Suicide bombings: process of care of mass casualties in the developing world.
In recent times Pakistan's biggest city, Karachi, has witnessed numerous terrorist attacks. The city does not have an emergency response system and only one of the three public sector hospitals has a trauma centre. We describe the pattern of injuries and management of two terror-related mass casualty incidents involving suicide bombers in a developing nation with limited resources. The first incident occurred in May 2002 with 36 casualties, of whom 13 (36%) died immediately and 11 (30.5%) died at the primary receiving hospitals. The second incident was targeted against the local population in May 2004. The blast resulted in 104 casualties, of which 14 (13.46%) died at the site. All patients had their initial assessment and treatment based on Advanced Trauma and Life Support principles and documented on a trauma form.


Caring Through Web-Based Communication: A Qualitative Evaluation of a Nursing Intervention to Create Holistic Well-Being Among Patients With Hematological Disease.
To examine how written communication between patients with hematological diseases and a nurse within a web-based communication service can be caring. The study is based on qualitative deductive content analysis of 109 written messages between 10 patients and a responding nurse. The evaluated nursing intervention is a web-based communication service where patients could request support from a responding nurse during 2 months of use. A structured theoretical matrix based on Swanson's theory of caring including compassion, competence, and upholding trust is used for the analysis. Nursing compassion emerges when patients share personal matters and the nurse has an opportunity to explicitly display genuine interest and understanding. Nursing competence is required when patients ask for or are in need of information, advice, and emotional support. The nurse can uphold trust when compassion and competence are exhibited and patients share their innermost feelings. Web-based communication has the potential to contribute to holistic well-being according to Swanson's theory of caring. The written word lasts, can be read repeatedly, and in connection with writing there is time for reflection. However, the lack of nonverbal cues makes it important that the nurse answers in a fully accurate and explicitly caring way.


Light-induced rearrangements of chemisorbed dyes on anatase(101).
Photoinduced molecular rearrangements are important in daily events essential for life such as visual perception and photo-protection of light harvesting complexes in plants. In this study we demonstrate that similar photoarrangements appear in an analogous technological application where the device performance is controlled by chromophores in sensitized anatase TiO(2), one of the main components for light-harvesting in dye-sensitized solar cells (DSC). STM reveals that illumination leads to distortions of organic dyes containing conjugated backbones and of cis-bis(isothiocyanate)-bis-(2,2'-bipyridyl-4,4'-dicarboxylate)ruthenium(II)-bis(tetrabutylammonium), known as N719. The dyes were adsorbed in a closed-packed mode on an anatase(101) single crystal surface and imaged in the dark and under white light illumination in an ultra-high vacuum (UHV). STM images of N719 clearly suggest rearrangements caused by rotation of the dye. Conversely, organic dyes rearrange by photoisomerization depending on the number of double bonds, their position in the molecular structure and on the ligand modifications.


Protective effects of Propolis extract on allyl alcohol-induced liver injury in mice.
Potential protective effects of ethanolic extract of Cuban red propolis against toxicity induced by allyl alcohol in mice was investigated. Propolis at doses of 25, 50 and 100 mg/i.p. significantly decreased the activity of alanine amino transferase (EC 188.8.131.52) in serum and the levels of mal-ondialdehyde in mouse liver after induction with a dose of 64 mg/kg of allyl alcohol. However, propolis did not increase the concentration of reduced glutathione in mouse liver which is depleted by allyl alcohol. Propolis also reduced liver damage induced by allyl alcohol in mice. This effect was observed by electron microscopy. The hepatoprotective effects of propolis were dose-dependent and they were produced when propolis was administered 30 min before allyl alcohol administration. It is indicated that the ethanolic extract of red propolis exerts potential hepatoprotective effects in this experimental model which is probably caused by antioxidative properties (e.g. scavenging action against oxygen radicals) of this extract.


Promoter analysis of the DHCR24 (3β-hydroxysterol Δ(24)-reductase) gene: characterization of SREBP (sterol-regulatory-element-binding protein)-mediated activation.
DHCR24 (3β-hydroxysterol Δ(24)-reductase) catalyses the reduction of the C-24 double bond of sterol intermediates during cholesterol biosynthesis. DHCR24 has also been involved in cell growth, senescence and cellular response to oncogenic and oxidative stress. Despite its important roles, little is known about the transcriptional mechanisms controlling DHCR24 gene expression. We analysed the proximal promoter region and the cholesterol-mediated regulation of DHCR24. A putative SRE (sterol-regulatory element) at -98/-90 bp of the transcription start site was identified. Other putative regulatory elements commonly found in SREBP (SRE-binding protein)-targeted genes were also identified. Sterol responsiveness was analysed by luciferase reporter assays of approximately 1 kb 5'-flanking region of the human DHCR24 gene in HepG2 and SK-N-MC cells. EMSAs (electrophoretic mobility-shift assays) and ChIP (chromatin immunoprecipitation) assays demonstrated cholesterol-dependent recruitment and binding of SREBPs to the putative SRE. Given the presence of several CACCC-boxes in the DHCR24 proximal promoter, we assessed the role of KLF5 (Krüppel-like factor 5) in androgen-regulated DHCR24 expression. DHT (dihydrotestosterone) increased DHCR24 expression synergistically with lovastatin. However, DHT was unable to activate the DHCR24 proximal promoter, whereas KLF5 did, indicating that this mechanism is not involved in the androgen-induced stimulation of DHCR24 expression. The results of the present study allow the elucidation of the mechanism of regulation of the DHCR24 gene by cholesterol availability and identification of other putative cis-acting elements which may be relevant for the regulation of DHCR24 expression.


Prevalence of dental caries and dental fluorosis among 12 and 15 years old school children in relation to fluoride concentration in drinking water in an endemic fluoride belt of Andhra Pradesh.
The published literature on the prevalence and severity of dental caries and dental fluorosis among school going children in Nalgonda district - An Endemic Fluoride belt was lacking . To assess the prevalence and severity of dental fluorosis and dental caries among 12 and 15 years old children in relation to fluoride concentration in drinking water . It was a cross-sectional study, done in Nalgonda district of Andhra Pradesh, India (endemic fluoride belt) . 5 of the 59 mandals in the district of Nalgonda were selected by simple random sampling. Then, 3 schools from each of these selected mandals were chosen at random. All the eligible 6 th and 9 th standard children were considered for final analysis. The demographic and other relevant information was collected by 3 trained and calibrated dentists, using a structured questionnaire. Dental caries were recorded using dentition status and treatment needs and fluorosis were recorded by Dean's fluorosis index. The statistical analysis was done using SPSS version 16. The prevalence of dental caries among children was 56.3% with the highest in below optimal fluoride area (71.3%) and lowest in optimal fluoride area (24.3%). The prevalence of dental fluorosis was 71.5%. The prevalence was 39.7% in below optimal fluoride area and 100% in high and very fluoride areas. The prevalence and severity of fluorosis increased with increasing fluoride concentration. The caries experience was more among boys than girls. There was a negative correlation between dental caries and fluoride concentration for the entire study population. However, in high fluoride areas, there was a positive correlation between fluoride concentration and dental caries. Water defluoridation on an urgent basis is a priority here than water fluoridation, because the prevalence and severity of dental flurorosis is very high.


Urinary tract infections in pregnancy: evaluation of diagnostic framework.
This study was performed with the objective to examine the diagnostic framework for urinary tract infection (UTI) in pregnancy and physician response to the clinical diagnosis and to correlate responses to the results of urine culture and sensitivity. Over a 6-month period, 81 consecutive patients attending the labor ward admission of a district general hospital with the diagnosis of UTI during pregnancy were analyzed. Relevant information on symptom complex, result of dipstick urinalysis and culture and sensitivity were recorded. Data were analyzed using descriptive statistics. Of the 78 patients analyzed, 79% had increased urinary frequency, 73.1% had suprapubic pains and 53.1% had dysuria. All the patients had urinalysis with dipsticks, 41 (52.6%) were positive for nitrites and 64 (82.1%) were positive for leukocyte esterase. All 78 patients had urine culture and sensitivity, 21 (26.8%) of who were positive, and coliforms were the most commonly isolated pathogens. The sensitivity for nitrite was 80.9%, specificity 57.9% and positive predictive value 41.4%. The corresponding figures for leukocyte esterase were sensitivity 100%, specificity 24.6% and positive predictive value 32.8%. Sixty-six (84.6%) patients had treatment started on the basis of the clinical diagnosis, mostly with co-amoxyclavullinic acid or amoxicillin alone. A high resistance rate to these empirically chosen antibiotics was seen in the sensitivity pattern of isolated pathogens. Current clinical diagnostic algorithms for the diagnosis of UTI when applied in the context of pregnancy have low specificity and positive predictive values; yet, empirical antibiotics are frequently employed on this basis. These are often not in keeping with the sensitivity pattern of isolated organisms. There is need for a continuing research for more specific bedside tests.


Replacement of Val3 in human thymidylate synthase affects its kinetic properties and intracellular stability .
Human and other mammalian thymidylate synthase (TS) enzymes have an N-terminal extension of approximately 27 amino acids that is not present in bacterial TSs. The extension, which is disordered in all reported crystal structures of TSs, has been considered to play a primary role in protein turnover but not in catalytic activity. In mammalian cells, the variant V3A has a half-life similar to that of wild-type human TS (wt hTS) while V3T is much more stable; V3L, V3F, and V3Y have half-lives approximately half of that for wt hTS. Catalytic turnover rates for most Val3 mutants are only slightly diminished, as expected. However, two mutants, V3L and V3F, have strongly compromised dUMP binding, with K(m,app) values increased by factors of 47 and 58, respectively. For V3L, this observation can be explained by stabilization of the inactive conformation of the loop of residues 181-197, which prevents substrate binding. In the crystal structure of V3L, electron density corresponding to a leucine residue is present in a position that stabilizes the loop of residues 181-197 in the inactive conformation. Since this density is not observed in other mutants and all other leucine residues are ordered in this structure, it is likely that this density represents Leu3. In the crystal structure of a V3F.FdUMP binary complex, the nucleotide is bound in an alternative mode to that proposed for the catalytic complex, indicating that the high K(m,app) value is caused not by stabilization of the inactive conformer but by substrate binding in a nonproductive, inhibitory site. These observations show that the N-terminal extension affects the conformational state of the hTS catalytic region. Each of the mechanisms leading to the high K(m,app) values can be exploited to facilitate design of compounds acting as allosteric inhibitors of hTS.


DNA cage delivery to mammalian cells.
DNA cages are nanometer-scale polyhedral structures formed by self-assembly from synthetic DNA oligonucleotides. Potential applications include in vivo imaging and the targeted delivery of macromolecules into living cells. We report an investigation of the ability of a model cage, a DNA tetrahedron, to enter live cultured mammalian cells. Cultured human embryonic kidney cells were treated with a range of fluorescently labeled DNA tetrahedra and subsequently examined using confocal microscopy and flow cytometry. Substantial uptake of tetrahedra into cells was observed both when the cells were treated with tetrahedra alone and when the cells were treated with a mixture of tetrahedra and a transfection reagent. Analysis of the subcellular localization of transfected tetrahedra using confocal microscopy and organelle staining indicates that the cages are located in the cytoplasm. FRET experiments indicate that the DNA cages remain substantially intact within the cells for at least 48 h after transfection. This is a first step toward the use of engineered DNA nanostructures to deliver and control the activity of cargoes within cells.


Identifying barriers from home to the appropriate hospital through near-miss audits in developing countries.
Near-miss cases often arrive in critical condition in referral hospitals in developing countries. Understanding the reasons why women arrive at these hospitals in a moribund state is crucial to the reduction of the incidence and case fatality of severe obstetric complications. This paper discusses how near-miss audits can empower the hospital teams to document and help reduce barriers to obstetric care in the most useful way and makes practical suggestions on interviews, analytical framework, ethical issues and staff motivation. Review of the evidence shows that case reviews and confidential enquiries appear particularly suitable to the understanding of delays. Criterion-based audits can also achieve this by establishing criteria for referral. However, hospital staff have limited intervention tools at their disposal to address barriers to emergency care at the community level. It is therefore important to involve the district management team and representatives of the community in auditing the health care seeking and treatment of women with near-miss complications.


Co-Labeling for Multi-View Weakly Labeled Learning.
It is often expensive and time consuming to collect labeled training samples in many real-world applications. To reduce human effort on annotating training samples, many machine learning techniques (e.g., semi-supervised learning (SSL), multi-instance learning (MIL), etc.) have been studied to exploit weakly labeled training samples. Meanwhile, when the training data is represented with multiple types of features, many multi-view learning methods have shown that classifiers trained on different views can help each other to better utilize the unlabeled training samples for the SSL task. In this paper, we study a new learning problem called multi-view weakly labeled learning, in which we aim to develop a unified approach to learn robust classifiers by effectively utilizing different types of weakly labeled multi-view data from a broad range of tasks including SSL, MIL and relative outlier detection (ROD). We propose an effective approach called co-labeling to solve the multi-view weakly labeled learning problem. Specifically, we model the learning problem on each view as a weakly labeled learning problem, which aims to learn an optimal classifier from a set of pseudo-label vectors generated by using the classifiers trained from other views. Unlike traditional co-training approaches using a single pseudo-label vector for training each classifier, our co-labeling approach explores different strategies to utilize the predictions from different views, biases and iterations for generating the pseudo-label vectors, making our approach more robust for real-world applications. Moreover, to further improve the weakly labeled learning on each view, we also exploit the inherent group structure in the pseudo-label vectors generated from different strategies, which leads to a new multi-layer multiple kernel learning problem. Promising results for text-based image retrieval on the NUS-WIDE dataset as well as news classification and text categorization on several real-world multi-view datasets clearly demonstrate that our proposed co-labeling approach achieves state-of-the-art performance for various multi-view weakly labeled learning problems including multi-view SSL, multi-view MIL and multi-view ROD.


Structure of monoubiquitinated PCNA: implications for DNA polymerase switching and Okazaki fragment maturation.
Ubiquitination of proliferating cell nuclear antigen (PCNA) to ub-PCNA is essential for DNA replication across bulky template lesions caused by UV radiation and alkylating agents, as ub-PCNA orchestrates the recruitment and switching of translesion synthesis (TLS) polymerases with replication polymerases. This allows replication to proceed, leaving the DNA to be repaired subsequently. Defects in a TLS polymerase, Pol η, lead to a form of Xeroderma pigmentosum, a disease characterized by severe skin sensitivity to sunlight damage and an increased incidence of skin cancer. Structurally, however, information on how ub-PCNA orchestrates the switching of these two classes of polymerases is lacking. We have solved the structure of ub-PCNA and demonstrate that the ubiquitin molecules in ub-PCNA are radially extended away from the PCNA without structural contact aside from the isopeptide bond linkage. This unique orientation provides an open platform for the recruitment of TLS polymerases through ubiquitin-interacting domains. However, the ubiquitin moieties, to the side of the equatorial PCNA plane, can place spatial constraints on the conformational flexibility of proteins bound to ub-PCNA. We show that ub-PCNA is impaired in its ability to support the coordinated actions of Fen1 and Pol δ in assays mimicking Okazaki fragment processing. This provides evidence for the novel concept that ub-PCNA may modulate additional DNA transactions other than TLS polymerase recruitment and switching.


New NodW- or NifA-regulated Bradyrhizobium japonicum genes.
A cluster of genes coding for putative plant cell-wall degrading enzymes (i.e., genes for two endoglucanases [gunA and gunA2], one pectinmethylesterase [pme], and one polygalacturonase [pgl]) was identified by sequence similarities in the symbiotic region of the Bradyrhizobium japonicum chromosome. In addition, a systematic screen of the region revealed several genes potentially transcribed by the sigma(54)-RNA polymerase and activated by the transcriptional regulator NifA (i.e., genes for proteins with similarity to outer membrane proteins [id117 and id525] and a citrate carrier [id331 or citA] and one open reading frame without similarity to known proteins [id747]). Expression studies using transcriptional lacZ fusions showed that gunA2 and pgl were strongly induced by the isoflavone genistein in a NodW-dependent manner, suggesting a role of the gene products in early events of the nodulation process; by contrast, gunA and pme expression was very weak in the conditions tested. The gunA2 gene product was purified and was shown to have cellulase activity. beta-Galactosidase activity expressed from transcriptional lacZ fusions to id117, id525, and id747 in the wild type and in nifA and rpoN mutant backgrounds confirmed that their transcription was dependent on NifA and sigma(54). Despite the presence of a -24/-12-type promoter and a NifA binding site upstream of citA, no regulation could be demonstrated in this case. Null mutations introduced in gunA, gunA2, pgl, pme, citA, id117, id525, and id747 did not impair the symbiosis with the host plants.


Differences on Primary Care Labor Perceptions in Medical Students from 11 Latin American Countries.
The shortage in Latin-American Primary Care (PC) workforce may be due to negative perceptions about it. These perceptions might be probably influenced by particular features of health systems and academic environments, thus varying between countries. Observational, analytic and cross-sectional multicountry study that evaluated 9,561 first and fifth-year medical students from 63 medical schools of 11 Latin American countries through a survey. Perceptions on PC work was evaluated through a previously validated scale. Tertiles of the scores were created in order to compare the different countries. Crude and adjusted prevalence ratios were calculated using simple and multiple Poisson regression with robust variance. Approximately 53% of subjects were female; mean age was 20.4±2.9 years; 35.5% were fifth-year students. Statistically significant differences were found between the study subjects' country, using Peru as reference. Students from Chile, Colombia, Mexico and Paraguay perceived PC work more positively, while those from Ecuador showed a less favorable position. No differences were found among perceptions of Bolivian, Salvadoran, Honduran and Venezuelan students when compared to their Peruvian peers. Perceptions of PC among medical students from Latin America vary according to country. Considering such differences can be of major importance for potential local specific interventions.


Quinolone-based antibacterial chemoprophylaxis in neutropenic patients: effect of augmented gram-positive activity on infectious morbidity. National Cancer Institute of Canada Clinical Trials Group.
To determine whether augmented quinolone-based antibacterial prophylaxis in neutropenic patients with cancer reduces infections caused by gram-positive cocci and preserves the protective effect against aerobic gram-negative bacilli. Open, randomized, controlled, multicenter clinical trial. Centers participating in the National Cancer Institute of Canada Clinical Trials Group. 111 eligible and evaluable patients hospitalized for severe neutropenia (neutrophil count < 0.5 x 10(9)/L lasting at least 14 days) who were receiving cytotoxic therapy for acute leukemia or bone marrow autografting. One of three oral antibacterial prophylactic regimens (norfloxacin, 400 mg every 12 hours; ofloxacin, 400 mg every 12 hours; or ofloxacin, 400 mg, plus rifampin, 300 mg every 12 hours) beginning with cytotoxic therapy. Incidence and cause of suspected or proven infection. Microbiologically documented overall infection rates for norfloxacin, ofloxacin, and ofloxacin plus rifampin were 47%, 24%, and 9%, respectively (P < 0.001). Corresponding rates were 24%, 13%, and 3%, respectively for staphylococcal bacteremia (P = 0.03) and, 21%, 3%, and 3%, respectively for streptococcal bacteremia (P < 0.01). The pattern of bacteremia suggested that rifampin played a role in suppressing staphylococcal infection. Both ofloxacin alone and ofloxacin plus rifampin had a clinically significant antistreptococcal effect. Aerobic gram-negative rods were cleared from rectal surveillance cultures in all patients after a median of 5.5 days and caused infection in only one patient (0.9%). The reductions in the number of microbiologically documented infections among ofloxacin recipients and ofloxacin plus rifampin recipients were offset by concomitant increases in the number of unexplained fevers (24% of norfloxacin recipients, 53% of ofloxacin recipients, and 49% of ofloxacin plus rifampin recipients; P = 0.02). No statistically significant difference was found among the treatment arms with respect to the overall incidence of febrile neutropenic episodes as defined for this trial (79% for the norfloxacin group, 82% for the ofloxacin group, and 77% for the ofloxacin plus rifampin group). Quinolone-based antibacterial chemoprophylaxis protected patients from aerobic gram-negative bacillary infections. Augmentation of the gram-positive activity reduced the incidence of gram-positive infections but did not influence the overall incidence of febrile neutropenic episodes.


Mutations in DNA methyltransferase DNMT3B in ICF syndrome affect its regulation by DNMT3L.
Deficiency in DNA methyltransferase DNMT3B causes a recessive human disorder characterized by immunodeficiency, centromeric instability and facial anomalies (ICF) in association with defects in genomic methylation. The majority of ICF mutations are single amino acid substitutions in the conserved catalytic domain of DNMT3B, which are believed to impair its enzymatic activity directly. The establishment of intact genomic methylation patterns in development requires a fine regulation of the de novo methylation activity of the two related methyltransferases DNMT3A and DNMT3B by regulatory factors including DNMT3L which has a stimulatory effect. Here, we show that two DNMT3B mutant proteins with ICF-causing substitution (A766P and R840Q) displayed a methylation activity similar to the wild-type enzyme both in vitro and in vivo. However, their stimulation by DNMT3L was severely compromised due to deficient protein interaction. Our findings suggest that methylation defects in ICF syndrome may also result from impaired stimulation of DNMT3B activity by DNMT3L or other unknown regulatory factors as well as from a weakened basal catalytic activity of the mutant DNMT3B protein per se.


Reconfigurable paramagnetic microswimmers: Brownian motion affects non-reciprocal actuation.
Swimming at low Reynolds number is typically dominated by a large viscous drag, therefore microscale swimmers require non-reciprocal body deformation to generate locomotion. Purcell described a simple mechanical swimmer at the microscale consisting of three rigid components connected together with two hinges. Here we present a simple microswimmer consisting of two rigid paramagnetic particles with different sizes. When placed in an eccentric magnetic field, this simple microswimmer exhibits non-reciprocal body motion and its swimming locomotion can be directed in a controllable manner. Additional components can be added to create a multibody microswimmer, whereby the particles act cooperatively and translate in a given direction. For some multibody swimmers, the stochastic thermal forces fragment the arm, which therefore modifies the swimming strokes and changes the locomotive speed. This work offers insight into directing the motion of active systems with novel time-varying magnetic fields. It also reveals that Brownian motion not only affects the locomotion of reciprocal swimmers that are subject to the Scallop theorem, but also affects that of non-reciprocal swimmers.


Induction of olfaction and cancer-related genes in mice fed a high-fat diet as assessed through the mode-of-action by network identification analysis.
The pathophysiological mechanisms underlying the development of obesity and metabolic diseases are not well understood. To gain more insight into the genetic mediators associated with the onset and progression of diet-induced obesity and metabolic diseases, we studied the molecular changes in response to a high-fat diet (HFD) by using a mode-of-action by network identification (MNI) analysis. Oligo DNA microarray analysis was performed on visceral and subcutaneous adipose tissues and muscles of male C57BL/6N mice fed a normal diet or HFD for 2, 4, 8, and 12 weeks. Each of these data was queried against the MNI algorithm, and the lists of top 5 highly ranked genes and gene ontology (GO)-annotated pathways that were significantly overrepresented among the 100 highest ranked genes at each time point in the 3 different tissues of mice fed the HFD were considered in the present study. The 40 highest ranked genes identified by MNI analysis at each time point in the different tissues of mice with diet-induced obesity were subjected to clustering based on their temporal patterns. On the basis of the above-mentioned results, we investigated the sequential induction of distinct olfactory receptors and the stimulation of cancer-related genes during the development of obesity in both adipose tissues and muscles. The top 5 genes recognized using the MNI analysis at each time point and gene cluster identified based on their temporal patterns in the peripheral tissues of mice provided novel and often surprising insights into the potential genetic mediators for obesity progression.


A fuzzy locally adaptive Bayesian segmentation approach for volume determination in PET.
Accurate volume estimation in positron emission tomography (PET) is crucial for different oncology applications. The objective of our study was to develop a new fuzzy locally adaptive Bayesian (FLAB) segmentation for automatic lesion volume delineation. FLAB was compared with a threshold approach as well as the previously proposed fuzzy hidden Markov chains (FHMC) and the fuzzy C-Means (FCM) algorithms. The performance of the algorithms was assessed on acquired datasets of the IEC phantom, covering a range of spherical lesion sizes (10-37 mm), contrast ratios (4:1 and 8:1), noise levels (1, 2, and 5 min acquisitions), and voxel sizes (8 and 64 mm(3)). In addition, the performance of the FLAB model was assessed on realistic nonuniform and nonspherical volumes simulated from patient lesions. Results show that FLAB performs better than the other methodologies, particularly for smaller objects. The volume error was 5%-15% for the different sphere sizes (down to 13 mm), contrast and image qualities considered, with a high reproducibility (variation < 4%). By comparison, the thresholding results were greatly dependent on image contrast and noise, whereas FCM results were less dependent on noise but consistently failed to segment lesions < 2 cm. In addition, FLAB performed consistently better for lesions < 2 cm in comparison to the FHMC algorithm. Finally the FLAB model provided errors less than 10% for nonspherical lesions with inhomogeneous activity distributions. Future developments will concentrate on an extension of FLAB in order to allow the segmentation of separate activity distribution regions within the same functional volume as well as a robustness study with respect to different scanners and reconstruction algorithms.


PHOTOREFRACTIVE SURGERY WITH EXCIMER LASER AND ITS IMPACT ON THE DIAGNOSIS AND FOLLOW-UP OF GLAUCOMA. A REVIEW.
Excimer laser refractive surgery is a procedure performed worldwide to solve refractive errors and reduce dependence on glasses or contact lenses. There has been an increase in the number of procedures performed around the world. Myopia is the most common indication for corneal photorefractive surgery. Myopic patients have a higher risk of developing some type of glaucoma in their lifetime, such as primary open-angle glaucoma and others. Refractive surgery ablates central corneal stromal tissue, altering its thickness and biomechanics, which in turn makes it difficult to accurately measure intraocular pressure (IOP), since it underestimates it. This underestimation of IOP may delay the diagnosis of de novo glaucoma in patients with a history of refractive surgery. Each patient who wishes to undergo corneal refractive surgery should undergo a thorough glaucoma examination in order to monitor and detect the possible development and / or progression of glaucoma. A very useful practical approach is to perform a series of IOP measurements before and after surgery, when the eye is already stable, and the difference between the averages of the two sets of readings can then be used as a personalised correction factor for postoperative IOP monitoring in that eye. Also, if there is any suspicion of a possible glaucoma, paraclinical tests, such as coherent optical tomography of the retinal nerve fibre layer (RNFL), visual fields and photos of the optic nerve should be requested. All this data prior to refractive surgery should be provided to these patients, so that they can save it and give it to their treating ophthalmologists in the future.


Associations of Benzodiazepines, Z-Drugs, and Other Anxiolytics With Subsequent Dementia in Patients With Affective Disorders: A Nationwide Cohort and Nested Case-Control Study.
Benzodiazepines and Z-drugs are two of the most prescribed agents worldwide. However, because of their cognitive side effects, the question of their influence on the risk of dementia has been raised. The authors examined the association of benzodiazepines, Z-drugs, and other anxiolytics with incident dementia in patients with affective disorders. The authors conducted a cohort and nested case-control study of 235,465 patients over age 20 who were identified in the Danish National Patient Registry as having had a first-time hospital contact for an affective disorder between 1996 and 2015. From the Danish National Prescription Registry, information was obtained on all prescriptions for benzodiazepines, Z-drugs, and other anxiolytics, and patients were followed for incident dementia (defined by hospital discharge diagnosis or acetylcholinesterase inhibitor use). Cox proportional hazards and conditional logistic regression models were used to calculate hazard ratios and odds ratios with adjustment for sociodemographic and clinical variables. A total of 75.9% (N=171,287) of patients had any use of benzodiazepines or Z-drugs, and during the median follow-up of 6.1 years (interquartile range, 2.7-11), 9,776 (4.2%) patients were diagnosed with dementia. Any use of benzodiazepines or Z-drugs showed no association with dementia after multiple adjustments in either the cohort analysis or a nested case-control design. In the cohort analysis, the number of prescriptions and the cumulated dose of benzodiazepines or Z-drugs at baseline were not associated with dementia. In the nested case-control study, where prescriptions were counted from 1995 until 2 years before the index date, there was a slightly higher odds ratio of dementia in patients with the lowest use of benzodiazepines or Z-drugs (odds ratio=1.08, 95% CI=1.01, 1.15) compared with no lifetime use. However, patients with the highest use had the lowest odds of developing dementia (odds ratio=0.83, 95% CI=0.77, 0.88). This large cohort study did not reveal associations between use of benzodiazepines or Z-drugs and subsequent dementia, even when exposures were cumulated or divided into long- and short-acting drugs. Some results were compatible with a protective effect.


All-Digital Time-Domain CMOS Smart Temperature Sensor with On-Chip Linearity Enhancement.
This paper proposes the first all-digital on-chip linearity enhancement technique for improving the accuracy of the time-domain complementary metal-oxide semiconductor (CMOS) smart temperature sensor. To facilitate on-chip application and intellectual property reuse, an all-digital time-domain smart temperature sensor was implemented using 90 nm Field Programmable Gate Arrays (FPGAs). Although the inverter-based temperature sensor has a smaller circuit area and lower complexity, two-point calibration must be used to achieve an acceptable inaccuracy. With the help of a calibration circuit, the influence of process variations was reduced greatly for one-point calibration support, reducing the test costs and time. However, the sensor response still exhibited a large curvature, which substantially affected the accuracy of the sensor. Thus, an on-chip linearity-enhanced circuit is proposed to linearize the curve and achieve a new linearity-enhanced output. The sensor was implemented on eight different Xilinx FPGA using 118 slices per sensor in each FPGA to demonstrate the benefits of the linearization. Compared with the unlinearized version, the maximal inaccuracy of the linearized version decreased from 5 °C to 2.5 °C after one-point calibration in a range of -20 °C to 100 °C. The sensor consumed 95 μW using 1 kSa/s. The proposed linearity enhancement technique significantly improves temperature sensing accuracy, avoiding costly curvature compensation while it is fully synthesizable for future Very Large Scale Integration (VLSI) system.


Cloning and characterization of a viral α2-3-sialyltransferase (vST3Gal-I) for the synthesis of sialyl Lewisx.
Sialyl Lewis(x) (SLe(x), Siaα2-3Galβ1-4(Fucα1-3)GlcNAcβOR) is an important sialic acid-containing carbohydrate epitope involved in many biological processes such as inflammation and cancer metastasis. In the biosynthetic process of SLe(x), α2-3-sialyltransferase-catalyzed sialylation generally proceeds prior to α1-3-fucosyltransferase-catalyzed fucosylation. For the chemoenzymatic synthesis of SLe(x) containing different sialic acid forms, however, it would be more efficient if diverse sialic acid forms are transferred in the last step to the fucosylated substrate Lewis(x) (Le(x)). An α2-3-sialyltransferase obtained from myxoma virus-infected European rabbit kidney RK13 cells (viral α2-3-sialyltransferase (vST3Gal-I)) was reported to be able to tolerate fucosylated substrate Le(x). Nevertheless, the substrate specificity of the enzyme was only determined using partially purified protein from extracts of cells infected with myxoma virus. Herein we demonstrate that a previously reported multifunctional bacterial enzyme Pasteurella multocida sialyltransferase 1 (PmST1) can also use Le(x) as an acceptor substrate, although at a much lower efficiency compared to nonfucosylated acceptor. In addition, N-terminal 30-amino-acid truncated vST3Gal-I has been successfully cloned and expressed in Escherichia coli Origami™ B(DE3) cells as a fusion protein with an N-terminal maltose binding protein (MBP) and a C-terminal His(6)-tag (MBP-Δ30vST3Gal-I-His(6)). The viral protein has been purified to homogeneity and characterized biochemically. The enzyme is active in a broad pH range varying from 5.0 to 9.0. It does not require a divalent metal for its α2-3-sialyltransferase activity. It has been used in one-pot multienzyme sialylation of Le(x) for the synthesis of SLe(x) containing different sialic acid forms with good yields.


A Case of Alveolar Haemorrhage Induced by Iodinated Contrast Medium Use.
An 81-year-old man complaining of exertional dyspnoea underwent coronary angiography using an iodinated contrast medium. After angiography, the patient required systemic corticosteroid therapy because of respiratory failure due to alveolar haemorrhage. Percutaneous coronary intervention was performed 29 days after angiography using the same contrast medium. After the intervention, the patient required intubated mechanical ventilation and renal replacement therapy. Bronchoalveolar lavage was bloody with many haemosiderin-filled macrophages. Systemic corticosteroid therapy again improved his clinical condition. Iodinated contrast media may cause alveolar haemorrhage and re-exposure to contrast media may induce a more severe adverse reaction. Iodinated contrast media may cause alveolar haemorrhage.Re-exposure to iodinated contrast media may induce a more severe adverse reaction.


Common variants spanning PLK4 are associated with mitotic-origin aneuploidy in human embryos.
Aneuploidy, the inheritance of an atypical chromosome complement, is common in early human development and is the primary cause of pregnancy loss. By screening day-3 embryos during in vitro fertilization cycles, we identified an association between aneuploidy of putative mitotic origin and linked genetic variants on chromosome 4 of maternal genomes. This associated region contains a candidate gene, Polo-like kinase 4 (PLK4), that plays a well-characterized role in centriole duplication and has the ability to alter mitotic fidelity upon minor dysregulation. Mothers with the high-risk genotypes contributed fewer embryos for testing at day 5, suggesting that their embryos are less likely to survive to blastocyst formation. The associated region coincides with a signature of a selective sweep in ancient humans, suggesting that the causal variant was either the target of selection or hitchhiked to substantial frequency.


Effect of testosterone propionate on performance and carcass characteristics of heifers and cows.
Two experiments were conducted to evaluate the effect of testosterone on growth and composition of cattle. In the first experiment, crossbred yearling heifers (n = 48) were assigned to four treatments: 1) control (no implant), 2) Synovex-H implants on d 1 and 84, 3) one testosterone propionate implant administered on d 1 and a second on d 84 and 4) two testosterone propionate implants administered on d 1. Heifers were fed a high-energy diet for the 157-d study. Implanting with the high-testosterone treatment improved (P less than .05) daily gain and feed efficiency compared with the other treatments. Marbling score was reduced (P less than .05) with the high-testosterone treatment. In Exp. 2, mature cows (n = 36) were assigned to one of three feeding periods (0, 42, or 84 d) with the cows fed 42 or 84 d subdivided into two groups (implanted with testosterone propionate or nonimplanted control). Cows were fed a high-energy diet and slaughtered at the end of each feeding period. Testosterone did not influence (P greater than .05) feedlot performance. Increased time on feed reduced (P less than .01) daily gain (live weight basis) and feed efficiency but did not influence feed intake. Testosterone treatment had little influence on the fat and moisture contents of the carcass soft tissue or on the palatability characteristics of loin steaks. Time on feed increased lean muscle mass and carcass fat (P less than .05). Sensory traits were improved at 42 d on feed (P less than .05), but no further sensory improvement was observed at 84 d.(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of mis-alignment between dispersal traits and landscape structure on dispersal success in fragmented landscapes.
Dispersal is fundamental to population dynamics and hence extinction risk. The dispersal success of animals depends on the biophysical structure of their environments and their biological traits; however, comparatively little is known about how evolutionary trade-offs among suites of biological traits affect dispersal potential. We developed a spatially explicit agent-based simulation model to evaluate the influence of trade-offs among a suite of biological traits on the dispersal success of vagile animals in fragmented landscapes. We specifically chose traits known to influence dispersal success: speed of movement, perceptual range, risk of predation, need to forage during dispersal, and amount of suitable habitat required for successful settlement in a patch. Using the metric of relative dispersal success rate, we assessed how the costs and benefits of evolutionary investment in these biological traits varied with landscape structure. In heterogeneous environments with low habitat availability and scattered habitat patches, individuals with more equal allocation across the trait spectrum dispersed most successfully. Our analyses suggest that the dispersal success of animals in heterogeneous environments is highly dependent on hierarchical interactions between trait trade-offs and the geometric configurations of the habitat patches in the landscapes through which they disperse. In an applied sense, our results indicate potential for ecological mis-alignment between species' evolved suites of dispersal-related traits and altered environmental conditions as a result of rapid global change. In many cases identifying the processes that shape patterns of animal dispersal, and the consequences of abiotic changes for these processes, will require consideration of complex relationships among a range of organism-specific and environmental factors.


Mortality related to novel psychoactive substances in Scotland, 2012: an exploratory study.
The growth of novel psychoactive substances (NPS) over the last decade, both in terms of availability and consumption, is of increasing public health concern. Despite recent increases in related mortality, the circumstances surrounding and characteristics of individuals involved in NPS deaths at a population level remain relatively unknown. The Scottish National Drug Related Death Database (NDRDD) collects a wide-range of data relating to the nature and circumstances of individuals who have died a drug-related death (DRD). We conducted exploratory descriptive analysis of DRDs involving NPS recorded by the NDRDD in 2012. Statistical testing of differences between sub-groups was also conducted where appropriate. In 2012, we found 36 DRDs in Scotland to have NPS recorded within post-mortem toxicology. However, in only 23 of these cases were NPS deemed by the reporting pathologist to be implicated in the actual cause of death. The majority of NPS-implicated DRDs involved Benzodiazepine-type drugs (13), mainly Phenazepam (12). The remaining 10 NPS-implicated deaths featured a range of different Stimulant-type drugs. The majority of these NPS-implicated deaths involved males and consumption of more than one drug was recorded by toxicology in all except one case. NPS-implicated deaths involving Benzodiazepine-type NPS drugs appeared to involve older individuals known to be using drugs for a considerable period of time, many of whom had been in prison at some point in their lives. They also typically involved combinations of opioids and benzodiazepines; no stimulant drugs were co-implicated. Deaths where stimulant-type NPS drugs were implicated appeared to be a younger group in comparison, all consuming two or more Stimulant-type drugs in combination. This exploratory study provides an important insight into the circumstances surrounding and characteristics of individuals involved in NPS deaths at a population level. It identifies important issues for policy and practice, not least the prominent role of unlicensed benzodiazepines in drug-related mortality, but also the need for a range of harm reduction strategies to prevent future deaths.


Modeling semantic aspects for cross-media image indexing.
To go beyond the query-by-example paradigm in image retrieval, there is a need for semantic indexing of large image collections for intuitive text-based image search. Different models have been proposed to learn the dependencies between the visual content of an image set and the associated text captions, then allowing for the automatic creation of semantic indices for unannotated images. The task, however, remains unsolved. In this paper, we present three alternatives to learn a Probabilistic Latent Semantic Analysis model (PLSA) for annotated images, and evaluate their respective performance for automatic image indexing. Under the PLSA assumptions, an image is modeled as a mixture of latent aspects that generates both image features and text captions, and we investigate three ways to learn the mixture of aspects. We also propose a more discriminative image representation than the traditional Blob histogram, concatenating quantized local color information and quantized local texture descriptors. The first learning procedure of a PLSA model for annotated images is a standard EM algorithm, which implicitly assumes that the visual and the textual modalities can be treated equivalently. The other two models are based on an asymmetric PLSA learning, allowing to constrain the definition of the latent space on the visual or on the textual modality. We demonstrate that the textual modality is more appropriate to learn a semantically meaningful latent space, which translates into improved annotation performance. A comparison of our learning algorithms with respect to recent methods on a standard dataset is presented, and a detailed evaluation of the performance shows the validity of our framework.


Cutting-edge technology for public health workforce training in comparative effectiveness research.
A critical mass of public health practitioners with expertise in analytic techniques and best practices in comparative effectiveness research is needed to fuel informed decisions and improve the quality of health care. The purpose of this case study is to describe the development and formative evaluation of a technology-enhanced comparative effectiveness research learning curriculum and to assess its potential utility to improve core comparative effectiveness research competencies among the public health workforce. Selected public health experts formed a multidisciplinary research collaborative and participated in the development and evaluation of a blended 15-week comprehensive e-comparative effectiveness research training program, which incorporated an array of health informatics technologies. Results indicate that research-based organizations can use a systematic, flexible, and rapid means of instructing their workforce using technology-enhanced authoring tools, learning management systems, survey research software, online communities of practice, and mobile communication for effective and creative comparative effectiveness research training of the public health workforce.


Glyphosate-based herbicides produce teratogenic effects on vertebrates by impairing retinoic acid signaling.
The broad spectrum herbicide glyphosate is widely used in agriculture worldwide. There has been ongoing controversy regarding the possible adverse effects of glyphosate on the environment and on human health. Reports of neural defects and craniofacial malformations from regions where glyphosate-based herbicides (GBH) are used led us to undertake an embryological approach to explore the effects of low doses of glyphosate in development. Xenopus laevis embryos were incubated with 1/5000 dilutions of a commercial GBH. The treated embryos were highly abnormal with marked alterations in cephalic and neural crest development and shortening of the anterior-posterior (A-P) axis. Alterations on neural crest markers were later correlated with deformities in the cranial cartilages at tadpole stages. Embryos injected with pure glyphosate showed very similar phenotypes. Moreover, GBH produced similar effects in chicken embryos, showing a gradual loss of rhombomere domains, reduction of the optic vesicles, and microcephaly. This suggests that glyphosate itself was responsible for the phenotypes observed, rather than a surfactant or other component of the commercial formulation. A reporter gene assay revealed that GBH treatment increased endogenous retinoic acid (RA) activity in Xenopus embryos and cotreatment with a RA antagonist rescued the teratogenic effects of the GBH. Therefore, we conclude that the phenotypes produced by GBH are mainly a consequence of the increase of endogenous retinoid activity. This is consistent with the decrease of Sonic hedgehog (Shh) signaling from the embryonic dorsal midline, with the inhibition of otx2 expression and with the disruption of cephalic neural crest development. The direct effect of glyphosate on early mechanisms of morphogenesis in vertebrate embryos opens concerns about the clinical findings from human offspring in populations exposed to GBH in agricultural fields.


Phenological Variation in Ambrosia artemisiifolia L. Facilitates Near Future Establishment at Northern Latitudes.
The invasive weed Ambrosia artemisiifolia (common ragweed) constitutes a great threat to public health and agriculture in large areas of the globe. Climate change, characterized by higher temperatures and prolonged vegetation periods, could increase the risk of establishment in northern Europe in the future. However, as the species is a short-day plant that requires long nights to induce bloom formation, it might still fail to produce mature seeds before the onset of winter in areas at northern latitudes characterized by short summer nights. To survey the genetic variation in flowering time and study the effect of latitudinal origin on this trait, a reciprocal common garden experiment, including eleven populations of A. artemisiifolia from Europe and North America, was conducted. The experiment was conducted both outside the range limit of the species, in Sweden and within its invaded range, in Croatia. Our main hypothesis was that the photoperiodic-thermal requirements of A. artemisiifolia constitute a barrier for reproduction at northern latitudes and, thus, halts the northern range shift despite expected climate change. Results revealed the presence of a north-south gradient in flowering time at both garden sites, indicating that certain European populations are pre-adapted to photoperiodic and thermal conditions at latitudes up to, at least, 60° N. This was confirmed by phenological recordings performed in a region close to the northern range limit, the north of Germany. Thus, we conclude that there exists a high risk for establishment and spread of A. artemisiifolia in FennoScandinavia in the near future. The range shift might occur independently of climate change, but would be accelerated by it.


Genetic and environmental influences on food preferences in adolescence.
Food preferences vary substantially among adults and children. Twin studies have established that genes and aspects of the shared family environment both play important roles in shaping children's food preferences. The transition from childhood to adulthood is characterized by large gains in independence, but the relative influences of genes and the environment on food preferences in late adolescence are unknown. The aim of this study was to quantify the contribution of genetic and environmental influences on food preferences in older adolescents. Participants were 2865 twins aged 18-19 y from the TEDS (Twins Early Development Study), a large population-based cohort of British twins born during 1994-1996. Food preferences were measured by using a self-report questionnaire of 62 individual foods. Food items were categorized into 6 food groups (fruit, vegetables, meat or fish, dairy, starch foods, and snacks) by using factor analysis. Maximum likelihood structural equation modeling established genetic and environmental contributions to variations in preferences for each food group. Genetic factors influenced a significant and substantial proportion of the variation in preference scores of all 6 food groups: vegetables (0.54; 95% CI: 0.47, 0.59), fruit (0.49; 95% CI: 0.43, 0.55), starchy foods (0.32; 95% CI: 0.24, 0.39), meat or fish (0.44; 95% CI: 0.38, 0.51), dairy (0.44; 95% CI: 0.37, 0.50), and snacks (0.43; 95% CI: 0.36, 0.49). Aspects of the environment that are not shared by 2 twins in a family explained all of the remaining variance in food preferences. Food preferences had a moderate genetic basis in late adolescence, in keeping with findings in children. However, by this older age, the influence of the shared family environment had disappeared, and only aspects of the environment unique to each individual twin influenced food preferences. This finding suggests that shared environmental experiences that influence food preferences in childhood may not have effects that persist into adulthood.


Efficient doubling of femtosecond pulses in aperiodically and periodically poled KTP crystals.
Efficient doubling of femtosecond pulses in periodically and aperiodically poled KTP crystals is demonstrated by employing the quasiphasematched frequency conversion technique. Conversion efficiencies as high as 60% were achieved using either aperiodically or periodically poled KTP nonlinear crystals in an extracavity, single-pass configuration using a diode-pumped femtosecond Yb:KYW laser as the pump source. The temporal characteristics of the frequency-doubled pulses as a function of focusing conditions in a "thick" nonlinear crystal regime have been investigated experimentally and pulses as short as 177 fs have been generated at around 520 nm under strong focusing conditions using a KTP crystal with aperiodic poling.


Dietary restriction: critical co-factors to separate health span from life span benefits.
Dietary restriction (DR), typically a 20%-40% reduction in ad libitum or "normal" nutritional energy intake, has been reported to extend life span in diverse organisms, including yeast, nematodes, spiders, fruit flies, mice, rats, and rhesus monkeys. The magnitude of the life span enhancement appears to diminish with increasing organismal complexity. However, the extent of life span extension has been notoriously inconsistent, especially in mammals. Recently, Mattison et al. reported that DR does not extend life span in rhesus monkeys in contrast to earlier work of Colman et al. Examination of these papers identifies multiple potential confounding factors. Among these are the varied genetic backgrounds and composition of the "normal" and DR diets. In monkeys, the correlation of DR with increased health span is stronger than that seen with life span and indeed may be separable. Recent mechanistic studies in Drosophila implicate non-genetic co-factors such as level of physical activity and muscular fatty acid metabolism in the benefits of DR. These results should be followed up in mammals. Perhaps levels of physical activity among the cohorts of rhesus monkeys contribute to inconsistent DR effects. To understand the maximum potential benefits from DR requires differentiating fundamental effects on aging at the cellular and molecular levels from suppression of age-associated diseases, such as cancer. To that end, it is important that investigators carefully evaluate the effects of DR on biomarkers of molecular aging, such as mutation rate and epigenomic alterations. Several short-term studies show that humans may benefit from DR in as little as 6 months, by achieving lowered fasting insulin levels and improved cardiovascular health. Optimized health span engineering will require a much deeper understanding of DR.


A meta-analysis of the efficacy of over-the-counter nicotine replacement.
To determine whether over-the-counter (OTC) nicotine replacement therapy (NRT) is pharmacologically efficacious, whether it produces abstinence rates similar to those in prescription settings, and to estimate the long term (that is, greater than six month) abstinence rate with OTC NRT. Systematic literature review. Medline, Psych Abstracts, bibliographies, requests of scientists. Studies comparing OTC NRT versus OTC placebo or studies comparing OTC NRT versus prescription NRT that reported abstinence rates and for which a full study report was available. Two of the authors independently reviewed studies and compared results. Meta-analysis was performed by first testing for homogeneity across studies, then combining odds ratios (ORs) weighting by inverse variance and proportions weighting by study sample size. One OTC NRT versus OTC placebo nicotine gum study was excluded due to small sample size and different setting. The four remaining studies were randomised trials of nicotine versus placebo patch with ORs of 2.1-3.2. These outcomes were homogenous and when combined resulted in an OR favouring NRT of 2.5 (95% confidence interval (CI) 1.8 to 3.6). Among the two randomised and two non-randomised trials of OTC NRT versus prescription NRT, one small study had an OR of 0.3, two others had ORs of 1.0 and 1.4, and a fourth study had an OR of 3.6. These results were not homogenous; however, when combined via a random effects model the estimated OR was not less than 1.0--that is, OR 1.4 (95% CI 0.6 to 3.3). The long term (that is, greater than six months) quit rates for OTC NRT was 1% and 6% in two studies and 8-11% in five other studies. These results were not homogenous; however, when combined the estimated OR was 7% (95% CI 4% to 11%). OTC NRT is pharmacologically efficacious and produces modest quit rates similar to that seen in real world prescription practice.


Awareness in early-stage Alzheimer's disease: relationship to outcome of cognitive rehabilitation.
Awareness of difficulties may have an important impact on functioning and response to intervention in early-stage Alzheimer's disease (AD). Clinical reports and retrospective studies suggest an association, but this has not previously been tested in a prospective study. Using a new measure of awareness, the Memory Awareness Rating Scale (MARS), which was designed to take account of methodological limitations identified in a review of previous studies, the present study explored the relationship between awareness of difficulties and outcome of a cognitive rehabilitation (CR) intervention in 12 participants with a diagnosis of early-stage Alzheimer's disease. The relationship between awareness and mood, behaviour and executive function was also assessed. The results provide the first demonstration in a prospective study that higher levels of awareness are related to better CR outcomes. Awareness was associated with depression and reported behaviour problems, but not with performance on tests of executive function. These results suggest that variations in level of awareness in early-stage AD are influenced by psychological factors, and that explanatory models need to take these factors into account. Awareness of difficulties may serve as a useful predictor of the likely effectiveness of CR, andthis may assist clinicians in selecting appropriate interventions for individuals with early-stage AD.


Mass primaquine treatment to eliminate vivax malaria: lessons from the past.
Recent successes in malaria control have put malaria eradication back on the public health agenda. A significant obstacle to malaria elimination in Asia is the large burden of Plasmodium vivax, which is more difficult to eliminate than Plasmodium falciparum. Persistent P. vivax liver stages can be eliminated only by radical treatment with a ≥ seven-day course of an 8-aminoquinoline, with the attendant risk of acute haemolytic anaemia in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Primaquine is the only generally available 8-aminoquinoline. Testing for G6PD deficiency is not widely available, and so whilst it is widely recommended, primaquine is often not prescribed. In the past, some countries aiming for vivax malaria eradication deployed mass treatments with primaquine on a massive scale, without G6PD testing. In Azerbaijan, Tajikistan (formerly USSR), North Afghanistan and DPR Korea 8,270,185 people received either a 14-day "standard" or a 17-day "interrupted" primaquine treatment to control post-eradication malaria epidemics. These mass primaquine preventive treatment campaigns were conducted by dedicated teams who administered the drugs under supervision and then monitored the population for adverse events. Despite estimated G6PD prevalences up to 38.7%, the reported frequency of severe adverse events related to primaquine was very low. This experience shows that with careful planning and implementation of mass treatment strategies using primaquine and adequate medical support to manage haemolytic toxicity, it is possible to achieve high population coverage, substantially reduce malaria transmission, and manage the risk of severe acute haemolytic anaemia in communities with a relatively high prevalence of G6PD deficiency safely.


Psychopaths know right from wrong but don't care.
Adult psychopaths have deficits in emotional processing and inhibitory control, engage in morally inappropriate behavior, and generally fail to distinguish moral from conventional violations. These observations, together with a dominant tradition in the discipline which sees emotional processes as causally necessary for moral judgment, have led to the conclusion that psychopaths lack an understanding of moral rights and wrongs. We test an alternative explanation: psychopaths have normal understanding of right and wrong, but abnormal regulation of morally appropriate behavior. We presented psychopaths with moral dilemmas, contrasting their judgments with age- and sex-matched (i) healthy subjects and (ii) non-psychopathic, delinquents. Subjects in each group judged cases of personal harms (i.e. requiring physical contact) as less permissible than impersonal harms, even though both types of harms led to utilitarian gains. Importantly, however, psychopaths' pattern of judgments on different dilemmas was the same as those of the other subjects. These results force a rejection of the strong hypothesis that emotional processes are causally necessary for judgments of moral dilemmas, suggesting instead that psychopaths understand the distinction between right and wrong, but do not care about such knowledge, or the consequences that ensue from their morally inappropriate behavior.


National intervention study of mastitis control in dairy herds in England and Wales.
An intervention study was carried out on 52 dairy farms in England and Wales to determine whether the implementation of a well-specified mastitis control plan in herds with an incidence of clinical mastitis of more than 35 cases per 100 cows per year would reduce the incidence of clinical mastitis, and also reduce the incidence of increases in the somatic cell counts of individual cows. A clearly defined plan for the diagnosis and control of mastitis was developed by two veterinary specialists from the research literature. The herds were randomly allocated to receive the plan either at the start of the study (intervention herds) or after one year (control herds). Data on mastitis management and the farm environment were collected during farm visits. After one year there was a significant 22 per cent reduction in the proportion of cows affected with clinical mastitis on the intervention farms compared with the control farms. There were also significant reductions of approximately 20 per cent in the incidence of clinical mastitis and in the occurrence of increases in the somatic cell counts of individual cows from below, to above 200,000 cells/ml.


The Team to Address Bariatric Care in Canadian Children (Team ABC3): Team Grant Research Proposal.
Severe obesity (SO) in Canadian children remains poorly understood. However, based on international data, the prevalence of SO appears to be increasing and is associated with a number of psychosocial, bio-mechanical, and cardiometabolic health risks. The purpose of our national Team to Address Bariatric Care in Canadian Children (Team ABC3) is to develop and lead a series of inter-related studies to enhance the understanding and management of SO in Canadian children and adolescents (0-18 years). From 2015 to 2019, Team ABC3 will conduct a series of projects at the regional, provincial, and national levels using multiple methods and study designs to respond to key knowledge gaps by (i) generating evidence on the prevalence of SO and its impact on health services utilization in children using existing Canadian data sources from primary care settings, (ii) exploring contemporary definitions of SO that link with health outcomes, (iii) comparing and contrasting health risks across the continuum of SO, (iv) understanding potential barriers to and facilitators of treatment success in children with SO, and (v) examining innovative lifestyle and behavioral interventions designed to successfully manage SO in children and their families. Furthermore, to examine the impact of innovative interventions on the management SO, we will (vi) evaluate whether adding a health coach, who provides support via text, email, and/or phone, improves children's ability to adhere to a web-based weight management program and (vii) test the feasibility and impact of a community-based weight management program for pre-school children with SO and their parents that combines group-based parenting sessions with in-home visits. Our research aligns with national priorities in obesity research, brings together leading scientists, clinicians, and stakeholders from across Canada, and will inform health services delivery throughout the country to provide the best care possible for children with SO and their families.


Human Cognitive Neuroscience as It Is Taught.
Cognitive neuroscience increasingly relies on complex data analysis methods. Researchers in this field come from highly diverse scientific backgrounds, such as psychology, engineering, and medicine. This poses challenges with respect to acquisition of appropriate scientific computing and data analysis skills, as well as communication among researchers with different knowledge and skills sets. Are researchers in cognitive neuroscience adequately equipped to address these challenges? Here, we present evidence from an online survey of methods skills. Respondents (n = 307) mainly comprised students and post-doctoral researchers working in the cognitive neurosciences. Multiple choice questions addressed a variety of basic and fundamental aspects of neuroimaging data analysis, such as signal analysis, linear algebra, and statistics. We analyzed performance with respect to the following factors: undergraduate degree (grouped into Psychology, Methods, and Biology), current researcher status (undergraduate student, PhD student, and post-doctoral researcher), gender, and self-rated expertise levels. Overall accuracy was 72%. Not surprisingly, the Methods group performed best (87%), followed by Biology (73%) and Psychology (66%). Accuracy increased from undergraduate (59%) to PhD (74%) level, but not from PhD to post-doctoral (74%) level. The difference in performance for the Methods vs. non-methods (Psychology/Biology) groups was especially striking for questions related to signal analysis and linear algebra, two areas particularly relevant to neuroimaging research. Self-rated methods expertise was not strongly predictive of performance. The majority of respondents (93%) indicated they would like to receive at least some additional training on the topics covered in this survey. In conclusion, methods skills among junior researchers in cognitive neuroscience can be improved, researchers are aware of this, and there is strong demand for more skills-oriented training opportunities. We hope that this survey will provide an empirical basis for the development of bespoke skills-oriented training programs in cognitive neuroscience institutions. We will provide practical suggestions on how to achieve this.


Extending and Applying Spartan to Perform Temporal Sensitivity Analyses for Predicting Changes in Influential Biological Pathways in Computational Models.
Through integrating real time imaging, computational modelling, and statistical analysis approaches, previous work has suggested that the induction of and response to cell adhesion factors is the key initiating pathway in early lymphoid tissue development, in contrast to the previously accepted view that the process is triggered by chemokine mediated cell recruitment. These model derived hypotheses were developed using spartan, an open-source sensitivity analysis toolkit designed to establish and understand the relationship between a computational model and the biological system that model captures. Here, we extend the functionality available in spartan to permit the production of statistical analyses that contrast the behavior exhibited by a computational model at various simulated time-points, enabling a temporal analysis that could suggest whether the influence of biological mechanisms changes over time. We exemplify this extended functionality by using the computational model of lymphoid tissue development as a time-lapse tool. By generating results at twelve- hour intervals, we show how the extensions to spartan have been used to suggest that lymphoid tissue development could be biphasic, and predict the time-point when a switch in the influence of biological mechanisms might occur.


Eccentric Left Ventricular Hypertrophy and Sudden Death in Patients with End-Stage Kidney Disease.
Both all-cause and cardiovascular mortality risks are extremely high in patients with end-stage kidney disease (ESKD). Sudden death accounts for approximately one-quarter of all fatal events. Left ventricular hypertrophy (LVH) is a known risk factor for mortality and can be divided in 2 types: concentric and eccentric. This study evaluated possible differences in all-cause mortality, cardiovascular mortality and sudden death between prevalent ESKD patients with concentric and eccentric LVH. Participants of the CONvective TRAnsport STudy (CONTRAST) who underwent transthoracic echocardiography (TTE) at baseline were analyzed. In patients with LVH, a relative wall thickness of ≤0.42 was considered eccentric and >0.42 was considered concentric hypertrophy. Cox proportional hazards models, adjusted for potential confounders, were used to calculate hazard ratios (HRs) of patients with eccentric LVH versus patients with concentric LVH for all-cause mortality, cardiovascular mortality and sudden death. TTE was performed in 328 CONTRAST participants. LVH was present in 233 participants (71%), of which 87 (37%) had concentric LVH and 146 (63%) eccentric LVH. The HR for all-cause mortality of eccentric versus concentric LVH was 1.14 (p = 0.52), 1.79 (p = 0.12) for cardiovascular mortality and 4.23 (p = 0.02) for sudden death in crude analyses. Propensity score-corrected HR for sudden death in patients with eccentric LVH versus those with concentric LVH was 5.22 (p = 0.03). (1) The hazard for all-cause mortality, cardiovascular mortality and sudden death is markedly increased in patients with LVH. (2) The sudden death risk is significantly higher in ESKD patients with eccentric LVH compared to subjects with concentric LVH.


Epidemiology of methicillin-susceptible Staphylococcus aureus lineages in five major African towns: high prevalence of Panton-Valentine leukocidin genes.
The epidemiology of methicillin-susceptible Staphylococcus aureus (MSSA) in Africa is poorly documented. From January 2007 to March 2008, 555 S. aureus isolates were collected from five African towns in Cameroon, Madagascar, Morocco, Niger, and Senegal; among these, 456 unique isolates were susceptible to methicillin. Approximately 50% of the MSSA isolates from each different participating centre were randomly selected for further molecular analysis. Of the 228 isolates investigated, 132 (58%) belonged to five major multilocus sequence typing (MLST) clonal complexes (CCs) (CC1, CC15, CC30, CC121 and CC152) that were not related to any successful methicillin-resistant S. aureus (MRSA) clones previously identified in the same study population. The luk-PV genes encoding Panton-Valentine leukocidin (PVL), present in 130 isolates overall (57%), were highly prevalent in isolates from Cameroon, Niger, and Senegal (West and Central Africa). This finding is of major concern, with regard to both a source of severe infections and a potential reservoir for PVL genes. This overrepresentation of PVL in MSSA could lead to the emergence and spread of successful, highly virulent PVL-positive MRSA clones, a phenomenon that has already started in Africa.


Acoustic sequences in non-human animals: a tutorial review and prospectus.
Animal acoustic communication often takes the form of complex sequences, made up of multiple distinct acoustic units. Apart from the well-known example of birdsong, other animals such as insects, amphibians, and mammals (including bats, rodents, primates, and cetaceans) also generate complex acoustic sequences. Occasionally, such as with birdsong, the adaptive role of these sequences seems clear (e.g. mate attraction and territorial defence). More often however, researchers have only begun to characterise - let alone understand - the significance and meaning of acoustic sequences. Hypotheses abound, but there is little agreement as to how sequences should be defined and analysed. Our review aims to outline suitable methods for testing these hypotheses, and to describe the major limitations to our current and near-future knowledge on questions of acoustic sequences. This review and prospectus is the result of a collaborative effort between 43 scientists from the fields of animal behaviour, ecology and evolution, signal processing, machine learning, quantitative linguistics, and information theory, who gathered for a 2013 workshop entitled, 'Analysing vocal sequences in animals'. Our goal is to present not just a review of the state of the art, but to propose a methodological framework that summarises what we suggest are the best practices for research in this field, across taxa and across disciplines. We also provide a tutorial-style introduction to some of the most promising algorithmic approaches for analysing sequences. We divide our review into three sections: identifying the distinct units of an acoustic sequence, describing the different ways that information can be contained within a sequence, and analysing the structure of that sequence. Each of these sections is further subdivided to address the key questions and approaches in that area. We propose a uniform, systematic, and comprehensive approach to studying sequences, with the goal of clarifying research terms used in different fields, and facilitating collaboration and comparative studies. Allowing greater interdisciplinary collaboration will facilitate the investigation of many important questions in the evolution of communication and sociality.


In Support of a Distinction between Voluntary and Stimulus-Driven Control: A Review of the Literature on Proportion Congruent Effects.
Cognitive control is by now a large umbrella term referring collectively to multiple processes that plan and coordinate actions to meet task goals. A common feature of paradigms that engage cognitive control is the task requirement to select relevant information despite a habitual tendency (or bias) to select goal-irrelevant information. At least since the 1970s, researchers have employed proportion congruent (PC) manipulations to experimentally establish selection biases and evaluate the mechanisms used to control attention. PC manipulations vary the frequency with which irrelevant information conflicts (i.e., is incongruent) with relevant information. The purpose of this review is to summarize the growing body of literature on PC effects across selective attention paradigms, beginning first with Stroop, and then describing parallel effects in flanker and task-switching paradigms. The review chronologically tracks the expansion of the PC manipulation from its initial implementation at the list-wide level, to more recent implementations at the item-specific and context-specific levels. An important theoretical aim is demonstrating that PC effects at different levels (e.g., list-wide vs. item or context-specific) support a distinction between voluntary forms of cognitive control, which operate based on anticipatory information, and relatively automatic or reflexive forms of cognitive control, which are rapidly triggered by the processing of particular stimuli or stimulus features. A further aim is to highlight those PC manipulations that allow researchers to dissociate stimulus-driven control from other stimulus-driven processes (e.g., S-R responding; episodic retrieval). We conclude by discussing the utility of PC manipulations for exploring the distinction between voluntary control and stimulus-driven control in other relevant paradigms.


Dementia in western Europe: epidemiological evidence and implications for policy making.
Dementia is receiving increasing attention from governments and politicians. Epidemiological research based on western European populations done 20 years ago provided key initial evidence for dementia policy making, but these estimates are now out of date because of changes in life expectancy, living conditions, and health profiles. To assess whether dementia occurrence has changed during the past 20-30 years, investigators of five different studies done in western Europe (Sweden [Stockholm and Gothenburg], the Netherlands [Rotterdam], the UK [England], and Spain [Zaragoza]) have compared dementia occurrence using consistent research methods between two timepoints in well-defined geographical areas. Findings from four of the five studies showed non-significant changes in overall dementia occurrence. The only significant reduction in overall prevalence was found in the study done in the UK, powered and designed explicitly from its outset to detect change across generations (decrease in prevalence of 22%; p=0.003). Findings from the study done in Zaragoza (Spain) showed a significant reduction in dementia prevalence in men (43%; p=0.0002). The studies estimating incidence done in Stockholm and Rotterdam reported non-significant reductions. Such reductions could be the outcomes from earlier population-level investments such as improved education and living conditions, and better prevention and treatment of vascular and chronic conditions. This evidence suggests that attention to optimum health early in life might benefit cognitive health late in life. Policy planning and future research should be balanced across primary (policies reducing risk and increasing cognitive reserve), secondary (early detection and screening), and tertiary (once dementia is present) prevention. Each has their place, but upstream primary prevention has the largest effect on reduction of later dementia occurrence and disability.


Ligand binding and protein relaxation in heme proteins: a room temperature analysis of NO geminate recombination.
Ultrafast absorption spectroscopy is used to study heme-NO recombination at room temperature in aqueous buffer on time scales where the ligand cannot leave its cage environment. While a single barrier is observed for the cage recombination of NO with heme in the absence of globin, recombination in hemoglobin and myoglobin is nonexponential. Examination of hemoglobin with and without inositol hexaphosphate points to proximal constraints as important determinants of the geminate rebinding kinetics. Molecular dynamics simulations of myoglobin and heme-imidazole subsequent to ligand dissociation were used to investigate the transient behavior of the Fe-proximal histidine coordinate and its possible involvement in geminate recombination. The calculations, in the context of the absorption measurements, are used to formulate a distinction between nonexponential rebinding that results from multiple protein conformations (substates) present at equilibrium or from nonequilibrium relaxation of the protein triggered by a perturbation such as ligand dissociation. The importance of these two processes is expected to depend on the time scale of rebinding relative to equilibrium fluctuations and nonequilibrium relaxation. Since NO rebinding occurs on the picosecond time scale of the calculated myoglobin relaxation, a time-dependent barrier is likely to be an important factor in the observed nonexponential kinetics. The general implications of the present results for ligand binding in heme proteins and its time and temperature dependence are discussed. It appears likely that, at low temperatures, inhomogeneous protein populations play an important role and that as the temperature is raised, relaxation effects become significant as well.


Treatment of primary insomnia.
Ten percent to 40% of adults have intermittent insomnia, and 15% have long-term sleep difficulties. This article provides a review of the classification, differential diagnosis, and treatment options available for insomnia. We performed a MEDLINE search using OVID and the key words "insomnia," "sleeplessness," "behavior modification," "herbs," "medicinal," and "pharmacologic therapy." Articles were selected based on their relevance to the topic. Evaluation of insomnia includes a careful sleep history, review of medical history, review of medication use (including over-the-counter and herbal medications), family history, and screening for depression, anxiety, and substance abuse. Treatment should be individualized based on the nature and severity of symptoms. Nonpharmacologic treatments are effective and have minimal side effects compared with drug therapies. Medications such as diphenhydramine, doxylamine, and trazodone can be used initially, but patients may not tolerate their side effects. Newer medications such as zolpidem and zaleplon have short half-lives and minimal side effects. Both are approved for short-term use in the insomniac.


Immunodetection of aldose reductase in normal and diseased human liver.
Aldose reductase is an NADPH-dependent aldo-keto reductase best known as the rate-limiting enzyme of the polyol pathway that is implicated in the complications of diabetes. Aldose reductase appears to be involved in a variety of disease states other than diabetes, presumably due to its ability to catalyze the reduction of a broad spectrum of aldehydes, including some cytotoxic products of lipid peroxidation. Although the data regarding expression of aldose reductase in normal liver are conflicting, prior studies have suggested that the enzyme may be induced in diseased liver. The goal of these studies was to characterize expression of aldose reductase in normal and diseased human liver, using RT-PCR, Western analysis and immunohistochemistry. Aldose reductase transcripts and protein were detected at low levels in control human livers. In contrast, levels of aldose reductase mRNA and protein were increased in chronically diseased human livers. Immunohistochemistry demonstrated localization of aldose reductase in sinusoidal lining cells; dual immunofluorescence confocal microscopy with the macrophage marker, CD68, confirmed that the aldose reductase-positive sinusoidal lining cells were Kupffer cells. Abundant aldose reductase-positive, CD68-positive cells were present in the fibrous septa of cirrhotic livers, accounting for the increase in immunoreactive aldose reductase in diseased livers. Immunostaining of human lung, spleen and lymph node revealed that macrophages in those tissues also express aldose reductase. These data are the first to demonstrate that aldose reductase is expressed by human macrophages in various tissues and suggest that this enzyme may play a role in immune or inflammatory processes.


A two-tiered mechanism by which Cdc42 controls the localization and activation of an Arp2/3-activating motor complex in yeast.
The establishment of cell polarity in budding yeast involves assembly of actin filaments at specified cortical domains. Elucidation of the underlying mechanism requires an understanding of the machinery that controls actin polymerization and how this machinery is in turn controlled by signaling proteins that respond to polarity cues. We showed previously that the yeast orthologue of the Wiskott-Aldrich Syndrome protein, Bee1/Las17p, and the type I myosins are key regulators of cortical actin polymerization. Here, we demonstrate further that these proteins together with Vrp1p form a multivalent Arp2/3-activating complex. During cell polarization, a bifurcated signaling pathway downstream of the Rho-type GTPase Cdc42p recruits and activates this complex, leading to local assembly of actin filaments. One branch, which requires formin homologues, mediates the recruitment of the Bee1p complex to the cortical site where the activated Cdc42p resides. The other is mediated by the p21-activated kinases, which activate the motor activity of myosin-I through phosphorylation. Together, these findings provide insights into the essential processes leading to polarization of the actin cytoskeleton.


Radiation and ATM inhibition: the heart of the matter.
Numerous in vitro studies have shown that human cell lines lacking functional ATM are extremely radiosensitive. In this issue, Moding et al. demonstrate using a murine model of sarcoma that deletion of the Atm gene has much less of a radiosensitizing effect on normal cardiac endothelia than on rapidly proliferating tumor endothelia. This work confounds our assumptions about the generality of the role of ATM in radiation sensitivity and the potential use of ATM inhibitors as radiosensitizers.


Enriching the drinking water of rats with extracts of Salvia officinalis and Thymus vulgaris increases their resistance to oxidative stress.
Nature is an attractive source of therapeutic compounds. In comparison to the artificial drugs, natural compounds cause less adverse side effects and are suitable for current molecularly oriented approaches to drug development and their mutual combining. Medicinal plants represent one of the most available remedy against various diseases. Proper examples are Salvia officinalis L. and Thymus vulgaris L. which are known aromatic medicinal plants. They are very popular and frequently used in many countries. The molecular mechanism of their biological activity has not yet been fully understood. The aim of this study was to ascertain if liver cells of experimental animals drinking extracts of sage or thyme will manifest increased resistance against oxidative stress. Adult Sprague-Dawley rats were divided into seven groups. They drank sage or thyme extracts for 2 weeks. At the end of the drinking period, blood samples were collected for determination of liver biochemical parameters and hepatocytes were isolated to analyze (i) oxidatively generated DNA damage (conventional and modified comet assay), (ii) activities of antioxidant enzymes [superoxide dismutase (SOD), glutathione peroxidase (GPx)] and (iii) content of glutathione. Intake of sage and thyme had no effect either on the basal level of DNA damage or on the activity of SOD in rat hepatocytes and did not change the biochemical parameters of blood plasma. Simultaneously, the activity of GPx was significantly increased and the level of DNA damage induced by oxidants was decreased. Moreover, sage extract was able to start up the antioxidant protection expressed by increased content of glutathione. Our results indicate that the consumption of S.officinalis and T.vulgaris extracts positively affects resistency of rat liver cells against oxidative stress and may have hepatoprotective potential.


Catalyst-solvent interactions in a dinuclear Ru-based water oxidation catalyst.
Photocatalytic water oxidation represents a key process in conversion of solar energy into fuels and can be facilitated by the use of molecular transition metal-based catalysts. A novel straightforward approach for covalent linking of the catalytic units to other moieties is demonstrated by preparation of a dinuclear complex containing two [Ru(pdc)(pic)3]-derived units (pdc = 2,6-pyridinedicarboxylate, pic = 4-picoline). The activity of this complex towards chemical and photochemical oxidation of water was evaluated and a detailed insight is given into the interactions between the catalyst and acetonitrile, a common co-solvent employed to increase solubility of water oxidation catalysts. The solvent-induced transformations were studied by electrochemical and spectroscopic techniques and the relevant quantitative parameters were extracted.


Darusentan, a selective endothelin A receptor antagonist, for the oral treatment of resistant hypertension.
Resistant hypertension is defined as failure to lower blood pressure to target when a patient adheres to the maximum tolerated doses of three antihypertensive drugs including a diuretic. Notwithstanding the wide availability of several antihypertensive agents and the continued recommendation of dietary and lifestyle modifications, the prevalence of resistant hypertension remains high and is expected to increase thus underscoring the need for potential new treatment modalities in resistant hypertension. Endothelin-1 is a long-lasting potent vasoconstrictor and plays a key role in cardiovascular haemostasis. Endothelin mediates its biological activity in humans through the endothelin A and B receptors. The clinical experience and the evidence for therapy with darusentan in resistant systemic hypertension are reviewed. The leading journals that publish basic science and clinical research in the area of cardiovascular diseases and PubMed were scanned. While results from early clinical studies suggested that darusentan might emerge as new treatment option in patients with resistant hypertension, results from recent studies suggests that darusentan appears unlikely to find its way in the armamentarium for treatment of resistant hypertension.


Stereotactic body radiation therapy for non-spine bone metastases--a review of the literature.
Stereotactic body radiation therapy (SBRT) has the ability to deliver significantly higher biologically equivalent doses (BED) compared to conventional radiation treatment. The main goal of SBRT is to improve local tumor control while reducing pain. The side effects however may be greater than those of conventional treatment. A review of the literature was conducted and articles pertaining to studies of SBRT in non-spine bone metastases were included. Data on outcomes and toxicities were collected in addition to inclusion and exclusion criteria for each study. A total of 14 studies were included in this review. Very rarely were grade 3 and 4 toxicities reported. Endpoints for the studies varied significantly, which made conclusions of overall local control and progression free survival near impossible. In studies that reported local control rates, these rates were all greater than 85%. Progression free survival varied significantly between studies. Due to the lack of consistency in endpoint definitions, it is difficult to compare outcomes across trials. There is a need for consensus in endpoint definitions.


Steroid-based facial amphiphiles for stabilization and crystallization of membrane proteins.
Amphiphile selection is a critical step for structural studies of membrane proteins (MPs). We have developed a family of steroid-based facial amphiphiles (FAs) that are structurally distinct from conventional detergents and previously developed FAs. The unique FAs stabilize MPs and form relatively small protein-detergent complexes (PDCs), a property considered favorable for MP crystallization. We attempted to crystallize several MPs belonging to different protein families, including the human gap junction channel protein connexin 26, the ATP binding cassette transporter MsbA, the seven-transmembrane G protein-coupled receptor-like bacteriorhodopsin, and cytochrome P450s (peripheral MPs). Using FAs alone or mixed with other detergents or lipids, we obtained 3D crystals of the above proteins suitable for X-ray crystallographic analysis. The fact that FAs enhance MP crystallizability compared with traditional detergents can be attributed to several properties, including increased protein stability, formation of small PDCs, decreased PDC surface flexibility, and potential to mediate crystal lattice contacts.


HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44+ Natural Killer Cells in Ulcerative Colitis.
Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, genetic associations of UC and HLA-DP haplotypes and their functional implications were investigated. HLA-DP haplotype and UC risk association analyses were performed (UC: n = 13,927; control: n = 26,764). Expression levels of HLA-DP on intestinal epithelial cells (IECs) in individuals with and without UC were quantified. Human intestinal 3-dimensional (3D) organoid cocultures with human NK cells were used to determine functional consequences of interactions between HLA-DP and NKp44. These studies identified HLA-DPA1∗01:03-DPB1∗04:01 (HLA-DP401) as a risk haplotype and HLA-DPA1∗01:03-DPB1∗03:01 (HLA-DP301) as a protective haplotype for UC in European populations. HLA-DP expression was significantly higher on IECs of individuals with UC compared with controls. IECs in human intestinal 3D organoids derived from HLA-DP401pos individuals showed significantly stronger binding of NKp44 compared with HLA-DP301pos IECs. HLA-DP401pos IECs in organoids triggered increased degranulation and tumor necrosis factor production by NKp44+ NK cells in cocultures, resulting in enhanced epithelial cell death compared with HLA-DP301pos organoids. Blocking of HLA-DP401-NKp44 interactions (anti-NKp44) abrogated NK cell activity in cocultures. We identified an UC risk HLA-DP haplotype that engages NKp44 and activates NKp44+ NK cells, mediating damage to intestinal epithelial cells in an HLA-DP haplotype-dependent manner. The molecular interaction between NKp44 and HLA-DP401 in UC can be targeted by therapeutic interventions to reduce NKp44+ NK cell-mediated destruction of the intestinal epithelium in UC.


Musical syntax is processed in Broca's area: an MEG study.
The present experiment was designed to localize the neural substrates that process music-syntactic incongruities, using magnetoencephalography (MEG). Electrically, such processing has been proposed to be indicated by early right-anterior negativity (ERAN), which is elicited by harmonically inappropriate chords occurring within a major-minor tonal context. In the present experiment, such chords elicited an early effect, taken as the magnetic equivalent of the ERAN (termed mERAN). The source of mERAN activity was localized in Broca's area and its right-hemisphere homologue, areas involved in syntactic analysis during auditory language comprehension. We find that these areas are also responsible for an analysis of incoming harmonic sequences, indicating that these regions process syntactic information that is less language-specific than previously believed.


Escherichia coli bacteraemia in pregnant women is life-threatening for foetuses.
In order to improve knowledge on Escherichia coli bacteraemia during pregnancy, we studied clinical data and performed molecular characterization of strains for 29 E. coli bacteraemia occurring in pregnant women. Bacteraemia mostly occurred in the third trimester of pregnancy (45%) and was community-acquired (79%). Portals of entry were urinary (55%) and genital (45%). E. coli strains belonged mainly to phylogroups B2 (72%) and D (17%). Four clonal lineages (i.e. sequence type complex (STc) 73, STc95, STc12 and STc69) represented 65% of the strains. The strains exhibited a high number of virulence factor coding genes (10 (3-16)). Six foetuses died (27%), five of them due to bacteraemia of genital origin (83%). Foetal deaths occurred despite adequate antibiotic regimens. Strains associated with foetal mortality had fewer virulence factors (8 (6-10)) than strains involved in no foetal mortality (11 (4-12)) (p 0.02). When comparing E. coli strains involved in bacteraemia with a urinary portal of entry in non-immunocompromised pregnant vs. non-immunocompromised non-pregnant women from the COLIBAFI study, there was no significant difference of phylogroups and virulence factor coding genes. These results show that E. coli bacteraemia in pregnant women involve few highly virulent clones but that severity, represented by foetal death, is mainly related to bacteraemia of genital origin.