Short-term metabolic fate of L-[13N]glutamate in the Walker 256 carcinosarcoma in vivo.
In vivo studies with L-[13N]glutamate in the Walker 256 carcinosarcoma implanted under the renal capsule of female Sprague-Dawley rats demonstrate that uptake of glutamate and the rate of incorporation of the nitrogen label from this amino acid into metabolites is slower in the tumor than in nontumorous kidney tissue. Glutamate dehydrogenase, glutaminase, and alanine aminotransferase activities are significantly lower within the tumor than within the adjoining kidney. However, the tumor expresses high levels of aspartate aminotransferase, attesting to the importance of this enzyme in the metabolism of glutamate. Indeed, high performance liquid chromatographic analysis showed that the principal metabolic fate of label derived from L-[13N]glutamate in the tumor is incorporation into aspartate. Measurement of specific activity ratios of glutamate to aspartate shows that the transfer of nitrogen from glutamate to aspartate is rapid and that equilibration of label among components of the aspartate aminotransferase reaction is attained within minutes after tumor uptake. Analyses of the nontumorous portion of the implanted kidney also showed that aspartate is the major recipient of glutamate nitrogen. However, high performance liquid chromatographic analyses of deproteinized tissue revealed that glutamine and ammonia are also significant 13N-labeled metabolites formed from L-[13N]glutamate within the kidney. Proportionately lower amounts of these labeled metabolites were found in the tumor.


The influence of spirituality on family management of Parkinson's disease.
This study examined the role of spirituality in defining and managing Parkinson's disease (PD) for people with PD and their families. A content-analysis approach was used to interpret and analyze individual and family interviews from 27 families. Participants primarily were Caucasian dyads representing different geographic areas and socioeconomic statuses. Findings revealed that the ways persons with PD and their families managed the chronic illness were influenced by belief and faith, purpose and meaning, prayer, the support of family and friends, and hope. Healthcare providers need to understand the role of spirituality in influencing ways that persons with PD and their families define and manage the disease and to support people in their efforts.


Biased growth processes and the "rich-get-richer" principle.
We study a simple stochastic system with a "rich-get-richer" behavior, in which there are 2 states, and N particles that are successively assigned to one of the states, with a probability p(i) that depends on the states' occupation n(i) as p(i) = n(gamma)(i)/ n(gamma)(1) + n(gamma)(2)). We show that there is a phase transition as gamma crosses the critical value gamma(c) =1. For gamma<1, in the thermodynamic limit the occupations are approximately the same, n(1) approximately n(2). For gamma>1, however, a spontaneous symmetry breaking occurs, and the system goes to a highly clustered configuration, in which one of the states has almost all the particles. These results also hold for any finite number of states (not only two). We show that this "rich-get-richer" principle governs the growth dynamics in a simple model of gravitational aggregation, and we argue that the same is true in all growth processes mediated by long-range forces like gravity.


Diseased Region Detection of Longitudinal Knee Magnetic Resonance Imaging Data.
Magnetic resonance imaging (MRI) has become an important imaging technique for quantifying the spatial location and magnitude/direction of longitudinal cartilage morphology changes in patients with osteoarthritis (OA). Although several analytical methods, such as subregion-based analysis, have been developed to refine and improve quantitative cartilage analyses, they can be suboptimal due to two major issues: the lack of spatial correspondence across subjects and time and the spatial heterogeneity of cartilage progression across subjects. The aim of this paper is to present a statistical method for longitudinal cartilage quantification in OA patients, while addressing these two issues. The 3D knee image data is preprocessed to establish spatial correspondence across subjects and/or time. Then, a Gaussian hidden Markov model (GHMM) is proposed to deal with the spatial heterogeneity of cartilage progression across both time and OA subjects. To estimate unknown parameters in GHMM, we employ a pseudo-likelihood function and optimize it by using an expectation-maximization (EM) algorithm. The proposed model can effectively detect diseased regions in each OA subject and present a localized analysis of longitudinal cartilage thickness within each latent subpopulation. Our GHMM integrates the strengths of two standard statistical methods including the local subregion-based analysis and the ordered value approach. We use simulation studies and the Pfizer longitudinal knee MRI dataset to evaluate the finite sample performance of GHMM in the quantification of longitudinal cartilage morphology changes. Our results indicate that GHMM significantly outperforms several standard analytical methods.


The Effects of Spatial Frequency on the Accommodative Responses of Myopic and Emmetropic Chinese Children.
The spatial frequency (SF) characteristics of accommodation in children are not well understood. In this study, we measured accommodative responses to grating targets to investigate the SF dependence of accommodation in children. The effects of SF and contrast on the accommodative system were evaluated in two groups of children, including 22 with emmetropia and 20 with myopia. The contrast detection thresholds at five SFs were measured using a near-contrast sensitivity function test. The accommodative responses to grating targets with low (1.5 cycles per degree [cpd]), medium (6 cpd), and high (18 cpd) SFs were measured with a Grand Seiko WAM-5500 in dynamic mode for 30 seconds under standard and detection threshold contrast conditions. The accommodative lag and accommodative microfluctuations (AMFs) were compared between the two groups. Under standard contrast conditions, no significant difference was found in the accommodative lag across SFs (F = 2.03, P = 0.14) or between the two groups (F = 3.57, P = 0.07). The AMFs were lowest at 6 cpd in emmetropia group (F = 6.51, P = 0.003) and in total (F = 10.82, P < 0.001). Children in emmetropia group showed greater AMFs at high SFs under detection threshold contrast conditions than under standard contrast conditions (P < 0.05). This study demonstrated that the instability of accommodation was SF dependent in children. The AMFs in children were smallest at the medium SF for standard contrast grating targets. Myopic children are less sensitive to the low-contrast-induced blur for high SFs than emmetropic children. This study provides a possibility to stabilize accommodative response of children by transforming SF components of fixation targets.


Challenges in understanding the epidemiology of acquired brain injury in India.
An acquired brain injury (ABI) is an injury to the brain, which is not hereditary, congenital, degenerative, or induced by birth trauma. In India, rapid urbanization, economic growth and changes in lifestyle have led to a tremendous increase in the incidence of ABI, so much so that it is being referred to as a 'silent epidemic'. Unlike developed countries, there is no well-established system for collecting and managing information on various diseases in India. Thus it is a daunting task to obtain reliable information about acquired brain injury. In the course of conducting a systematic review on the epidemiology of ABI in India, we recognized several challenges which hampered our effort. Inadequate case definition, lack of centralized reporting mechanisms, lack of population based studies, absence of standardized survey protocols and inadequate mortality statistics are some of the major obstacles. Following a standard case definition, linking multiple hospital-based registries, initiating a state or nationwide population-based registry, conducting population-based studies that are methodologically robust and introducing centralized, standard reporting mechanisms for ABI, are some of the strategies that could help facilitate a thorough investigation into the epidemiology and understanding of ABI. This may help improve policies on prevention and management of acquired brain injury in India.


Spatio-temporally controlled transfection by quantitative injection into a single cell.
Transfection-based cellular control has been widely used in biology; however, conventional transfection methods cannot control spatio-temporal differences in gene expression or the quantity of delivered materials such as external DNA or RNA. Here, we present a non-viral and spatio-temporally controlled transfection technique of a quantitative injection into a single cell. DNA was quantitatively injected into a single cell at a desired location and time, and the optimal gene delivery and expression conditions were determined based on the amount of the delivered DNA and the transfection efficacy. Interestingly, an injection of 1500 DNAs produced an about average 30% gene expression efficiency, which was the optimal condition, and gene expression was sustained for more than 14 days. In a single cell, fluorescent intensity and polymerase chain reaction (PCR) results were compared for the quantity of gene expression. The high coincidence of both results suggests that the fluorescence intensity can reveal gene expression level which was investigated by PCR. In addition, 3 multiple DNA genes were successfully expressed in a single cell with different ratio. Overall, these results demonstrate that spatio-temporally controlled transfection by quantitative transfection is a useful technique for regulating gene expression in a single cell, which suggests that this technique may be used for stem cell research, including the creation of induced pluripotent stem (iPS) cells.


Treatment of muscle-invasive bladder cancer: A systematic review.
There is uncertainty regarding the use of bladder-sparing alternatives to standard radical cystectomy, optimal lymph node dissection techniques, and optimal chemotherapeutic regimens. This study was conducted to systematically review the benefits and harms of bladder-sparing therapies, lymph node dissection, and systemic chemotherapy for patients with clinically localized muscle-invasive bladder cancer. Systematic literature searches of MEDLINE (from 1990 through October 2014), the Cochrane databases, reference lists, and the ClinicalTrials.gov Web site were performed. A total of 41 articles were selected for review. Bladder-sparing therapies were found to be associated with worse survival compared with radical cystectomy, although the studies had serious methodological shortcomings, findings were inconsistent, and only a few studies evaluated currently recommended techniques. More extensive lymph node dissection might be more effective than less extensive dissection at improving survival and decreasing local disease recurrence, but there were methodological shortcomings and some inconsistency. Six randomized trials found cisplatin-based combination neoadjuvant chemotherapy to be associated with a decreased mortality risk versus cystectomy alone. Four randomized trials found adjuvant chemotherapy to be associated with decreased mortality versus cystectomy alone, but none of these trials reported a statistically significant effect. There was insufficient evidence to determine optimal chemotherapeutic regimens.


Nutritional status modulates box C/D snoRNP biogenesis by regulated subcellular relocalization of the R2TP complex.
Box C/D snoRNPs, which are typically composed of box C/D snoRNA and the four core protein components Nop1, Nop56, Nop58, and Snu13, play an essential role in the modification and processing of pre-ribosomal RNA. The highly conserved R2TP complex, comprising the proteins Rvb1, Rvb2, Tah1, and Pih1, has been shown to be required for box C/D snoRNP biogenesis and assembly; however, the molecular basis of R2TP chaperone-like activity is not yet known. Here, we describe an unexpected finding in which the activity of the R2TP complex is required for Nop58 protein stability and is controlled by the dynamic subcellular redistribution of the complex in response to growth conditions and nutrient availability. In growing cells, the complex localizes to the nucleus and interacts with box C/D snoRNPs. This interaction is significantly reduced in poorly growing cells as R2TP predominantly relocalizes to the cytoplasm. The R2TP-snoRNP interaction is mainly mediated by Pih1. The R2TP complex exerts a novel regulation on box C/D snoRNP biogenesis that affects their assembly and consequently pre-rRNA maturation in response to different growth conditions.


Calcium signaling in sperm: help from prostasomes.
Mammalian sperm cells are equipped with sophisticated Ca2+ signaling mechanisms that are fundamental to sperm's success in fertilization. Unlike most other cells, however, mature sperm generally do not have the luxury of synthesizing new proteins. New evidence indicates that human sperm have a very clever way to solve the conflict between the critical demand for Ca2+ signaling tools and the silence of protein translation. Just before encountering the female reproductive tract, sperm acquire some of the key molecules for Ca2+ signaling from the male reproductive tract itself: prostasomes secreted by the prostate gland.


Delayed discharge.
Essential facts Delays in discharging older people from hospital cost the NHS £820 million a year, according to a report from the National Audit Office (NAO).


Incidence and recurrence of autoimmune/alloimmune hepatitis in liver transplant recipients.
We prospectively collected data on 1,429 liver transplant recipients between December 1984 and December 1998. Fifty-five patients (3.8%; 10 men, 45 women; median age, 44.5 +/- 13 [SD] years) with autoimmune hepatitis (AIH) underwent orthotopic liver transplantation (OLT). Transplant recipients with AIH were younger, more likely to be women, and had a greater likelihood of rejection in the first 3, 6, and 12 months. There was no difference in patient survival or graft survival. There were 11 biopsy-proven recurrences (1 man, 10 women) of AIH after OLT. Almost half the episodes occurred within the first year after OLT. No patient required re-OLT because of recurrent disease. AIH has an incidence of 4% and a recurrence rate of 20% in OLT. Transplant recipients are more likely to be young women and have an increased incidence of acute cellular rejection (ACR) during the first post-OLT year. Recurrence should be suspected in those with abnormal liver function test results in the absence of ACR, especially during the first year after OLT. We cannot establish with certainty whether the observed process represents recurrence of the original autoimmune disease, an alloimmune phenomenon, or allograft dysfunction mimicking AIH.


A miR-335/COX-2/PTEN axis regulates the secretory phenotype of senescent cancer-associated fibroblasts.
Senescent cancer-associated fibroblasts (CAF) develop a senescence-associated secretory phenotype (SASP) that is believed to contribute to cancer progression. The mechanisms underlying SASP development are, however, poorly understood. Here we examined the functional role of microRNA in the development of the SASP in normal fibroblasts and CAF. We identified a microRNA, miR-335, up-regulated in the senescent normal fibroblasts and CAF and able to modulate the secretion of SASP factors and induce cancer cell motility in co-cultures, at least in part by suppressing the expression of phosphatase and tensin homologue (PTEN). Additionally, elevated levels of cyclo-oxygenase 2 (PTGS2; COX-2) and prostaglandin E2 (PGE2) secretion were observed in senescent fibroblasts, and inhibition of COX-2 by celecoxib reduced the expression of miR-335, restored PTEN expression and decreased the pro-tumourigenic effects of the SASP. Collectively these data demonstrate the existence of a novel miRNA/PTEN-regulated pathway modulating the inflammasome in senescent fibroblasts.


Exercise induced hypercoagulability, increased von Willebrand factor and decreased thyroid hormone concentrations in sled dogs.
Sled dogs performing endurance races have been reported to have a high incidence of gastric erosions or ulcerations and an increased risk of gastro intestinal bleeding leading to death in some cases. In addition, these dogs also become hypothyroid during training and exercise. Canine hypothyroidism has been shown to correlate with decreased von Willebrand factor antigen and potentially increased bleeding tendency. Whether increased gastro intestinal bleeding risk is exacerbated due to changes in the hemostatic balance is unknown. The aim of this study was to investigate the hemostatic balance in sled dogs before and after exercise and in addition evaluate any correlation to thyroid status. Twenty sled dogs have been assessed in untrained and trained condition and immediately after exercise. The first sample was collected in the autumn following a resting period, and subsequently the dogs were exposed to increased intensity of training. After four months the peak of physical condition was reached and a 68 km long sled pulling exercise was performed. Samples were collected before and immediately after the exercise. Evaluated parameters were: plasma thromboelastographic (TEG) R, SP, α and MA, activated partial thromboplastin time (aPTT), prothrombin time (PT), fibrinogen, von Willebrand factor (vWf), D-dimer, platelet number, thyroid hormones, hematocrit and C-reactive protein (CRP). Exercise induced an overall hypercoagulable state characterized by significant decreases of TEG R and SP and an increase of α, increased concentrations of plasma vWf and decreased aPTT. In addition, a proinflammatory status was seen by a significant increase of serum CRP concentrations. Thyroid status was confirmed to be hypothyroid as training and exercise induced significant decrease of thyroxin (T4), free thyroxin (fT4) and thyroxin stimulating hormone (TSH) concentrations. Fibrinogen decreased significantly and PT increased. The training-induced changes showed correlation between T4, fT4 and aPTT and correlation between TSH and fibrinogen. Exercise-induced changes showed correlation between T4 and PT. Exercise was associated with a hypercoagulable state and an increase of vWf concentration in this group of sled dogs. Decreased thyroid hormone concentrations after training and exercise were confirmed, but were associated with increased and not decreased vWf in this group of sled dogs.


A complete developmental sequence of a Drosophila neuronal lineage as revealed by twin-spot MARCM.
Drosophila brains contain numerous neurons that form complex circuits. These neurons are derived in stereotyped patterns from a fixed number of progenitors, called neuroblasts, and identifying individual neurons made by a neuroblast facilitates the reconstruction of neural circuits. An improved MARCM (mosaic analysis with a repressible cell marker) technique, called twin-spot MARCM, allows one to label the sister clones derived from a common progenitor simultaneously in different colors. It enables identification of every single neuron in an extended neuronal lineage based on the order of neuron birth. Here we report the first example, to our knowledge, of complete lineage analysis among neurons derived from a common neuroblast that relay olfactory information from the antennal lobe (AL) to higher brain centers. By identifying the sequentially derived neurons, we found that the neuroblast serially makes 40 types of AL projection neurons (PNs). During embryogenesis, one PN with multi-glomerular innervation and 18 uniglomerular PNs targeting 17 glomeruli of the adult AL are born. Many more PNs of 22 additional types, including four types of polyglomerular PNs, derive after the neuroblast resumes dividing in early larvae. Although different offspring are generated in a rather arbitrary sequence, the birth order strictly dictates the fate of each post-mitotic neuron, including the fate of programmed cell death. Notably, the embryonic progenitor has an altered temporal identity following each self-renewing asymmetric cell division. After larval hatching, the same progenitor produces multiple neurons for each cell type, but the number of neurons for each type is tightly regulated. These observations substantiate the origin-dependent specification of neuron types. Sequencing neuronal lineages will not only unravel how a complex brain develops but also permit systematic identification of neuron types for detailed structure and function analysis of the brain.


The contribution of glycoprotein VI to stable platelet adhesion and thrombus formation illustrated by targeted gene deletion.
Platelet interaction with exposed adhesive ligands at sites of vascular injury is required to initiate a normal hemostatic response and may become a pathogenic factor in arterial diseases leading to thrombosis. We report a targeted disruption in a key receptor for collagen-induced platelet activation, glycoprotein (GP) VI. The breeding of mice with heterozygous GP VI alleles produced the expected frequency of wild-type, heterozygous, and homozygous genotypes, indicating that these animals had no reproductive problems and normal viability. GP VInull platelets failed to aggregate in response to type I fibrillar collagen or convulxin, a snake venom protein and known platelet agonist of GP VI. Nevertheless, tail bleeding time measurements revealed no severe bleeding tendency as a consequence of GP VI deficiency. Ex vivo platelet thrombus formation on type I collagen fibrils was abolished using blood from either GP VInull or FcR-gammanull animals. Reflection interference contrast microscopy revealed that the lack of thrombus formation by GP VInull platelets could be linked to a defective platelet activation following normal initial tethering to the surface, visualized as lack of spreading and less stable adhesion. These results illustrate the role of GP VI in postadhesion events leading to the development of platelet thrombi on collagen fibrils.


Acute management of shoulder dislocations.
The shoulder joint has the greatest range of motion of any joint in the body. However, it relies on soft-tissue restraints, including the capsule, ligaments, and musculature, for stability. Therefore, this joint is at the highest risk for dislocation. Thorough knowledge of the shoulder's anatomy as well as classification of dislocations, anesthetic techniques, and reduction maneuvers is crucial for early management of acute shoulder dislocation. Given the lack of comparative studies on various reduction techniques, the choice of technique is based on physician preference. The orthopaedic surgeon must be well versed in several reduction methods and ascertain the best technique for each patient.


Functional disability and social participation restriction associated with chronic conditions in middle-aged and older adults.
We examine the population impact on functional disability and social participation of physical and mental chronic conditions individually and in combination. Cross-sectional, population-based data from community-dwelling people aged 45 years and over living in the 10 Canadian provinces in 2008-2009 were used to estimate the population attributable risk (PAR) for functional disability in basic (ADL) and instrumental (IADL) activities of daily living and social participation restrictions for individual and combinations of chronic conditions, stratified by age and gender, after adjusting for confounding variables. Five chronic conditions (arthritis, depression, diabetes, heart disease and eye disease) made the largest contributions to ADL-related and IADL-related functional disability and social participation restrictions, with variation in magnitude and ranking by age and gender. While arthritis was consistently associated with higher PARs across gender and most age groups, depression, alone and in combination with the physical chronic conditions, was associated with ADL and IADL disability as well as social participation restrictions in the younger age groups, especially among women. Compared to women, the combinations of conditions associated with higher PARs in men more often included heart disease and diabetes. Our findings suggest that in community-dwelling middle-aged and older adults, the impact of combinations of mental and physical chronic conditions on functional disability and social participation restriction is substantial and differed by gender and age. Recognising the differences in the drivers of PAR by gender and age group will ultimately increase the efficiency of clinical and public health interventions.


ESL Placement and Schools: Effects on Immigrant Achievement.
In this study, the authors explore English as a Second Language (ESL) placement as a measure of how schools label and process immigrant students. Using propensity score matching and data from the Adolescent Health and Academic Achievement Study and the National Longitudinal Study of Adolescent Health, the authors estimate the effect of ESL placement on immigrant achievement. In schools with more immigrant students, the authors find that ESL placement results in higher levels of academic performance; in schools with few immigrant students, the effect reverses. This is not to suggest a one-size-fits-all policy; many immigrant students, regardless of school composition, generational status, or ESL placement, struggle to achieve at levels sufficient for acceptance to a 4-year university. This study offers several factors to be taken into consideration as schools develop policies and practices to provide immigrant students opportunities to learn.


Interactions of the DNA polymerase X of African swine fever virus with double-stranded DNA. Functional structure of the complex.
Interactions of the polymerase X of African swine fever virus with the double-stranded DNA (dsDNA) have been studied with fluorescent dsDNA oligomers, using quantitative fluorescence titrations, analytical ultracentrifugation, and fluorescence energy transfer techniques. Studies with unmodified dsDNAs were performed, using competition titration method. ASV pol X binds the dsDNA with a site-size of n=10(+/-2) base-pairs, which is significantly shorter than the total site-size of 16(+/-2) nucleotides of the enzyme-ssDNA complex. The small site size indicates that the enzyme binds the dsDNA exclusively using the proper DNA-binding subsite. Fluorescence energy transfer studies between the tryptophan residue W92 and the acceptor, located at the 5' or 3' end of the dsDNA, suggest strongly that the proper DNA-binding subsite is located on the non-catalytic C-terminal domain. Moreover, intrinsic interactions with the dsDNA 10-mer or 20-mer are accompanied by the same net number of ions released, independent of the length of the DNA, indicating the same length of the DNA engaged in the complex. The dsDNA intrinsic affinity is about two orders of magnitude higher than the ssDNA affinity, indicating that the proper DNA-binding subsite is, in fact, the specific dsDNA-binding site. Surprisingly, ASFV pol X binds the dsDNA with significant positive cooperativity, which results from protein-protein interactions. Cooperative interactions are accompanied by the net ion release, with anions participating in the ion-exchange process. The significance of these results for ASFV pol X activity in the recognition of damaged DNA is discussed.


Quantitative FRET studies and integrative modeling unravel the structure and dynamics of biomolecular systems.
Förster Resonance Energy Transfer (FRET) combined with single-molecule spectroscopy probes macromolecular structure and dynamics and identifies coexisting conformational states. We review recent methodological developments in integrative structural modeling by satisfying spatial restraints on networks of FRET pairs (hybrid-FRET). We discuss procedures to incorporate prior structural knowledge and to obtain optimal distance networks. Finally, a workflow for hybrid-FRET is presented that automates integrative structural modeling and experiment planning to put hybrid-FRET on rails. To test this workflow, we simulate realistic single-molecule experiments and resolve three protein conformers, exchanging at 30μs and 10ms, with accuracies of 1-3Å RMSD versus the target structure. Incorporation of data from other spectroscopies and imaging is also discussed.


Effects of emphysema and training on glutathione oxidation in the hamster diaphragm.
Loading of skeletal muscles is associated with increased generation of oxidants, which in turn may impair muscle contractility. We investigated whether the load on the hamster diaphragm imposed by pulmonary emphysema induces oxidative stress, as indicated by glutathione oxidation, and whether the degree of glutathione oxidation is correlated with contractility of the diaphragm. In addition, the effect of 12 wk of treadmill exercise training on contractility and glutathione content in the normal (NH) and emphysematous hamster (EH) diaphragm was investigated. Training started 6 mo after elastase instillation. After the training period, glutathione content and in vitro contractility of the diaphragm were determined. Twitch force and maximal tetanic force were significantly reduced (by approximately 30 and approximately 15%, respectively) in EH compared with NH. In sedentary hamsters, the GSSG-to-GSH ratio was significantly elevated in the EH compared with the NH diaphragm. A significant inverse correlation was found between GSSG-to-GSH ratio and twitch force in the diaphragm (P < 0. 01). Training improved maximal tetanic force and reduced fatigability of the EH diaphragm but did not alter its glutathione content. In conclusion, 1) emphysema induces oxidative stress in the diaphragm, 2) training improves the contractile properties of the EH diaphragm, and 3) this improvement is not accompanied by changes in glutathione redox status.


A knot polymer mediated non-viral gene transfection for skin cells.
A knot polymer, poly[bis(2-acryloyl)oxyethyl disulphide-co-2-(dimethylamino) ethyl methacrylate] (DSP), was synthesized, optimized and evaluated as a non-viral vector for gene transfection for skin cells, keratinocytes. With recessive dystrophic epidermolysis bullosa keratinocytes (RDEBK-TA4), the DSP exhibited high transfection efficacy with both Gaussia luciferase marker DNA and the full length COL7A1 transcript encoding the therapeutic type VII collagen protein (C7). The effective restoration of C7 in C7 null-RDEB skin cells indicates that DSP is promising for non-viral gene therapy of recessive dystrophic epidermolysis bullosa (RDEB).


Basaltic rocks analyzed by the Spirit Rover in Gusev Crater.
The Spirit landing site in Gusev Crater on Mars contains dark, fine-grained, vesicular rocks interpreted as lavas. Pancam and Mini-Thermal Emission Spectrometer (Mini-TES) spectra suggest that all of these rocks are similar but have variable coatings and dust mantles. Magnified images of brushed and abraded rock surfaces show alteration rinds and veins. Rock interiors contain </=25% megacrysts. Chemical analyses of rocks by the Alpha Particle X-ray Spectrometer are consistent with picritic basalts, containing normative olivine, pyroxenes, plagioclase, and accessory FeTi oxides. Mössbauer, Pancam, and Mini-TES spectra confirm the presence of olivine, magnetite, and probably pyroxene. These basalts extend the known range of rock compositions composing the martian crust.


SU-E-I-10: Putting Teeth into Your CT Dosimetry Program: Approaches to Cone- Beam Dental/Maxillofacial CT Dosimetry.
To review and compare different approaches to the problem of dosimetry for limited field-of-view (FOV) cone beam CT devices for dental and maxillofacial applications. The determination of patient doses from specialized, cone-beam CT devices for dental and maxillofacial work requires medical physicists to re-evaluate their dosimetry methods. These devices work in cone-beam geometry, with an axial field dimension on the order of the lengths of the standard head CTDI phantom and pencil ionization chamber. They may also utilize less than 360 degree scans, resulting in asymmetrical radiation distributions. This operating regime is far from that for which conventional CT dosimetry was designed, and alternative approaches must be considered. The alternatives include extensions of conventional CT dosimetry currently used for large axial FOV scanners (e.g. the extended CTDI parameter (CTDIe) for the Toshiba Aquillion One with 160 mm axial FOV) and the new method based on point dosimetry measurements recently formalized in AAPM Report TG-111. Conventional, modified-conventional, and TG-111 dosimetry measurements are used in two CT dose phantoms (adult head and pediatric head) to obtain dose indices for the Planmeca ProMax 3D Max dental CT scanner. Surface dose maps are generated using radiochromic film for correlation with the chamber dosimetry. Results for the three dosimetry approaches are compared for the specific case of the ProMax 3D Max scanner. Strengths and weaknesses of the three measurement paradigms for this type of application are compared. The increasing availability of specialized scanners operating in full cone-beam mode will require the clinical medical physicist to be conversant with extensions to the CT dose index methodology suitable for this equipment.


An evaluation of association between a novel hippocampal biology related SNP (rs7294919) and schizophrenia.
Recent genetic analyses have implicated several candidate susceptibility variants for schizophrenia. The single nucleotide polymorphism (SNP) rs7294919 is likely a schizophrenia-susceptibility variant according to its significant association with hippocampal volume, hippocampus function, and cognitive performance as well as the nominal association with schizophrenia. However, all previous analyses were conducted only in Europeans, and whether rs7294919 is associated with schizophrenia in other populations are yet to be tested. Here, we conducted a case-control analysis of rs7294919 with schizophrenia in six independent Chinese (N = 3) and Japanese (N = 3) samples, including a total of 7,352 cases and 10,824 controls. The results of our association analysis were not able to confirm the association of rs7294919 with schizophrenia (p = 0.51 in total samples, odds ratio = 1.02 for allele[C]). The absence of rs7294919's association in Chinese and Japanese suggest a potential genetic heterogeneity in the susceptibility of schizophrenia on this locus and also demonstrate the difficulties in replicating associations of schizophrenia across different ethnic populations.


The implementation road: engaging community partnerships in evidence-based cancer control interventions.
Southern rural and underserved counties have high proportions of individuals with increased mortality for cervical and breast cancers. To improve the integration of behavioral research into practice, the dissemination and implementation of efficacious interventions to encourage the use of screening have increased in recent years. This study addressed gaps in the dissemination and implementation of evidence-based interventions with a pilot called Team Up. Qualitative interviews with 24 key individuals in six state-level partnerships explored partnership characteristics that influenced selection and use of evidence-based interventions among low-income, rarely or never screened women. Guided by diffusion of innovations theory and the Lasker and Weiss partnership functioning model, interviews about the intervention centered on (a) knowledge surrounding evidence base; (b) identification, selection, and adoption; (c) planning and adaptation; (d) implementation; and (e) partnership reflections and impact. Using grounded theory and content analysis, data revealed that lack of communication and high partner turnover hindered adoption and adaptation, whereas failure of partnership leaders to engage local stakeholders and lack of sufficient funds hampered implementation. Delivery of evidence-based interventions was more effective when partnerships included local partners in early decision making and when coaches were introduced to facilitate strategic thinking about translating evidence-based interventions into practice. A challenge for public health partnerships was the translation of interventions into successful programs, such that underserved communities benefited from early detection intervention research.


Performance in the heat-physiological factors of importance for hyperthermia-induced fatigue.
This article presents a historical overview and an up-to-date review of hyperthermia-induced fatigue during exercise in the heat. Exercise in the heat is associated with a thermoregulatory burden which mediates cardiovascular challenges and influence the cerebral function, increase the pulmonary ventilation, and alter muscle metabolism; which all potentially may contribute to fatigue and impair the ability to sustain power output during aerobic exercise. For maximal intensity exercise, the performance impairment is clearly influenced by cardiovascular limitations to simultaneously support thermoregulation and oxygen delivery to the active skeletal muscle. In contrast, during submaximal intensity exercise at a fixed intensity, muscle blood flow and oxygen consumption remain unchanged and the potential influence from cardiovascular stressing and/or high skin temperature is not related to decreased oxygen delivery to the skeletal muscles. Regardless, performance is markedly deteriorated and exercise-induced hyperthermia is associated with central fatigue as indicated by impaired ability to sustain maximal muscle activation during sustained contractions. The central fatigue appears to be influenced by neurotransmitter activity of the dopaminergic system, but inhibitory signals from thermoreceptors arising secondary to the elevated core, muscle and skin temperatures and augmented afferent feedback from the increased ventilation and the cardiovascular stressing (perhaps baroreceptor sensing of blood pressure stability) and metabolic alterations within the skeletal muscles are likely all factors of importance for afferent feedback to mediate hyperthermia-induced fatigue during submaximal intensity exercise. Taking all the potential factors into account, we propose an integrative model that may help understanding the interplay among factors, but also acknowledging that the influence from a given factor depends on the exercise hyperthermia situation.


Deflazacort in comparison to other steroids for nephrotic syndrome.
Patients with nephrotic syndrome require steroids for long time and sometimes repeatedly resulting in various adverse effects. Deflazacort (DFZ) had been described as equally effective and with fewer side effects as compared with other steroids. This review evaluates the literature on efficacy and toxicity of DFZ as compared with other therapies for nephrotic syndrome. A systematic review of Pubmed database and Cochrane Central Register of Controlled Trials with last search date of 20(th) April 2011. Search terms included "nephrotic AND deflazacort" without any limitations. Randomized control trials comparing DFZ vs placebo or other therapies in subjects with nephrotic syndrome were included. Two authors extracted data independently. Three studies meet inclusion criteria and data were synthesized qualitatively. The limited evidence suggested that DFZ appeared to be equally effective in inducing remission or decreasing proteinuria in patients with nephrotic syndrome. It caused significantly less decrease in bone mineral content (BMC) in spine as compared with prednisolone. The results related to weight change, blood pressure change, Cushingoid symptoms, and urinary calcium excretion were inconsistent between included studies. By reviewing the available limited evidence, DFZ appears to be of similar efficacy for nephrotic patients, but there were inconsistent results regarding side effect profile of DFZ as compared with other steroids except for decrease in BMC where DFZ was better. There is need for larger randomized controlled trials to evaluate effectiveness and adverse effect profile of DFZ as compared with other steroids in nephrotic syndrome.


In vivo functional requirement of the mouse Ifitm1 gene for germ cell development, interferon mediated immune response and somitogenesis.
The mammalian Interferon induced transmembrane protein 1 (Ifitm1) gene was originally identified as a member of a gene family highly inducible by type I and type II interferons. Based on expression analyses, it was suggested to be required for normal primordial germ cell migration. The knockdown of Ifitm1 in mouse embryos provided evidence for a role in somitogenesis. We generated the first targeted knockin allele of the Ifitm1 gene to systematically reassess all inferred functions. Sperm motility and the fertility of male and female mutant mice are as in wild type littermates. Embryonic somites and the adult vertebral column appear normal in homozygous Ifitm1 knockout mice, demonstrating that Ifitm1 is not essential for normal segmentation of the paraxial mesoderm. Proportions of leucocyte subsets, including granulocytes, monocytes, B-cells, T-cells, NK-cells, and NKT-cells, are unchanged in mutant mice. Based on a normal immune response to Listeria monocytogenes infection, there is no evidence for a dysfunction in downstream IFNγ signaling in Ifitm1 mutant mice. Expression from the Ifitm1 locus from E8.5 to E14.5 is highly dynamic. In contrast, in adult mice, Ifitm1 expression is highly restricted and strong in the bronchial epithelium. Intriguingly, IFITM1 is highly overexpressed in tumor epithelia cells of human squamous cell carcinomas and in adenocarcinomas of NSCLC patients. These analyses underline the general importance of targeted in vivo studies for the functional annotation of the mammalian genome. The first comprehensive description of the Ifitm1 expression pattern provides a rational basis for the further examination of Ifitm1 gene functions. Based on our data, the fact that IFITM1 can function as a negative regulator of cell proliferation, and because the gene maps to chromosome band 11p15.5, previously associated with NSCLC, it is likely that IFITM1 in man has a key role in tumor formation.


Predicting responses in patients with rheumatoid arthritis to disease-modifying agents using baseline clinical data.
The optimal treatment for active rheumatoid arthritis (RA) is unresolved, particularly in early RA. We used data from an observational cohort to develop the simple predictor algorithm and evaluated its application in two completed clinical trials in early and established RA. We assessed whether using a simple algorithm can identify patients who have persisting active disease despite treatment with disease-modifying drugs (DMARDs). We also examined if patients who have lower likelihoods of persisting active RA are likely to benefit from intensive treatment. We developed a simple predictive score for persisting disease activity using conventional clinical assessments in an observational cohort of patients with early RA (ERAN). It was tested in two trials in early (CARDERA) and established (TACIT) RA. Persistent disease activity was defined as disease activity score for 28 joints (DAS28) >3.2 at both 6 and 12 months. Regression modelling identified three main predictors of persisting active disease in ERAN; tender joint counts, health assessment questionnaire (HAQ) scores and ESR. We dichotomised these predictors (≥6 tender joint counts, ≥1.0 HAQ ≥20 mm/h ESR) in a four-point prediction score. This simple prediction score predicted persisting active disease in the ERAN cohort and both CARDERA and TACIT trials. Patients with high scores were more likely to have persistently active disease at 6 and 12 months. The relationship was weaker in TACIT because no patients were without any predictive factors. Combining tender joint counts, ESR and HAQ in a simple predictive score prospectively identifies patients with higher risks of persistent disease activity over the next 12 months. More patients with all three risk factors had persistent active disease than those with none or one risk factor.


Adenosine promotes histamine H1-mediated negative chronotropic and inotropic effects on human atrial myocardium.
Because histamine and adenosine are coreleased from the ischemic heart, we investigated the effects of their interaction on human myocardium. Surgical specimens of human right atrium (i.e., pectinate muscles) responded to histamine with increases in spontaneous rate and contractile force. Adenosine, and the A1-selective adenosine agonist N6-cyclopentyladenosine (CPA), reduced the spontaneous rate and suppressed the positive chronotropic and inotropic effects of histamine. CPA was more potent than adenosine in slowing the spontaneous rate and in suppressing histamine's positive chronotropic effect, suggesting that the responses to CPA and adenosine are A1-mediated. CPA was also more potent than adenosine in attenuating histamine's positive inotropic effect on human ventricular papillary muscle. The adenosine-induced suppression of histamine's effects on pectinate muscles was mimicked by carbachol, which like adenosine is known to attenuate H2-mediated histamine-induced adenylate cyclase activation. The H1-selective histamine antagonist pyrilamine potentiated histamine's chronotropic and inotropic responses, and inhibited the attenuation of these responses by adenosine or carbachol. In contrast, pyrilamine failed to modify the adenosine-induced attenuation of the cardiac stimulatory effects of dimaprit, an H2-selective histamine agonist. Our data suggest that adenosine-induced suppression of histamine's positive chronotropic and inotropic effects on human myocardium results both from an A1-mediated attenuation of H2-stimulatory effects and from the uncovering of H1 negative chronotropic and inotropic effects. Thus, the results of the histamine-adenosine interaction may exceed the "retaliatory" purpose of adenosine release and uncover H1-mediated myocardial depression.


In situ total scattering experiments of nucleation and crystallisation of tantalum-based oxides: from highly dilute solutions via cluster formation to nanoparticles.
The exact formation mechanism of tantalum oxides (and in general, metal/mixed metal oxides) from alkoxide precursors is still not fully understood, particularly when forming cluster-like or amorphous materials. The structural evolution of Ta-based oxides was studied in detail using X-ray total scattering experiments along with subsequent pair distribution function (PDF) analyses. Starting from a tantalum alkoxide precursor (Ta2(OEt)10), the formation of hydrolysed TaxOyHz clusters in highly diluted aqueous solution was analysed. From the PDF data, the connectivity and arrangement of TaxOy octahedra in the cluster could be deduced as well as the approximate size of the clusters (<1 nm). Construction of cluster models allowed for identification of common structural motifs in the TaxOyHz clusters, ruling out the formation of chain- or ring-like clusters. More likely, bulky clusters with a high number of corner-sharing octahedra are formed. After separation of the amorphous solid from the liquid, temperature-induced crystallisation processes were monitored via in situ total scattering experiments. Between room temperature and 600 °C, only small rearrangements of the amorphous structure are observed. At about 610 °C, amorphous TaxOyHz transforms directly into crystalline orthorhombic L-Ta2O5 without formation of any crystalline intermediate structures.


Effects of sepsis on neonatal thrombopoiesis.
We serially evaluated the effects of sepsis and/or necrotizing enterocolitis (NEC) on neonatal thrombopoiesis, using a panel of tests that included platelet counts, thrombopoietin concentrations (Tpo), circulating megakaryocyte progenitor concentrations (CMPs), and reticulated platelets (RPs). Variables analyzed included sepsis type, time after onset of sepsis, platelet counts, and gestational (GA) and postconceptional ages (PCA). Twenty neonates were enrolled. Ten had Gram-negative, six had Gram-positive, and four had presumed sepsis. Four neonates had NEC stage II or higher, and six developed thrombocytopenia. Overall, septic neonates had significantly elevated Tpo concentrations and circulating megakaryocyte progenitors. The highest Tpo levels were associated with Gram-negative or presumed sepsis. RP percentages were increased only in neonates with low platelet counts, while RP counts (RP% x platelet count) were elevated in neonates with high platelet counts. Our findings suggest that septic neonates up-regulate Tpo production, leading to increased megakaryocytopoiesis and platelet release, although the degree of upregulation is moderate. The changes in RP% and RP count most likely reflect increased thrombopoiesis with variable degrees of platelet consumption. In addition, our findings suggest that different factors, likely including level of illness and/or specific platelet or bacterial products, can down-regulate the magnitude of the thrombopoietic response.


Chemical data intelligence for sustainable chemistry.
This study highlights new opportunities for optimal reaction route selection from large chemical databases brought about by the rapid digitalisation of chemical data. The chemical industry requires a transformation towards more sustainable practices, eliminating its dependencies on fossil fuels and limiting its impact on the environment. However, identifying more sustainable process alternatives is, at present, a cumbersome, manual, iterative process, based on chemical intuition and modelling. We give a perspective on methods for automated discovery and assessment of competitive sustainable reaction routes based on renewable or waste feedstocks. Three key areas of transition are outlined and reviewed based on their state-of-the-art as well as bottlenecks: (i) data, (ii) evaluation metrics, and (iii) decision-making. We elucidate their synergies and interfaces since only together these areas can bring about the most benefit. The field of chemical data intelligence offers the opportunity to identify the inherently more sustainable reaction pathways and to identify opportunities for a circular chemical economy. Our review shows that at present the field of data brings about most bottlenecks, such as data completion and data linkage, but also offers the principal opportunity for advancement.


Chromatin compaction by a polycomb group protein complex.
Polycomb group proteins preserve body patterning through development by maintaining transcriptional silencing of homeotic genes. A long-standing hypothesis is that silencing involves creating chromatin structure that is repressive to gene transcription. We demonstrate by electron microscopy that core components of Polycomb Repressive Complex 1 induce compaction of defined nucleosomal arrays. Compaction by Polycomb proteins requires nucleosomes but not histone tails. Each Polycomb complex can compact about three nucleosomes. A region of Posterior Sex Combs that is important for gene silencing in vivo is also important for chromatin compaction, linking the two activities. This mechanism of chromatin compaction might be central to stable gene silencing by the Polycomb group.


Assessment of Two Personal Breathing Recording Devices in a Simulated Healthcare Environment.
In the field of respiratory protection for healthcare workers (HCWs), few data are available on respiratory airflow rate when HCWs are performing their work activities. The objective of this study was to assess the performance of two wearable breathing recording devices in a simulated healthcare environment. Breathing recording devices from two different manufactures "A" and "B" were assessed using 15 subjects while performing a series of simulated healthcare work activities (patient assessment; vitals; IV treatment; changing linen; carrying weight while walking; normal breathing while standing). The minute volume (MV, L/min), mean inhalation flow (MIF, L/min), peak inhalation flow (PIF, L/min), breathing frequency (f, breaths/min), and tidal volume (TV, L/min) measured by each device were analyzed. Bland-Altman method was applied to explore the variability of devices A and B. Duncan's multiple range test was used to investigate the differences among activity-specific inspiratory flow rates. The average MV, MIF and PIF reported by device A were 23, 54, and 82 L/min with 95% upper confidence intervals (CIs) of 25, 60 and 92 L/min; the mean differences of MV, MIF and PIF presented by the two units of device A were 0.9, 1.3, and 2.8 L/min, respectively. The average values and mean differences of MV, MIF and PIF found with device B were significantly higher than device A (P<0.05), showing a high variability. During non-speech activities, the PIF/MV and MIF/MV ratios were >3.14 and >2, while with speech, the ratios increased to >6 and >3. The f during speech (15 breaths/min) was significantly lower than non-speech activities (20-25 breaths/min). Among different simulated work activities, the PIF of "patient assessment" was the highest. This study demonstrated a novel approach to characterize respiratory flow for healthcare workers using an innovative wearable flow recording device. Data from this investigation could be useful in the development of future respirator test standards.


Alignment of sparse freehand 3-D ultrasound with preoperative images of the liver using models of respiratory motion and deformation.
We present a method for alignment of an interventional plan to optically tracked two-dimensional intraoperative ultrasound (US) images of the liver. Our clinical motivation is to enable the accurate transfer of information from three-dimensional preoperative imaging modalities [magnetic resonance (MR) or computed tomography (CT)] to intraoperative US to aid needle placement for thermal ablation of liver metastases. An initial rigid registration to intraoperative coordinates is obtained using a set of US images acquired at maximum exhalation. A preprocessing step is applied to both the preoperative images and the US images to produce evidence of corresponding structures. This yields two sets of images representing classification of regions as vessels. The registration then proceeds using these images. The preoperative images and plan are then warped to correspond to a single US slice acquired at an unknown point in the breathing cycle where the liver is likely to have moved and deformed relative to the preoperative image. Alignment is constrained using a patient-specific model of breathing motion and deformation. Target registration error is estimated by carrying out simulation experiments using resliced MR volumes to simulate real US and comparing the registration results to a "bronze-standard" registration performed on the full MR volume. Finally, the system is tested using real US and verified using visual inspection.


Acute lymphoblastic leukemia in young adults: two chemotherapeutic protocols for the treatment of 46 patients.
Acute lymphoblastic leukemia (ALL) in adults has a very poor prognosis. Many chemotherapeutic protocols have been designed to try to improve treatment results for adult ALL. Two chemotherapeutic protocols were used to treat young adult ALL patients in our institute and treatment results are reported. From 1984 through 1997, 46 young adult patients with ALL were treated. There were 43 males and three females. Their ages ranged from 16 to 38 years, with a median of 24 years. Thirty-two patients (group A) received a four-week conventional induction regimen with daunomycin, vincristine, prednisolone, and L-asparaginase, followed by prophylaxis of the central nervous system (CNS) with intrathecal methotrexate and cranial irradiation, as well as maintenance therapy with oral 6-mercaptopurine and methotrexate. Fourteen patients (group B) received the modified protocol of the German multicenter trial for adult ALL (GMALL) with a two-phase induction regimen, CNS prophylaxis and maintenance therapy. In group A, 25 of 32 patients achieved complete remission (CR), three obtained partial remission and four died of treatment-related complications during induction therapy. The median duration of remission (DR) was 12 months (range, 3-39 months) and the median overall survival time (OST) was 13 months (range, 0.5-50 months). Of the 25 patients who achieved CR, 21 relapsed and died. In group B, 11 of 14 patients obtained CR and three died of leukopenia-related infectious complications during induction. The median DR was 12 months (range, 8-37 months) and the median OST was 15 months (range, 0.5-39 months). During follow-up, 10 of 11 patients relapsed from ALL and died. Only one patient who received allogeneic bone marrow transplantation first CR is still alive. No statistical differences between the two groups were noted in terms of CR rate, DR (p = 0.87) and OST (p = 0.34). However, the the GMALL protocol had during the significantly more hematologic toxicity during induction therapy. Our results suggest that young adult ALL is a disease with a very poor prognosis and conventional chemotherapy is not adequate for its treatment. The notion that GMALL protocol is better than conventional therapy in the treatment of adult ALL cannot be justified by our data.


Damp housing and asthma: a case-control study.
Several epidemiological studies have reported a higher prevalence of respiratory symptoms in subjects living in damp housing, but links with specific respiratory diseases such as asthma have not been satisfactorily established. One hundred and two subjects with physician diagnosed asthma and 196 age and sex matched controls were interviewed; 222 (75%) then agreed to have their dwelling surveyed for dampness. The prevalence of both self-reported and observed dampness in the homes of the asthmatic subjects and controls were compared. Both asthma and the severity of the dampness were quantified so that the possibility of a dose-response relationship could be investigated. Asthmatic subjects reported dampness in their current (odds ratio (OR) 1.92, 95% confidence interval (CI) 1.18 to 3.12) and previous (OR 2.11, 95% CI 1.29 to 3.47) dwellings more frequently than control subjects. The surveyor confirmed dampness in 58 of 90 (64%) dwellings of asthmatic subjects compared with 54 of 132 (41%) dwellings of control subjects (OR 2.62, 95% CI 1.50 to 4.55). This association persisted after controlling for socioeconomic and other confounding variables (adjusted OR 3.03, 95% CI 1.65 to 5.57). The severity of asthma was found to correlate statistically with measures of total dampness (r = 0.30, p = 0.006) and mould growth (r = 0.23, p = 0.035) in the dwelling. Patients living in homes with confirmed areas of dampness had greater evidence of airflow obstruction than those living in dry homes (mean difference in forced expiratory volume in one second (FEV1) 10.6%, 95% CI 1.0 to 20.3). Asthma is associated with living in damp housing and there appears to be a dose-response relationship. Action to improve damp housing conditions may therefore favourably influence asthma morbidity.


The caa3 terminal oxidase of Bacillus stearothermophilus. Transient spectroscopy of electron transfer and ligand binding.
The thermophilic bacterium Bacillus stearothermophilus possesses a caa3-type terminal oxidase, which was previously purified (De Vrij, W., Heyne, R. I. R., and Konings, W. N. (1989) Eur. J. Biochem. 178, 763-770). We have carried out extensive kinetic experiments on the purified enzyme by stopped-flow time-resolved optical spectroscopy combined with singular value decomposition analysis. The results indicate a striking similarity of behavior between this enzyme and the electrostatic complex between mammalian cytochrome c and cytochrome c oxidase. CO binding to fully reduced caa3 occurs with a second order rate constant (k = 7.8 x 10(4)M-1 s-1) and an activation energy (E* = 6.1 kcal mol-1) similar to those reported for beef heart cytochrome c oxidase. Dithionite reduces cytochrome a with bimolecular kinetics, while cytochrome a3 (and CuB) is reduced via intramolecular electron transfer. When the fully reduced enzyme is mixed with O2, cytochrome a3, and cytochrome c are rapidly oxidized, whereas cytochrome a remains largely reduced in the first few milliseconds. When cyanide-bound caa3 is mixed with ascorbate plus TMPD, cytochrome c and cytochrome a are synchronously reduced; the value of the second order rate constant (k = 3 x 10(5) M-1 s-1 at 30 degrees C) suggests that cytochrome c is the electron entry site. Steady-state experiments indicate that cytochrome a has a redox potential higher than cytochrome c. The data from the reaction with O2 reveal a remarkable similarity in the kinetic, equilibrium, and optical properties of caa3 and the electrostatic complex cytochrome c/cytochrome c oxidase.


Multigene Family Evolution: Perspectives from Insect Chemoreceptors.
Understanding the birth and diversification of multigene families is a fundamental evolutionary problem. I argue for the insect chemoreceptor superfamily as an outstanding model. Although these receptors are currently the preserve of neuroscientists, putative homologous genes exist in diverse animal and plant genomes, implying an ancient origin. Moreover, functional studies suggest that they act as ligand-gated ion channels in both chemosensory and non-chemosensory processes. This family permits synergism of investigations into its structural and regulatory evolution with ecological studies of the selective pressures driving these changes. In addition, sequence divergence in these receptors can be exploited through co-evolutionary and comparative genomics analyses to help to elucidate their 3D structure and signaling mechanisms, and to reveal experimentally-accessible candidate loci to explore the genetic basis of adaptation.


Oily fish reduces plasma triacylglycerols: a primary prevention study in overweight men and women.
Previous studies have demonstrated benefits of high-dose long-chain omega-3 polyunsaturated fatty acid (LC omega-3 PUFA) supplements on metabolic risk. Effects of increased dietary omega-3 PUFA, via oily fish and/or plant-derived omega-3 PUFAs, are less clear and may be modulated by the omega-6:omega-3 PUFA of the habitual diet. This study examined the effect on cardiovascular disease risk markers of reducing dietary omega-6:omega-3 PUFA by changes in linoleic acid:alpha-linolenic acid (LA:LNA) and/or increasing LC omega-3 PUFA. It tested whether decreases in LA:LNA modulate effects of LC omega-3 PUFA. One hundred forty-two subjects, recruited to a 24-wk randomized study, were assigned to a control group or one of four interventions. Intervention groups received two portions of oily fish (4.5 g eicosapentaenoic acid + docosahexanoic acid) or white fish (0.7 g eicosapentaenoic acid + docosahexanoic acid) per week, and replaced habitual household fats with ones high in sunflower (high LA:LNA) or rapeseed (low LA:LNA) oil. Modest dietary manipulations of omega-6 and omega-3 PUFAs resulted in significant group x time interactions for serum triacylglycerols (TAGs; P = 0.05); at 24 wk the control and two oily fish groups showed lower TAG than did the white fish/sunflower group (P = 0.05). Reductions in TAG, associated with increased oily fish intakes, were maximized when combined with lower dietary LA:LNA. There were no significant changes in several other cardiovascular disease risk markers. Two portions of oily fish per week led to significant reductions in TAG relative to consumption of two portions of white fish per week. Changes in TAG were maximized when combined with lower LA:LNA.


Chemotherapy and Glycemic Control in Patients with Type 2 Diabetes and Cancer: A Comparative Case Analysis.
Individuals with diabetes who develop cancer have a worse 5-year overall survival rate and are more likely to develop an infection and/or be hospitalized when compared to those without diabetes. Patients with diabetes and cancer receiving chemotherapy have an increased risk for developing glycemic issues. The relationship between chemotherapy and glycemic control is not completely understood. The aim of this study was to explore the relationship between glycemic control, symptoms, physical and mental function, development of adverse events, and chemotherapy reductions or stoppages in adults with Type 2 diabetes (T2D) and cancer. A prospective 12-week longitudinal cohort study recruited 24 adults with T2D, solid tumor cancer, or lymphoma receiving outpatient intravenous chemotherapy. Eighteen individuals completed baseline data and were included in the analysis. A comparative case analysis was performed to analyze the results. Potential predictors of occurrence of an adverse event include sex (relative risk [RR] = 1.5), treatment with insulin (RR = 2.17), years with diabetes (RR = 3.85), and baseline glycated hemoglobin (HbA1c) (odds ratio [OR] = 1.67). Baseline body mass index (BMI) (OR = 1.16) and HbA1c (OR = 1.61) were potentially predictive of a chemotherapy stoppage. Level of glycemic control at the time an individual begins treatment for cancer appears to contribute to the occurrence of an adverse event, developing an infection and/or being hospitalized during treatment, and the increased risk of having a chemotherapy reduction or stoppage. Clinicians working with patients receiving chemotherapy for a solid tumor cancer who have pre-existing diabetes, need to be aware of how the patients glycemic level at the start of treatment may impact successful treatment completion.


Optimized data fusion for kernel k-means clustering.
This paper presents a novel optimized kernel k-means algorithm (OKKC) to combine multiple data sources for clustering analysis. The algorithm uses an alternating minimization framework to optimize the cluster membership and kernel coefficients as a nonconvex problem. In the proposed algorithm, the problem to optimize the cluster membership and the problem to optimize the kernel coefficients are all based on the same Rayleigh quotient objective; therefore the proposed algorithm converges locally. OKKC has a simpler procedure and lower complexity than other algorithms proposed in the literature. Simulated and real-life data fusion applications are experimentally studied, and the results validate that the proposed algorithm has comparable performance, moreover, it is more efficient on large-scale data sets. (The Matlab implementation of OKKC algorithm is downloadable from http://homes.esat.kuleuven.be/~sistawww/bio/syu/okkc.html.).


Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells.
Sir2 and insulin/IGF-1 are the major pathways that impinge upon aging in lower organisms. In Caenorhabditis elegans a possible genetic link between Sir2 and the insulin/IGF-1 pathway has been reported. Here we investigate such a link in mammals. We show that Sirt1 positively regulates insulin secretion in pancreatic beta cells. Sirt1 represses the uncoupling protein (UCP) gene UCP2 by binding directly to the UCP2 promoter. In beta cell lines in which Sirt1 is reduced by SiRNA, UCP2 levels are elevated and insulin secretion is blunted. The up-regulation of UCP2 is associated with a failure of cells to increase ATP levels after glucose stimulation. Knockdown of UCP2 restores the ability to secrete insulin in cells with reduced Sirt1, showing that UCP2 causes the defect in glucose-stimulated insulin secretion. Food deprivation induces UCP2 in mouse pancreas, which may occur via a reduction in NAD (a derivative of niacin) levels in the pancreas and down-regulation of Sirt1. Sirt1 knockout mice display constitutively high UCP2 expression. Our findings show that Sirt1 regulates UCP2 in beta cells to affect insulin secretion.


Structural insight into metallocofactor maturation in carbon monoxide dehydrogenase.
The nickel-dependent carbon monoxide dehydrogenase (CODH) employs a unique heterometallic nickel-iron-sulfur cluster, termed the C-cluster, to catalyze the interconversion of CO and CO2 Like other complex metalloenzymes, CODH requires dedicated assembly machinery to form the fully intact and functional C-cluster. In particular, nickel incorporation into the C-cluster depends on the maturation factor CooC; however, the mechanism of nickel insertion remains poorly understood. Here, we compare X-ray structures (1.50-2.48 Å resolution) of CODH from Desulfovibrio vulgaris (DvCODH) heterologously expressed in either the absence (DvCODH-CooC) or presence (DvCODH+CooC) of co-expressed CooC. We find that the C-cluster of DvCODH-CooC is fully loaded with iron but does not contain any nickel. Interestingly, the so-called unique iron ion (Feu) occupies both its canonical site (80% occupancy) and the nickel site (20% occupancy), with addition of reductant causing further mismetallation of the nickel site (60% iron occupancy). We also demonstrate that a DvCODH variant that lacks a surface-accessible iron-sulfur cluster (the D-cluster) has a C-cluster that is also replete in iron but lacks nickel, despite co-expression with CooC. In this variant, all Feu is in its canonical location, and the nickel site is empty. This D-cluster-deficient CODH is inactive despite attempts to reconstitute it with nickel. Taken together, these results suggest that an empty nickel site is not sufficient for nickel incorporation. Based on our findings, we propose a model for C-cluster assembly that requires both CooC and a functioning D-cluster, involves precise redox-state control, and includes a two-step nickel-binding process.


Conservation status and regional habitat priorities for the Orinoco crocodile: Past, present, and future.
Conservation of large predator species has historically been a challenge because they often overlap in resource utilization with humans; furthermore, there is a general lack of in-depth knowledge of their ecology and natural history. We assessed the conservation status of the Orinoco crocodile (Crocodylus intermedius), defining regional habitat priorities/crocodile conservation units (RHP/CCU) and regional research priorities (RRP) for this species. We also estimated a species distribution model (SDM) to define current suitable areas where the species might inhabit and/or that might be successfully colonized. The SDM area obtained with a suitable habitat probability ≥ 0.5 was 23,621 km2. Out of 2,562 km2 are included within protected areas in both Colombia (1,643 km2) and Venezuela (919 km2), which represents only 10.8% of C. intermedius' potential range. Areas such as Laguna de Chigüichigüe (flood plain lagoon) exhibited an increase in population abundance. In contrast, localities such as the Cojedes and Manapire Rivers reported a significant reduction in relative abundance values. In Colombia, disparity in previous survey methods prevented accurate estimation of population trends. Only one study in this country described an increase over a 13 years span in the Ele, Lipa, and Cravo Norte River populations based on nest surveys. We defined 34 critical areas (16 in Colombia, 17 in Venezuela, and one covering both countries) where we need to preserve/research/monitor and/or generate management actions, 10 RHP/CCU (six from Venezuela and four from Colombia) and 24 RRP (11 from Venezuela, 12 from Colombia, and one in both countries). Caño Guaritico (Creek) and the Capanaparo River in Venezuela and the Ele, Lipa, Cravo Norte River System and the Guayabero River in Colombia were defined as areas with the most optimal conditions for long-term preservation and maintenance of C. intermedius populations. We conclude that the conservation status of this species is still critical, which implies the necessity to increase efforts to recover the species, especially in Colombia, to guarantee its survival as a structural and functional component of the ecosystems it inhabits.


Specificity of basolateral organic cation transport in snake renal proximal tubules.
We examined the specificity of basolateral organic cation transport in isolated snake (Thamnophis spp.) renal proximal tubules by determining the inhibitory effect of a series of n-tetraalkylammonium (n-TAA) compounds (n = 1-5) on the basolateral uptake of [3H]tetraethylammonium (TEA). The inhibitory potency increased with increasing alkyl chain length, with the apparent Michaelis constants for inhibition of TEA uptake ranging from 3.3 mM for tetramethylammonium (TMA) to 1.0 microM for tetrapentylammonium (TPeA). Thus the apparent affinity of the carrier for n-TAA compounds increases with their increasing hydrophobicity. Because previous data suggested that TEA transport across the basolateral membrane may be asymmetrical and that the exit step may be regulated differently from the entry step, we examined the kinetics of [3H]TEA efflux across the basolateral membrane, Efflux, like entry, occurred by a saturable process that could be described adequately by Michaelis-Menten kinetics. However, the concentration of TEA at one-half Jmax (Kt) for efflux (approximately 110 microM) was about six times the Kt for uptake (approximately 18 muM), indicating that the affinity of the carrier for TEA is greater in the uptake direction than in the efflux direction or that there are separate carriers with different affinities for uptake and efflux. In either case, this difference would favor movement of TEA taken up at the basolateral side across the cells and into the lumen over movement back into the peritubular fluid.


Estimated average annual rate of change of CD4(+) T-cell counts in patients on combination antiretroviral therapy.
Patients receiving combination antiretroviral therapy (cART) might continue treatment with a virologically failing regimen. We sought to identify annual change in CD4(+) T-cell count according to levels of viraemia in patients on cART. A total of 111,371 CD4(+) T-cell counts and viral load measurements in 8,227 patients were analysed. Annual change in CD4(+) T-cell numbers was estimated using mixed models. After adjustment, the estimated average annual change in CD4(+) T-cell count significantly increased when viral load was <500 copies/ml (30.4 cells/mm(3), 95% confidence interval [CI] 26.6-34.3), was stable when viral load was 500-9,999 copies/ml (3.1 cells/mm(3), 95% CI -5.3-11.5) and decreased when viral load was > or =10,000 copies/ml (-14.8 cells/mm(3), 95% CI -4.5--25.1). Patients taking a boosted protease inhibitor (PI) regimen had more positive annual CD4(+) T-cell count changes than patients taking other regimens for any given viral load strata: 30.9 cells/mm(3) (95% CI 27.7-34.1) when viral load was <500 copies/ml, 14.2 cells/mm(3) (95% CI -2.1-30.4) when viral load was 500-9,999 copies/ml and -19.9 cells/mm(3) (95% CI -36.6--3.3) when viral load was >or =10,000 copies/ml. By contrast, among patients taking a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen, the CD4(+) T-cell count significantly decreased when the viral load was 500-9,999 copies/ml (-18.6 cells/mm(3), 95% CI -33.8--3.5) and decreased at a faster rate when the viral load was > or =10,000 copies/ml (-44.4 cells/mm(3), 95% CI -62.0--26.9; P=0.0012, test for interaction). On average, CD4(+) T-cell counts did not significantly decrease until the viral load exceeded 10,000 copies/ml in patients treated with a boosted PI-containing cART regimen, but decreased in patients taking an NNRTI-based cART regimen when viral load was 500-9,999 copies/ml.


Apportionment and districting by Sum of Ranking Differences.
Sum of Ranking Differences is an innovative statistical method that ranks competing solutions based on a reference point. The latter might arise naturally, or can be aggregated from the data. We provide two case studies to feature both possibilities. Apportionment and districting are two critical issues that emerge in relation to democratic elections. Theoreticians invented clever heuristics to measure malapportionment and the compactness of the shape of the constituencies, yet, there is no unique best method in either cases. Using data from Norway and the US we rank the standard methods both for the apportionment and for the districting problem. In case of apportionment, we find that all the classical methods perform reasonably well, with subtle but significant differences. By a small margin the Leximin method emerges as a winner, but-somewhat unexpectedly-the non-regular Imperiali method ties for first place. In districting, the Lee-Sallee index and a novel parametric method the so-called Moment Invariant performs the best, although the latter is sensitive to the function's chosen parameter.


Comparing free water imaging and magnetization transfer measurements in schizophrenia.
Diffusion weighted imaging (DWI) has been extensively used to study the microarchitecture of white matter in schizophrenia. However, popular DWI-derived measures such as fractional anisotropy (FA) may be sensitive to many types of pathologies, and thus the interpretation of reported differences in these measures remains difficult. Combining DWI with magnetization transfer ratio (MTR) - a putative measure of white matter myelination - can help us reveal the underlying mechanisms. Previous findings hypothesized that MTR differences in schizophrenia are associated with free water concentrations, which also affect the DWIs. In this study we use a recently proposed DWI-derived method called free-water imaging to assess this hypothesis. We have reanalyzed data from a previous study by using a fiber-based analysis of free-water imaging, providing a free-water fraction, as well as mean diffusivity and FA corrected for free-water, in addition to MTR along twelve major white matter fiber bundles in 40 schizophrenia patients and 40 healthy controls. We tested for group differences in each fiber bundle and for each measure separately and computed correlations between the MTR and the DWI-derived measures separately for both groups. Significant higher average MTR values in patients were found for the right uncinate fasciculus, the right arcuate fasciculus and the right inferior-frontal occipital fasciculus. No significant results were found for the other measures. No significant differences in correlations were found between MTR and the DWI-derived measures. The results suggest that MTR and free-water imaging measures can be considered complementary, promoting the acquisition of MTR in addition to DWI to identify group differences, as well as to better understand the underlying mechanisms in schizophrenia.


Electrical stimulation-induced osteogenesis of human adipose derived stem cells using a conductive graphene-cellulose scaffold.
The versatile properties of graphene-based materials are enabling various tissue regeneration, towards meeting an ever increasing demand for replacement tissues due to injury through trauma and disease. In particular, an innate ability for graphene to promote osteogenic differentiation of stem cells, combined with the potential to enhance the biological activity of cells through electrical stimulation (ES) using graphene, supports its use for osteoinduction or reconstruction. In this paper, we describe a miniaturized graphene-cellulose (G-C) scaffold-based device that incorporates electroactive G-C 'paper' within a polystyrene chamber for concomitant cell culture and ES. The G-C electrodes possessed lower impedance and higher charge injection capacity than gold (Au) electrodes, with high stability. By coupling ES with previously reported properties of the G-C scaffolds, we have advanced the platform for improved adipose derived stem cell (ADSC) support and osteogenic differentiation. We anticipate using the G-C scaffold-based ES device for in vitro modelling of osteogenic induction, bone tissue engineering and in vivo bone regeneration towards new therapeutic strategies for bone injury and disease. Furthermore, the device could reasonably be used for ES and culture of other cell types and engineering other tissues.


Design and application of oligonucleotide probes for fluorescent in situ identification of the filamentous bacterial morphotype Nostocoida limicola in activated sludge.
16S rRNA targeted probes, designed using sequence data from pure cultures of the three morphotypes of the filamentous bulking bacteria Nostocoida limicola I, II and III and their successful application to the in situ identification of these bacteria in activated sludge biomass samples are described here. Two probes were required to detect all the sequenced N. limicola II isolates. Results from fluorescent in situ hybridization suggest that the morphotypes N. limicola I and II contain at least two phylogenetically unrelated bacteria. The N. limicola II filaments that did not respond to the probes designed in this study fluoresced instead with the probes previously designed for the alpha-Proteobacteria. The data also suggest that both N. limicola I and III can exist in activated sludge as single, paired or clumped cells and thus in a form not recognizable microscopically as this morphotype. Some N. limicola II filaments which responded to the probes designed here were much thinner than the filaments conventionally 'identified' as this morphotype and better fitted the descriptions often used in the literature for N. limicola I.


Hippocampal subfields and visuospatial associative memory across stages of schizophrenia-spectrum disorder.
While previous studies have identified relationships between hippocampal volumes and memory performance in schizophrenia, these relationships are not apparent in healthy individuals. Further, few studies have examined the role of hippocampal subfields in illness-related memory deficits, and no study has examined potential differences across varying illness stages. The current study aimed to investigate whether individuals with early and established psychosis exhibited differential relationships between visuospatial associative memory and hippocampal subfield volumes. Measurements of visuospatial associative memory performance and grey matter volume were obtained from 52 individuals with a chronic schizophrenia-spectrum disorder, 28 youth with recent-onset psychosis, 52 older healthy controls, and 28 younger healthy controls. Both chronic and recent-onset patients had impaired visuospatial associative memory performance, however, only chronic patients showed hippocampal subfield volume loss. Both chronic and recent-onset patients demonstrated relationships between visuospatial associative memory performance and hippocampal subfield volumes in the CA4/dentate gyrus and the stratum that were not observed in older healthy controls. There were no group by volume interactions when chronic and recent-onset patients were compared. The current study extends the findings of previous studies by identifying particular hippocampal subfields, including the hippocampal stratum layers and the dentate gyrus, that appear to be related to visuospatial associative memory ability in individuals with both chronic and first-episode psychosis.


Multicenter review of preoperative risk factors for endarterectomy for asymptomatic carotid artery stenosis.
The benefit of carotid endarterectomy is highly dependent on surgical risk. However, little data are available concerning factors affecting the risk of endarterectomy performed for asymptomatic carotid artery stenosis outside the setting of a randomized controlled trial. The purpose of this study was to analyze the impact of potential preoperative risk factors on the frequency of postoperative complications in patients undergoing the operation for asymptomatic disease in academic medical centers. Data regarding postoperative complications were systematically abstracted from the medical records of a random sample of patients who underwent carotid endarterectomy at 12 academic medical centers. Of 1160 procedures reviewed, 463 (40%) were performed for asymptomatic disease. Postoperative stroke or death occurred in 13 (2.8%), and myocardial infarction occurred in 8 (1.7%). The rate of postoperative stroke or death was lower in asymptomatic patients than in those with a history of cerebrovascular symptoms in a different vascular distribution, but the difference was not significant (1.8% versus 4.2%; P=.21). There were no significant differences in these rates based on race, a history of angina, recent myocardial infarction, chronic obstructive pulmonary disease, hypertension, the degree of stenosis of the contralateral or ipsilateral carotid artery, or the presence of angiographically recognized ulceration, intraluminal thrombus, or siphon stenosis in the ipsilateral vessel (chi(2); P>.05). Postoperative stroke or death was more frequent in women (5.3% versus 1.6% in men; P=.02), in those aged 75 years or older (7.8% versus 1.8% in those younger than 75 years; P=.01), and in those with a history of congestive heart failure (8.6% versus 2.3% in those without a history of congestive heart failure; P=.03). The risk of stroke or death was higher in the 16 patients who had carotid endarterectomy performed in combination with coronary artery bypass surgery than in those who had only endarterectomy (18.7% versus 2.1%; P<.001). The overall risk of postoperative stroke or death was nearly twice that reported by Asymptomatic Carotid Atherosclerosis Study (ACAS) investigators in the setting of a clinical trial but was within acceptable guidelines. Women were at higher postoperative risk than men, which supported ACAS findings. Additional high-risk groups were those aged 75 years or older, those with a history of congestive heart failure, and those undergoing prophylactic endarterectomy for asymptomatic stenosis in combination with coronary surgery. Knowledge of these rates may help to better assess an individual's postoperative risk and therefore the anticipated benefit of surgery.


Trex1 regulates lysosomal biogenesis and interferon-independent activation of antiviral genes.
The sensing of viral nucleic acids by the innate immune system triggers the production of type I interferons, which activates interferon-stimulated genes (ISGs) and directs a multifaceted antiviral response. ISGs can also be activated through interferon-independent pathways, although the precise mechanisms remain elusive. Here we found that the cytosolic exonuclease Trex1 regulated the activation of a subset of ISGs independently of interferon. Both Trex1(-/-) mouse cells and Trex1-mutant human cells had high expression of genes encoding antiviral molecules ('antiviral genes') and were refractory to viral infection. The interferon-independent activation of antiviral genes in Trex1(-/-) cells required the adaptor STING, the kinase TBK1 and the transcription factors IRF3 and IRF7. We also found that Trex1-deficient cells had an expanded lysosomal compartment, altered subcellular localization of the transcription factor TFEB and diminished activity of the regulator mTORC1. Together our data identify Trex1 as a regulator of lysosomal biogenesis and interferon-independent activation of antiviral genes and show that dysregulation of lysosomes can elicit innate immune responses.


The A-B neuropsychological assessment schedule (ABNAS): the relationship between patient-perceived drug related cognitive impairment and results of neuropsychological tests.
Our intention was to evaluate the relationships between the A-B neuropsychological assessment schedule (ABNAS) as a measure of patient-perceived cognitive effects of antiepileptic drugs (AEDs) and the results of neuropsychological tests. The measure was developed specifically to assess patient-perceived cognitive effects of AED treatment. Evidence of its reliability and validity has been previously documented. In this study 96 patients were included using stratified inclusion-criteria to guarantee variability of performance: 55 patients were included from a 'low risk condition' with respect to possible cognitive effect (i.e. monotherapy carbamazepine within a dose range of 600-1200 mg/day) and 41 patients were included from a 'high risk condition' (i.e. polytherapy of three or two AEDs including either phenytoin, phenobarbitone or a benzodiazepine; treatment with topiramate with a titration speed using 50 mg or higher increments per week and within the first 6 months of treatment). All patients were prospectively assessed using the ABNAS and five neuropsychological tests (all part of the FePsy test system) with proven sensitivity of cognitive effects of antiepileptics: three tasks using reaction-time to measure speed ('simple (visual) reaction-time measurement', 'the binary choice reaction test' and 'the computerized visual searching task'); one test measuring motor speed ('the finger tapping task'); and a memory test ('recognition of words'). The three reaction-time tasks and the finger tapping test were significantly correlated with the ABNAS-score with correlations ranging from 0.22 to 0.35. The highest correlation was with 'simple (visual) reaction-time measurement' (0.35). Discriminant analysis showed that with the neuropsychological tests 61.5% of the patients were correctly identified as having high/low ABNAS-scores. The ABNAS underestimated impairment in 17.8% of the patients ( = low ABNAS-score but impairment on the neuropsychological tests). The present study contributes to the already existing evidence of validity of the ABNAS as a screening instrument for clinical practice as the relationship between the ABNAS-score and results of neuropsychological tests can help to identify who is at risk and needs further referral for neuropsychological assessment. Moreover the correlation between ABNAS-score and those neuropsychological tests that are sensitive for drug-effects may provide a sensitive instrument in early drug-development phases while keeping the burden on financial and time resources to a minimum.


Current Practice of Airway Stenting in the Adult Population in Europe: A Survey of the European Association of Bronchology and Interventional Pulmonology (EABIP).
Airway stenting (AS) commenced in Europe circa 1987 with the first placement of a dedicated silicone airway stent. Subsequently, over the last 3 decades, AS was spread throughout Europe, using different insertion techniques and different types of stents. This study is an international survey conducted by the European Association of Bronchology and Interventional Pulmonology (EABIP) focusing on AS practice within 26 European countries. A questionnaire was sent to all EABIP National Delegates in February 2015. National delegates were responsible for obtaining precise and objective data regarding the current AS practice in their country. The deadline for data collection was February 2016. France, Germany, and the UK are the 3 leading countries in terms of number of centres performing AS. These 3 nations represent the highest ranked nations within Europe in terms of gross national income. Overall, pulmonologists perform AS exclusively in 5 countries and predominately in 12. AS is performed almost exclusively in public hospitals. AS performed under general anaesthesia is the rule for the majority of institutions, and local anaesthesia is an alternative in 9 countries. Rigid bronchoscopy techniques are predominant in 20 countries. Amongst commercially available stents, both Dumon and Ultraflex are by far the most commonly deployed. Finally, 11 countries reported that AS is an economically viable activity, while 10 claimed that it is not. This EABIP survey demonstrates that there is significant heterogeneity in AS practice within Europe. Therapeutic bronchoscopy training and economic issues/reimbursement for procedures are likely to be the primary reasons explaining these findings.


The Minimum Clinically Important Improvement and Patient-acceptable Symptom State in the BASDAI and BASFI for Patients with Ankylosing Spondylitis.
To establish cutoffs for the minimum clinically important improvement (MCII) and the patient-acceptable symptom state (PASS) for the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Bath Ankylosing Spondylitis Functional Index (BASFI) in patients with ankylosing spondylitis (AS). Patients with AS who started nonsteroidal antiinflammatory drugs were included. After 4 weeks, the PASS and the MCII were defined using external anchor questions (for the PASS, patients considering their condition of AS over the prior 48 h as "acceptable" forever; and for the MCII, those reporting moderate or slightly important improvement). Consistency of the MCII and PASS were tested according to HLA-B27 status, presence/absence of SpA extraarticular manifestations, age, sex, disease duration, and baseline BASDAI/BASFI score. The 75th percentile of the cumulative distribution was used to determine the MCII and PASS. In total, 283 patients from a multinational cohort were included. Overall cutoffs for the PASS were 4.1 in the BASDAI and 3.8 in the BASFI. Cutoffs for the MCII were 0.7 and 0.4 for the BASDAI and BASFI, respectively. Subgroup analyses revealed that disease duration and baseline BASDAI/BASFI were significantly associated with the PASS and MCII. In a subanalysis limited to patients with active disease (baseline BASDAI ≥ 4), the MCII was 1.1 for the BASDAI and 0.6 for the BASFI. The conceptual viability of the PASS for the BASDAI is questionable because levels approach those required for the start of biological therapy. Because the MCII is less variable than the PASS, we propose its exclusive use, with cutoffs of 1.1/0.6 for the BASDAI/BASFI in patients with active disease. Because these values are based on a subset of the study population, we recommend confirmation in larger studies focused on patients with baseline BASDAI ≥ 4.


Targeted Assessment and Context-Tailored Implementation of Change Strategies (TACTICS) to increase evidence based psychotherapy in military behavioral health clinics: Design of a cluster-randomized stepped-wedge implementation study.
Despite efforts by the U.S. Department of Defense to train behavioral health (BH) providers in evidence-based psychotherapies (EBPs) for posttraumatic stress disorder (PTSD), numerous barriers limit EBP implementation. A context-tailored implementation approach called TACTICS (Targeted Assessment and Context-Tailored Implementation of Change Strategies) holds promise for increasing the use of EBPs such as prolonged exposure therapy (PE) in military treatment facilities. TACTICS combines a needs assessment, a rubric for selecting implementation strategies based on local barriers, an implementation toolkit, and external facilitation to support local champions and their implementation teams in enacting changes. This paper describes the rationale for and design of a study that will evaluate whether TACTICS can increase implementation of PE for PTSD and improve patient outcomes in military BH clinics relative to provider training in PE alone. The study is a multi-site, cluster randomized, stepped-wedge trial, with the military treatment facility as the unit of analysis. Eight facilities undergo a provider-training phase, followed by 5 months of TACTICS implementation. The timing of TACTICS at each facility is randomly assigned to begin 9, 14, or 19 months after beginning the provider-training phase. Primary analyses will compare the proportion of PTSD patients receiving PE and patients' mean improvement in PTSD symptoms before and after the onset of TACTICS. TACTICS endeavors to balance standardization of empirically-supported implementation strategies with the flexibility of application necessary for success across varied clinical settings. If successful, TACTICS may represent a systematic and scalable method of promoting and supporting EBP implementation. Clinicaltrials.gov Identifier: NCT03663452.


Primary cutaneous immunocytoma/marginal zone B-cell lymphoma: a case with unusual course.
Although primary cutaneous immunocytoma/marginal zone B-cell lymphoma (PCI/MZBL) is considered as an indolent lymphoma with excellent prognosis, extracutaneous spread and even death due to disseminated disease have been reported. This is a case report of a PCI/MZBL showing dissemination to the regional lymph node and bone marrow, 22 months after the initial diagnosis. Furthermore, in the lymph node, there were focal areas of high-grade transformation. On the other hand, the bone marrow involvement displayed low-grade morphology. We suggest that it should be kept in mind that there is still a possibility of systemic involvement in PCI/MZBL.


Fair and unfair punishers coexist in the Ultimatum Game.
In the Ultimatum Game, a proposer suggests how to split a sum of money with a responder. If the responder rejects the proposal, both players get nothing. Rejection of unfair offers is regarded as a form of punishment implemented by fair-minded individuals, who are willing to impose the cooperation norm at a personal cost. However, recent research using other experimental frameworks has observed non-negligible levels of antisocial punishment by competitive, spiteful individuals, which can eventually undermine cooperation. Using two large-scale experiments, this note explores the nature of Ultimatum Game punishers by analyzing their behavior in a Dictator Game. In both studies, the coexistence of two entirely different sub-populations is confirmed: prosocial punishers on the one hand, who behave fairly as dictators, and spiteful (antisocial) punishers on the other, who are totally unfair. The finding has important implications regarding the evolution of cooperation and the behavioral underpinnings of stable social systems.