. In hepatocytes, IL-6 activates JAK1-STAT3 signaling that induces the negative feedback regulator SOCS3 and expression of APPs. While different inhibitors of IL-6-induced JAK1-STAT3-signaling have been developed, understanding their precise impact on signaling dynamics requires a systems biology approach. Here we present a mathematical model of IL-6-induced JAK1-STAT3 signaling that quantitatively links physiological IL-6 concentrations to the dynamics of IL-6-induced signal transduction and expression of target genes in hepatocytes. The mathematical model consists of coupled ordinary differential equations (ODE) and the model parameters were estimated by a maximum likelihood approach, whereas identifiability of the dynamic model parameters was ensured by the Profile Likelihood. Using model simulations coupled with experimental validation we could optimize the long-term impact of the JAK-inhibitor Ruxolitinib, a therapeutic compound that is quickly metabolized. Model-predicted doses and timing of treatments helps to improve the reduction of inflammatory APP gene expression in primary mouse hepatocytes close to levels observed during regenerative conditions. The concept of improved efficacy of the inhibitor through multiple treatments at optimized time intervals was confirmed in primary human hepatocytes. Thus, combining quantitative data generation with mathematical modeling suggests that repetitive treatment with Ruxolitinib is required to effectively target excessive inflammatory responses without exceeding doses recommended by the clinical guidelines.


What Alert Thresholds Should Be Used to Identify Critical Risk Results: A Systematic Review of the Evidence.
Pathology laboratories are required to immediately report results which indicate a patient is at critical risk, but there is little consensus about what values are deemed critical. The aim of this review was to systematically review the literature on alert thresholds for common chemistry and hematology tests in adults and to provide an explicit and ranked source of this evidence. The literature search covered the period of 1995-2014. Evidence sources were critically appraised and ranked using the 1999 Stockholm hierarchy for analytical performance specifications in laboratory medicine modified for establishing decision limits. The 30 most frequently reported laboratory tests with alert thresholds are presented with evidence rankings. Similar thresholds were reported in North America, Europe and Asia. Seventy percent of papers reported thresholds set by individual institutions, while 18% contained thresholds from surveys of laboratories or clinicians. Forty-six percent of the papers referred to 1 or both of the 2 American laboratory surveys from the early 1990s. "Starter sets" of alert thresholds were recommended by 6 professional bodies, 3 of which were collaborations between pathologists and clinicians. None of the 9 outcome studies identified dealt with confounding factors. Recommendations by professional bodies based on outdated surveys of the former state of the art or consensus are currently the best sources of evidence for laboratories to build their alert list. Well-designed outcome studies and greater collaboration between clinicians and the laboratory are needed to identify the most appropriate alert thresholds that signify actionable, critical or significant risk to patient well-being.


Exploring dependence with data on spatial lattices.
The application of Markov random field models to problems involving spatial data on lattice systems requires decisions regarding a number of important aspects of model structure. Existing exploratory techniques appropriate for spatial data do not provide direct guidance to an investigator about these decisions. We introduce an exploratory quantity that is directly tied to the structure of Markov random field models based on one-parameter exponential family conditional distributions. This exploratory diagnostic is shown to be a meaningful statistic that can inform decisions involved in modeling spatial structure with statistical dependence terms. In this article, we develop the diagnostic, illustrate its use in guiding modeling decisions with simulated examples, and reexamine a previously published application.


Brachial artery low-flow-mediated constriction is increased early after coronary intervention and reduces during recovery after acute coronary syndrome: characterization of a recently described index of vascular function.
The endothelium plays a role in regulating vascular tone. Acute and dynamic changes in low-flow-mediated constriction (L-FMC) and how it changes with regard to traditional flow-mediated dilatation (FMD) have not been described. We aimed to investigate the changes in brachial artery L-FMC following percutaneous coronary intervention (PCI) and during recovery from non-ST-segment elevation myocardial infarction (NSTEMI). FMD was performed in accordance with a previously described technique in patients before and after PCI and in the recovery phase of NSTEMI, but in addition, L-FMC data were acquired from the last 30 s of cuff inflation. About 135 scans were performed in 96 participants (10 healthy volunteers and 86 patients). Measurement of brachial L-FMC was reproducible over hours. L-FMC was greater among patients with unstable vs. stable coronary atherosclerosis (-1.33 ±1.09% vs. -0.03 ± 1.26%, P < 0.01). Following PCI, FMD reduced (4.43 ± 2.93% vs. 1.66 ± 2.16%, P < 0.01) and L-FMC increased (-0.33 ± 0.76% vs. -1.63 ± 1.15%, P = 0.02). Furthermore, during convalescence from NSTEMI, L-FMC reduced (-1.37 ± 1.19% vs. 0.01 ± 0.82%, P = 0.02) in parallel with improvements in FMD (2.54 ± 2.19% vs. 5.15 ± 3.07%, P < 0.01). Brachial L-FMC can be measured reliably. Differences were observed between patients with stable and unstable coronary disease. L-FMC was acutely increased following PCI associated with reduced FMD and, in the recovery from NSTEMI, L-FMC reduced associated with increased FMD. These novel findings characterize acute and subacute variations in brachial L-FMC. The pathophysiological and clinical implications of these observations require further study.


MR imaging findings in some rare neurological complications of paediatric cancer.
Neurological complications of paediatric cancers are a substantial problem. Complications can be primary from central nervous system (CNS) spread or secondary from indirect or remote effects of cancer, as well as cancer treatments such as chemotherapy and radiation therapy. In this review, we present the clinical and imaging findings of rare but important neurological complications in paediatric patients with cancer. Neurological complications are classified into three phases: pre-treatment, treatment and post-remission. Paraneoplastic neurological syndromes, hyperviscosity syndrome, haemophagocytic lymphohistiocytosis and infection are found in the pre-treatment phase, while Trousseau's syndrome, posterior reversible encephalopathy syndrome and methotrexate neurotoxicity are found in the treatment phase; though some complications overlap between the pre-treatment and treatment phases. Hippocampal sclerosis, radiation induced tumour, radiation induced focal haemosiderin deposition and radiation-induced white matter injury are found in the post-remission phase. With increasingly long survival after treatment, CNS complications have become more common. It is critical for radiologists to recognise neurological complications related to paediatric cancer or treatment. Magnetic resonance imaging (MRI) plays a significant role in the recognition and proper management of the neurological complications of paediatric cancer. TEACHING POINTS: • Neurological complications of paediatric cancer include various entities. • Neurological complications are classified into three phases: pre-treatment, treatment and post-remission. • Radiologists should be familiar with clinical and imaging findings of neurological complications. • MRI features may be characteristic and lead to early diagnosis and proper treatments.


Extrarenal potassium adaptation: the role of aldosterone.
1. Prior adaptation to a high potassium (HK) diet reduces the increment in plasma potassium after nephrectomy and acute potassium loading. Previous work has suggested that this 'extrarenal potassium adaptation' is due to direct stimulation of cellular potassium uptake by chronic hyperaldosteronism. 2. In contrast, we have shown that when dietary potassium is withdrawn from HK rats, large urinary potassium losses persist, resulting in 'paradoxical potassium depletion'. This potassium depletion facilitates cellular potassium uptake and is, at least in part, responsible for extrarenal potassium adaptation. 3. To try to reconcile these observations, we explored further the role of aldosterone in extrarenal potassium adaptation. When dietary potassium was withdrawn from chronically adrenalectomized HK rats, paradoxical potassium depletion was markedly blunted and extrarenal potassium adaptation could not be demonstrated. Similarly, urinary potassium losses and potassium depletion were reduced when acute adrenalectomy was performed concomitantly with dietary potassium withdrawal. 4. We were unable to confirm previous studies showing extrarenal potassium adaptation in the absence of potassium depletion. Thus, extrarenal potassium adaptation did not occur after pretreatment with chronic high-dose mineralocorticoid, after prior adaptation to a sodium-free diet, or after prior adaptation to an extremely HK diet in the absence of dietary potassium withdrawal. 5. We conclude that chronic hyperaldosteronism is important in extrarenal potassium adaptation, but probably not via direct enhancement of cellular potassium uptake. Rather, in HK animals, hyperaldosteronism magnifies urinary potassium losses during fasting and thus promotes potassium depletion, which in turn facilitates the uptake of an acute potassium load.


The ironic effect of significant results on the credibility of multiple-study articles.
Cohen (1962) pointed out the importance of statistical power for psychology as a science, but statistical power of studies has not increased, while the number of studies in a single article has increased. It has been overlooked that multiple studies with modest power have a high probability of producing nonsignificant results because power decreases as a function of the number of statistical tests that are being conducted (Maxwell, 2004). The discrepancy between the expected number of significant results and the actual number of significant results in multiple-study articles undermines the credibility of the reported results, and it is likely that questionable research practices have contributed to the reporting of too many significant results (Sterling, 1959). The problem of low power in multiple-study articles is illustrated using Bem's (2011) article on extrasensory perception and Gailliot et al.'s (2007) article on glucose and self-regulation. I conclude with several recommendations that can increase the credibility of scientific evidence in psychological journals. One major recommendation is to pay more attention to the power of studies to produce positive results without the help of questionable research practices and to request that authors justify sample sizes with a priori predictions of effect sizes. It is also important to publish replication studies with nonsignificant results if these studies have high power to replicate a published finding.


Mechanical integrity of hemodialysis catheters after exposure to a novel catheter lock solution.
To examine the mechanical integrity of hemodialysis catheters after exposure to the combination of N-acetylcysteine, tigecycline, and heparin, compared with that of catheters exposed to heparin alone. We used 3 types of hemodialysis catheters: polyurethane, silicone, and carbothane catheters. Catheter segments were incubated in vitro for various time intervals of up to 2 weeks either in a novel catheter lock solution (novel CLS), which consisted of N-acetylcysteine, tigecycline, and heparin, or in heparin alone (as a control). At the time of testing, each segment was rinsed and cut longitudinally into 2 sections. All catheter sections were scanned using an optical dissecting microscope to check for surface abnormalities and to measure wall thickness. We also carried out tensile strength testing of another set of catheters using a universal testing machine. Tested parameters included stress at yield, strain at yield, stress at break, strain at break, modulus of elasticity, and force at break. The surfaces of catheters in both groups appeared similar by microscopy. The mean thickness of the catheter wall was not significantly different for the catheters exposed to the novel CLS and the catheters exposed to heparin (P > .05). Results for most of the tensile strength parameters tested were similar in the 2 groups of catheters at the end of 2 weeks of incubation. In particular, the force-at-break value of all tested catheters remained much greater than that recommended by industry standards. The use of the novel catheter lock solution did not impair the mechanical integrity or increase the propensity for fracture of hemodialysis catheters.


Sex differences in LRRK2 G2019S and idiopathic Parkinson's Disease.
To evaluate sex differences and the relative effect of G2019S LRRK2 mutations in Parkinson's disease (PD). 530 LRRK2 PD carriers and 759 noncarrier PD (idiopathic, IPD) evaluated as part of the Fox Foundation (MJFF) Consortium were included. All participants completed a study visit including information on clinical features, treatment, examination, and motor and nonmotor questionnaires. Clinical features were compared between men and women separately for IPD and LRRK2 PD; and features were compared between IPD and LRRK2 PD separately for men and women. Among IPD: men had higher levodopa equivalency dose (LED), worse activities of daily living and motoric severity but lower complications of therapy (UPDRS-IV). IPD women had higher olfaction and thermoregulatory scores and were more likely to report family history of PD. Among LRRK2 PD: Male predominance was not observed among G2019S LRRK2 cases. Women had worse UPDRS-IV but better olfaction. Among same sex:LRRK2 men and women had better olfaction than IPD counterparts. LRRK2 men demonstrated lower motor and higher cognitive, RBD and thermoregulation scores than IPD men and LRRK2 women had greater UDPRS-IV and rates of dyskinesia. There were clinical differences between sexes with a more severe phenotype in IPD men and more complications of therapy in women. The more severe male phenotype was moderated by LRRK2, with LRRK2 men and women showing less diversity of phenotype. Our study supports that both genetics and sex drive phenotype, and thus trials in LRRK2 and IPD should consider gender stratification in design or analysis.


Trajectories of cultural innovation from the Middle to Later Stone Age in Eastern Africa: Personal ornaments, bone artifacts, and ocher from Panga ya Saidi, Kenya.
African Middle Stone Age (MSA) populations used pigments, manufactured and wore personal ornaments, made abstract engravings, and produced fully shaped bone tools. However, ongoing research across Africa reveals variability in the emergence of cultural innovations in the MSA and their subsequent development through the Later Stone Age (LSA). When present, it appears that cultural innovations manifest regional variability, suggestive of distinct cultural traditions. In eastern Africa, several Late Pleistocene sites have produced evidence for novel activities, but the chronologies of key behavioral innovations remain unclear. The 3 m deep, well-dated, Panga ya Saidi sequence in eastern Kenya, encompassing 19 layers covering a time span of 78 kyr beginning in late Marine Isotope Stage 5, is the only known African site recording the interplay between cultural and ecological diversity in a coastal forested environment. Excavations have yielded worked and incised bones, ostrich eggshell beads (OES), beads made from seashells, worked and engraved ocher pieces, fragments of coral, and a belemnite fossil. Here, we provide, for the first time, a detailed analysis of this material. This includes a taphonomic, archeozoological, technological, and functional study of bone artifacts; a technological and morphometric analysis of personal ornaments; and a technological and geochemical analysis of ocher pieces. The interpretation of the results stemming from the analysis of OES beads is guided by an ethnoarcheological perspective and field observations. We demonstrate that key cultural innovations on the eastern African coast are evident by 67 ka and exhibit remarkable diversity through the LSA and Iron Age. We suggest the cultural trajectories evident at Panga ya Saidi were shaped by both regional traditions and cultural/demic diffusion.


Spectroscopic properties of Cr(4+):Lu(3)Al(5)O(12).
We report on the near-infrared absorption, emission, and lifetime data of Cr(4+):Lu(3)Al(5)O(12) (Cr:LAG) and compare the results with the known laser material Cr(4+)-doped Y(3)Al(5)O(12) (Cr:YAG). Lu(3)Al(5)O(12) has a smaller unit cell than Y(3)Al(5)O(12), and this feature is reflected in its spectroscopic properties. The low-temperature luminescence spectrum is shifted by 85 cm(-1) to higher energy compared with Cr:YAG. The luminescence lifetime of Cr:LAG at 10 K is 28.7 micros (Cr:YAG, 30.6 micros) and at 300 K is 4.3 micros (Cr:YAG, 3.5 micros). From these lifetimes we postulate that the quantum efficiency in Cr:LAG is higher than in Cr:YAG. We discuss the potential of Cr:LAG as a tunable near-infrared laser.


Spell checker for consumer language (CSpell).
Automated understanding of consumer health inquiries might be hindered by misspellings. To detect and correct various types of spelling errors in consumer health questions, we developed a distributable spell-checking tool, CSpell, that handles nonword errors, real-word errors, word boundary infractions, punctuation errors, and combinations of the above. We developed a novel approach of using dual embedding within Word2vec for context-dependent corrections. This technique was used in combination with dictionary-based corrections in a 2-stage ranking system. We also developed various splitters and handlers to correct word boundary infractions. All correction approaches are integrated to handle errors in consumer health questions. Our approach achieves an F1 score of 80.93% and 69.17% for spelling error detection and correction, respectively. The dual-embedding model shows a significant improvement (9.13%) in F1 score compared with the general practice of using cosine similarity with word vectors in Word2vec for context ranking. Our 2-stage ranking system shows a 4.94% improvement in F1 score compared with the best 1-stage ranking system. CSpell improves over the state of the art and provides near real-time automatic misspelling detection and correction in consumer health questions. The software and the CSpell test set are available at https://umlslex.nlm.nih.gov/cSpell.


The MERCI Retrieval System for the management of acute ischaemic stroke--the NNI Singapore experience.
Systemic and local intra-arterial thrombolysis in patients with large vessel ischaemic stroke is hampered by poor re-canalisation rates and risk of haemorrhage. The Merci Retrieval System is an endovascular device for removal of acute intracranial thrombus. We present our initial experience using this device in conjunction with existing thrombolytic therapy already in place in our institute. Prospective data in all patients presenting with large vessel ischaemic stroke treated using the Merci Retrieval System from July 2007 to March 2009 were analysed. Selection criteria for patients were similar to the multi- Merci trial of 2008. We compared re-canalisation rate, National Institutes of Health Stroke Score (NIHSS) and modified Rankin score (mRS) outcomes to the published trial results. Seventeen patients were reviewed; none suffered immediate post-procedural complications. Fifteen underwent successful thrombus retrieval but in 2 cases the device failed due to technical considerations. Sites of vascular occlusion included: ICA/ICA-'T' junctions 27%, middle cerebral artery 13% and vertebrobasilar artery 60%. Of the 15 patients treated by MERCI with or without adjuvant thrombolytic therapy, complete re-canalisation was achieved in 60%, partial re-canalisation in 20%, partial re-canalisation with persistent distal vessel occlusion in 6% and failure of re-canalisation in 14%. Asymptomatic haemorrhage occurred in 33% and there was 1 death (6%) from symptomatic haemorrhage. Pre-treatment median NIHSS was 17.88 and 9.5 immediately post-treatment. Median mRS at 30 days was 2.6 for patients who achieved complete re-canalisation and 4.5 in failure or partial re-canalisation with or without persistent distal vessel occlusion. Re-canalisation rates using the Merci Retrieval System was comparable to the multi-Merci trial. Haemorrhagic complications and safety were also found to be satisfactory. Importantly, treatment success with eventual good clinical outcome hinges strongly on the ability of the device to achieve complete re-canalisation.


MR of the endolymphatic duct and sac: findings in Menière disease.
To compare the visibility of the endolymphatic duct and sac on high-resolution MR images with the symptoms and clinical course in patients with Menière disease. Twenty-two patients with unilateral Menière disease were sorted into two groups on the basis of the clinical stage of their disease at the time of imaging. Group 1 included patients in the acute phase, who presented with vertigo. Group 2 comprised patients in the nonacute phase of the disease, who were studied 9 days or more after an episode of vertigo. During acute attacks, the endolymphatic duct and sac were not adequately visible in the affected ear but were visible in the unaffected ear. During remission, the endolymphatic duct and sac were not observed in clinically advanced patients, but they were seen in patients in the early and intermediate stages. High-resolution MR imaging can be used to evaluate the endolymphatic duct and sac: visible abnormalities and lack of a visible endolymphatic duct and sac correlate with the clinical course of Menière disease.


Female PCP-using jail detainees: proneness to violence and gender differences.
Previous studies indicate that PCP users have different characteristics from other drug users and that female PCP use is more common than use among males. Furthermore, there is evidence that those who respond to PCP with violence may differ from those who do not. This study attempted to examine comprehensively the psychological, behavioral, and background factors among female jail inmates that may contribute to a PCP preference and subjects' perception of various behavioral states while using PCP. Female PCP users were further examined relative to male PCP users to differentiate them on the basis of these perceptual factors. A distinction was further made between females and males prone to PCP-induced violence and those who do not become violent with respect to the above psychological and behavioral measures. Our results showed differences between male and female PCP users that are discrepant with the assumption that men and women perceive similar drug-related experiences. In particular, female PCP using subjects reported more dysphoria and aggressiveness when not using PCP, while male subjects were more likely to report aggressive behavior and dysphoria under the influence. Overall, these results suggest that males who prefer PCP may be self-stimulating and females who prefer PCP may be attempting to self-medicate.


Cortical Components of Reaction-Time during Perceptual Decisions in Humans.
The mechanisms of perceptual decision-making are frequently studied through measurements of reaction time (RT). Classical sequential-sampling models (SSMs) of decision-making posit RT as the sum of non-overlapping sensory, evidence accumulation, and motor delays. In contrast, recent empirical evidence hints at a continuous-flow paradigm in which multiple motor plans evolve concurrently with the accumulation of sensory evidence. Here we employ a trial-to-trial reliability-based component analysis of encephalographic data acquired during a random-dot motion task to directly image continuous flow in the human brain. We identify three topographically distinct neural sources whose dynamics exhibit contemporaneous ramping to time-of-response, with the rate and duration of ramping discriminating fast and slow responses. Only one of these sources, a parietal component, exhibits dependence on strength-of-evidence. The remaining two components possess topographies consistent with origins in the motor system, and their covariation with RT overlaps in time with the evidence accumulation process. After fitting the behavioral data to a popular SSM, we find that the model decision variable is more closely matched to the combined activity of the three components than to their individual activity. Our results emphasize the role of motor variability in shaping RT distributions on perceptual decision tasks, suggesting that physiologically plausible computational accounts of perceptual decision-making must model the concurrent nature of evidence accumulation and motor planning.


Identification of Novel Immunogenic Proteins of Neisseria gonorrhoeae by Phage Display.
Neisseria gonorrhoeae is one of the most prevalent sexually transmitted diseases worldwide with more than 100 million new infections per year. A lack of intense research over the last decades and increasing resistances to the recommended antibiotics call for a better understanding of gonococcal infection, fast diagnostics and therapeutic measures against N. gonorrhoeae. Therefore, the aim of this work was to identify novel immunogenic proteins as a first step to advance those unresolved problems. For the identification of immunogenic proteins, pHORF oligopeptide phage display libraries of the entire N. gonorrhoeae genome were constructed. Several immunogenic oligopeptides were identified using polyclonal rabbit antibodies against N. gonorrhoeae. Corresponding full-length proteins of the identified oligopeptides were expressed and their immunogenic character was verified by ELISA. The immunogenic character of six proteins was identified for the first time. Additional 13 proteins were verified as immunogenic proteins in N. gonorrhoeae.


Ldb1- and Rnf12-dependent regulation of Lhx2 controls the relative balance between neurogenesis and gliogenesis in the retina.
Precise control of the relative ratio of retinal neurons and glia generated during development is essential for visual function. We show that Lhx2, which encodes a LIM-homeodomain transcription factor essential for specification and differentiation of retinal Müller glia, also plays a crucial role in the development of retinal neurons. Overexpression of Lhx2 with its transcriptional co-activator Ldb1 triggers cell cycle exit and inhibits both Notch signaling and retinal gliogenesis. Lhx2/Ldb1 overexpression also induces the formation of wide-field amacrine cells (wfACs). In contrast, Rnf12, which encodes a negative regulator of LDB1, is necessary for the initiation of retinal gliogenesis. We also show that Lhx2-dependent neurogenesis and wfAC formation requires Ascl1 and Neurog2, and that Lhx2 is necessary for their expression, although overexpression of Lhx2/Ldb1 does not elevate expression of these proneural bHLH factors. Finally, we demonstrate that the relative level of the LHX2-LDB1 complex in the retina decreases in tandem with the onset of gliogenesis. These findings show that control of Lhx2 function by Ldb1 and Rnf12 underpins the coordinated differentiation of neurons and Müller glia in postnatal retina.


The evolution of metabolic networks of E. coli.
Despite the availability of numerous complete genome sequences from E. coli strains, published genome-scale metabolic models exist only for two commensal E. coli strains. These models have proven useful for many applications, such as engineering strains for desired product formation, and we sought to explore how constructing and evaluating additional metabolic models for E. coli strains could enhance these efforts. We used the genomic information from 16 E. coli strains to generate an E. coli pangenome metabolic network by evaluating their collective 76,990 ORFs. Each of these ORFs was assigned to one of 17,647 ortholog groups including ORFs associated with reactions in the most recent metabolic model for E. coli K-12. For orthologous groups that contain an ORF already represented in the MG1655 model, the gene to protein to reaction associations represented in this model could then be easily propagated to other E. coli strain models. All remaining orthologous groups were evaluated to see if new metabolic reactions could be added to generate a pangenome-scale metabolic model (iEco1712_pan). The pangenome model included reactions from a metabolic model update for E. coli K-12 MG1655 (iEco1339_MG1655) and enabled development of five additional strain-specific genome-scale metabolic models. These additional models include a second K-12 strain (iEco1335_W3110) and four pathogenic strains (two enterohemorrhagic E. coli O157:H7 and two uropathogens). When compared to the E. coli K-12 models, the metabolic models for the enterohemorrhagic (iEco1344_EDL933 and iEco1345_Sakai) and uropathogenic strains (iEco1288_CFT073 and iEco1301_UTI89) contained numerous lineage-specific gene and reaction differences. All six E. coli models were evaluated by comparing model predictions to carbon source utilization measurements under aerobic and anaerobic conditions, and to batch growth profiles in minimal media with 0.2% (w/v) glucose. An ancestral genome-scale metabolic model based on conserved ortholog groups in all 16 E. coli genomes was also constructed, reflecting the conserved ancestral core of E. coli metabolism (iEco1053_core). Comparative analysis of all six strain-specific E. coli models revealed that some of the pathogenic E. coli strains possess reactions in their metabolic networks enabling higher biomass yields on glucose. Finally the lineage-specific metabolic traits were compared to the ancestral core model predictions to derive new insight into the evolution of metabolism within this species. Our findings demonstrate that a pangenome-scale metabolic model can be used to rapidly construct additional E. coli strain-specific models, and that quantitative models of different strains of E. coli can accurately predict strain-specific phenotypes. Such pangenome and strain-specific models can be further used to engineer metabolic phenotypes of interest, such as designing new industrial E. coli strains.


Emergency contraception: a national survey of adolescent health experts.
In a survey of 167 physicians with expertise in adolescent health, 84% said they prescribe contraception to adolescents, but only 80% of these prescribe emergency contraception, generally a few times a year at most. Some 12% of respondents said they believe that providing emergency contraception to adolescents would encourage contraceptive risk-taking, 25% said they think it would discourage correct use of other methods and 29% said they think repeated use of the method could post health risks. Physicians who were more likely than their colleagues to prescribe emergency contraception included obstetrician-gynecologists (92%), those who graduated from medical school after 1970 (77%) and those who describe their practice as being in an "academic" setting (76%). Physicians may restrict use of the method by limiting treatment to adolescents who seek it within 48 hours after unprotected intercourse (29%), by requiring a pregnancy test (64%) or an office visit (68%), or by using the timing of menses as a criterion for providing the method (46%). While 41% of physicians who provide emergency contraception counsel adolescents about the method during family planning visits, only 28% do so during visits for routine health care; 16% counsel women who are not yet sexually active about the method.


Superfocusing of light below the diffraction limit by photonic crystals with negative refraction.
Usual optical elements cannot focus a light beam to a spot with diameter smaller than half of the wavelength of the light; however overcoming this limit is of great importance in several applications in high-tech, such as optical lithography or magneto-optical date storage and numerous other fields of science and industry. Here we show that it is possible to focus light to spots below the diffraction limit (superfocusing) by the combination of two main elements: one which creates weak near-field evanescent components of the beam, like a wavelength-scale aperture, and an amplifier of these evanescent fields, like a slab of a photonic crystal with negative refraction.


Fetal growth, stillbirth, infant mortality and other birth outcomes near UK municipal waste incinerators; retrospective population based cohort and case-control study.
Some studies have reported associations between municipal waste incinerator (MWI) exposures and adverse birth outcomes but there are few studies of modern MWIs operating to current European Union (EU) Industrial Emissions Directive standards. Associations between modelled ground-level particulate matter ≤10 μm in diameter (PM10) from MWI emissions (as a proxy for MWI emissions) within 10 km of each MWI, and selected birth and infant mortality outcomes were examined for all 22 MWIs operating in Great Britain 2003-10. We also investigated associations with proximity of residence to a MWI. Outcomes used were term birth weight, small for gestational age (SGA) at term, stillbirth, neonatal, post-neonatal and infant mortality, multiple births, sex ratio and preterm delivery sourced from national registration data from the Office for National Statistics. Analyses were adjusted for relevant confounders including year of birth, sex, season of birth, maternal age, deprivation, ethnicity and area characteristics and random effect terms were included in the models to allow for differences in baseline rates between areas and in incinerator feedstock. Analyses included 1,025,064 births and 18,694 infant deaths. There was no excess risk in relation to any of the outcomes investigated during pregnancy or early life of either mean modelled MWI PM10 or proximity to an MWI. We found no evidence that exposure to PM10 from, or living near to, an MWI operating to current EU standards was associated with harm for any of the outcomes investigated. Results should be generalisable to other MWIs operating to similar standards.


Hepatitis C virus NS3 protein polynucleotide-stimulated nucleoside triphosphatase and comparison with the related pestivirus and flavivirus enzymes.
Sequence motifs within the nonstructural protein NS3 of members of the Flaviviridae family suggest that this protein possesses nucleoside triphosphatase (NTPase) and RNA helicase activity. The RNA-stimulated NTPase activity of this protein from prototypic members of the Pestivirus and Flavivirus genera has recently been established and enzymologically characterized. Here, we experimentally demonstrate that the NS3 protein from a member of the third genus of Flaviviridae, human hepatitis C virus (HCV), also possesses a polynucleotide-stimulated NTPase activity. Characterization of the purified HCV NTPase activity showed that it exhibited reaction condition optima with respect to pH, MgCl2, and salt identical to those of the representative pestivirus and flavivirus enzymes. However, each NTPase also possessed several unique properties when compared with one another. Notably, the profile of polynucleotide stimulation of the NTPase activity was distinct for the three enzymes. The HCV NTPase was the only one whose activity was significantly enhanced by a deoxyribopolynucleotide. Additional distinguishing features among the three enzymes relating to the kinetic properties of their NTPase activities are discussed. These studies provide a foundation for investigation of the putative RNA helicase activity of these proteins and for further study of the role of the NS3 proteins of members of the Flaviviridae in the replication cycle of these viruses.


Monitoring malaria vector control interventions: effectiveness of five different adult mosquito sampling methods.
Long-term success of ongoing malaria control efforts based on mosquito bed nets (long-lasting insecticidal net) and indoor residual spraying is dependent on continuous monitoring of mosquito vectors, and thus on effective mosquito sampling tools. The objective of our study was to identify the most efficient mosquito sampling tool(s) for routine vector surveillance for malaria and lymphatic filariasis transmission in coastal Kenya. We evaluated relative efficacy of five collection methods--light traps associated with a person sleeping under a net, pyrethrum spray catches, Prokopack aspirator, clay pots, and urine-baited traps--in four villages representing three ecological settings along the south coast of Kenya. Of the five methods, light traps were the most efficient for collecting female Anopheles gambiae s.l. (Giles) (Diptera: Culicidae) and Anopheles funestus (Giles) (Diptera: Culicidae) mosquitoes, whereas the Prokopack aspirator was most efficient in collecting Culex quinquefasciatus (Say) (Diptera: Culicidae) and other culicines. With the low vector densities here, and across much of sub-Saharan Africa, wherever malaria interventions, long-lasting insecticidal nets, and/or indoor residual spraying are in place, the use of a single mosquito collection method will not be sufficient to achieve a representative sample of mosquito population structure. Light traps will remain a relevant tool for host-seeking mosquitoes, especially in the absence of human landing catches. For a fair representation of the indoor mosquito population, light traps will have to be supplemented with aspirator use, which has potential for routine monitoring of indoor resting mosquitoes, and can substitute the more labor-intensive and intrusive pyrethrum spray catches. There are still no sufficiently efficient mosquito collection methods for sampling outdoor mosquitoes, particularly those that are bloodfed.


Substance-associated elevations in monocyte activation among methamphetamine users with treated HIV infection.
Microbial translocation and monocyte activation predict mortality in treated HIV. We examined whether substance use independently contributes to these pathophysiologic processes. Cross-sectional study at baseline for a randomized controlled trial. HIV-positive, methamphetamine-using MSM with undetectable HIV viral load (less than 40 copies/ml) were enrolled. We examined if plasma biomarkers of monocyte activation and intestinal barrier integrity were associated with the following: reactive urine toxicology results (Tox+) for stimulants (i.e., methamphetamine or cocaine) and substance use severity measured by the Addiction Severity Index. Multiple linear regression models adjusted for age, antiretroviral therapy regimen, CD4 T-cell count, interleukin-6, and alcohol use severity. The sample of 84 virally suppressed MSM had a median CD4 T-cell count of 645 cells/μl. Those who were Tox+ for stimulants displayed higher soluble CD14 (sCD14) levels (2087 versus 1801 ng/ml; P = 0.009), and this difference remained significant after adjusting for covariates (standardized beta = 0.23, P = 0.026). Greater substance use severity was also independently associated with higher sCD14 after adjusting for covariates (standardized beta = 0.29, P = 0.013). Being Tox+ for stimulants and substance use severity were not associated with soluble CD163 (sCD163) or intestinal fatty acid binding protein (iFABP) levels (P > 0.05). Monocyte activation is one plausible mechanism by which stimulant use may increase clinical HIV progression.


The impact of dental metal artifacts on head and neck IMRT dose distributions.
To quantify the cold or hot spot induced in IMRT treatment plans due to the presence of metal artifact in CT image data sets stemming from dental work. Metal artifact corrected image data sets of five patients have been analyzed. IMRT plans were generated using five different planning image data sets: (a) uncorrected (UC) (b) homogeneous uncorrected (HUC), (c) sinogram completion corrected (SCC), (d) minimum value corrected (MVC), and (e) image set (d) subsequently corrected with a streak artifacts reduction algorithm (SAR-MVC). The SAR-MVC data set is assumed to be the closest approximation to the absence of metal artifacts and has therefore been taken as the reference image data set. An IMRT plan was generated for each of the image datasets (a)-(e). The resulting IMRT treatment plans for data sets (a)-(d) were then projected onto the reference data set (e) and recalculated. The reference dose distribution (e) was then subtracted from these recalculated dose distributions. Using dose difference analysis, the cold and hot spots in organs at risk (OARs) and the target volumes (TVs) were quantified. When compared to the reference dose distribution, the UC, HUC, and SCC plans exhibited hot spots showing on average more than 1.0 Gy hot dose in the left and right parotids. For the UC, HUC, and SCC recalculated plans, subvolumes of the clinical target volumes (CTV) were under dosed on average by more than 0.9 Gy. On the other hand, the MVC plan showed less than 0.3 Gy hot dose in both parotids, and the cold dose in the CTVs were reduced by up to 0.8 Gy. The presence of dental metal artifacts in head and neck planning CT data sets can lead to relative hot spots in OARs and relative cold spots in regions of the TVs when compared to the reference data set that more closely approximates the patient anatomy. This effect can be reduced if a simple minimum value correction (MVC) method for the dental metal artifacts is employed.


Sub1 globally regulates RNA polymerase II C-terminal domain phosphorylation.
The transcriptional coactivator Sub1 has been implicated in several aspects of mRNA metabolism in yeast, such as activation of transcription, termination, and 3'-end formation. Here, we present evidence that Sub1 plays a significant role in controlling phosphorylation of the RNA polymerase II large subunit C-terminal domain (CTD). We show that SUB1 genetically interacts with the genes encoding all four known CTD kinases, SRB10, KIN28, BUR1, and CTK1, suggesting that Sub1 acts to influence CTD phosphorylation at more than one step of the transcription cycle. To address this directly, we first used in vitro kinase assays, and we show that, on the one hand, SUB1 deletion increased CTD phosphorylation by Kin28, Bur1, and Ctk1 but, on the other, it decreased CTD phosphorylation by Srb10. Second, chromatin immunoprecipitation assays revealed that SUB1 deletion decreased Srb10 chromatin association on the inducible GAL1 gene but increased Kin28 and Ctk1 chromatin association on actively transcribed genes. Taken together, our data point to multiple roles for Sub1 in the regulation of CTD phosphorylation throughout the transcription cycle.


Comprehensive EST analysis of tomato and comparative genomics of fruit ripening.
A large tomato expressed sequence tag (EST) dataset (152 635 total) was analyzed to gain insights into differential gene expression among diverse plant tissues representing a range of developmental programs and biological responses. These ESTs were clustered and assembled to a total of 31 012 unique gene sequences. To better understand tomato gene expression at a plant system level and to identify differentially expressed and tissue-specific genes, we developed and implemented a digital expression analysis protocol. By clustering genes according to their relative abundance in the various EST libraries, expression patterns of genes across various tissues were generated and genes with similar patterns were grouped. In addition, tissues themselves were clustered for relatedness based on relative gene expression as a means of validating the integrity of the EST data as representative of relative gene expression. Arabidopsis and grape EST collections were also characterized to facilitate cross-species comparisons where possible. Tomato fruit digital expression data was specifically compared with publicly available grape EST data to gain insight into molecular manifestation of ripening processes across diverse taxa and resulted in identification of common transcription factors not previously associated with ripening.


In vivo detection of GABA and glutamate with MEGA-PRESS: reproducibility and gender effects.
To evaluate the reproducibility of γ-amino-butyric acid (GABA) and glutamate concentrations derived using three different spectral fitting methods, and to investigate gender-related differences in neurotransmitter levels. Single voxel MEGA-edited PRESS MR spectra were acquired from a 30-mL voxel in the dorso-lateral prefrontal cortex in 14 adult volunteers (7 female) at 3 Tesla (3T). For each participant, four consecutive resting spectra were acquired within the same scanning session. Metabolite concentrations were derived using LCModel, jMRUI, and locally written peak fitting software. The within-session reproducibility for each analysis method was calculated as the average coefficient of variation (CV) of the GABA and Glx (glutamate+glutamine) concentrations. Gender differences in GABA and Glx were evaluated using a two-tailed unpaired t-test. LCModel provided the best reproducibility for both GABA (CV 7%) and Glx (CV 6%). GABA, Glx, and glutamate concentrations were significantly higher in the male participants, (P = 0.02, P = 0.001, and P < 0.001, respectively). GABA and glutamate can be quantified in vivo with high reproducibility (CV 6-7%) using frequency-domain spectral fitting methods like LCModel. However, the GABA and glutamate concentrations vary significantly between men and women, emphasizing the importance of gender-matching for studies investigating differences in neurotransmitter concentrations between mixed-cohort groups.


Gamma-glutamyl transferase variability and the risk of hospitalisation for heart failure.
Gamma-glutamyl transferase (GGT) is associated with oxidative stress, inflammation, cardiovascular disease and mortality. Variability in metabolic parameters has recently emerged as an indicator of adverse health outcomes, including heart failure (HF). We investigated whether GGT variability was associated with the incidence of hospitalisation for heart failure (HHF) in a Korean population without previous HF, ischaemic heart disease or liver disease. This longitudinal cohort study analysed 119 201 individuals from the Korean National Health Insurance Service-National Health Screening Cohort. GGT variability was calculated as the coefficient of variation (CV), SD and variability independent of the mean (VIM). During the 8.4 years of follow-up, 1387 cases of HHF (1.16%) developed. In the multivariable-adjusted model, the HR of HHF was 1.22 (95% CI 1.05 to 1.42) in the highest quartile of GGT variability compared with the lowest quartile, as assessed by CV after adjusting for confounding factors, including alcohol consumption and mean GGT levels. Consistent results were obtained using other indices of GGT variability such as SD (HR 1.37, 95% CI 1.16 to 1.62) and VIM (HR 1.29, 95% CI 1.11 to 1.50). In a subgroup analysis stratified by risk factor variables, although a similar relationship was observed, it was more prominent in individuals with dyslipidaemia. The results of the present study demonstrated that variability in GGT was independently associated with the incidence of HHF. These findings suggest that higher GGT variability may be useful as an indicator of future risk of HF.