Isolation and characterization of glycosylphosphatidylinositol-anchored, mucin-like surface glycoproteins from bloodstream forms of the freshwater-fish parasite Trypanosoma carassii.
Wild and farmed freshwater fishes are widely and heavily parasitized by the haemoflagellate Trypanosoma carassii. In contrast, common carp, a natural host, can effectively control experimental infections by the production of specific anti-parasite antibodies. In this study we have identified and partially characterized mucin-like glycoproteins which are expressed in high abundance [(6. 0+/-1.7)x10(6) molecules.cell(-1)] at the surface of the bloodstream trypomastigote stage of the parasite. The polypeptide backbone of these glycoproteins is dominated by threonine, glycine, serine, alanine, valine and proline residues, and is modified at its C-terminus by a glycosylphosphatidylinositol membrane anchor. On average, each polypeptide carries carbohydrate chains composed of about 200 monosaccharide units (galactose, N-acetylglucosamine, xylose, sialic acid, fucose, mannose and arabinose), which are most probably O-linked to hydroxy amino acids. The mucin-like molecules are the target of the fish's humoral immune response, but do not undergo antigenic variation akin to that observed for the variant surface glycoprotein in salivarian trypanosomes. The results are discussed with reference to the differences between natural and experimental infections, and in relation to the recently delineated molecular phylogeny of trypanosomes.


A system to measure the kinematics during the entire ski jump sequence using inertial sensors.
Three-dimensional analysis of the entire sequence in ski jumping is recommended when studying the kinematics or evaluating performance. Camera-based systems which allow three-dimensional kinematics measurement are complex to set-up and require extensive post-processing, usually limiting ski jumping analyses to small numbers of jumps. In this study, a simple method using a wearable inertial sensors-based system is described to measure the orientation of the lower-body segments (sacrum, thighs, shanks) and skis during the entire jump sequence. This new method combines the fusion of inertial signals and biomechanical constraints of ski jumping. Its performance was evaluated in terms of validity and sensitivity to different performances based on 22 athletes monitored during daily training. The validity of the method was assessed by comparing the inclination of the ski and the slope at landing point and reported an error of -0.2±4.8°. The validity was also assessed by comparison of characteristic angles obtained with the proposed system and reference values in the literature; the differences were smaller than 6° for 75% of the angles and smaller than 15° for 90% of the angles. The sensitivity to different performances was evaluated by comparing the angles between two groups of athletes with different jump lengths and by assessing the association between angles and jump lengths. The differences of technique observed between athletes and the associations with jumps length agreed with the literature. In conclusion, these results suggest that this system is a promising tool for a generalization of three-dimensional kinematics analysis in ski jumping.


Correlation between genetic distances based on single loci and on skeletal morphology in inbred mice.
Genetic and morphometric distances between 12 inbred strains of mice ranging from closely related substrains to a sub-species were estimated using published data on single locus polymorphisms, and on the basis of up to 44 measurements on seven different bones, respectively. Simulation was also used to investigate sampling effects for the single loci. There were strong and statistically highly significant correlations among all measures of genetic distance ranging from 0.58 for the comparison of single loci with the logarithm of the Mahalanobis distance based on 24 measurements on four bones, to 0.72 for estimates of genetic distance based on single loci and the morphology of the mandible. These findings are in sharp contrast with those of Wayne & O'Brien (1986) who claimed that 'structural gene and morphometric variation of mandible traits are uncoupled between mouse strains'. Their failure to find such a correlation is probably because their sample of inbred strains included only a single pair of closely related substrains, and no substrains separated for less than 40 years, and because they failed to correct for non-linearity between morphometric and single-locus measurement scales. Simulations and regression analysis suggested that genetic distances could be estimated with approximately equal precision using morphological data on bone measurements or about 10 cladistically informative single loci, which would usually involve sampling about 50 loci. Data based on single-gene markers is usually more informative than morphometric data for studying the similarity of independently-derived strains. However, similarities among closely related populations such as sublines of an inbred strain can usually be studied more efficiently using morphometry.


Discontinuation of adalimumab after achieving remission in patients with established rheumatoid arthritis: 1-year outcome of the HONOR study.
To investigate the possibility of discontinuing adalimumab (ADA) for 1 year without flaring (DAS28-erythrocyte sedimentation rate (ESR) ≥3.2), and to identify factors enabling established patients with rheumatoid arthritis (RA) to remain ADA-free. Of 197 RA patients treated with ADA+methotrexate (MTX), 75 patients who met the ADA-free criteria (steroid-free and sustained DAS28-ESR remission for 6 months with stable MTX doses) were studied for 1 year. The mean disease duration and DAS28-ESR score in 75 patients was 7.5 years and 5.1 at baseline, respectively. The proportion of patients who sustained DAS28-ESR <2.6 (48%) and DAS28-ESR <3.2 (62%) for 1 year were significantly lower in the ADA discontinuation group than in the ADA continuation group; however, in patients with deep remission (DAS28-ESR ≤1.98) identified by receiver operating characteristics analysis following logistic analysis, these rates increased to 68% and 79%, respectively, with no significant difference between both groups. Remarkably, ADA readministration to patients with flare was effective in returning DAS28-ESR to <3.2 within 6 months in 90% and 9 months in 100% patients; among the patients who sustained DAS28-ESR <3.2 during ADA discontinuation, 100% remained in structural remission and 94% in functional remission. The possibility of remaining ADA-free for 1 year was demonstrated in established patients with RA with outcomes that ADA can be discontinued without flaring in 79% patients with deep remission, with similar rates in the ADA continuation group, and showed no functional or structural damage in patients with DAS28-ESR <3.2. ADA readministration to patients with flare during ADA discontinuation was effective.


Chemistry-based functional proteomics: mechanism-based activity-profiling tools for ubiquitin and ubiquitin-like specific proteases.
Determining the biological function of newly discovered gene products requires the development of novel functional approaches. To facilitate this task, recent developments in proteomics include small molecular probes that target proteolytic enzyme families including serine, threonine, and cysteine proteases. For the families of ubiquitin (Ub) and ubiquitin-like (UBL)-specific proteases, such tools were lacking until recently. Here, we review the advances made in the development of protein-based active site-directed probes that target proteases specific for ubiquitin and ubiquitin-like proteins. Such probes were applied successfully to discover and characterize novel Ub/UBL-specific proteases. Ub/UBL processing and deconjugation are performed by a diverse set of proteases belonging to several different enzyme families, including members of the ovarian tumor domain (OTU) protease family. A further definition of this family of enzymes will benefit from a directed chemical proteomics approach. Some of the Ub/UBL-specific proteases react with multiple Ub/UBLs and members of the same protease family can recognize multiple Ub/UBLs, underscoring the need for tools that appropriately address enzyme specificity.


Dermatofibrosarcoma protuberans: a study of clinical, pathologic, genetic, and therapeutic features in Korean patients.
Dermatofibrosarcoma protuberans (DFSP) carries a translocation resulting in the collagen type I alpha 1 (COL1A1)-platelet-derived growth factor beta (PDGFB) fusion gene, which is responsible for PDGFB activation. The purpose of this study is to evaluate the clinicopathological, genetic, and therapeutic features of DFSP in Korean patients. Clinicopathological features of 37 patients with DFSP were reviewed. Multiplex reverse transcriptase-polymerase chain reaction (PCR) was carried out in 16 patients using formalin-fixed, paraffin-embedded tissues and specific primers for COL1A1 and PDGFB. The mean age of 37 patients was 37.4 years old. The most common tumor location was the trunk. All patients were treated primarily with surgery: 34 (91.7%) cases with Mohs micrographic surgery (MMS) and 3 (8.3%) cases with wide local excision. The median follow-up time was 33.7 months. Two patients, one in each treatment group, demonstrated local recurrence during the follow-up period. The COL1A1-PDGFB fusion gene was expressed in 14 (87.5%) cases, demonstrated by reverse transcriptase PCR analysis. No association was found among the different COL1A1-PDGFB fusion transcripts, the various histological subtypes and clinical features. Our results support the effectiveness of MMS in treating DFSP. The COL1A1-PDGFB fusion transcript was observed in 87.5% of patients. Therefore, COL1A1-PDGFB is a useful and accurate tool in diagnosing DFSP in Koreans.


Nutrition knowledge in athletes: a systematic review.
Nutrition education aims to enhance knowledge and improve dietary intake in athletes. Understanding athletes' nutrition knowledge and its influence on dietary intake will inform nutrition-education programs in this population. To systematically review the level of nutrition knowledge in athletes, benchmark this against nonathlete comparison groups, and determine the impact of nutrition knowledge on dietary intake. An extensive literature search from the earliest record to March 2010 using the terms nutrition knowledge or diet knowledge and athlete or sport was conducted. Included studies recruited able or physically disabled, male or female, competitive (recreational or elite) athletes over the age of 13 yr. Quantitative assessment of knowledge and, if available, diet intake was required. Because of variability in the assessment of nutrition knowledge and dietary intake, meta-analysis was not conducted. Twenty-nine studies (17 published before 2000) measuring nutrition knowledge (7 including a nonathlete comparison group) met inclusion criteria. Athletes' knowledge was equal to or better than that of nonathletes but lower than comparison groups including nutrition students. When found statistically significant, knowledge was greater in females than males. A weak (r < .44), positive association between knowledge and dietary intake was reported in 5 of 9 studies assessing this. Common flaws in articles included inadequate statistical reporting, instrument validation, and benchmarking. The nutrition knowledge of athletes and its impact on their dietary intake is equivocal. There is a need for high-quality, contemporary research using validated tools to measure nutrition knowledge and its impact on dietary intake.


Biofeedback in the treatment of epilepsy.
This review traces the application of electroencephalographic (EEG) operant conditioning, or biofeedback, from animal research to its emergence as an alternative treatment for the major types of seizure disorder. Initial animal studies focusing on brain mechanisms that mediate learned behavioral inhibition revealed a uniquely correlated 12- to 15-Hz EEG rhythm localized to sensorimotor cortex. We labeled this the sensorimotor rhythm, or SMR. The similarity of the SMR to the known EEG spindle pattern during quiet sleep led to the novel idea of attempting to increase the SMR using EEG operant conditioning. The hypothesis was that this might produce a corresponding increase in sleep spindle activity, thus establishing a common EEG marker for the state of motor inhibition. Results supported this hypothesis but led also to the accidental discovery of an anticonvulsant effect on drug-induced seizures in cats and monkeys. Continuing animal studies identified a pattern of neurophysiologic responses correlated with the SMR in primary motor pathways. These and other findings were indicative of reduced motor excitability. Simultaneously, we undertook studies in human epileptic subjects that documented a significant reduction in seizure incidence and severity, together with EEG pattern normalization. This work expanded internationally, resulting in numerous well-controlled group and single-case studies summarized in recent meta-analyses. Exciting new findings in functional neuroimaging/EEG correlation studies provide a rational model for the basis of these clinical effects. In recognition of the diversity of clinical applications of EEG biofeedback and the complexity of seizure disorders, this review also details specific methods used in our EEG biofeedback program.


Hidden destruction of older forests threatens Brazil's Atlantic Forest and challenges restoration programs.
Understanding the dynamics of native forest loss and gain is critical for biodiversity conservation and ecosystem services, especially in regions experiencing intense forest transformations. We quantified native forest cover dynamics on an annual basis from 1990 to 2017 in Brazil's Atlantic Forest. Despite the relative stability of native forest cover during this period (~28 Mha), the ongoing loss of older native forests, mostly on flatter terrains, have been hidden by the increasing gain of younger native forest cover, mostly on marginal lands for mechanized agriculture. Changes in native forest cover and its spatial distribution increased forest isolation in 36.4% of the landscapes. The clearance of older forests associated with the recut of 27% of younger forests has resulted in a progressive rejuvenation of the native forest cover. We highlight the need to include native forest spatiotemporal dynamics into restoration programs to better estimate their expected benefits and unexpected problems.


A Modified Delphi Study to Identify Factors Associated With Clinical Deterioration in Hospitalized Children.
Hospitalized children who are admitted to the inpatient ward can deteriorate and require unplanned transfer to the PICU. Studies designed to validate early warning scoring systems have focused mainly on abnormalities in vital signs in patients admitted to the inpatient ward. The objective of this study was to determine the patient and system factors that experienced clinicians think are associated with progression to critical illness in hospitalized children. We conducted a modified Delphi study with 3 iterations, administered electronically. The expert panel consisted of 11 physician and nonphysician health care providers from hospitals in Canada and the United States. Consensus was reached that 21 of the 57 factors presented are associated with clinical deterioration in hospitalized children. The final list of variables includes patient characteristics, signs and symptoms in the emergency department, emergency department management, and system factors. We generated a list of variables that can be used in future prospective studies to determine if they are predictors of clinical deterioration on the inpatient ward.


Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity.
We studied the outcomes at school age in children who had participated in a double-blind, placebo-controlled trial of early postnatal dexamethasone therapy (initiated within 12 hours after birth) for the prevention of chronic lung disease of prematurity. Of the 262 children included in the initial study, 159 lived to school age. Of these children, 146 (72 in the dexamethasone group and 74 in the control group) were included in our study. All the infants had had severe respiratory distress syndrome requiring mechanical ventilation shortly after birth. In the dexamethasone group, 0.25 mg of dexamethasone per kilogram of body weight was given intravenously every 12 hours for one week, and then the dose was tapered. We evaluated the children's growth, neurologic and motor function, cognition, and school performance. Children in the dexamethasone group were significantly shorter than the controls (P=0.03 for boys, P=0.01 for girls, and P=0.03 for all children) and had a significantly smaller head circumference (P=0.04). Children in the dexamethasone group had significantly poorer motor skills (P<0.001), motor coordination (P<0.001), and visual-motor integration (P=0.02). As compared with the controls, children in the dexamethasone group also had significantly lower full IQ scores (mean [+/-SD], 78.2+/-15.0 vs. 84.4+/-12.6; P=0.008), verbal IQ scores (84.1+/-13.2 vs. 88.4+/-11.8, P=0.04), and performance IQ scores (76.5+/-14.6 vs. 84.5+/-12.7, P=0.001). The frequency of clinically significant disabilities was higher among children in the dexamethasone group than among controls (28 of 72 [39 percent] vs. 16 of 74 [22 percent], P=0.04). Early postnatal dexamethasone therapy should not be recommended for the routine prevention or treatment of chronic lung disease, because it leads to substantial adverse effects on neuromotor and cognitive function at school age.


The central nervous system--an additional consideration in 'rotator cuff tendinopathy' and a potential basis for understanding response to loaded therapeutic exercise.
Tendinopathy is a term used to describe a painful tendon disorder but despite being a well-recognised clinical presentation, a definitive understanding of the pathoaetiology of rotator cuff tendinopathy remains elusive. Current explanatory models, which relate to peripherally driven nocioceptive mechanisms secondary to structural abnormality, or failed healing, appear inadequate on their own in the context of current literature. In light of these limitations this paper presents an extension to current models that incorporates the integral role of the central nervous system in the pain experience. The role of the central nervous system (CNS) is described and justified along with a potential rationale to explain the favourable response to loaded therapeutic exercises demonstrated by previous studies. This additional consideration has the potential to offer a useful way to explain pain to patients, for clinicians to prescribe appropriate therapeutic management strategies and for researchers to advance knowledge in relation to this clinically challenging problem.


The centrosome in cells and organisms.
The centrosome acts as the main microtubule-nucleating organelle in animal cells and plays a critical role in mitotic spindle orientation and in genome stability. Yet, despite its central role in cell biology, the centrosome is not present in all multicellular organisms or in all cells of a given organism. The main outcome of centrosome reproduction is the transmission of polarity to daughter cells and, in most animal species, the sperm-donated centrosome defines embryo polarity. Here I will discuss the role of the centrosome in cell polarity, resulting from its ability to position the nucleus at the cell center, and discuss how centrosome innovation might have been critical during metazoan evolution.


Microvascular reconstruction of the pediatric mandible.
Free tissue transfer for adult mandibular reconstruction is a well-established technique; however, there are few reports of pediatric microvascular lower jaw reconstruction. This retrospective study was undertaken to review the range of indications, choices, safety, and efficacy of pediatric free tissue transfer to the lower jaw. All patients underwent a parascapular, scapular, or fibula free tissue transfer. Flap choice was based on preoperative clinical examination, radiographic findings, need for linear or multiplanar mandibular reconstruction, need for dental restoration, severity of soft-tissue deficit, and peroneal artery anatomy. Over a 10-year period (1989 to 1999), we performed eight free tissue transfers to reconstruct the mandibles of seven children, aged 6 to 17 years. Indications included radiation-induced hypoplasia (n = 1), postsurgical resection of fibrous dysplasia (n = 1), hemifacial microsomia (n = 3), Robin sequence with severe micrognathia (n = 1), and osteomyelitis (n = 1). The authors transferred four parascapular osseocutaneous, two scapular osseocutaneous, one fibular osseocutaneous, and one fibular osseous flap to reconstruct five ramus, four condyle, and two subtotal mandibular defects. All bony defects were successfully bridged and all osseous flaps successfully integrated. Postoperatively, mandibular symmetry and Angle class I occlusion were restored in all patients throughout the 10.5-year follow-up period (range, 9 to 14 years). Two patients received osseointegrated dental implants. Our only complication was the partial loss of a skin paddle. Microvascular reconstruction of the pediatric mandible, in selected patients, is a safe, reliable procedure that provides the bone stock and soft tissue necessary to restore normal maxillomandibular growth and dental rehabilitation.


Osteoarthritic cartilage is more homogeneous than healthy cartilage: identification of a superior region of interest colocalized with a major risk factor for osteoarthritis.
Cartilage loss as determined by magnetic resonance imaging (MRI) or joint space narrowing as determined by x-ray is the result of cartilage erosion. However, metabolic processes within the cartilage that later result in cartilage loss may be a more sensitive assessment method for early changes. Recently, it was shown that cartilage homogeneity visualized by MRI representing the biochemical changes undergoing in the cartilage is a potential marker for early detection of knee osteoarthritis (OA) and is also able to significantly separate groups of healthy subjects from those with OA. The purpose of this study was twofold. First, we wished to evaluate whether the results on cartilage homogeneity from the previous study can be reproduced using an independent population. Second, based on the homogeneity framework, we present an automatic technique that partitions the region of interest in the cartilage that contributes most to discrimination between healthy and OA subjects and allows for identification of the most implicated areas in early OA. These findings may allow further investigation of whether cartilage homogeneity reveals a predisposition for OA or whether it evolves as a consequence to disease and thereby can be used as a progression biomarker. A total of 283 right and left knees from 159 subjects aged 21 to 81 years were scanned using a Turbo 3D T1 sequence on a 0.18-T MRI Esaote scanner. The medial compartment of the tibial cartilage sheet was segmented using a fully automatic voxel classification scheme based on supervised learning. From the segmented cartilage sheet, homogeneity was quantified by measuring entropy from the distribution of signal intensities inside the compartment. Each knee was examined by radiography, and the knees were categorized by the Kellgren and Lawrence (KL) Index. Next, based on a gradient descent optimization technique, the cartilage region that contributed to the maximum statistical significance of homogeneity in separating healthy subjects from the diseased was partitioned. The generalizability of the region was evaluated by testing for overfitting. Three different regularization techniques were evaluated for reducing overfitting errors. The P values for separating the different groups based on cartilage homogeneity were 2 x 10(-5) (KL 0 versus KL 1) and 1 x 10(-7) (KL 0 versus KL >0). Using the automatic gradient descent technique, the partitioned region was toward the peripheral part of the cartilage sheet. Using this region, the P values for separating the different groups based on homogeneity were 5 x 10(-9) (KL 0 versus KL 1) and 1 x 10(-15) (KL 0 versus KL >0). The precision of homogeneity for the partitioned region assessed as a test-retest root-mean-square coefficient of variation was 3.3%. Bootstrapping proved to be an effective regularization tool in reducing overfitting errors. The validation study supported the use of cartilage homogeneity as a tool for the early detection of knee OA and for separating groups of healthy subjects from those who have disease. Our automatic, unbiased partitioning algorithm based on a general statistical framework outlined the cartilage region of interest that best separated healthy from OA conditions on the basis of homogeneity discrimination. We have shown that OA affects certain areas of the cartilage more distinctly, and these areas are located more toward the peripheral region of the cartilage. We propose that this region corresponds anatomically to cartilage covered by the meniscus in healthy subjects. This finding may provide valuable clues in the early detection and monitoring of OA and thus may improve treatment efficacy.


Comparison of clinical characteristics and frequency of adverse outcomes in patients with Marfan syndrome diagnosed in adulthood versus childhood.
Patients with Marfan syndrome (MFS) continue to elude diagnosis until well into adulthood. The purpose of this study was to compare the clinical characteristics and outcomes of adult survivors with MFS diagnosed during adulthood (age, >or=18 years) with those of adult survivors with MFS diagnosed in childhood (<18 years). We conducted a retrospective review of 66 adult (age, >18 years) MFS patients seen at a combined pediatric and adult multidisciplinary MFS clinic from 2004 to 2006. Demographic, clinical, and cardiac variables were collected and a comparative analysis was performed between the two groups: patients diagnosed with MFS during childhood and patients diagnosed in adulthood. The primary outcome measures were the presence of aortic dissection and the need for urgent cardiovascular surgery. Despite a similar incidence of clinical characteristics, 39 of the 66 MFS patients were not diagnosed until adulthood. The overall incidence of major cardiac involvement was comparable between the two groups, although the patients diagnosed at a younger age were found to have a reduced need for aortic surgery (33% vs. 59%; P < 0.04) and fewer adverse cardiac outcomes (0% vs. 46%; P < 0.001). Moreover, the patients diagnosed with MFS in adulthood were more likely to require repeated surgical intervention for distal aortic disease (13% vs. 0%; P = 0.07). In conclusion, patients with MFS who remain undiagnosed until adulthood have well-established cardiovascular pathology frequently requiring surgical intervention. Due to this delay in diagnosis and management, they often suffer from a suboptimal clinical outcome. Our research demonstrates the importance of educating pediatric clinicians in early MFS diagnosis in hopes of improving the long-term outcome of all MFS patients.


Advances in the molecular biology of malignant mesothelioma.
Malignant mesothelioma (MM) is a highly aggressive tumor with a dismal prognosis. The incidence of MM is increasing as a result of widespread exposure to asbestos. As for the molecular alterations that occur in MM, chromosome alterations including homo-deletion of the P16 and P14 genes located in the 9p21 are well known. Mutations are rare in the P53 and Ras genes, which are frequently present in epithelial solid tumors. However, mutations are frequently present in the neurofibromatosis type 2 gene. Epigenetic alterations including DNA methylation have been found in the MM, the profile of which is different from that of lung cancer, although differential diagnosis is sometimes clinically difficult. As in other malignant tumors, genes that are related to immortalization, proliferation, metastasis, angiogenesis, and anti-apoptosis are also overexpressed in MM, contributing to its malignant phenotype. It is of interest that simian virus 40 has been implicated to be one of the causative factors of MM in western countries. Although the causative role of asbestos is well-known in MM, much less information is available for MM than for other malignant tumors regarding the molecular alterations that occur in the disease. In terms of future tasks, it will be necessary to apply the knowledge that is learned about molecular alterations to clinical practice and to further elucidate the pathogenesis of MM with extensive research.


Systematic mapping of the state dependence of voltage- and Ca2+-dependent inactivation using simple open-channel measurements.
The state from which channel inactivation occurs is both biologically and mechanistically critical. For example, preferential closed-state inactivation is potentiated in certain Ca(2+) channel splice variants, yielding an enhancement of inactivation during action potential trains, which has important consequences for short-term synaptic plasticity. Mechanistically, the structural substrates of inactivation are now being resolved, yielding a growing library of molecular snapshots, ripe for functional interpretation. For these reasons, there is an increasing need for experimentally direct and systematic means of determining the states from which inactivation proceeds. Although many approaches have been devised, most rely upon numerical models that require detailed knowledge of channel-state topology and gating parameters. Moreover, prior strategies have only addressed voltage-dependent forms of inactivation (VDI), and have not been readily applicable to Ca(2+)-dependent inactivation (CDI), a vital form of regulation in numerous contexts. Here, we devise a simple yet systematic approach, applicable to both VDI and CDI, for semiquantitative mapping of the states from which inactivation occurs, based only on open-channel measurements. The method is relatively insensitive to the specifics of channel gating and does not require detailed knowledge of state topology or gating parameters. Rather than numerical models, we derive analytic equations that permit determination of the states from which inactivation occurs, based on direct manipulation of data. We apply this methodology to both VDI and CDI of Ca(V)1.3 Ca(2+) channels. VDI is found to proceed almost exclusively from the open state. CDI proceeds equally from the open and nearby closed states, but is disfavored from deep closed states distant from the open conformation. In all, these outcomes substantiate and enrich conclusions of our companion paper in this issue (Tadross et al. 2010. J. Gen. Physiol. doi:10.1085/jgp.200910308) that deduces endpoint mechanisms of VDI and CDI in Ca(V)1.3. More broadly, the methods introduced herein can be readily generalized for the analysis of other channel types.


Mean-field density functional theory of a three-phase contact line.
A three-phase contact line in a three-phase fluid system is modeled by a mean-field density functional theory. We use a variational approach to find the Euler-Lagrange equations. Analytic solutions are obtained in the two-phase regions at large distances from the contact line. We employ a triangular grid and use a successive overrelaxation method to find numerical solutions in the entire domain for the special case of equal interfacial tensions for the two-phase interfaces. We use the Kerins-Boiteux formula to obtain a line tension associated with the contact line. This line tension turns out to be negative. We associate line adsorption with the change of line tension as the governing potentials change.


Occupational nanosafety considerations for carbon nanotubes and carbon nanofibers.
Carbon nanotubes (CNTs) are carbon atoms arranged in a crystalline graphene lattice with a tubular morphology. CNTs exhibit high tensile strength, possess unique electrical properties, are durable, and can be functionalized. These properties allow applications as structural materials, in electronics, as heating elements, in batteries, in the production of stain-resistant fabric, for bone grafting and dental implants, and for targeted drug delivery. Carbon nanofibers (CNFs) are strong, flexible fibers that are currently used to produce composite materials. Agitation can lead to aerosolized CNTs and CNFs, and peak airborne particulate concentrations are associated with workplace activities such as weighing, transferring, mixing, blending, or sonication. Most airborne CNTs or CNFs found in workplaces are loose agglomerates of micrometer diameter. However, due to their low density, they linger in workplace air for a considerable time, and a large fraction of these structures are respirable. In rat and mouse models, pulmonary exposure to single-walled carbon nanotubes (SWCNTs), multi-walled carbon nanotubes (MWCNTs), or CNFs causes the following pulmonary reactions: acute pulmonary inflammation and injury, rapid and persistent formation of granulomatous lesions at deposition sites of large CNT agglomerates, and rapid and progressive alveolar interstitial fibrosis at deposition sites of more dispersed CNT or CNF structures. Pulmonary exposure to SWCNTs can induce oxidant stress in aortic tissue and increases plaque formation in an atherosclerotic mouse model. Pulmonary exposure to MWCNTs depresses the ability of coronary arterioles to respond to dilators. These cardiovascular effects may result from neurogenic signals from sensory irritant receptors in the lung. Pulmonary exposure to MWCNTs also upregulates mRNA for inflammatory mediators in selected brain regions, and pulmonary exposure to SWCNTs upregulates the baroreceptor reflex. In addition, pulmonary exposure to MWCNTs may induce levels of inflammatory mediators in the blood, which may affect the cardiovascular system. Intraperitoneal instillation of MWCNTs in mice has been associated with abdominal mesothelioma. MWCNTs deposited in the distal alveoli can migrate to the intrapleural space, and MWCNTs injected in the intrapleural space can cause lesions at the parietal pleura. However, further studies are required to determine whether pulmonary exposure to MWCNTs can induce pleural lesions or mesothelioma. In light of the anticipated growth in the production and use of CNTs and CNFs, worker exposure is possible. Because pulmonary exposure to CNTs and CNFs causes inflammatory and fibrotic reactions in the rodent lung, adverse health effects in workers represent a concern. NIOSH has conducted a risk assessment using available animal exposure-response data and is developing a recommended exposure limit for CNTs and CNFs. Evidence indicates that engineering controls and personal protective equipment can significantly decrease workplace exposure to CNTs and CNFs. Considering the available data on health risks, it appears prudent to develop prevention strategies to minimize workplace exposure. These strategies would include engineering controls (enclosure, exhaust ventilation), worker training, administrative controls, implementation of good handling practices, and the use of personal protective equipment (such as respirators) when necessary. NIOSH has published a document containing recommendations for the safe handling of nanomaterials.


DHA and EPA reverse cystic fibrosis-related FA abnormalities by suppressing FA desaturase expression and activity.
Patients and models of cystic fibrosis (CF) exhibit consistent abnormalities of polyunsaturated fatty acid composition, including decreased linoleate (LA) and docosahexaenoate (DHA) and variably increased arachidonate (AA), related in part to increased expression and activity of fatty acid desaturases. These abnormalities and the consequent CF-related pathologic manifestations can be reversed in CF mouse models by dietary supplementation with DHA. However, the mechanism is unknown. This study investigates this mechanism by measuring the effect of exogenous DHA and eicosapentaenoate (EPA) supplementation on fatty acid composition and metabolism, as well as on metabolic enzyme expression, in a cell culture model of CF. We found that both DHA and EPA suppress the expression and activity of Δ5- and Δ6-desaturases, leading to decreased flux through the n-3 and n-6 PUFA metabolic pathways and decreased production of AA. The findings also uncover other metabolic abnormalities, including increased fatty acid uptake and markedly increased retroconversion of DHA to EPA, in CF cells. These results indicate that the fatty acid abnormalities of CF are related to intrinsic alterations of PUFA metabolism and that they may be reversed by supplementation with DHA and EPA.


Functional consequences of relocating the C-terminal calmodulin-binding autoinhibitory domains of the plasma membrane Ca2+ pump near the N-terminus.
A mutant of the plasma membrane Ca2+ pump (PMCA) called (nCI)hPMCA4b(ct120), in which the C-terminal regulatory segment including the calmodulin-binding autoinhibitory domains C and I had been relocated near the N-terminus, has been expressed in COS-1 cells. The measurements of Ca2+ transport in microsomal preparations showed that the rearranged enzyme was functional. The activity of the (nCI)hPMCA4b(ct120) mutant was compared with those of the wild-type hPMCA4b and the fully active calmodulin-insensitive mutant hPMCA4b(ct120). In the absence of calmodulin the activity of (nCI)hPMCA4b(ct120) was higher than that of hPMCA4b but only 45% of that of hPMCA4b(ct120). Mutant (nCI)hPMCA4b(ct120) exhibited an apparent affinity for Ca2+ similar to that of hPMCA4b, typical of the inhibited state of the enzyme. Calmodulin at concentrations that fully activated hPMCA4b increased the activity of (nCI)hPMCA4b(ct120) to 68% of that of hPMCA4b(ct120). The lower maximal activity of (nCI)hPMCA4b(ct120) was not due to a lower affinity for calmodulin because the concentration of calmodulin required for half-maximal activation of (nCI)hPMCA4b(ct120) was equal to that of the wild-type hPMCA4b. These results indicate that (1) the disturbance of the N-terminal region of the PMCA by the insertion of the C-terminal segment decreased the ability of the pump to transport Ca2+, and (2) the calmodulin-binding autoinhibitory domain was still able to access its acceptor site from the N-terminal end of the molecule. However, although the calmodulin-binding and inhibitory functions of the C-domain were fully preserved, the I domain at its new position seemed less effective at inhibiting the pump.


Patient Hospital Experience Improved Modestly, But No Evidence Medicare Incentives Promoted Meaningful Gains.
The Centers for Medicare and Medicaid Services (CMS) has played a leading role in efforts to improve patients' experiences with hospital care. Yet little is known about how much patient experience has changed over the past decade, and even less is known about the impact of CMS's most recent strategy: tying payments to performance under the Value-Based Purchasing (VBP) program. We examined trends in multiple measures of patient satisfaction in the period 2008-14. We found that patient experience has improved modestly at US hospitals-both those participating in the VBP program and others-with the majority of improvement concentrated in the period before the program was implemented. While certain subsets of hospitals improved more than others, we found no evidence that the program has had a beneficial effect. As policy makers continue to promote value-based payment as a way to improve patient experience, it will be critical to ensure that payment is structured in ways that actually drive improvement.


Mice lacking the beta3 subunit of the GABAA receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome.
Angelman syndrome (AS) is a severe neurodevelopmental disorder resulting from a deletion/mutation in maternal chromosome 15q11-13. The genes in 15q11-13 contributing to the full array of the clinical phenotype are not fully identified. This study examines whether a loss or reduction in the GABAA receptor beta3 subunit (GABRB3) gene, contained within the AS deletion region, may contribute to the overall severity of AS. Disrupting the gabrb3 gene in mice produces electroencephalographic abnormalities, seizures, and behavior that parallel those seen in AS. The seizures that are observed in these mice showed a pharmacological response profile to antiepileptic medications similar to that observed in AS. Additionally, these mice exhibited learning and memory deficits, poor motor skills on a repetitive task, hyperactivity, and a disturbed rest-activity cycle, features all common to AS. The loss of the single gene, gabrb3, in these mice is sufficient to cause phenotypic traits that have marked similarities to the clinical features of AS, indicating that impaired expression of the GABRB3 gene in humans probably contributes to the overall phenotype of Angelman syndrome. At least one other gene, the E6-associated protein ubiquitin-protein ligase (UBE3A) gene, has been implicated in AS, so the relative contribution of the GABRB3 gene alone or in combination with other genes remains to be established.


Iterated Local Search and Other Algorithms for Buffered Two-Machine Permutation Flow Shops with Constant Processing Times on One Machine.
The two-machine permutation flow shop scheduling problem with buffer is studied for the special case that all processing times on one of the two machines are equal to a constant c. This case is interesting because it occurs in various applications, for example, when one machine is a packing machine or when materials have to be transported. Different types of buffers and buffer usage are considered. It is shown that all considered buffer flow shop problems remain NP-hard for the makespan criterion even with the restriction to equal processing times on one machine. However, the special case where the constant c is larger or smaller than all processing times on the other machine is shown to be polynomially solvable by presenting an algorithm (2BF-OPT) that calculates optimal schedules in O(nlogn) steps. Two heuristics for solving the NP-hard flow shop problems are proposed: (i) a modification of the commonly used NEH heuristic (mNEH) and (ii) an Iterated Local Search heuristic (2BF-ILS) that uses the mNEH heuristic for computing its initial solution. It is shown experimentally that the proposed 2BF-ILS heuristic obtains better results than two state-of-the-art algorithms for buffered flow shop problems from the literature and an Ant Colony Optimization algorithm. In addition, it is shown experimentally that 2BF-ILS obtains the same solution quality as the standard NEH heuristic, however, with a smaller number of function evaluations.


Crystallization and preliminary X-ray diffraction studies of the ISC-like [2Fe-2S] ferredoxin (FdxB) from Pseudomonas putida JCM 20004.
The iron-sulfur (Fe-S) cluster-biosynthesis (ISC) system of the gamma-proteobacterium Pseudomonas putida JCM 20004 contains a constitutively expressed vertebrate-type [2Fe-2S] ferredoxin, FdxB, which lacks the conserved free cysteine residue near the Fe-S cluster site that has been proposed to function in the catalysis of biological Fe-S cluster assembly in other bacterial homologues. Recombinant FdxB was heterologously overproduced in Escherichia coli, purified and crystallized in its oxidized form by the hanging-drop vapour-diffusion and streak-seeding methods using 1.6 M trisodium citrate dihydrate pH 6.5. The thin needle-shaped crystals diffract to 1.90 A resolution and belong to the hexagonal space group P6(1)22, with unit-cell parameters a = 87.58, c = 73.14 A. The asymmetric unit contains one protein molecule.


Biomarker-driven stratification of disease-risk in non-metastatic medulloblastoma: Results from the multi-center HIT-SIOP-PNET4 clinical trial.
To improve stratification of risk-adapted treatment for non-metastatic (M0), standard-risk medulloblastoma patients by prospective evaluation of biomarkers of reported biological or prognostic significance, alongside clinico-pathological variables, within the multi-center HIT-SIOP-PNET4 trial. Formalin-fixed paraffin-embedded tumor tissues were collected from 338 M0 patients (>4.0 years at diagnosis) for pathology review and assessment of the WNT subgroup (MBWNT) and genomic copy-number defects (chromosome 17, MYC/MYCN, 9q22 (PTCH1) and DNA ploidy). Clinical characteristics were reviewed centrally. The favorable prognosis of MBWNT was confirmed, however better outcomes were observed for non-MBWNT tumors in this clinical risk-defined cohort compared to previous disease-wide clinical trials. Chromosome 17p/q defects were heterogeneous when assessed at the cellular copy-number level, and predicted poor prognosis when they occurred against a diploid (ch17(im)/diploid(cen)), but not polyploid, genetic background. These factors, together with post-surgical tumor residuum (R+) and radiotherapy delay, were supported as independent prognostic markers in multivariate testing. Notably, MYC and MYCN amplification were not associated with adverse outcome. In cross-validated survival models derived for the clinical standard-risk (M0/R0) disease group, (ch17(im)/diploid(cen); 14% of patients) predicted high disease-risk, while the outcomes of patients without (ch17(im)/diploid(cen)) did not differ significantly from MBWNT, allowing re-classification of 86% as favorable-risk. Biomarkers, established previously in disease-wide studies, behave differently in clinically-defined standard-risk disease. Distinct biomarkers are required to assess disease-risk in this group, and define improved risk-stratification models. Routine testing for specific patterns of chromosome 17 imbalance at the cellular level, and MBWNT, provides a strong basis for incorporation into future trials.


Bringing home the trash: do colony-based differences in foraging distribution lead to increased plastic ingestion in Laysan albatrosses?
When searching for prey, animals should maximize energetic gain, while minimizing energy expenditure by altering their movements relative to prey availability. However, with increasing amounts of marine debris, what once may have been 'optimal' foraging strategies for top marine predators, are leading to sub-optimal diets comprised in large part of plastic. Indeed, the highly vagile Laysan albatross (Phoebastria immutabilis) which forages throughout the North Pacific, are well known for their tendency to ingest plastic. Here we examine whether Laysan albatrosses nesting on Kure Atoll and Oahu Island, 2,150 km apart, experience different levels of plastic ingestion. Twenty two geolocators were deployed on breeding adults for up to two years. Regurgitated boluses of undigestable material were also collected from chicks at each site to compare the amount of plastic vs. natural foods. Chicks from Kure Atoll were fed almost ten times the amount of plastic compared to chicks from Oahu despite boluses from both colonies having similar amounts of natural food. Tracking data indicated that adults from either colony did not have core overlapping distributions during the early half of the breeding period and that adults from Kure had a greater overlap with the putative range of the Western Garbage Patch corroborating our observation of higher plastic loads at this colony. At-sea distributions also varied throughout the year suggesting that Laysan albatrosses either adjusted their foraging behavior according to constraints on time away from the nest or to variation in resources. However, in the non-breeding season, distributional overlap was greater indicating that the energy required to reach the foraging grounds was less important than the total energy available. These results demonstrate how a marine predator that is not dispersal limited alters its foraging strategy throughout the reproductive cycle to maximize energetic gain and how this has led to differences in plastic ingestion.


Task difficulty modulates the activity of specific neuronal populations in primary visual cortex.
Spatial attention enhances our ability to detect stimuli at restricted regions of the visual field. This enhancement is thought to depend on the difficulty of the task being performed, but the underlying neuronal mechanisms for this dependency remain largely unknown. We found that task difficulty modulates neuronal firing rate at the earliest stages of cortical visual processing (area V1) in monkey (Macaca mulatta). These modulations were spatially specific: increasing task difficulty enhanced V1 neuronal firing rate at the focus of attention and suppressed it in regions surrounding the focus. Moreover, we found that response enhancement and suppression are mediated by distinct populations of neurons that differ in direction selectivity, spike width, interspike-interval distribution and contrast sensitivity. Our results provide strong support for center-surround models of spatial attention and suggest that task difficulty modulates the activity of specific populations of neurons in the primary visual cortex.


The phylogenetic relationships of basal archosauromorphs, with an emphasis on the systematics of proterosuchian archosauriforms.
The early evolution of archosauromorphs during the Permo-Triassic constitutes an excellent empirical case study to shed light on evolutionary radiations in deep time and the timing and processes of recovery of terrestrial faunas after a mass extinction. However, macroevolutionary studies of early archosauromorphs are currently limited by poor knowledge of their phylogenetic relationships. In particular, one of the main early archosauromorph groups that need an exhaustive phylogenetic study is "Proterosuchia," which as historically conceived includes members of both Proterosuchidae and Erythrosuchidae. A new data matrix composed of 96 separate taxa (several of them not included in a quantitative phylogenetic analysis before) and 600 osteological characters was assembled and analysed to generate a comprehensive higher-level phylogenetic hypothesis of basal archosauromorphs and shed light on the species-level interrelationships of taxa historically identified as proterosuchian archosauriforms. The results of the analysis using maximum parsimony include a polyphyletic "Prolacertiformes" and "Protorosauria," in which the Permian Aenigmastropheus and Protorosaurus are the most basal archosauromorphs. The enigmatic choristoderans are either found as the sister-taxa of all other lepidosauromorphs or archosauromorphs, but consistently placed within Sauria. Prolacertids, rhynchosaurs, allokotosaurians and tanystropheids are the major successive sister clades of Archosauriformes. The Early Triassic Tasmaniosaurus is recovered as the sister-taxon of Archosauriformes. Proterosuchidae is unambiguosly restricted to five species that occur immediately after and before the Permo-Triassic boundary, thus implying that they are a short-lived "disaster" clade. Erythrosuchidae is composed of eight nominal species that occur during the Early and Middle Triassic. "Proterosuchia" is polyphyletic, in which erythrosuchids are more closely related to Euparkeria and more crownward archosauriforms than to proterosuchids, and several species are found widespread along the archosauromorph tree, some being nested within Archosauria (e.g., "Chasmatosaurus ultimus," Youngosuchus). Doswelliids and proterochampsids are recovered as more closely related to each other than to other archosauromorphs, forming a large clade (Proterochampsia) of semi-aquatic to aquatic forms that includes the bizarre genus Vancleavea. Euparkeria is one of the sister-taxa of the clade composed of proterochampsians and archosaurs. The putative Indian archosaur Yarasuchus is recovered in a polytomy with Euparkeria and more crownward archosauriforms, and as more closely related to the Russian Dongusuchus than to other species. Phytosaurs are recovered as the sister-taxa of all other pseudosuchians, thus being nested within Archosauria.


ZIP Genes Are Involved in the Retransfer of Zinc Ions during the Senescence of Zinc-Deficient Rice Leaves.
Rice lacks sufficient amounts of zinc despite its vitality for human health. Leaf senescence enables redistribution of nutrients to other organs, yet Zn retransfer during deficiency is often overlooked. In this hydroponic experiment, we studied the effect of Zn deficiency on rice seedlings, focusing on the fourth leaf under control and deficient conditions. Growth phenotype analysis showed that the growth of rice nodal roots was inhibited in Zn deficiency, and the fourth leaf exhibited accelerated senescence and increased Zn ion transfer. Analyzing differentially expressed genes showed that Zn deficiency regulates more ZIP family genes involved in Zn ion retransfer. OsZIP3 upregulation under Zn-deficient conditions may not be induced by Zn deficiency, whereas OsZIP4 is only induced during Zn deficiency. Gene ontology enrichment analysis showed that Zn-deficient leaves mobilized more biological pathways (BPs) during aging, and the enrichment function differed from that of normal aging leaves. The most apparent "zinc ion transport" BP was stronger than that of normal senescence, possibly due to Zn-deficient leaves mobilizing large amounts of BP related to lipid metabolism during senescence. These results provide a basis for further functional analyses of genes and the study of trace element transfer during rice leaf senescence.


Participation in online patient support groups endorses patients' empowerment.
Although much has been expected of the empowering effect of taking part in online patient support groups, there is no direct evidence thus far for the effects of participation on patient empowerment. Hence our exploring to what extent patients feel empowered by their participation in online support groups, and which processes that occur in these groups are related to the empowering outcomes. An online questionnaire was completed by 528 individuals who were active in online groups for patients with breast cancer, fibromyalgia and arthritis. The respondents felt empowered in several ways by their participation. The empowering outcomes that were experienced to the strongest degree were 'being better informed' and 'enhanced social well-being'. No significant differences in empowering outcomes between diagnostic groups were found. The empowering outcomes could only be predicted in a modest way by the processes that took place in the online support groups. This study indicates that participation in online support groups can make a valuable contribution to the empowerment of patients. Health care providers should acquaint their patients with the existence of online support groups and with the benefits that participation in these groups can offer.


Patterns of User Engagement With the Mobile App, Manage My Pain: Results of a Data Mining Investigation.
Pain is one of the most prevalent health-related concerns and is among the top 3 most common reasons for seeking medical help. Scientific publications of data collected from pain tracking and monitoring apps are important to help consumers and healthcare professionals select the right app for their use. The main objectives of this paper were to (1) discover user engagement patterns of the pain management app, Manage My Pain, using data mining methods; and (2) identify the association between several attributes characterizing individual users and their levels of engagement. User engagement was defined by 2 key features of the app: longevity (number of days between the first and last pain record) and number of records. Users were divided into 5 user engagement clusters employing the k-means clustering algorithm. Each cluster was characterized by 6 attributes: gender, age, number of pain conditions, number of medications, pain severity, and opioid use. Z tests and chi-square tests were used for analyzing categorical attributes. Effects of gender and cluster on numerical attributes were analyzed using 2-way analysis of variances (ANOVAs) followed up by pairwise comparisons using Tukey honest significant difference (HSD). The clustering process produced 5 clusters representing different levels of user engagement. The proportion of males and females was significantly different in 4 of the 5 clusters (all P ≤.03). The proportion of males was higher than females in users with relatively high longevity. Mean ages of users in 2 clusters with high longevity were higher than users from other 3 clusters (all P <.001). Overall, males were significantly older than females (P <.001). Across clusters, females reported more pain conditions than males (all P <.001). Users from highly engaged clusters reported taking more medication than less engaged users (all P <.001). Females reported taking a greater number of medications than males (P =.04). In 4 of 5 clusters, the percentage of males taking an opioid was significantly greater (all P ≤.05) than that of females. The proportion of males with mild pain was significantly higher than that of females in 3 clusters (all P ≤.008). Although most users of the app reported being female, male users were more likely to be highly engaged in the app. Users in the most engaged clusters self-reported a higher number of pain conditions, a higher number of current medications, and a higher incidence of opioid usage. The high engagement by males in these clusters does not appear to be driven by pain severity which may, in part, be the case for females. Use of a mobile pain app may be relatively more attractive to highly-engaged males than highly-engaged females, and to those with relatively more complex chronic pain problems.


Real in vivo kinematic differences between mobile-bearing and fixed-bearing total knee arthroplasties.
We did an in vivo fluoroscopic study comparing the sagittal plane kinematics of mobile-bearing and fixed-bearing total knee arthroplasties in a unique group of patients. These patients were part of a larger bilateral randomized controlled outcome trial with each patient having received both types of total knee arthroplasties. Invited patients did three exercises with each of their different knee replacements; extension against gravity, flexion against gravity, and a step-up. These exercises were recorded using video fluoroscopy, and a series of still digital images over the flexion range were retrieved. The relationship of patella tendon angle to knee flexion angle for each patient was derived. The patella tendon angle to knee flexion angle of the mobile-bearing knee behaved in a linear manner more closely replicating the normal knee, whereas the fixed-bearing knee behaved in a nonlinear, more variable manner. This pattern of results was similar for all three exercises with each patient having one knee replacement that behaved differently in the sagittal plane when compared with their other knee replacement. These kinematic differences may explain the clinical differences observed in the randomized controlled trials that compared these two total knee arthroplasties.


Two major QTLs and several others relate to factors of metabolic syndrome in the family blood pressure program.
Genome-wide variance components linkage analysis was performed on 4 latent factors underlying metabolic syndrome derived from 10 risk factors. The latent factors represent obesity and insulin, blood pressure, lipids and insulin, and central obesity. The metabolic syndrome factor scores were derived in 4 ethnic groups recruited in 3 Networks of the Family Blood Pressure Program: GENOA (blacks, Hispanics, and whites), HyperGEN (blacks and whites), SAPPHIRe (Asians). Heritabilities of metabolic syndrome factors ranged from 66% for obesity and insulin to 11% for blood pressure factor. We observed higher heritabilities for obesity and insulin, and lipids and insulin, whereas those for blood pressure and central obesity were smaller. Linkage analysis detected two major quantitative trait loci. One of them linked to the obesity and insulin factor with a lod score of 3.94 (P=0.00001, marker GATA11A06, D18S53, 41.24 cM) at marker positions linkage (lod 4.71, at 46.84 cM at 1-cM-apart distances linkage), located on chromosome 18p11.21 in GENOA black. The other linked to the blood pressure factor with a lod score of 3.22 (P=0.000059, marker GATA49C09, D17S1290, 82 cM) at marker positions linkage (lod 3.56, at 84.63 cM for 1 cM apart distances linkage) located on chromosome 17q23.1 in Hispanics. These quantitative trait loci, together with 4 additional ones with lod scores >2.5, and 30 additional ones with lod score >1.7, offer hope for dissecting the genetic architecture of metabolic syndrome with beneficial implications for molecular diagnosis, prognosis, and in potential medical intervention.


Factors influencing the regional deposition of inhaled particles in man.
1. Although ventilation in normal human lungs has been shown to decrease from apex to base, comparable observations are lacking in regard to particle deposition. 2. We compared regional ventilation and particle deposition in normal subjects by using radioactive xenon and a radioactive aerosol while sitting, lying, and while breathing at an increased rate. Both smokers and non-smokers were studied. 3. Particle deposition and ventilation were closely related, and the greater the ventilation the greater the deposition of particles, a situation which prevailed irrespective of position and breathing rate. While supine, the apex to base gradient for both ventilation and particle deposition decreased but did not entirely disappear. At higher respiratory rates, central deposition of particles, especially in smokers, increased. 4. We concluded that there are regional differences in the deposition of particles and that such differences are closely related to regional ventilation.


Molecular analysis of pyrethroid resistance conferred by target insensitivity and increased metabolic detoxification in Plutella xylostella.
The pyrethroid resistance of the diamondback moth Plutella xylostella (L.) is conferred by increased gene expression of cytochrome P450 to detoxify the insecticide and/or through gene mutation of the sodium channel, which makes the individual insensitive to pyrethroids. However, no information is available about the correlation between the increased metabolic detoxification and the target insensitivity in pyrethroid resistance. Frequencies of pyrethroid-resistant alleles (L1014F, T929I and M918I) and two resistance-related mutations (A1101T and P1879S) at the sodium channel and expression levels of the cytochrome P450 gene CYP6BG1 were examined individually using laboratory and field strains of P. xylostella. Real-time quantitative PCR analysis using the laboratory strains revealed that levels of larval expression of the resistant strain, homozygous for the pyrethroid-resistant alleles other than the M918I, are significantly higher than those of the susceptible strain. In the field strains, the expression levels in insects having the same resistant alleles as those of the resistant strains varied greatly among individuals. The expression levels were not significantly higher than those in the heterozygotes. Significant correlation between the target insensitivity and the increased metabolic detoxification in pyrethroid resistance of P. xylostella was observed in the laboratory but not in the field.


When Do We Use Automatic Tools Rather Than Doing a Task Manually? Influence of Automatic Tool Speed.
In our everyday lives we tend to minimize effort, by using automatic tools, for instance. But we also tend to avoid idleness by engaging in various activities. What happens when minimizing effort and avoiding idleness are concurrent? This article explores the influence of waiting time as compared with a fixed manual task completion on people's preference for waiting or doing the task. In 2 experiments, participants were asked to choose performing a manual task or waiting while an automatic tool performed the task for them. The time required by the automatic tool to complete the task was manipulated and was equal to or shorter than the time needed for manual completion. Results indicated that the faster the automatic tool (i.e., the shorter the waiting time) the more participants used it instead of doing the task manually. However, participants favored the waiting option only when the waiting time was less than half as long as doing the task manually. These results suggest that people prefer to avoid idleness rather than to minimize effort.


Discovery of Tricyclic Clerodane Diterpenes as Sarco/Endoplasmic Reticulum Ca(2+)-ATPase Inhibitors and Structure-Activity Relationships.
Tricyclic clerodane diterpenes (TCDs) are natural compounds that often show potent cytotoxicity for cancer cells, but their mode of action remains elusive. A computationally based similarity search (CDRUG), combined with principal component analysis (ChemGPS-NP) and docking calculations (GOLD 5.2), suggested TCDs to be inhibitors of the sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) pump, which is also the target of the sesquiterpene lactone thapsigargin. Biochemical studies were performed with 11 TCDs on purified rabbit skeletal muscle sarcoplasmic reticulum membranes, which are highly enriched with the SERCA1a isoform. Casearborin D (2) exhibited the highest affinity, with a KD value of 2 μM and giving rise to complete inhibition of SERCA1a activity. Structure-activity relationships revealed that functionalization of two acyl side chains (R1 and R4) and the hydrophobicity imparted by the aliphatic chain at C-9, as well as a C-3,C-4 double bond, play crucial roles for inhibitory activity. Docking studies also suggested that hydrophobic interactions in the binding site, especially with Phe256 and Phe834, may be important for a strong inhibitory activity of the TCDs. In conclusion, a novel class of SERCA inhibitory compounds is presented.


Contextual weighting for Support Vector Machines in literature mining: an application to gene versus protein name disambiguation.
The ability to distinguish between genes and proteins is essential for understanding biological text. Support Vector Machines (SVMs) have been proven to be very efficient in general data mining tasks. We explore their capability for the gene versus protein name disambiguation task. We incorporated into the conventional SVM a weighting scheme based on distances of context words from the word to be disambiguated. This weighting scheme increased the performance of SVMs by five percentage points giving performance better than 85% as measured by the area under ROC curve and outperformed the Weighted Additive Classifier, which also incorporates the weighting, and the Naive Bayes classifier. We show that the performance of SVMs can be improved by the proposed weighting scheme. Furthermore, our results suggest that in this study the increase of the classification performance due to the weighting is greater than that obtained by selecting the underlying classifier or the kernel part of the SVM.


Multiplexed protein analysis using encoded antibody-conjugated microbeads.
We describe a method for multiplexed analysis of proteins using fluorescently encoded microbeads. The sensitivity of our method is comparable to the sensitivity obtained by enzyme-linked immunosorbent assay while only 5 µl sample volumes are needed. Streptavidin-coated, 1 µm beads are encoded with a combination of fluorophores at different intensity levels. As a proof of concept, we demonstrate that 27 microbead populations can be readily encoded by affinity conjugation using three intensity levels for each of three different biotinylated fluorescent dyes. Four populations of encoded microbeads are further conjugated with biotinylated capture antibodies and then combined and immobilized in a microfluidic flow cell for multiplexed protein analysis. Using four uniquely encoded microbead populations, we show that a cancer biomarker and three cytokine proteins can be analysed quantitatively in the picogram per millilitre range by fluorescence microscopy in a single assay. Our method will allow for the fabrication of high density, bead-based antibody arrays for multiplexed protein analysis using integrated microfluidic devices and automated sample processing.


Fluoride therapy in osteoporosis: acute effects on parathyroid and mineral homoeostasis.
1. Acute metabolic effects of sodium fluoride therapy were analysed among 41 osteoporotic patients already receiving large calcium supplements, 33 of whom underwent simultaneous metabolic balance studies. 2. Mean serum calcium fell transiently within 24-48 h by 0.03 +/- 0.07 (SD) mmol/l (P less than 0.01) and phosphorus by 0.06 +/- 0.08 (SD) mmol/l (P less than 0.001). In a subgroup, ionized calcium fell and biologically active parathyroid hormone (bio-PTH) rose more than fivefold (P less than 0.01). Urine calcium rose after an insignificant fall. 3. Pretreatment calcium and phosphorus balances were significantly positive and did not change overall during the first 8 days of treatment. However, on analysing balances in two groups relative to serum changes, in patients whose serum levels changed least sodium fluoride increased faecal calcium (P less than 0.025) and phosphorus (P less than 0.01) and reduced calcium balance (P less than 0.01), giving a mean balance difference between the two groups of 2.1 mmol daily (P less than 0.001). 4. Very small changes in serum levels therefore indicate well-marked metabolic responses: sodium fluoride acutely stimulates bio-PTH activity and must also enhance mineral uptake from circulation into tissue(s). By separate and opposing action(s) it inhibits intestinal calcium and phosphorus absorption, predominantly in those whose serum levels remain stable. All these effects may be relevant to long-term therapeutic results.


Real-time dynamics of quantized vortices in a unitary Fermi superfluid.
We introduce a comprehensive theoretical framework for the fermionic superfluid dynamics, grounded on a local extension of the time-dependent density functional theory. With this approach, we describe the generation and the real-time evolution and interaction of quantized vortices, the large-amplitude collective modes, as well as the loss of superfluidity at high flow velocities. We demonstrate the formation of vortex rings and provide a microscopic description of the crossing and reconnection of quantized vortex lines in a fermion superfluid, which provide the mechanism for the emergence of quantum turbulence at very low temperatures. We observe that superfluidity often survives when these systems are stirred with velocities far exceeding the speed of sound.


Hepatitis C virus-infected, HCV-RNA-negative patients with bleeding disorders--relationship to age, HIV and treatment.
All 155 anti-hepatitis C-virus (HCV) positive patients with haemostatic disorders at our unit were tested for HCV-RNA in order to determine the prevalence of a negative result. The patients were also characterized in order to find predictors for a negative HCV-RNA test. The prevalence of a negative HCV-RNA test was 15.5% (24 of 155) and this was similar among anti-HIV positive and negative patients. A common denominator for the 4 HIV-infected, HCV-RNA negative haemophiliacs was treatment with azidothymidin prior to the first test. Among the anti-HIV negative patients, those < 40 y of age had a significantly greater chance of being HCV-RNA-negative than the older ones (27.3 vs 3.6%). They also had a lower consumption of plasma products than age-matched HCV-RNA positive cases. Absence of co-infection with hepatitis B was not correlated with a negative HCV-RNA test. Young age and a low requirement for factor concentrates thus seem to be predictors for a negative HCV-RNA test in patients with bleeding disorders.


Pharmacological targets in the ubiquitin system offer new ways of treating cancer, neurodegenerative disorders and infectious diseases.
Recent advances in the development and discovery of pharmacological interventions within the ubiquitin-proteasome system (UPS) have uncovered an enormous potential for possible novel treatments of neurodegenerative disease, cancer, immunological disorder and microbial infection. Interference with proteasome activity, although initially considered unlikely to be exploitable clinically, has already proved to be very effective against haematological malignancies, and more specific derivatives that target subsets of proteasomes are emerging. Recent small-molecule screens have revealed inhibitors against ubiquitin-conjugating and -deconjugating enzymes, many of which have been evaluated for their potential use as therapeutics, either as single agents or in synergy with other drugs. Here, we discuss recent advances in the characterisation of novel UPS modulators (in particular, inhibitors of ubiquitin-conjugating and -deconjugating enzymes) and how they pave the way towards new therapeutic approaches for the treatment of proteotoxic disease, cancer and microbial infection.


The autonomous notch signal pathway is activated by baicalin and baicalein but is suppressed by niclosamide in K562 cells.
The Notch signaling pathway plays important roles in a variety of cellular processes. Aberrant transduction of Notch signaling contributes to many diseases and cancers in humans. The Notch receptor intracellular domain, the activated form of Notch receptor, is extremely difficult to detect in normal cells. However, it can activate signaling at very low protein concentration to elicit its biological effects. In the present study, a cell based luciferase reporter gene assay was established in K562 cells to screen drugs which could modulate the endogenous CBF1-dependent Notch signal pathway. Using this system, we found that the luciferase activity of CBF1-dependent reporter gene was activated by baicalin and baicalein but suppressed by niclosamide in both dose- and time-dependent manners. Treatment with these drugs modulated endogenous Notch signaling and affected mRNA expression levels of Notch1 receptor and Notch target genes in K562 cells. Additionally, erythroid differentiation of K562 cells was suppressed by baicalin and baicalein yet was promoted by niclosamide. Colony-forming ability in soft agar was decreased after treatment with baicalin and baicalein, but was not affected in the presence of niclosamide. Thus, modulation of Notch signaling after treatment with any of these three drugs may affect tumorigenesis of K562 cells suggesting that these drugs may have therapeutic potential for those tumors associated with Notch signaling. Taken together, this system could be beneficial for screening of drugs with potential to treat Notch signal pathway-associated diseases.


Apomorphine Subcutaneous Injection for the Management of Morning Akinesia in Parkinson's Disease.
In patients with motor fluctuations complicating Parkinson's disease (PD), delays in time-to-ON with levodopa are common. This open-label study aimed to assess the effect of apomorphine on time-to-ON in PD patients with morning akinesia. The safety population included 127 enrolled patients, and the full analysis set (FAS) included 88 patients. Patients completed a 7-day levodopa baseline period recording their time-to-ON following each morning dose of levodopa. Patients were titrated to an optimal dose of apomorphine (2-6 mg) while taking trimethobenzamide antiemetic therapy. Apomorphine was injected each morning for a 7-day treatment period and time-to-ON was self-recorded in 5-minute blocks. The primary efficacy variable was time-to-ON in the apomorphine treatment period versus the baseline levodopa period. Secondary assessments included and global impression scales. Safety and tolerability were assessed through adverse events (AEs). Patients receiving apomorphine achieved mean ± standard deviation (SD) time-to-ON 23.72 ± 14.55 minutes, reduced from 60.86 ± 18.11 minutes with levodopa (P < 0.0001). Dose failures (defined as time-to-ON >60 minutes) were more commonly reported with levodopa versus apomorphine (46% vs. 7% of diary entries, respectively). Secondary endpoints supported the primary efficacy findings, with significant improvements from levodopa baseline to apomorphine treatment period (all P < 0.0001). The most common AEs were nausea and dizziness. Most patients who discontinued because of AEs did so in the titration phase. Apomorphine injections significantly reduced time-to-ON in PD patients experiencing delayed onset of their morning levodopa dose, and was well tolerated in most patients. After apomorphine treatment, fluctuating patients with morning akinesia experienced rapid and reliable improvement of time-to-ON.


Sprayable, Large-Area Metal-Organic Framework Films and Membranes of Varying Thickness.
Despite their huge potential for efficient molecular separation, the fabrication of membranes from metal-organic frameworks (MOFs) remains a major challenge. The powders obtained by the conventional solvothermal MOF syntheses are difficult to process, and as a result the fabrication of well-performing, large-area MOF-based membranes is still awaiting success. The deposition of MOF thin films suited for membrane applications is demonstrated by employing a step-by-step spray method. This method can be scaled up to obtain industrially relevant membrane areas and a continuous process is also possible. The performance of sprayed HKUST-1-based membranes by the separation of a binary H2 /CO2 mixture is also demonstrated. Furthermore, this approach enables the control of the MOF film thickness, and thus controlling the permeance and the selectivity of the membrane.


Interleukin (IL)-18 Binding Protein Deficiency Disrupts Natural Killer Cell Maturation and Diminishes Circulating IL-18.
The cytokine interleukin (IL)-18 is a crucial amplifier of natural killer (NK) cell function. IL-18 signaling is regulated by the inhibitory effects of IL-18 binding protein (IL-18BP). Using mice deficient in IL-18BP (IL-18BPKO), we investigated the impact of mismanaged IL-18 signaling on NK cells. We found an overall reduced abundance of splenic NK cells in the absence of IL-18BP. Closer examination of NK cell subsets in spleen and bone marrow using CD27 and CD11b expression revealed that immature NK cells were increased in abundance, while the mature population of NK cells was reduced. Also, NK cells were polarized to greater production of TNF-α, while dedicated IFN-γ producers were reduced. A novel subset of IL-18 receptor α- NK cells contributed to the expansion of immature NK cells in IL-18BPKO mice. Splenocytes cultured with IL-18 resulted in alterations similar to those observed in IL-18BP deficiency. NK cell changes were associated with significantly reduced levels of circulating plasma IL-18. However, IL-18BPKO mice exhibited normal weight gain and responded to LPS challenge with a >10-fold increase in IFN-γ compared to wild type. Finally, we identified that the source of splenic IL-18BP was among dendritic cells/macrophage localized to the T cell-rich regions of the spleen. Our results demonstrate that IL-18BP is required for normal NK cell abundance and function and also contributes to maintaining steady-state levels of circulating IL-18. Thus, IL-18BP appears to have functions suggestive of a carrier protein, not just an inhibitor.


TERVA: system for long-term monitoring of wellness at home.
Long-term monitoring of physiological and psychosocial variables in out-hospital conditions would be beneficial for investigating changes in wellness status of an individual or to understand interaction between physiological and behavioral processes. We aimed to design a personal wellness monitoring system (TERVA), which would allow monitoring of wellness-related variables at home for several weeks or even months. The designed TERVA system runs on a laptop computer and interfaces with different measurement devices through a serial interface. Measured variables include beat-to-beat heart rate, motor activity, blood pressure, weight, body temperature, respiration, ballistocardiography, movements, and sleep stages. In addition, self-assessments of daily well-being and activities are stored by keeping a behavioral diary. To test the system, one healthy man used the system for 10 weeks. The system was successfully applied in out-hospital conditions. The success rate of the measurements was 70-91%, depending on the variable under consideration. The pilot study indicated that the recorded data accurately reflected the health status of the subject. The TERVA system provides a method to record and investigate wellness-related data over several weeks, or even months, outside the hospital among subjects capable of using a personal computer. Several applications of the system are discussed.


Organization of projections to the lateral amygdala from auditory and visual areas of the thalamus in the rat.
Projections to the amygdala from the auditory thalamus have been implicated in the associative conditioning of fear responses to acoustic stimuli. Thalamo-amygdala auditory projections enter the amygdala via the lateral nucleus (LA). It is well documented that these projections originate in the medial division (MGm) of the medial geniculate nucleus (MGN), the posterior intralaminar nucleus (PIN), and the suprageniculate nucleus (Sg). It is not known, however, whether these thalamic projections terminate in a topographic fashion within the LA. We therefore used several retrograde tract tracing techniques to determine whether the terminations of thalamo-amygdala fibers have a topographic organization within the LA. These tracers were injected into various locations within the LA, and the distribution of the retrogradely labeled cells throughout the thalamus was analyzed. In general, rostral to caudal distinctions in the thalamus are maintained in the LA, such that projections from throughout the MGN terminate in the anterior part of the LA, whereas the caudal part of the MGN projects to the caudal part of the LA. Furthermore, the density of cells that give rise to thalamo-amygdala projections varies within each thalamic nucleus along the rostro-caudal axis. The patterns of thalamo-amygdala connectivity observed support previous parcellation schemes that segregate the LA into dorsal, medial, and lateral areas, and suggest that the LA should be further divided into anterior and posterior parts. In addition to the well-known projections to the LA originating from PIN, MGN, and Sg, we also found substantial projections from the dorsal portion of the MGN (MGd) and the lateral posterior thalamic nucleus (LP). These findings suggest that some of the functional segregation in the thalamus may be preserved in the LA, and that the role of the MGd and LP in thalamo-amygdala transmission should be reconsidered.


Usefulness of the Atrial Emptying Fraction to Predict Maintenance of Sinus Rhythm After Direct Current Cardioversion for Atrial Fibrillation.
Atrial volumes indexed to body surface area (AVI) are robust predictors of nonvalvular atrial fibrillation (AF) recurrence after direct current cardioversion (DCCV). The incremental value of atrial emptying fraction (EmF) compared with atrial volumes as a predictor for recurrent AF after DCCV has not been evaluated. We sought to compare the predictive ability of baseline left atrial (LA) EmF, right atrial (RA) EmF, LAVI, and RAVI for post-DCCV AF recurrence at 6 months. The first 95 patients enrolled in the AF Clinic Registry with adequate echocardiogram imaging constituted the study cohort. Each patient underwent echocardiogram within 6 months before cardioversion. Maximal LAVI and RAVI, LA EmF, and RA EmF were performed offline using 4-chamber single-plane Simpson's method, averaged over 5 cycles. The mean age of the study cohort was 64 ± 12 years, and 67% were men. Only 28 patients (29%) who underwent DCCV remained in sinus rhythm at 6 months of follow-up. The remaining, 67 (71%) had reverted to AF or underwent ablation during the 6 months of follow-up. The overall performance for prediction of AF recurrence was greatest for RA EmF, area under the receiver operator characteristic curve (AUC): RA EmF 0.92, LA EmF 0.89, RAVI 0.76, and LAVI 0.63. RA and LA EmF AUCs were significantly higher than for LAVI or RAVI (max p = 0.02). In conclusion, although RAVI and LAVI are strong predictors of AF recurrence after DCCV, RA and LA EmF outperformed in this cohort.


Implementation of a Community Walking Program (Walk On!) for Functionally-Limited Older Adults.
Walking interventions improve physical function, reduce fall risk, and prevent mobility disability-even in those with compromised walking ability. However, most prior studies have been conducted in controlled research settings, with no dissemination of an evidence-based walking program for older adults who have mobility limitations and/or are socially isolated. This study reports data on the feasibility and acceptability of a community-based walking program (Walk On!) for older adults who are functionally limited, and assesses changes in physical function among attendees. The program sessions focused on long-distance walking, and took place for one-hour, for two days/week, and for 12 weeks at a time. Pilot implementation study. Local church in Winston-Salem, NC. 49 program participants; Measurements: Physical function battery and satisfaction survey data, as well as formative evaluation data from six attendees of a focus group, are reported. The majority of the participants were >75 years (71%), female (65%), and presented with low levels of physical function (usual gait speed=0.79±0.16; 30.6% used an assistive device). Satisfaction with the program was high (100% would recommend it to others) and focus group results were overwhelmingly positive. Mean attendance to scheduled sessions was 77%±21%, and 63% of participants attended at least 75% of scheduled sessions (n=8 attended 100%). On average, participants improved their 6-min walk distance by 8.9%, their SPPB score by 15.4%, their timed-up-go time by 9.0%, and their usual gait speed by 11.4%. The results of the initial evaluation of Walk On! show high feasibility and acceptability of the program, as well as efficacy for improving physical function. Further research is needed to evaluate a delivery method for wider implementation of the program and to definitively test its effectiveness for improving function and other health benefits.


Extending the golden hour: Partial resuscitative endovascular balloon occlusion of the aorta in a highly lethal swine liver injury model.
Combat-injured patients may require rapid and sustained support during transport; however, the prolonged aortic occlusion produced by conventional resuscitative endovascular balloon occlusion of the aorta (REBOA) may lead to substantial morbidity. Partial REBOA (P-REBOA) may permit longer periods of occlusion by allowing some degree of distal perfusion. However, the ability of this procedure to limit exsanguination is unclear. We evaluated the impact of P-REBOA on immediate survival and ongoing hemorrhage in a highly lethal swine liver injury model. Fifteen Yorkshire-cross swine were anesthetized, instrumented, splenectomized, and subjected to rapid 10% total blood loss followed by 30% liver amputation. Coagulopathy was created through colloid hemodilution. Randomized swine received no intervention (control), P-REBOA, or complete REBOA (C-REBOA). Central mean arterial pressure (cMAP), carotid blood flow, and blood loss were recorded. Balloons remained inflated in the P-REBOA and C-REBOA groups for 90 minutes followed by graded deflation. The study ended at 180 minutes from onset of hemorrhage or death of the animal. Survival analysis was performed, and data were analyzed using repeated-measures analysis of variance with post hoc pairwise comparisons. Mean survival times in the control, P-REBOA, and C-REBOA groups were, 25 ± 21, 86 ± 40, and 163 ± 20 minutes, respectively (p < 0.001). Blood loss was greater in the P-REBOA group than the C-REBOA or control groups, but this difference was not significant (4,722 ± 224, 3,834 ± 319, 3,818 ± 37 mL, respectively, p = 0.10). P-REBOA resulted in maintenance of near-baseline carotid blood flow and cMAP, while C-REBOA generated extreme cMAP and prolonged supraphysiologic carotid blood flow. Both experimental groups experienced profound decreases in cMAP following balloon deflation. In the setting of severe ongoing hemorrhage, P-REBOA increased survival time beyond the golden hour while maintaining cMAP and carotid flow at physiologic levels.


Response of religious groups to HIV/AIDS as a sexually transmitted infection in Trinidad.
HIV/AIDS-related stigma and discrimination are significant determinants of HIV transmission in the Caribbean island nation of Trinidad and Tobago (T&T), where the adult HIV/AIDS prevalence is 2.5%. T&T is a spiritually-aware society and over 104 religious groups are represented. This religious diversity creates a complex social environment for the transmission of a sexually transmitted infection like HIV/AIDS. Religious leaders are esteemed in T&T's society and may use their position and frequent interactions with the public to promote HIV/AIDS awareness, fight stigma and discrimination, and exercise compassion for people living with HIV/AIDS (PWHA). Some religious groups have initiated HIV/AIDS education programs within their membership, but previous studies suggest that HIV/AIDS remains a stigmatized infection in many religious organizations. The present study investigates how the perception of HIV/AIDS as a sexually transmitted infection impacts religious representatives' incentives to respond to HIV/AIDS in their congregations and communities. In correlation, the study explores how the experiences of PWHA in religious gatherings impact healing and coping with HIV/AIDS. Between November 2002 and April 2003, in-depth interviews were conducted with 11 religious representatives from 10 Christian, Hindu and Muslim denominations. The majority of respondents were leaders of religious services, while two were active congregation members. Religious groups were selected based upon the methods of Brathwaite. Briefly, 26 religious groups with the largest followings according to 2000 census data were identified in Trinidad and Tobago. From this original list, 10 religious groups in Northwest Trinidad were selected to comprise a representative sample of the island's main denominations. In-depth interviews with PWHA were conducted during the same study period, 2002-2003. Four individuals were selected from a care and support group located in Port of Spain based upon their perceived willingness to discuss religious affiliation and describe how living with a terminal infection has affected their spiritual lives. The interviewer, a United States Fulbright Scholar, explained the nature and purpose of the study to all participants. Relevant ethical procedures associated with the collection of interview data were adopted: interviews were conducted in a non-coercive manner and confidentiality was assured. All participants provided verbal consent, and agreed to be interviewed without financial or other incentive. Ethics approval was granted on behalf of the Caribbean Conference of Churches Ethics Committee. Interview questions followed a guideline, and employed an open-ended format to facilitate discussion. All interviews were recorded and transcribed by the interviewer. Religious representatives' opinions were grouped into the following categories: rationale for the spread of HIV/AIDS, abstinence, condom use, sexuality and homosexuality, compassion, experiences with PWHA, recommendations and current approach to addressing HIV/AIDS in congregations. Religious representatives expressed a measure of acceptance of HIV/AIDS and overwhelmingly upheld compassion for PWHA. Some statements, however, suggested that HIV/AIDS stigma pervades Trinidad's religious organizations. For many representatives, HIV/AIDS was associated with a promiscuous lifestyle and/or homosexuality. Representatives had varying levels of interaction with PWHA, but personal experiences were positively associated with current involvement in HIV/AIDS initiatives. All 4 PWHA interviewed identified themselves as belonging to Christian denominations. Three out of the 4 PWHA described discriminatory experiences with pastors or congregation members during gatherings for religious services. Nonetheless, PWHA expressed an important role for faith and religion in coping with HIV. Religious groups in Trinidad are being challenged to promote a clear and consistent response to the HIV/AIDS epidemic; a response that may reflect personal experiences and respect religious doctrine in the context of sex and sexuality. The study suggests that (1) religious leaders could improve their role in the fight against HIV/AIDS with education and sensitization-specifically aimed at dismantling the myths about HIV transmission, and the stereotyping of susceptible sub-populations, and (2) a consultative dialogue between PWHAs and religious leaders is pivotal to a successful faith-based HIV intervention in Trinidad.


Fourier transform infrared spectroscopy investigation of water microenvironments in polyelectrolyte multilayers at varying temperatures.
Polyelectrolyte multilayers (PEMs) are thin films formed by the alternating deposition of oppositely charged polyelectrolytes. Water plays an important role in influencing the physical properties of PEMs, as it can act both as a plasticizer and swelling agent. However, the way in which water molecules distribute around and hydrate ion pairs has not been fully quantified with respect to both temperature and ionic strength. Here, we examine the effects of temperature and ionic strength on the hydration microenvironments of fully immersed poly(diallyldimethylammonium)/polystyrene sulfonate (PDADMA/PSS) PEMs. This is accomplished by tracking the OD stretch peak using attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy at 0.25-1.5 M NaCl and 35-70 °C. The OD stretch peak is deconvoluted into three peaks: (1) high frequency water, which represents a tightly bound microenvironment, (2) low frequency water, which represents a loosely bound microenvironment, and (3) bulk water. In general, the majority of water absorbed into the PEM exists in a bound state, with little-to-no bulk water observed. Increasing temperature slightly reduces the amount of absorbed water, while addition of salt increases the amount of absorbed water. Finally, a van't Hoff analysis is applied to estimate the enthalpy (11-22 kJ mol-1) and entropy (48-79 kJ mol-1 K-1) of water exchanging from low to high frequency states.


An information theory analysis of gene-environmental interactions in count/rate data.
To develop and critically evaluate an information theory method for identifying gene-gene and gene-environment interactions in count and rate data. The entropy-based metric k-way interaction information (KWII) was critically assessed for utility in detecting interactions with count data and over-dispersed count data in three simulation studies of increasing complexity and in datasets from animal models of depression and colitis. The results were compared to Poisson regression. The power and effect size dependence of the KWII for detecting interactions was also assessed. The KWII was capable of effectively identifying the genetic and environmental predictors and their interactions in all three simulated datasets. The results indicate that the KWII approach may produce more parsimonious results than regression. In a rat model of depression, we successfully identified a prominent gender effect as well as other published associations. Analysis of severity scores from an animal model of colitis identified markers from chromosome 3, as well as unique first- and second-order associations for the individual sections of the colon and cecum. The results demonstrate the utility and versatility of our entropy-based method for gene-environment interaction analysis of count and rate data with Poisson and over-dispersed distributions.


Multiplanar angled reconstructions of reconstructions--a dangerous practice using multidetector CT.
This case illustrates the dangers of using reconstructions to correct for positioning in multiplanar CT scans and using images that have already been reconstructed rather than the original source images. We present a case where a subdural haemorrhage was simulated by reconstructing already reconstructed images.


Immunomodulatory effects of polysaccharopeptide (PSP) in human PBMC through regulation of TRAF6/TLR immunosignal-transduction pathways.
Polysaccharopeptide (PSP) was extracted from Coriolus versicolor, and has been proved to be a valuable adjuvant for the combination with chemotherapy or radiotherapy in the treatment of various cancers. To understand the mechanism of PSP on immunomodulation, we examined gene expression and cytokine secretion associated with immunosignal-transduction signaling in human peripheral blood mononuclear cells (PBMCs). cDNA microarray and cytokine antibody array were used to identify differential gene expression profiles and cytokines secretion of PBMCs in the presence or absence of PSP for 24 h. The expression of the key genes and proteins related to Toll-like receptor (TLR) signaling and its downstream pathway was determined by RT-PCR or Western blot. Compared with the control group, PSP up-regulated 22 genes expression (such as IFN-γ, CXCL10, TLR4, TLR5) in 117 genes associated with TLR signaling. Twenty-three of genes (e.g., TLR9, TLR10, SARM1, TOLLIP) related with TLR signaling pathway were down-regulated in PBMCs under PSP treatments. Five of cytokines (GCSF, GM-CSF, IL-1α, IL-6, IFN-γ) were up-regulated more than 1.3 times by PSP. The mRNA levels of TRAM, TRIF, and TRAF6, which are the key molecules of TLR signaling pathway, were markedly increased (P < 0.05). Moreover, the protein level of TRAF6 was also markedly increased (P < 0.01). PSP-regulated gene expression and cytokine secretion related to TLR signaling pathway in human PBMCs. Especially, TRAM-TRIF-TRAF6 subsignaling pathway of TLR may be one of the key associated signaling pathways in the immunomodulation of PSP.