Single-photon position to time multiplexing using a fiber array.
A 1 x 8 fiber array is used as the front-end of a receiver system. Each channel has a different length of fiber, resulting in each channel signal arriving at the detector at a pre-determined interval relative to a constant repetitive frequency signal. We demonstrate that these eight channels can be efficiently coupled to an individual single-photon detector such that the arrival-time of a photon in each is distinguishable from the next. Thus, we demonstrate spatial position to time information exchange, resulting in a photon-counting array using a single detector. The receiver system could be implemented in numerous applications, including time-resolved photoluminescence, low-light level spectroscopy and quantum information processing.


Crystal structure of the human T cell receptor CD3 epsilon gamma heterodimer complexed to the therapeutic mAb OKT3.
The CD3 epsilon gamma heterodimer is essential for expression and function of the T cell receptor. The crystal structure of the human CD3 epsilon gamma heterodimer is described to 2.1-A resolution complexed with OKT3, a therapeutic mAb that not only activates and tolerizes mature T cells but also induces regulatory T cells. The mode of CD3 epsilon gamma dimerization provides a general structural basis for CD3 assembly and maps candidate T cell antigen receptor docking sites, including a duplicated linear region rich in acidic residues that is unique to human CD3 epsilon. OKT3 binds to an atypically small area of CD3 epsilon and has a low affinity for the isolated CD3 epsilon gamma heterodimer. The structure of the OKT3/CD3 epsilon gamma complex has implications for T cell signaling and therapeutic design.


Why develop photoactivated chemotherapy?
Photoactivated chemotherapy is an approach where a biologically active compound is protected against interaction with the cell environment by a light-cleavable protecting group, and unprotected by light irradiation. As such, PACT represents a major scientific opportunity for developing new bioactive inorganic compounds. However, the societal impact of this approach will only take off if the PACT field is used to address real societal challenges, i.e., therapeutic questions that make sense in a clinical context, rather than purely chemical questions. In particular, I advocate here that the field has become mature enough to switch from a compound-based approach, where a particular cancer model is chosen only to demonstrate the utility of a compound, to a disease-based approach, where the question of which disease to cure comes first: which PACT compound should I make to solve that particular clinical problem? The advantages and disadvantages of PACT vs. other phototherapeutic techniques are discussed, and a roadmap towards real clinical applications of PACT is drawn.


Changes in the atmospheric deposition of minor and rare elements between 1975 and 2000 in south Sweden, as measured by moss analysis.
Elements emitted to the atmosphere are partly exported to more remote areas and contribute to the regional and territorial deposition rates. This study is based on the principle that carpet-forming bryophytes (pleurocarpic mosses) absorb elements and particles from rain, melting snow and dry deposition. We compare the concentrations of 60 elements in carpets of the forest moss Pleurozium schreberi sampled in 1975 and 2000 within a sparsely inhabited area dominated by forest and bogland in south Sweden. As an average for all the 60 elements, the median concentration was 2.7 times higher in 1975 than in 2000. The greatest difference was measured for Pb, although In, Bi, Ge, V, Sn, As and Ag had more than 5 times higher concentrations in 1975 than in 2000. Somewhat lower 1975/2000 concentration ratios (3.0-3.8) were measured for U, Sb, Cd, W, Ga, Fe, Li, and Be. The rare-earth elements (Y, La, Ce, Pr, Nd, Sm, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu), except Eu as well as Th, Ni, Al, Ti, Hf, Nb, and Zr, had concentration ratios around the average (2.5-2.8). Possible causes of these changes are discussed. We conclude that reductions in anthropogenic dust emissions during recent decades have decreased the atmospheric deposition over northern Europe of most elements in the periodical system, as previously reported for a limited number of transition and heavy metals. Changes in the deposition of soil dust would be of minor importance to the decreased deposition rates.


Nonsmoker Exposure to Secondhand Cannabis Smoke. III. Oral Fluid and Blood Drug Concentrations and Corresponding Subjective Effects.
The increasing use of highly potent strains of cannabis prompted this new evaluation of human toxicology and subjective effects following passive exposure to cannabis smoke. The study was designed to produce extreme cannabis smoke exposure conditions tolerable to drug-free nonsmokers. Six experienced cannabis users smoked cannabis cigarettes [5.3% Δ(9)-tetrahydrocannabinol (THC) in Session 1 and 11.3% THC in Sessions 2 and 3] in a closed chamber. Six nonsmokers were seated alternately with smokers during exposure sessions of 1 h duration. Sessions 1 and 2 were conducted with no ventilation and ventilation was employed in Session 3. Oral fluid, whole blood and subjective effect measures were obtained before and at multiple time points after each session. Oral fluid was analyzed by ELISA (4 ng/mL cutoff concentration) and by LC-MS-MS (limit of quantitation) for THC (1 ng/mL) and total THCCOOH (0.02 ng/mL). Blood was analyzed by LC-MS-MS (0.5 ng/mL) for THC, 11-OH-THC and free THCCOOH. Positive tests for THC in oral fluid and blood were obtained for nonsmokers up to 3 h following exposure. Ratings of subjective effects correlated with the degree of exposure. Subjective effect measures and amounts of THC absorbed by nonsmokers (relative to smokers) indicated that extreme secondhand cannabis smoke exposure mimicked, though to a lesser extent, active cannabis smoking.


An experimental test of how parasites of predators can influence trophic cascades and ecosystem functioning.
Parasites can shape the structure and function of ecosystems by influencing both the density and traits of their hosts. Such changes in ecosystems are particularly likely when the host is a predator that mediates the dynamics of trophic cascades. Here, we experimentally tested how parasite load of a small predatory fish, the threespine stickleback, can affect the occurrence and strength of trophic cascades and ecosystem functioning. In a factorial mesocosm experiment, we manipulated the density of stickleback (low vs. high), and the level of parasite load (natural vs. reduced). In addition, we used two stickleback populations from different lineages: an eastern European lineage with a more pelagic phenotype (Lake Constance) and a western European lineage with a more benthic phenotype (Lake Geneva). We found that stickleback caused trophic cascades in the pelagic but not the benthic food chain. Evidence for pelagic trophic cascades was stronger in treatments where parasite load of stickleback was reduced with an antihelmintic medication, and where fish originated from Lake Constance (i.e., the more pelagic lineage). A structural equation model revealed that differences in stickleback lineage and parasite load were most likely to impact trophic cascades via changes in the composition, rather than overall biomass, of zooplankton communities. Overall, our results provide experimental evidence that parasites of predators can influence the cascading effects of fish on lower trophic levels with consequences on ecosystem functioning.


The Cassiopeia A supernova was of type IIb.
Cassiopeia A is the youngest supernova remnant known in the Milky Way and a unique laboratory for supernova physics. We present an optical spectrum of the Cassiopeia A supernova near maximum brightness, obtained from observations of a scattered light echo more than three centuries after the direct light of the explosion swept past Earth. The spectrum shows that Cassiopeia A was a type IIb supernova and originated from the collapse of the helium core of a red supergiant that had lost most of its hydrogen envelope before exploding. Our finding concludes a long-standing debate on the Cassiopeia A progenitor and provides new insight into supernova physics by linking the properties of the explosion to the wealth of knowledge about its remnant.


Urethral catheter-related bladder wall lesions simulating inflammatory pseudotumor in a neonate.
Inflammatory pseudotumors of the bladder are rare in newborns. Considering the potential for malignancy, invasive diagnostic assessment and therapeutic surgical excision have been described as the approach of choice. We present a case of urethral catheter-related injury causing multifocal lesions simulating inflammatory pseudotumors of the bladder, diagnosed in a newborn presenting with persistent priapism. This case is distinct by virtue of its very rapid spontaneous regression of the bladder wall lesions within 4 days. Our neonatal case, along with previously described pediatric pseudotumor of the bladder, show the potential for spontaneous regression of these lesions and emphasizes the importance of balancing the potential risks and benefits of aggressive diagnostic or therapeutic interventions. Frequent diagnostic imaging and close follow-up should be considered as an alternative in young pediatric populations.


First Report of Southern tomato virus on Tomatoes in Southwest France.
Southern tomato virus (STV) is a recently described virus of tomato reported to be associated with a new disorder in this crop, the tomato yellow stunt disease (2). However, its detection in asymptomatic seedlings of some tomato varieties raises doubts about its pathogenicity (2). STV has a small 3.5-kb dsRNA genome with properties that place it in an intermediate position between the Totiviridae and Partitiviridae families. STV also has an unusual biology because, while being seed-transmitted at a high rate, it is neither mechanically nor graft-transmitted (2). It has so far only been reported from North America (Mississipi and California in the United States, as well as Mexico) (2). Agents with similar genomic organizations but apparently not associated with specific disease symptoms have recently been reported from faba bean, rhododendrons, and blueberry and proposed to represent a novel family of dsRNA viruses tentatively named Amalgamaviridae (1). In the course of plant virus metagenomics experiments, double stranded RNAs extracted from tomato samples from Southwest France collected in 2011 (variety unknown) were analyzed by 454 pyrosequencing. BLAST analysis of the contigs assembled from individual sequencing reads revealed a ca. 2.2 kb long contig with very high (99.7%) identity with the STV reference sequence deposited in GenBank (NC_011591). In order to confirm the presence of STV, an STV-specific primer pair (STV-fw 5' CTGGAGATGAAGTGCTCGAAGA 3' and STV-rev 5' TGGCTCGTCTCGCATCCTTCG 3') was designed and used to amplify by RT-PCR an 894-bp fragment from the relevant tomato sample. A PCR product of the expected size was obtained and the identity of the amplified agent verified by sequencing of the amplicon. The sequence obtained was identical to contig obtained through pyrosequencing of purified dsRNAs and has been deposited in GenBank (KC333078). This is, to our knowledge, the first report of STV infecting tomato crops outside of North America. The tomato sample from France from which STV was recovered showed distinct viral infection symptoms (e.g., mosaics, leaf deformation), that are clearly different from the symptoms reported for the tomato yellow stunt disease (2). However, the plants were found to be also infected with Tomato mosaic virus and Potato virus Y, so that it is not possible to draw firm conclusions about a potential contribution of STV to the symptoms observed. The high rate of STV seed transmission and its reported presence in commercial seed lots of several varieties (2) suggest that its distribution could be much broader than is currently known and further efforts are clearly needed to provide a final and conclusive answer as to the potential pathogenicity of this agent to tomato crops. References: (1) R. R. Martin et al. Virus Res. 155:175, 2011. (2) S. Sabanadzovic et al. Virus Res. 140:130, 2009.


Spread in model climate sensitivity traced to atmospheric convective mixing.
Equilibrium climate sensitivity refers to the ultimate change in global mean temperature in response to a change in external forcing. Despite decades of research attempting to narrow uncertainties, equilibrium climate sensitivity estimates from climate models still span roughly 1.5 to 5 degrees Celsius for a doubling of atmospheric carbon dioxide concentration, precluding accurate projections of future climate. The spread arises largely from differences in the feedback from low clouds, for reasons not yet understood. Here we show that differences in the simulated strength of convective mixing between the lower and middle tropical troposphere explain about half of the variance in climate sensitivity estimated by 43 climate models. The apparent mechanism is that such mixing dehydrates the low-cloud layer at a rate that increases as the climate warms, and this rate of increase depends on the initial mixing strength, linking the mixing to cloud feedback. The mixing inferred from observations appears to be sufficiently strong to imply a climate sensitivity of more than 3 degrees for a doubling of carbon dioxide. This is significantly higher than the currently accepted lower bound of 1.5 degrees, thereby constraining model projections towards relatively severe future warming.


Large fragment Bst DNA polymerase for whole genome amplification of DNA from formalin-fixed paraffin-embedded tissues.
Formalin-fixed paraffin-embedded (FFPE) tissues represent the largest source of archival biological material available for genomic studies of human cancer. Therefore, it is desirable to develop methods that enable whole genome amplification (WGA) using DNA extracted from FFPE tissues. Multiple-strand Displacement Amplification (MDA) is an isothermal method for WGA that uses the large fragment of Bst DNA polymerase. To date, MDA has been feasible only for genomic DNA isolated from fresh or snap-frozen tissue, and yields a representational distortion of less than threefold. We amplified genomic DNA of five FFPE samples of normal human lung tissue with the large fragment of Bst DNA polymerase. Using quantitative PCR, the copy number of 7 genes was evaluated in both amplified and original DNA samples. Four neuroblastoma xenograft samples derived from cell lines with known N-myc gene copy number were also evaluated, as were 7 samples of non-small cell lung cancer (NSCLC) tumors with known Skp2 gene amplification. In addition, we compared the array comparative genomic hybridization (CGH)-based genome profiles of two NSCLC samples before and after Bst MDA. A median 990-fold amplification of DNA was achieved. The DNA amplification products had a very high molecular weight (> 23 Kb). When the gene content of the amplified samples was compared to that of the original samples, the representational distortion was limited to threefold. Array CGH genome profiles of amplified and non-amplified FFPE DNA were similar. Large fragment Bst DNA polymerase is suitable for WGA of DNA extracted from FFPE tissues, with an expected maximal representational distortion of threefold. Amplified DNA may be used for the detection of gene copy number changes by quantitative realtime PCR and genome profiling by array CGH.


A conceptual model for the instruction and supervision of treatment planning.
The process of treatment planning requires the effective application of complex problem-solving skills. The occupational therapy literature has described components of this process and has identified both the difficulty educators have in teaching and the difficulty clinicians have in articulating the process of clinical problem solving. This paper presents a conceptual model of the dynamic process of occupational therapy treatment planning based on the case method of problem solving. An analysis of the process provides a basis for academic and clinical educators to effectively instruct and supervise students in treatment planning. An analysis of critical concepts related to each stage is followed by (a) common clinical errors committed by students and new therapists and (b) suggestions for supervisory approaches specific to errors at each stage.


Asking mom: formative research for an HPV vaccine campaign targeting mothers of adolescent girls.
Vaccination against the types of human papillomavirus (HPV) that cause about 70% of cervical cancers is approved for use in girls and women between 9 and 26 years of age and recommended routinely in 11-12-year-old girls. This article reports on the systematic theory-based formative research conducted to develop HPV vaccine messages for a campaign targeting racially diverse mothers of nonvaccinated 11-12-year-old girls in rural Southeastern United States. A consortium of 13 county health departments concerned about high rates of cervical cancer in their region relative to state and national averages initiated the campaign. The research examined behavioral determinants for vaccination decisions as well as mothers' reactions to message frames and emotional appeals. On the basis of focus groups and intercept interviews (n = 79), the authors demonstrated how preproduction message research and production message testing were used to develop messages that would motivate mothers of preteen girls. Core emotional truths that emerged were a mother's instinct to protect her daughter from harm and to embrace aspirations for her daughter's future. Mothers also reacted more positively to text about preventing cervical cancer than about preventing HPV, a sexually transmitted disease. Mothers preferred message concepts with photos of minorities and Caucasian mothers and daughters.


Homologous recombination and stable transfection in the parasitic protozoan Trypanosoma brucei.
Development of methods for the manipulation of the genomes of parasitic protozoa will lead to enhanced understanding of parasite biology and host-parasite relationships. Efficient gene transfer and targeted integration by homologous recombination were achieved in the parasitic protozoan Trypanosoma brucei, the causative agent of sleeping sickness. An expression vector with the neomycin phosphotransferase gene (neo), under the control of a procyclic acidic repetitive protein (PARP) gene promoter, was targeted into an intergenic region in beta alpha-tubulin-gene tandem array. Sixteen copies of neo were found in a tandem array in one of the transfectants where the PARP promoter controlled alpha-amanitin-resistant transcription of neo, whereas transcription of tubulin genes remained alpha-amanitin-sensitive.


Expedient synthesis of trifunctional oligoethyleneglycol-amine linkers and their use in the preparation of PEG-based branched platforms.
We designed a convergent synthesis pathway that provides access to trifunctional oligoethyleneglycol-amine (OEG-amine) linkers. By applying the reductive coupling of a primary azide to bifunctional OEG-azide precursors, the corresponding symmetrical dialkylamine bearing two homo-functional end chain groups and a central nitrogen was obtained. These building blocks bear minimal structural perturbation compared to the native OEG backbone which makes them attractive for biomedical applications. The NMR investigations of the mechanism process reveal the formation of nitrile and imine intermediates which can react with the reduced free amine form. Additionally, these trifunctional OEG-amine linkers were employed in a coupling reaction to afford branched multifunctional PEG dendrons which are molecularly defined. These discrete PEG-based dendrons (n = 16, 18 and 36) could be useful for numerous applications where multivalency is required.


Ongoing chromosomal instability and karyotype evolution in human colorectal cancer organoids.
Chromosome segregation errors cause aneuploidy and genomic heterogeneity, which are hallmarks of cancer in humans. A persistent high frequency of these errors (chromosomal instability (CIN)) is predicted to profoundly impact tumor evolution and therapy response. It is unknown, however, how prevalent CIN is in human tumors. Using three-dimensional live-cell imaging of patient-derived tumor organoids (tumor PDOs), we show that CIN is widespread in colorectal carcinomas regardless of background genetic alterations, including microsatellite instability. Cell-fate tracking showed that, although mitotic errors are frequently followed by cell death, some tumor PDOs are largely insensitive to mitotic errors. Single-cell karyotype sequencing confirmed heterogeneity of copy number alterations in tumor PDOs and showed that monoclonal lines evolved novel karyotypes over time in vitro. We conclude that ongoing CIN is common in colorectal cancer organoids, and propose that CIN levels and the tolerance for mitotic errors shape aneuploidy landscapes and karyotype heterogeneity.


Tophaceous Gout in an Anorectic Patient Visualized by Dual Energy Computed Tomography (DECT).
BACKGROUND Gout is characterized by deposition of uric acid crystals (monosodium urate) in tissues and fluids. This can cause acute inflammatory arthritis. The 2015 ACR/EULAR criteria for the diagnosis of gout include dual energy computed tomography (DECT)-demonstrated monosodium urate crystals as a new criterion. DECT is a spectral decomposition that permits recognition of different types of tissues based on their characteristic energy-dependent photon attenuation. A positive scan is defined as the presence of urate at articular or periarticular sites. CASE REPORT We describe a 51-year-old woman known to have anorexia nervosa. During our clinical examination, we detected plenty of tophi on both hands, but no swollen joints. The diagnosis of gout was made by visualizing crystals in a biopsy from a tophus. The first line of treatment was allopurinol, the second line was rasburicase, and the current treatment is febuxostat 80 mg/day, allopurinol 300 mg twice a day, and colchicine 0.5 mg twice a day. The patient has unchanged arthralgia and the size and number of tophi remain the same as before treatment in spite of active treatment for 3 years. Previously the patient had problems with adherence, but now she claims that she follows the proposed treatment. The last plasma urate (P-urate) was 0.57 mmol/L. Following two years of treatment, DECT of hands visualized monosodium urate crystal deposits in the tophi, as seen on the clinical photos, but also crystals in relation to the tendons and soft tissue. CONCLUSIONS DECT is an imaging modality useful to assess urate crystal deposits at diagnosis of gout and could be considered during treatment evaluation. Lack of adherence to treatment should be considered when P-urate values vary significantly and when DECT scans over years persistently visualize monosodium urate crystals.


Regions of the herpes simplex virus scaffolding protein that are important for intermolecular self-interaction.
The herpes simplex virus type 1 (HSV-1) scaffolding protein encoded by gene UL26.5 promotes the formation of the icosahedral capsid shell through its association with the major capsid protein VP5 and through intermolecular interactions with itself. Inside the capsid shell, the UL26.5 product together with the maturational protease, a minor protein, form a spherical structure which is broken down and released from the capsid during packaging of the viral genome. Selected residues from four internal regions of the HSV-1 scaffolding protein that have significant conservation of amino acids within the scaffolding proteins of alphaherpesviruses were mutated, and the properties of the proteins were examined. Only the HSV-1 scaffolding protein with mutations in the conserved N-terminal domain showed reduced interaction with the varicella-zoster virus homologue in a cell-based immunofluorescence assay, providing the first evidence that this domain in the HSV-1 protein is likely to be involved in intermolecular self-interaction. Scaffolding protein with mutations in this domain or in either of two other domains failed to assemble into scaffold-like particles but retained the ability to self-interact, although the aggregates were significant smaller than most of the aggregates formed by the wild-type protein. These results suggest that there are multiple domains involved in the intermolecular self-association of the HSV-1 scaffolding protein that can act independently of one another. This conclusion was supported by the observation that none of the mutant proteins with lesions in an individual domain, including a protein with mutations in a central region previously implicated in self-interaction (A. Pelletier, F. Dô, J. J. Brisebois, L. Lagacé, and M. G. Cordingley, J. Virol. 71:5197-5208, 1997), interfered with capsid assembly in a baculovirus expression system. A protein mutated in the central region and another conserved domain, both of which had been predicted to form coiled coils, was impaired for capsid formation but still retained the capacity to interact with VP5.


Sudden sensorineural hearing loss and antiphospholipid syndrome.
The antiphospholipid syndrome is the association between the presence of antiphospholipid antibodies, thrombosis and/or pregnancy morbidity and mortality. This report presents two cases of antiphospholipid antibodies and sensorineural hearing loss and discusses the probable causative link. We recommend that patients presenting with sudden sensorineural hearing loss are investigated for evidence of antiphospholipid antibodies. Life long anticoagulation is necessary to prevent life threatening thrombotic or thromboembolic events.


Can a Novel ICU Data Display Positively Affect Patient Outcomes and Save Lives?
The aim of this study was to quantify the impact of ProCCESs AWARE, Ambient Clinical Analytics, Rochester, MN, a novel acute care electronic medical record interface, on a range of care process and patient health outcome metrics in intensive care units (ICUs). ProCCESs AWARE is a novel acute care EMR interface that contains built-in tools for error prevention, practice surveillance, decision support and reporting. We compared outcomes before and after AWARE implementation using a prospective cohort and a historical control. The study population included all critically ill adult patients (over 18 years old) admitted to four ICUs at Mayo Clinic, Rochester, MN, who stayed in hospital at least 24 h. The pre-AWARE cohort included 983 patients from 2010, and the post-AWARE cohort included 856 patients from 2014. We analyzed patient health outcomes, care process quality, and hospital charges. After adjusting for patient acuity and baseline demographics, overall in-hospital and ICU mortality odds ratios associated with AWARE intervention were 0.45 (95% confidence interval 0.30 to 0.70) and 0.38 (0.22, 0.66). ICU length of stay decreased by about 50%, hospital length of stay by 37%, and total charges for hospital stay by 30% in post AWARE cohort (by $43,745 after adjusting for patient acuity and demographics). Better organization of information in the ICU with systems like AWARE has the potential to improve important patient outcomes, such as mortality and length of stay, resulting in reductions in costs of care.


Gene expression profiling of human oocytes at different maturational stages and after in vitro maturation.
The purpose of this study was to catalog genes expressed in human oocytes at germinal vesicle (GV) or metaphase II (MII) stage and to compare gene profiles between oocytes matured in vivo (in vivo-MII) and in vitro (IVM-MII). University-based research utilizing unfertilized oocytes analyzed for > 29,000 genes with RNA amplification and microarray. GV, in vivo-MII, and IVM-MII oocytes expressed 12,219, 9735, and 8510 genes, respectively. There was extensive overlap among the 3 groups, but also some significant differences. In particular, in vivo-MII and IVM-MII oocytes shared very similar patterns of gene expression. However, some immature patterns of expression, reminiscent of GVs, persisted in IVM-MIIs. In vitro maturation is an attractive strategy for IVF treatment; however, current IVM methods produce oocytes that perform poorly in the context of IVF. Data from the current study suggest that although IVM-MII oocytes closely resemble in vivo-MII oocytes for cellular pathways related to nuclear maturity, several pathways associated with cytoplasmic functions continue to be expressed in an immature manner. Additionally, IVM-MII oocytes have differences in the expression of genes related to cellular storage and homeostasis. Differentially expressed genes/pathways provide clues for the optimization of IVM techniques.


Correlates of physical activity in black, Hispanic, and white middle school girls.
A need exists to better understand multilevel influences on physical activity among diverse samples of girls. This study examined correlates of moderate-to-vigorous physical activity (MVPA) among adolescent girls from different racial/ethnic backgrounds. 1,180 6th grade girls (24.5% black, 15.7% Hispanic, and 59.8% white) completed a supervised self-administered questionnaire that measured hypothesized correlates of PA. MVPA data were collected for 6 days using the ActiGraph accelerometer. Hierarchical regression analysis was used to examine correlates of PA in each racial/ethnic group. Hispanic girls (n = 185) engaged in 21.7 minutes of MVPA per day, black girls (n = 289) engaged in 19.5 minutes of MVPA per day, and white girls (n = 706) engaged in 22.8 minutes of MVPA per day. Perceived transportation barriers (+; P = .010) were significantly and positively related to MVPA for Hispanic girls. For black girls, Body Mass Index (BMI) (-; P = .005) and social support from friends (+; P = .006) were significant correlates of MVPA. For white girls, BMI (-; P < .001), barriers (-; P = .012), social support from friends (+; P = .010), participation in school sports (+; P = .009), and community sports (+; P = .025) were significant correlates of MVPA. Explained variance ranged from 30% to 35%. Correlates of MVPA varied by racial/ethnic groups. Effective interventions in ethnically diverse populations may require culturally tailored strategies.


5-cm(-1) band model option to LOWTRAN5.
Modifications to the atmospheric transmission and radiation code LOWTRAN5 are presented which include (1) an increase in the spectral resolution from 20 to 5 cm(-1), (2) the addition of temperature-dependent molecular absorption coefficients, (3) the use of a multiparameter Doppler-Lorentz band model for calculation of molecular transmittance, and (4) the use of the Curtis-Godson approximation for multilayered paths. Comparisons of predictions using the LOWTRAN5 5-cm(-1) band model option to measured transmittance and radiance data are also presented.


Exposure to statins and risk of common cancers: a series of nested case-control studies.
Many studies and meta-analyses have investigated the effects of statins on cancer incidence but without showing consistent effects. A series of nested case-control studies was conducted covering 574 UK general practices within the QResearch database. Cases were patients with primary cancers diagnosed between 1998 and 2008. The associations between statin use and risk of ten site-specific cancers were estimated with conditional logistic regression adjusted for co-morbidities, smoking status, socio-economic status, and use of non-steroidal anti-inflammatory drugs, cyclo-oxygenase-2 inhibitors and aspirin. 88125 cases and 362254 matched controls were analysed. The adjusted odds ratio for any statin use and cancer at any site were 1.01 (95%CI 0.99 to 1.04). For haematological malignancies there was a significant reduced risk associated with any statin use (odds ratio 0.78, 95%CI 0.71 to 0.86). Prolonged (more than 4 years) use of statins was associated with a significantly increased risk of colorectal cancer (odds ratio 1.23, 95%CI 1.10 to 1.38), bladder cancer (odds ratio 1.29, 95%CI 1.08 to 1.54) and lung cancer (odds ratio 1.18, 95%CI 1.05 to 1.34). There were no significant associations with any other cancers. In this large population-based case-control study, prolonged use of statins was not associated with an increased risk of cancer at any of the most common sites except for colorectal cancer, bladder cancer and lung cancer, while there was a reduced risk of haematological malignancies.


The Quest for Converting Biorenewable Bifunctional α-Methylene-γ-butyrolactone into Degradable and Recyclable Polyester: Controlling Vinyl-Addition/Ring-Opening/Cross-Linking Pathways.
α-Methylene-γ-butyrolactone (MBL), a naturally occurring and biomass-sourced bifunctional monomer, contains both a highly reactive exocyclic C═C bond and a highly stable five-membered γ-butyrolactone ring. Thus, all previous work led to exclusive vinyl-addition polymerization (VAP) product P(MBL)VAP. Now, this work reverses this conventional chemoselectivity to enable the first ring-opening polymerization (ROP) of MBL, thereby producing exclusively unsaturated polyester P(MBL)ROP with Mn up to 21.0 kg/mol. This elusive goal was achieved through uncovering the thermodynamic, catalytic, and processing conditions. A third reaction pathway has also been discovered, which is a crossover propagation between VAP and ROP processes, thus affording cross-linked polymer P(MBL)CLP. The formation of the three types of polymers, P(MBL)VAP, P(MBL)CLP, and P(MBL)ROP, can be readily controlled by adjusting the catalyst (La)/initiator (ROH) ratio, which is determined by the unique chemoselectivity of the La-X (X = OR, NR2, R) group. The resulting P(MBL)ROP is degradable and can be readily postfunctionalized into cross-linked or thiolated materials but, more remarkably, can also be fully recycled back to its monomer thermochemically. Computational studies provided the theoretical basis for, and a mechanistic understanding of, the three different polymerization processes and the origin of the chemoselectivity.


Trends in medication use for osteoarthritis treatment.
To investigate recent national trends in nonsteroidal antiinflammatory drug (NSAID) and acetaminophen use for osteoarthritis (OA). Using data from the 1989-98 National Ambulatory Medical Care Survey, a representative sample of US office based physician visits, we assessed 4471 visits by patients 45 years or older with a diagnosis of OA. We examined cross sectional and longitudinal patterns of OA pharmacotherapy. The independent effects of patient and physician characteristics on NSAID and acetaminophen use were examined using multiple logistic regression analysis. Pharmacological treatment for OA (either NSAID, acetaminophen, or both) has steadily decreased from 49% of visits (1989-91) to 46% (1992-94) to 40% (1995-98) (p = 0.001). Reduced NSAID use over this time period (46% to 33%; p = 0.001) was partially offset by a modest increase in acetaminophen use (5% to 10%; p = 0.001). Among individual NSAID, ibuprofen (5.7% of OA visits), nabumetone (4.9%), naproxen (4.6%), and aspirin (4.4%) were the most frequently reported in 1995-98. For patient visits in 1995-98, 45 to 59-year-olds (38%) received NSAID more often than 60 to 74-year-olds (34%) or patients older than 75 (28%; p = 0.029). Other possible predictors of OA therapy included patient race and physician specialty. The decline in the use of NSAID from 1989 to 1998, especially among elderly patients, and the frequent selection of safer medications may reflect awareness of the literature citing the risks of nonsteroidals for OA. However, variations in prescribing patterns among different patient populations and the modest use of acetaminophen, despite evidence supporting its efficacy, suggest that better assimilation of the literature into medical practice is needed to optimize OA therapy.


Serum brain-derived neurotrophic factor and glucocorticoid receptor levels in lymphocytes as markers of antidepressant response in major depressive patients: a pilot study.
Depressive patients often have altered cortisol secretion, an effect that likely derives from impaired activity of the glucocorticoid receptor (GR), the main regulator of the hypothalamus-pituitary-adrenal (HPA) axis. Glucocorticoids reduce the levels of brain-derived neurotrophic factor (BDNF), a downstream target of antidepressants. Antidepressants promote the transcriptional activity of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), a regulator of BDNF expression. To identify potential biomarkers for the onset of antidepressant action in depressive patients, GR and phospho-CREB (pCREB) levels in lymphocytes and serum BDNF levels were repeatedly measured during the course of antidepressant treatment. Thirty-four depressed outpatients (10 male and 24 female) were treated with venlafaxine (75mg/day), and individuals exhibiting a 50% reduction in their baseline 17-Item Hamilton Depression Rating Scale score by the 6th week of treatment were considered responders. Responders showed an early improvement in parallel with a rise in BDNF levels during the first two weeks of treatment. Non-responders showed increased GR levels by the third week and reduced serum BDNF by the sixth week of treatment. In contrast, venlafaxine did not affect levels of pCREB. We conclude that levels of BDNF in serum and GR levels in lymphocytes may represent biomarkers that could be used to predict responses to venlafaxine treatment.


Photoacoustic tomography imaging based on a 4f acoustic lens imaging system.
The theory of photoacoustic tomography (PAT) imaging using a 4f acoustic lens imaging system has been investigated, and the theoretical results show that a 4f acoustic lens has the ability of imaging and guarantees axial and lateral unit magnification of image. A system, a 4f acoustic lens imaging system combining with time-resolved technique, is developed to acquire PAT images. The 4f acoustic lens is able to image initial photoacoustic (PA) pressure distribution, which exactly resembles the absorption distribution, onto an imaging plane. Combining with time-resolved technique, the linear transducer array is adopted to acquire the PA pressure distribution to reconstruct the PAT images. Experimental results demonstrate that the system is able to obtain PAT images and the images contrast sharply with their backgrounds.


Targeting a G-protein-coupled receptor overexpressed in endocrine tumors by magnetic nanoparticles to induce cell death.
Nanotherapy using targeted magnetic nanoparticles grafted with peptidic ligands of receptors overexpressed in cancers is a promising therapeutic strategy. However, nanoconjugation of peptides can dramatically affect their properties with respect to receptor recognition, mechanism of internalization, intracellular trafficking, and fate. Furthermore, investigations are needed to better understand the mechanism whereby application of an alternating magnetic field to cells containing targeted nanoparticles induces cell death. Here, we designed a nanoplatform (termed MG-IONP-DY647) composed of an iron oxide nanocrystal decorated with a ligand of a G-protein coupled receptor, the cholecystokinin-2 receptor (CCK2R) that is overexpressed in several malignant cancers. MG-IONP-DY647 did not stimulate inflammasome of Raw 264.7 macrophages. They recognized cells expressing CCK2R with a high specificity, subsequently internalized via a mechanism involving recruitment of β-arrestins, clathrin-coated pits, and dynamin and were directed to lysosomes. Binding and internalization of MG-IONP-DY647 were dependent on the density of the ligand at the nanoparticle surface and were slowed down relative to free ligand. Trafficking of CCK2R internalized with the nanoparticles was slightly modified relative to CCK2R internalized in response to free ligand. Application of an alternating magnetic field to cells containing MG-IONP-DY647 induced apoptosis and cell death through a lysosomal death pathway, demonstrating that cell death is triggered even though nanoparticles of low thermal power are internalized in minute amounts by the cells. Together with pioneer findings using iron oxide nanoparticles targeting tumoral cells expressing epidermal growth factor receptor, these data represent a solid basis for future studies aiming at establishing the proof-of-concept of nanotherapy of cancers using ligand-grafted magnetic nanoparticles specifically internalized via cell surface receptors.


Conjugated linoleic acid and chromium lower body weight and visceral fat mass in high-fat-diet-fed mice.
More than half of the U.S. population has a body mass index of 25 kg/m2 or more, which classifies them as overweight or obese. Obesity is often associated with comorbidities such as diabetes, cardiovascular diseases, and cancer. CLA and chromium have emerged as major dietary supplements that reduce body weight and fat mass, and increase basal metabolic rate in animal models. However, studies show that CLA induces insulin resistance in mice and in humans, whereas Cr improves insulin sensitivity. Hence, we designed the present study to examine the combined effect of CLA and Cr on body composition and insulin sensitivity in a Balb/c mice (n = 10/group) model of high-fat-diet-induced obesity. CLA alone lowered body weight, total body fat mass, and visceral fat mass, the last of which decreased further with the combination of CLA and Cr. This effect was accompanied by decreased serum leptin levels in CLA-fed and CLA + Cr-fed mice, and by higher energy expenditure (EE) and oxygen consumption (OC) in CLA + Cr-fed mice. Serum levels of glucose, insulin, the pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6), as well as insulin resistance index (IRI), decreased with CLA, whereas CLA and Cr in combination had significant effects on insulin and IL-6 concentrations and IRI. In summary, CLA + Cr decreased body weight and fat mass in high-fat-diet-fed mice, which may be associated with decreased leptin levels and higher EE and OC.


Generation and optimization of superpixels as image processing kernels for Jones matrix optical coherence tomography.
Jones matrix-based polarization sensitive optical coherence tomography (JM-OCT) simultaneously measures optical intensity, birefringence, degree of polarization uniformity, and OCT angiography. The statistics of the optical features in a local region, such as the local mean of the OCT intensity, are frequently used for image processing and the quantitative analysis of JM-OCT. Conventionally, local statistics have been computed with fixed-size rectangular kernels. However, this results in a trade-off between image sharpness and statistical accuracy. We introduce a superpixel method to JM-OCT for generating the flexible kernels of local statistics. A superpixel is a cluster of image pixels that is formed by the pixels' spatial and signal value proximities. An algorithm for superpixel generation specialized for JM-OCT and its optimization methods are presented in this paper. The spatial proximity is in two-dimensional cross-sectional space and the signal values are the four optical features. Hence, the superpixel method is a six-dimensional clustering technique for JM-OCT pixels. The performance of the JM-OCT superpixels and its optimization methods are evaluated in detail using JM-OCT datasets of posterior eyes. The superpixels were found to well preserve tissue structures, such as layer structures, sclera, vessels, and retinal pigment epithelium. And hence, they are more suitable for local statistics kernels than conventional uniform rectangular kernels.


Haplotype effects on human survival: logistic regression models applied to unphased genotype data.
Haplotype based linkage disequilibrium (LD) mapping exhibits higher power than the single locus approach because it makes use of the LD information contained in the flanking markers. New statistical methods have been proposed to help to infer haplotype effects on human diseases using multi-locus genotype data collected from unrelated individuals. In this paper, we introduce a statistical procedure for measuring haplotype effects on human survival using the popular logistic regression model with haplotype based parameterizations. By modeling haplotype frequency as a function of age, our model infers haplotype effects by estimating and testing the slope parameters under different genetic mechanisms (multiplicative, dominant, or recessive). In addition, by estimating the sex-specific slope parameters, our model allows the detection of sex-specific haplotype effects or haplotype-sex interactions. As an example, we apply our model to an empirical dataset on a stress related gene, interleukin-6, to look for haplotypes that affect individual survival and for haplotype-sex interactions. We show that our logistic regression based haplotype model can be a helpful tool for researchers interested in the genetics of human aging and longevity.


Pax2, a new murine paired-box-containing gene and its expression in the developing excretory system.
The murine genome contains multiple genes with protein domains homologous to the Drosophila paired box, present in certain segmentation genes. At least one of these murine paired box (Pax) genes is associated with a developmental mutation. This report, in conjunction with the accompanying paper, describes a second member of this gene family, Pax2, that is also expressed during embryogenesis. Two overlapping cDNA clones were isolated and sequenced. At least two forms of the Pax2 protein can be deduced from the cDNA sequence. In addition to the highly conserved paired domain, an octapeptide sequence is located downstream. Expression of Pax2 is primarily restricted to the developing embryo in the excretory and central nervous systems. The transient nature of Pax2 expression during kidney organogenesis correlates with polarization and induction of epithelial structures and may indicate an important morphogenetic role for this gene.


The CHEMDNER corpus of chemicals and drugs and its annotation principles.
The automatic extraction of chemical information from text requires the recognition of chemical entity mentions as one of its key steps. When developing supervised named entity recognition (NER) systems, the availability of a large, manually annotated text corpus is desirable. Furthermore, large corpora permit the robust evaluation and comparison of different approaches that detect chemicals in documents. We present the CHEMDNER corpus, a collection of 10,000 PubMed abstracts that contain a total of 84,355 chemical entity mentions labeled manually by expert chemistry literature curators, following annotation guidelines specifically defined for this task. The abstracts of the CHEMDNER corpus were selected to be representative for all major chemical disciplines. Each of the chemical entity mentions was manually labeled according to its structure-associated chemical entity mention (SACEM) class: abbreviation, family, formula, identifier, multiple, systematic and trivial. The difficulty and consistency of tagging chemicals in text was measured using an agreement study between annotators, obtaining a percentage agreement of 91. For a subset of the CHEMDNER corpus (the test set of 3,000 abstracts) we provide not only the Gold Standard manual annotations, but also mentions automatically detected by the 26 teams that participated in the BioCreative IV CHEMDNER chemical mention recognition task. In addition, we release the CHEMDNER silver standard corpus of automatically extracted mentions from 17,000 randomly selected PubMed abstracts. A version of the CHEMDNER corpus in the BioC format has been generated as well. We propose a standard for required minimum information about entity annotations for the construction of domain specific corpora on chemical and drug entities. The CHEMDNER corpus and annotation guidelines are available at: http://www.biocreative.org/resources/biocreative-iv/chemdner-corpus/.


Kinetics of thermal cis-trans isomerization in a phototropic azobenzene-based single-component liquid crystal in its nematic and isotropic phases.
Single-component azobenzene-based phototropic liquid crystals (PtLC) are promising materials that have started to be explored for photonic applications. One of the essential factors determining the applicability of these materials is the rate of the thermally driven cis-trans isomerization. In this paper, the kinetics of the thermal back cis-to-trans reaction in a pure 4-hexyl-4'-methoxyazobenzene (6-AB-O1) compound in its isotropic liquid and nematic phases is studied (the undoped LC). The reaction rate constants, activation energies and thermal activation parameters were determined based on spectroscopic studies. The reaction kinetics is compared to that measured for the compound dissolved in chloroform. The results demonstrate that the thermal back reaction depends on the phase and molecular environment of the cis-isomer. Moreover, the effect of temperature on the absorption spectra of 6-AB-O1 in its isotropic, nematic and crystalline phases is examined. The changes in the compound's absorption spectra in the respective phases have been correlated to the positional order parameter S.


Awake stereotactic brainstem biopsy via a contralateral, transfrontal, transventricular approach.
The authors describe a novel approach to stereotactic biopsy of lesions of the lateral pons and medial cerebellar peduncle, and its diagnostic success without morbidity. A contralateral approach laterally expands the accessible infratentorial area. It may also confer a theoretical reduction in neurological deficit with passage through non-dominant right hemisphere.


Improving attitudes toward the disabled: a randomized controlled trial of direct contact versus Kids-on-the-Block.
Social interaction between able-bodied and disabled children (as in a "buddy" program) is known to improve children's attitudes toward handicapped peers. This randomized-factorial-design study evaluated the relative impact of two interventions--a buddy program and the Kids-on-the-Block (KOB) puppet program--singly and in combination. Outcomes included measures of attitudes, familiarity with disabled schoolmates, self-esteem, and parental attitude. The buddy program appeared to be a successful intervention. The KOB program alone had no measurable impact on any outcomes, compared with control children. Surprisingly, the combination of KOB and buddy programs produced a significantly smaller impact than the buddy program alone. The combination was also marginally significantly poorer than the change experienced by the control group. These results are discussed in relation to the probable dissonance between real disabled children and the puppets. Suggestions are advanced for possible strategies to enhance interventions to teach social interactional skills to able-bodied children.


Afforestation for climate change mitigation: Potentials, risks and trade-offs.
Afforestation is considered a cost-effective and readily available climate change mitigation option. In recent studies afforestation is presented as a major solution to limit climate change. However, estimates of afforestation potential vary widely. Moreover, the risks in global mitigation policy and the negative trade-offs with food security are often not considered. Here we present a new approach to assess the economic potential of afforestation with the IMAGE 3.0 integrated assessment model framework. In addition, we discuss the role of afforestation in mitigation pathways and the effects of afforestation on the food system under increasingly ambitious climate targets. We show that afforestation has a mitigation potential of 4.9 GtCO2 /year at 200 US$/tCO2 in 2050 leading to large-scale application in an SSP2 scenario aiming for 2°C (410 GtCO2 cumulative up to 2100). Afforestation reduces the overall costs of mitigation policy. However, it may lead to lower mitigation ambition and lock-in situations in other sectors. Moreover, it bears risks to implementation and permanence as the negative emissions are increasingly located in regions with high investment risks and weak governance, for example in Sub-Saharan Africa. Afforestation also requires large amounts of land (up to 1,100 Mha) leading to large reductions in agricultural land. The increased competition for land could lead to higher food prices and an increased population at risk of hunger. Our results confirm that afforestation has substantial potential for mitigation. At the same time, we highlight that major risks and trade-offs are involved. Pathways aiming to limit climate change to 2°C or even 1.5°C need to minimize these risks and trade-offs in order to achieve mitigation sustainably.


In vivo targets of human placental micro-vesicles vary with exposure time and pregnancy.
Throughout human gestation, the placenta extrudes vast quantities of extracellular vesicles (EVs) of different sizes into the maternal circulation. Although multinucleated macro-vesicles are known to become trapped in the maternal lungs and do not enter the peripheral circulation, the maternal organs and cells that smaller placental micro-vesicles interact with in vivo remain unknown. This study aimed to characterise the interaction between placental micro-vesicles and endothelial cells in vitro and to elucidate which organs placental micro-vesicles localise to in vivo Placental macro- and micro-vesicles were isolated from cultured human first trimester placental explants by sequential centrifugation and exposed to human microvascular endothelial cells for up to 72 h. In vivo, placental macro- and micro-vesicles were administered to both non-pregnant and pregnant CD1 mice, and after two or 30 min or 24 h, organs were imaged on an IVIS Kinetic Imager. Placental EVs rapidly interacted with endothelial cells via phagocytic and clathrin-mediated endocytic processes in vitro, with over 60% of maximal interaction being achieved by 30 min of exposure. In vivo, placental macro-vesicles were localised exclusively to the lungs regardless of time of exposure, whereas micro-vesicles were localised to the lungs, liver and kidneys, with different distribution patterns depending on the length of exposure and whether the mouse was pregnant or not. The fact that placental EVs can rapidly interact with endothelial cells and localise to different organs in vivo supports that different size fractions of placental EVs are likely to have different downstream effects on foeto-maternal communication.


Oral Biofilm: Development Mechanism, Multidrug Resistance, and Their Effective Management with Novel Techniques.
Biofilms are formed by the congregation of one or more types of microorganisms that can grow on a firm surface. Dental plaque is one of the most commonly forming biofilms in the oral cavity and appears as a slimy layer on the surface of the teeth. In general, the formation is slow, but biofilms are very adaptive to the changing environment, and a mature biofilm can cause many health-related problems in humans. These biofilms remain unaffected by antibiotics as they do not allow the penetration of antibiotics. Moreover, the increased level of virulence and antibiotic resistance of microorganisms in the oral biofilm or dental plaque has made its clinical management a serious challenge worldwide. Chlorhexidine-like antimicrobial drugs have been partially effective in removing such organisms; however, the precise and continuous elimination of these microorganisms without disturbing the normal microbial flora of the oral cavity is still a challenge. This review paper focuses on the process of oral biofilm formation, related complications, development of drug-resistant bacteria in these biofilms, and their effective management by the use of different novel techniques, available from various published research and review articles.


Design and Synthesis of Photodissociable Ligands Based on Azoimidazoles for Light-Driven Coordination-Induced Spin State Switching in Homogeneous Solution.
Light-switchable azoimidazoles were rationally designed and synthesized, and their performance was investigated as photodissociable ligands (PDL) and for spin state switching of Ni porphyrins. The rationally designed ligands exhibit a high photochemical conversion rate (trans → cis > 98%) and no measurable fatigue over a large number of switching cycles at room temperature under air. As compared to the known phenylazopyridines, the phenylazoimidazoles exhibit a much stronger affinity as axial ligands to Ni porphyrin in the binding trans configuration and a low affinity in their cis form. This affinity switching was used to control the coordination number of Ni(2+). Concomitant with the change in coordination number is the change of the spin state from triplet (high spin) to singlet state (low spin). We report on phenylazoimidazole-based PDLs that switch the paramagnetic ratio of the investigated nickel species by up to 70%. Consequently, azoimidazoles exhibit considerably higher switching efficiencies than previously described pyridine-based PDLs.


Characterization of Fluid Biomarkers Reveals Lysosome Dysfunction and Neurodegeneration in Neuronopathic MPS II Patients.
Mucopolysaccharidosis type II is a lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS) and characterized by the accumulation of the primary storage substrate, glycosaminoglycans (GAGs). Understanding central nervous system (CNS) pathophysiology in neuronopathic MPS II (nMPS II) has been hindered by the lack of CNS biomarkers. Characterization of fluid biomarkers has been largely focused on evaluating GAGs in cerebrospinal fluid (CSF) and the periphery; however, GAG levels alone do not accurately reflect the broad cellular dysfunction in the brains of MPS II patients. We utilized a preclinical mouse model of MPS II, treated with a brain penetrant form of IDS (ETV:IDS) to establish the relationship between markers of primary storage and downstream pathway biomarkers in the brain and CSF. We extended the characterization of pathway and neurodegeneration biomarkers to nMPS II patient samples. In addition to the accumulation of CSF GAGs, nMPS II patients show elevated levels of lysosomal lipids, neurofilament light chain, and other biomarkers of neuronal damage and degeneration. Furthermore, we find that these biomarkers of downstream pathology are tightly correlated with heparan sulfate. Exploration of the responsiveness of not only CSF GAGs but also pathway and disease-relevant biomarkers during drug development will be crucial for monitoring disease progression, and the development of effective therapies for nMPS II.


Left ventricular hypertrophy by ECG versus cardiac MRI as a predictor for heart failure.
To determine if there is a significant difference in the predictive abilities of left ventricular hypertrophy (LVH) detected by ECG-LVH versus LVH ascertained by cardiac MRI-LVH in a model similar to the Framingham Heart Failure Risk Score (FHFRS). This study included 4745 (mean age 61±10 years, 53.5% women, 61.7% non-whites) participants in the Multi-Ethnic Study of Atherosclerosis. ECG-LVH was defined using Cornell voltage product while MRI-LVH was derived from left ventricular mass. Cox proportional hazard regression was used to examine the association between ECG-LVH and MRI-LVH with incident heart failure (HF). Harrell's concordance C-index was used to estimate the predictive ability of the model when either ECG-LVH or MRI-LVH was included as one of its components. ECG-LVH was present in 291 (6.1%), while MRI-LVH was present in 499 (10.5%) of the participants. Both ECG-LVH (HR 2.25, 95% CI 1.38 to 3.69) and MRI-LVH (HR 3.80, 95% CI 1.56 to 5.63) were predictive of HF. The absolute risk of developing HF was 8.81% for MRI-LVH versus 2.26% for absence of MRI-LVH with a relative risk of 3.9. With ECG-LVH, the absolute risk of developing HF 6.87% compared with 2.69% for absence of ECG-LVH with a relative risk of 2.55. The ability of the model to predict HF was better with MRI-LVH (C-index 0.871, 95% CI 0.842 to 0.899) than with ECG-LVH (C-index 0.860, 95% CI 0.833 to 0.888) (p<0.0001). ECG-LVH and MRI-LVH are predictive of HF. Substituting MRI-LVH for ECG-LVH improves the predictive ability of a model similar to the FHFRS.


β2-Glycoprotein I/HLA class II complexes are novel autoantigens in antiphospholipid syndrome.
Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombosis and/or pregnancy complications. β2-glycoprotein I (β2GPI) complexed with phospholipid is recognized as a major target for autoantibodies in APS; however, less than half the patients with clinical manifestations of APS possess autoantibodies against the complexes. Therefore, the range of autoantigens involved in APS remains unclear. Recently, we found that human leukocyte antigen (HLA) class II molecules transport misfolded cellular proteins to the cell surface via association with their peptide-binding grooves. Furthermore, immunoglobulin G heavy chain/HLA class II complexes were specific targets for autoantibodies in rheumatoid arthritis. Here, we demonstrate that intact β2GPI, not peptide, forms a complex with HLA class II molecules. Strikingly, 100 (83.3%) of the 120 APS patients analyzed, including those whose antiphospholipid antibody titers were within normal range, possessed autoantibodies that recognize β2GPI/HLA class II complexes in the absence of phospholipids. In situ association between β2GPI and HLA class II was observed in placental tissues of APS patients but not in healthy controls. Furthermore, autoantibodies against β2GPI/HLA class II complexes mediated complement-dependent cytotoxicity against cells expressing the complexes. These data suggest that β2GPI/HLA class II complexes are a target in APS that might be involved in the pathogenesis.


Unified analysis and mathematical representation of film-thickness behavior of film-substrate systems.
The ellipsometric function p of a film-substrate system is studied as the film thickness d is kept constant and the angle of incidence phi is changed. The generated constant-thickness contours (CTCs) are characterized by an introduced mathematical behavior indicator that represents a group of CTCs. The behavior of each group is developed and studied in the four planes phi-d, X, Z, and p, where X is the film-thickness exponential function and Z is a previously introduced intermediate plane. In the phi-d plane the film-thickness domain is identified and divided into a sequence of disconnected thickness subdomains (DTSs), depending on only N0 and N1, and their number depending on the range in which N0/N1 lies. The behavior of the CTCs in the successive planes X, Z, and p is then studied in each DTS, and the CTC's space is divided into disconnected subfamilies according to the behavior indicator. Equivalence classes that reduce the infinite number of subfamilies into a finite number are then introduced. The transformation from each plane to the next is studied with the origin of the Z plane mapped onto the point at infinity of the p plane, forming a singularity. A multiple-film-thickness inequality is derived to determine the unique solution of the film thickness. The type of reflection being internal or external at both ambient-film and film-substrate interfaces affects the analysis and is also considered. To conclude we introduce the design of polarization-preserving devices and a novel oscillating single-element ellipsometer to fully characterize zero film-substrate systems as examples of applying the knowledge developed here.


Creating a false memory in the hippocampus.
Memories can be unreliable. We created a false memory in mice by optogenetically manipulating memory engram-bearing cells in the hippocampus. Dentate gyrus (DG) or CA1 neurons activated by exposure to a particular context were labeled with channelrhodopsin-2. These neurons were later optically reactivated during fear conditioning in a different context. The DG experimental group showed increased freezing in the original context, in which a foot shock was never delivered. The recall of this false memory was context-specific, activated similar downstream regions engaged during natural fear memory recall, and was also capable of driving an active fear response. Our data demonstrate that it is possible to generate an internally represented and behaviorally expressed fear memory via artificial means.


Prediction of Zamorano cheese quality by near-infrared spectroscopy assessing false non-compliance and false compliance at minimum permitted limits stated by designation of origin regulations.
Near-infrared transmittance (NIT) spectroscopy was used to predict the percentage in weight of the fat, dry matter, protein and fat/dry matter contents in Zamorano cheeses, protected with a Designation of Origin by the European Union. A total of 42 cheeses submitted to official control were analysed by reference methods. Samples were scanned (850-1050 nm) and predictive equations were developed using Partial Least Squares regression with a cross-validation step. Eight pretreatments independent from the remaining calibration samples were first considered. The most adequate one was that performing the second derivative (using a Savitzky-Golay method with a nine-point window and a second-order polynomial) followed by the standard normal variate transformation. Percentages of the root mean square error in cross-validation, the coefficient of determination and the mean of the absolute value of relative errors found were, respectively, for fat (0.62; 96.16; 1.05), dry matter (0.76; 96.03; 0.83), protein (0.41; 97.82; 0.81) and the fat/dry matter ratio (0.61; 92.51; 0.66). At a 99% confidence level, the trueness of the NIT+PLS methods for fat, dry matter and protein was verified. The official regulation for Zamorano cheese demands minimum permitted limits on the percentages in weight for protein (25%), dry matter (55%) and the ratio of fat to dry matter (45%). The adaptation of both the decision limit and the detection capability to the case of a minimum permitted limit (CDα and CDβ, respectively) when a Partial Least Squares calibration is used has been applied for the first time for a food product protected by a Designation of Origin. The values of CDα with a probability of false non-compliance equal to 0.05 and of CDβ when, in addition, the probability of false compliance was equal to or less than 0.05, both provided by the corresponding NIT+PLS-based method, were, respectively, for protein (24.78%; 24.57%), dry matter (54.14%; 53.28%) and the fat/dry matter ratio (44.39%; 43.78%).


Homocysteine serum concentration and uterine artery color Doppler examination in cases of recurrent miscarriages with unexplained etiology.
To study the assessment of diagnostic value and clinical usefulness of the determination of homocysteine concentration in blood serum in cases of recurrent miscarriages and the relation between the concentration of homocysteine in blood serum and parameter values determining the Doppler blood flow in the uterine arteries. Homocysteine concentration in blood serum was determined in a group of 30 women with at least two subsequent miscarriages with no clear reason and in the control group consisted of 20 non-pregnant women without a medical history of obstetric failures, having at least one healthy child. In all cases Color Doppler sonography was performed to determine flow velocity waveforms of the uterine arteries in luteal phase of the menstrual cycle. Both pulsatility (PI) and resistance indices (RI) were considerably higher (p<0.01, p<0.05) for the group of women with recurrent abortions. In the group of women with obstetrical failures high positive correlation (R=0.6903, p<0.001) and in the control group very high positive correlation (r=0.8163, p<0.001) was found, between average values of PI and average HC concentration. High positive correlation (R=0.6260, p<0.001) in the examined group and very high positive correlation (r=0.9201, p<0.001) in the control group was obtained between average values of RI, and average HC concentrations in blood serum . The recurring miscarriages occur in connection with the elevated homocysteine concentration, in consequence they can point out the pathology within the uterine-fetal blood vessels.


Smoldering multiple myeloma 40 years later: a story of unintended disease.
Introduction: Smoldering multiple myeloma (SMM) is a clonal plasma cell (PC) disorder considered a prelude to MM due to its greater malignant potential compared to monoclonal gammopathy of undetermined significance (MGUS). Despite tectonic changes in the SMM landscape that occurred since it was first distinguished four decades ago, SMM continues to represent a complex and controversial entity causing a great deal of diagnostic and management turmoil.Areas covered: Author addresses increasingly complicated, ambiguous, as well as some overlooked and misjudged aspects of SMM such as the disease identity, relationship to its counterparts, MGUS and overt MM, its niche in the modern classification of monoclonal gammopathies and management. The PubMed search (1980-2020) was conducted and the current NCCN guidelines reviewed in reference to the diagnosis and treatment of smoldering multiple myeloma.Expert opinion: A plethora of clinical and biological evidence points to SMM as a source of the ongoing and expanding uncertainty of this condition and calls into question its authenticity as a discrete entity. Until comprehensive testing can predict the progression of pre-myeloma conditions with the utmost precision, attempts at preemptive treatments will fail to answer the basic question of who will benefit from the early treatment and who will not.


Complete Genome Sequences of Two Genotype A2 Small Ruminant Lentiviruses Isolated from Infected U.S. Sheep.
Two distinct subgroups of genotype A2 small ruminant lentiviruses (SRLVs) have been identified in the United States that infect sheep with specific host transmembrane protein 154 (TMEM154) diplotypes. Here, we report the first two complete genome sequences of SRLV strains infecting U.S. sheep belonging to genotype A2, subgroups 1 and 2.


Dopamine acutely stimulates Na+/H+ exchanger (NHE3) endocytosis via clathrin-coated vesicles: dependence on protein kinase A-mediated NHE3 phosphorylation.
Dopamine (DA) is a key hormone in mammalian sodium homeostasis. DA induces natriuresis via acute inhibition of the renal proximal tubule apical membrane Na(+)/H(+) exchanger NHE3. We examined the mechanism by which DA inhibits NHE3 in a renal cell line. DA acutely decreases surface NHE3 antigen in dose- and time-dependent fashion without altering total cellular NHE3. Although DA(1) receptor agonist alone decreases surface NHE3, simultaneous DA(2) agonist synergistically enhances the effect of DA(1). Decreased surface NHE3 antigen, caused by stimulation of NHE3 endocytosis, is dependent on intact functioning of the GTPase dynamin and involves increased binding of NHE3 to the adaptor protein AP2. DA-stimulated NHE3 endocytosis can be blocked by pharmacologic or genetic protein kinase A inhibition or by mutation of two protein kinase A target serines (Ser-560 and Ser-613) on NHE3. We conclude that one mechanism by which DA induces natriuresis is via protein kinase A-mediated phosphorylation of proximal tubule NHE3 leading to endocytosis of NHE3 via clathrin-coated vesicles.


Violence, psychological distress and the risk of suicidal behaviour in young people in India.
Suicide among young people has emerged as a major public health issue in many low- and middle-income (LAMI) countries. Suicidal behaviour including ideation and attempt are the most important predictors of completed suicide and offer critical points for intervention. The aim of this study is to estimate the prevalence and risk factors for suicidal behaviour in young people in India. Cross-sectional study of 3662 youth (16-24 years) from rural and urban communities in Goa, India. Suicidal behaviour during the recent 3 months and associated factors were assessed using a structured interview. Overall 144; 3.9% [95% confidence interval (CI) 3.3-4.6] youth reported any suicidal behaviour in the previous 3 months. Suicidal behaviour was found to be associated with female gender Odds ratio (OR) 6.5 (95% CI 3.9-10.8), not attending school or college OR 1.6 (95% CI, 1.01-2.6), independent decision making OR 2.5 (95% CI 1.5-4.3), premarital sex OR 3.2 (95% CI 1.6-6.3), physical abuse at home OR 3.3 (95% CI 1.8-6.1), life time experience of sexual abuse OR 3.3 (95% CI 1.8-6.0) and probable common mental disorders (CMD) OR 9.5 (95% CI 6.3-14.5). Gender segregated analysis found independent decision making (P=0.68 for interaction), rural residence (P=0.01 for interaction) and premarital sex (P=0.41 for interaction) retained association with suicidal behaviour only among females (P<0.05). The population attributable fraction estimates were largest for CMD (42.8% for females; 35.9% for males); physical abuse in one's home (12.5% for females; 12.4% for males); sexual abuse (12.1% in females; 22.3% in males); and making independent decisions (22.9% for females). Analyses of the risk factors for the relatively less common outcome of suicide attempts found a similar set of factors as for suicidal behaviour; in addition, alcohol use was also an independent risk factor. Violence and psychological distress are independently associated with suicidal behaviour; factors associated with gender disadvantage-in particular for rural women, may increase their vulnerabilities. Prevention programs for youth suicide in India need to address both the structural determinants of gender disadvantage, and the individual experiences of violence and poor mental health.


VA OpenNotes: exploring the experiences of early patient adopters with access to clinical notes.
To explore the experience of early patient adopters who accessed their clinical notes online using the Blue Button feature of the My HealtheVet portal. A web-based survey of VA patient portal users from June 22 to September 15, 2013. 33.5% of respondents knew that clinical notes could be viewed, and nearly one in four (23.5%) said that they had viewed their notes at least once. The majority of VA Notes users agreed that accessing their notes will help them to do a better job of taking medications as prescribed (80.1%) and be better prepared for clinic visits (88.6%). Nine out of 10 users agreed that use of visit notes will help them understand their conditions better (91.8%), and better remember the plan for their care (91.9%). In contrast, 87% disagreed that VA Notes will make them worry more, and 88.4% disagreed that access to VA Notes will be more confusing than helpful. Users who had either contacted their provider or healthcare team (11.9%) or planned to (13.5%) primarily wanted to learn more about a health issue, medication, or test results (53.7%). Initial assessment of the patient experience within the first 9 months of availability provides evidence that patients both value and benefit from online access to clinical notes. These findings are congruent with OpenNotes study findings on a broader scale. Additional outreach and education is needed to enhance patient awareness. Healthcare professionals should author notes keeping in mind the opportunity patient access presents for enhanced communication.


Cardiovascular disease prevalence in patients with inflammatory arthritis, diabetes mellitus and osteoarthritis: a cross-sectional study in primary care.
There is accumulating evidence for an increased cardiovascular burden in inflammatory arthritis, but the true magnitude of this cardiovascular burden is still debated. We sought to determine the prevalence rate of non-fatal cardiovascular disease (CVD) in inflammatory arthritis, diabetes mellitus and osteoarthritis (non-systemic inflammatory comparator) compared to controls, in primary care. Data on CVD morbidity (ICPC codes K75 (myocardial infarction), K89 (transient ischemic attack), and/or K90 (stroke/cerebrovascular accident)) from patients with inflammatory arthritis (n = 1,518), diabetes mellitus (n = 11,959), osteoarthritis (n = 4,040) and controls (n = 158,439) were used from the Netherlands Information Network of General Practice (LINH), a large nationally representative primary care based cohort. Data were analyzed using multi-level logistic regression analyses and corrected for age, gender, hypercholesterolemia and hypertension. CVD prevalence rates were significantly higher in inflammatory arthritis, diabetes mellitus and osteoarthritis compared with controls. These results attenuated - especially in diabetes mellitus - but remained statistically significant after adjustment for age, gender, hypertension and hypercholesterolemia for inflammatory arthritis (OR = 1.5 (1.2-1.9)) and diabetes mellitus (OR = 1.3 (1.2-1.4)). The association between osteoarthritis and CVD reversed after adjustment (OR = 0.8 (0.7-1.0)). These results confirm an increased prevalence rate of CVD in inflammatory arthritis to levels resembling diabetes mellitus. By contrast, lack of excess CVD in osteoarthritis further suggests that the systemic inflammatory load is critical to the CVD burden in inflammatory arthritis.


Healthcare managers' perception of economies of scale.
Purpose The purpose of this paper is to explore how healthcare managers perceive economies of scale and the underlying mechanisms for how scale/size affects performance. Design/methodology/approach Data were collected in 20 in-depth interviews with healthcare professionals from 13 healthcare delivery organizations and from a public authority that finances and contracts healthcare services. Data were coded and analysed using content analysis. Findings The study concludes that the impact of scale on performance is perceived by healthcare professionals to be different for different types of healthcare services: For surgery, significant scale effects related to spreading of fixed cost, the experience curve, and potential for process improvement. For inpatient care, moderate scale effects related to spreading of fixed costs and costs of doctors on on-call duty. For outpatient care, small or no scale effects. Research limitations/implications The small sample of interviewees from a single geographical region and healthcare system limits the applicability of the findings. Originality/value The paper provides insights into how healthcare managers experience scale effects and how they consider economies of scale when planning hospital configuration. Also, past studies of economies of scale in hospitals proffer mixed results and the findings in this paper indicate a possible explanation for this inconclusiveness, i.e. differences in service mix between different hospitals.


Novel two-alternative forced choice paradigm for bilateral vibrotactile whisker frequency discrimination in head-fixed mice and rats.
Rats and mice receive a constant bilateral stream of tactile information with their large mystacial vibrissae when navigating in their environment. In a two-alternative forced choice paradigm (2-AFC), head-fixed rats and mice learned to discriminate vibrotactile frequencies applied simultaneously to individual whiskers on the left and right sides of the snout. Mice and rats discriminated 90-Hz pulsatile stimuli from pulsatile stimuli with lower repetition frequencies (10-80 Hz) but with identical kinematic properties in each pulse. Psychometric curves displayed an average perceptual threshold of 50.6-Hz and 53.0-Hz frequency difference corresponding to Weber fractions of 0.56 and 0.58 in mice and rats, respectively. Both species performed >400 trials a day (>200 trials per session, 2 sessions/day), with a peak performance of >90% correct responses. In general, rats and mice trained in the identical task showed comparable psychometric curves. Behavioral readouts, such as reaction times, learning rates, trial omissions, and impulsivity, were also very similar in the two species. Furthermore, whisking of the animals before stimulus presentation reduced task performance. This behavioral paradigm, combined with whisker position tracking, allows precise stimulus control in the 2-AFC task for head-fixed rodents. It is compatible with state-of-the-art neurophysiological recording techniques, such as electrophysiology and two-photon imaging, and therefore represents a valuable framework for neurophysiological investigations of perceptual decision-making.


Endoscopic thyroidectomy is safe in patients with a high body mass index.
Obesity is associated with a number of medical comorbidities and is considered a risk factor for surgical complications. However, the impact of obesity on the safety of minimally invasive video-assisted thyroidectomy (MIVAT) has not been well defined. We sought to determine the relationship between obesity and the risk of complications in patients undergoing MIVAT. A prospectively maintained database of all thyroid surgeries performed from January 2006 through June 2012 was searched and all cases of MIVAT were identified. Patients were stratified into three body mass index (BMI) groups according to the National Institutes of Health classification for obesity: normal (BMI ≤ 24.9 kg/m(2)), overweight (BMI 25-29.9 kg/m(2)) and obese (BMI ≥ 30 kg/m(2)). The total number of complications was compared among the three groups, and MIVAT patients were also compared to a cohort of patients undergoing conventional thyroid surgery. There were 233 MIVATs performed on 223 patients. The mean overall BMI for the study population was 25.4 kg/m(2). There were 123 procedures (52.8%) in the normal group, 76 procedures (32.6%) in the overweight group, and 34 procedures (14.6%) in the obese group. Complications included 1 case of cellulitis (0.4%), 6 cases of temporary hypocalcemia (2.6%), and 6 cases of transient vocal fold paresis (2.6%). No patients suffered permanent hypocalcemia or a permanent recurrent laryngeal nerve injury. There were 9 complications in the normal group (7.3%), 4 complications in the overweight group (5.3%), and no complications in the obese group. Due to the low number of complications in this series, the overweight and obese groups were combined into a high BMI group for further analysis. Statistical analysis using simple logistic regression models revealed that there was no significant difference in the number of complications in patients with a high BMI compared with patients with a normal BMI (odds ratio [OR] 0.48 [confidence interval (CI) 0.14-1.63], p=0.2). The MIVAT group had fewer overall complications than the conventional thyroidectomy group. Overweight and obese patients undergoing MIVAT in this series were not at an increased risk for surgical complications. The MIVAT procedure may be considered safe in patients with a high BMI, who may derive particular benefit from a minimally invasive approach.


Absence of chemokine (C-x-C motif) ligand 10 diminishes perfusion recovery after local arterial occlusion in mice.
In arteriogenesis, pre-existing anastomoses undergo enlargement to restore blood flow in ischemic tissues. Chemokine (C-X-C motif) ligand 10 (CXCL10) is secreted after Toll-like receptor activation. Toll-like receptors are involved in arteriogenesis; however, the role of CXCL10 is still unclear. In this study, we investigated the role for CXCL10 in a murine hindlimb ischemia model. Unilateral femoral artery ligation was performed in wild-type (WT) and CXCL10(-/-) knockout (KO) mice and perfusion recovery was measured using laser-Doppler perfusion analysis. Perfusion recovery was significantly lower in KO mice compared with WT at days 4 and 7 after surgery (KO versus WT: 28±5% versus 81±13% at day 4; P=0.003 and 57±12% versus 107±8% at day 7; P=0.003). Vessel measurements of α-smooth muscle actin-positive vessels revealed increasing numbers in time after surgery, which was significantly higher in WT when compared with that in KO. Furthermore, α-smooth muscle actin-positive vessels were significantly larger in WT when compared with those in KO at day 7 (wall thickness, P<0.001; lumen area, P=0.003). Local inflammation was assessed in hindlimb muscles, but this did not differ between WT and KO. Chimerization experiments analyzing perfusion recovery and histology revealed an equal contribution for bone marrow-derived and circulating CXCL10. Migration assays showed a stimulating role for both intrinsic and extrinsic CXCL10 in vascular smooth muscle cell migration. CXCL10 plays a causal role in arteriogenesis. Bone marrow-derived CXCL10 and tissue-derived CXCL10 play a critical role in accelerating perfusion recovery after arterial occlusion in mice probably by promoting vascular smooth muscle cell recruitment and maturation of pre-existing anastomoses.


Autophagosome-lysosome fusion in neurons requires INPP5E, a protein associated with Joubert syndrome.
Autophagy is a multistep membrane traffic pathway. In contrast to autophagosome formation, the mechanisms underlying autophagosome-lysosome fusion remain largely unknown. Here, we describe a novel autophagy regulator, inositol polyphosphate-5-phosphatase E (INPP5E), involved in autophagosome-lysosome fusion process. In neuronal cells, INPP5E knockdown strongly inhibited autophagy by impairing the fusion step. A fraction of INPP5E is localized to lysosomes, and its membrane anchoring and enzymatic activity are necessary for autophagy. INPP5E decreases lysosomal phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), one of the substrates of the phosphatase, that counteracts cortactin-mediated actin filament stabilization on lysosomes. Lysosomes require actin filaments on their surface for fusing with autophagosomes. INPP5E is one of the genes responsible for Joubert syndrome, a rare brain abnormality, and mutations found in patients with this disease caused defects in autophagy. Taken together, our data reveal a novel role of phosphoinositide on lysosomes and an association between autophagy and neuronal disease.


Contracting for quality: Medicare's quality improvement organizations.
This paper examines the role of quality improvement organizations (QIOs, formerly known as PROs, or peer review organizations) in improving the quality of medical care delivered to Medicare beneficiaries in both fee-for-service and managed care environments. It looks at the expansion of the QIOs' portfolio in their new contract cycle to include quality improvement activities in nursing homes, home health services, and physicians' offices as well as responsibilities for public education. The paper explores the evolution of QIOs, changes in their priorities over time, and the projects in which they are currently engaged. It also considers their role in the formulation and execution of a national quality agenda.


Multilevel analysis of neuropathogenesis of neurocognitive impairment in HIV.
The neuropathogenesis of HIV-associated neurocognitive disorders (HAND) remains puzzling. We interrogated several levels of data (host genetic, histopathology, brain viral load, and neurocognitive) to identify histopathological changes most relevant to HAND. The design of the study is a clinicopathological study employing genetic association analyses. Data and brain tissue from 80 HIV-infected adults were used. Markers in monocyte chemoattractant protein-1 (MCP-1), interleukin 1-alpha (IL1-α), macrophage inflammatory protein 1-alpha (MIP1-α), DRD3, DRD2, and apolipoprotein E (ApoE) were genotyped. Microtubule associated protein 2 (MAP2), synaptophysin (SYP), human leukocyte antigen-DR (HLA-DR), glial fibrillary acidic protein (GFAP), amyloid beta (A-Beta), and ionized calcium-binding adaptor molecule-1 (Iba-1) immunoreactivity were quantified in the frontal cortex, putamen, and hippocampus. A composite score for each marker (mean of the three brain regions) was used. Neurocognitive functioning and other clinical variables were determined within 1 year of death. Brain HIV RNA viral load was available for a subset of cases. MAP2 and SYP proved most relevant to neurocognitive functioning. Immunoreactivity of these markers, as well as A-Beta and Iba-1, was correlated with brain HIV RNA viral load. Several genetic markers in combination with other factors predicted histopathology: HIV blood viral load, MIP1-α genotype, and DRD3 genotype predicted Iba-1 immunoreactivity; the duration of infection and IL1-α genotype predicted GFAP immunoreactivity; ApoE genotype and age at death predicted A-Beta immunoreactivity. These data indicate that HIV replication in the brain is the primary driving force leading to neuroinflammation and dysfunctional protein clearance, as reflected by A-Beta and Iba-1. Downstream to these changes are synaptodendritic degeneration, which is the immediate histopathological substrate of the neurocognitive impairment characteristic of HAND. These intermediate histopathological phenotypes are influenced by host genetic polymorphisms in genes encoding cytokines/chemokines, neuronal protein clearance pathways, and dopaminergic factors.


A Case Report Presenting an Undifferentiated Pancreatic Carcinoma with Osteoclastic-Like Giant Cells with an Unusual Indolent Course.
BACKGROUND Undifferentiated pancreatic carcinoma with osteoclast-like giant cells represents less than 1% of pancreatic cancers. Histogenesis and prognosis are still debated. Three subtypes are defined by the World Health Organization: osteoclastic, pleomorphic, and mixed. The differential diagnosis of a pancreatic tumor with giant cells varies from a benign osteoclastoma to an undifferentiated pancreatic carcinoma with osteoclastic-like cells. The specimen should be carefully examined to rule out conventional pancreatic adenocarcinoma even in the presence of the giant cells. CASE REPORT A 77-year-old male was diagnosed with a pancreatic tail tumor with osteoclastic like cells revealed by a biopsy done by echo-endoscopy; the patient was lost to follow up for 24 months before he was admitted to our institute for severe abdominal pain. A computed tomography showed the same lesion without progression. He was operated on using laparoscopic distal pancreatectomy with splenectomy. Pathology analysis revealed the presence of osteoclast-like giant cells without pleomorphic cells. Mutated KRAS on molecular study confirmed the diagnosis of undifferentiated pancreatic carcinoma with osteoclast-like giant cells. The patient was in good performance status and disease-free 19 months after surgery without any sign of progression. CONCLUSIONS Undifferentiated pancreatic carcinoma with osteoclast-like cells has a challenging pathology diagnosis. Molecular and immunostaining are essential to diagnosis. The absence of pleomorphic cells in the present case has classified it into the osteoclastic subtype. Further cases and studies are needed to confirm the heterogeneity of the malignant course between subtypes.


The MOXFQ patient-reported questionnaire: assessment of data quality, reliability and validity in relation to foot and ankle surgery.
Previously validated for hallux valgus surgery, the Manchester-Oxford Foot Questionnaire (MOXFQ) is here evaluated for use with different regions of the foot and ankle. The study recruited 671 consecutive patients (87.8% of those eligible), mean age 52.8 years, 64% female, who completed the MOXFQ and SF-36 general health survey before foot or ankle surgery. Surgeons completed the American Orthopaedic Foot & Ankle Society (AOFAS) scales and indicated that the patients' main regions for surgery were: Hallux 210 (31.3%), Lesser toes 119 (17.7%), Mid foot 22 (3.3%), Ankle/hind foot 311 (46.3%), Multiple/whole foot 9 (1.3%). Individual MOXFQ items were assessed in terms of response rate and floor/ceiling effects, with the validity of the three MOXFQ scales (Walking/standing, Pain, and Social interaction) being assessed in terms of item-total correlations, internal and test-retest reliability, and construct validity. MOXFQ item response rates were high (all >98%). Cronbach's alphas of >0.7 confirmed internal consistency of all three scales. Test-retest ICCs were all ≥0.89. Correlations of >0.4 obtained with related SF-36 and AOFAS scales supported a priori hypotheses. Good measurement properties are confirmed for the MOXFQ in the context of baseline assessment of patients receiving surgery for a variety of foot or ankle problems.


Early reduction in painful physical symptoms is associated with improvements in long-term depression outcomes in patients treated with duloxetine.
To investigate the association of the change of painful physical symptoms (PPS) after 4 weeks, with the 6-month treatment outcomes of depressive symptoms in patients treated with duloxetine in clinical practice. Multicenter, prospective, 6-month, non-interventional study in adult outpatients with a depressive episode and starting treatment with duloxetine. Depression severity was assessed by the clinician (Inventory for Depressive Symptomatology [IDS-C]) and patient (Kurz-Skala Stimmung/Aktivierung [KUSTA]). Somatic symptoms and PPS were assessed using the patient-rated Somatic Symptom Inventory (SSI) and visual analog scales (VAS) for pain items. Association of change in PPS with outcomes of depressive symptoms was analyzed based on mean KUSTA scores (mean of items mood, activity, tension/relaxation, sleep) and achievement of a 50% reduction in the total IDS-C score after 6 months using linear and logistic regression models, respectively. Of the 4,517 patients enrolled (mean age: 52.2 years, 71.8% female), 3,320 patients (73.5%) completed the study. 80% of the patients had moderate to severe overall pain (VAS > 30 mm) at baseline. A 50% VAS overall pain reduction after 4 weeks was associated with a 13.32 points higher mean KUSTA score after 6 months, and a 50% pain reduction after 2 weeks with a 6.33 points improvement. No unexpected safety signals were detected in this naturalistic study. Pain reduction after 2 and 4 weeks can be used to estimate outcomes of long-term treatment with duloxetine. PPS associated with depression have a potential role in predicting remission of depressive symptoms in clinical practice.


Critical features for the perception of emotion from gait.
Human observers readily recognize emotions expressed in body movement. Their perceptual judgments are based on simple movement features, such as overall speed, but also on more intricate posture and dynamic cues. The systematic analysis of such features is complicated due to the difficulty of considering the large number of potentially relevant kinematic and dynamic parameters. To identify emotion-specific features we motion-captured the neutral and emotionally expressive (anger, happiness, sadness, fear) gaits of 25 individuals. Body posture was characterized by average flexion angles, and a low-dimensional parameterization of the spatio-temporal structure of joint trajectories was obtained by approximation with a nonlinear mixture model. Applying sparse regression, we extracted critical emotion-specific posture and movement features, which typically depended only on a small number of joints. The features we extracted from the motor behavior closely resembled features that were critical for the perception of emotion from gait, determined by a statistical analysis of classification and rating judgments of 21 observers presented with avatars animated with the recorded movements. The perceptual relevance of these features was further supported by another experiment showing that artificial walkers containing only the critical features induced high-level after-effects matching those induced by adaptation with natural emotional walkers.


Prognostic Factors for the Selection of Patients Eligible for Second-Line Chemotherapy in Advanced Biliary Tract Cancer.
The efficacy of second-line chemotherapy (CT2) after the failure of first-line chemotherapy (CT1) for advanced biliary tract cancer (BTC) has not been established. We investigated the favorable prognostic factors for CT2 to determine which patients could be expected to benefit from CT2. From a total of 168 patients who were treated with chemotherapy at our institution between January 2003 and December 2012, we retrospectively reviewed 50 patients who received CT2. Patients were treated with various chemotherapeutic combinations as CT1 and CT2. RESULts: The median overall survival (OS) of patients who received and CT2 was 10.2 and 5.5 months, respectively. Good performance status (PS), a serum albumin level >3.5 g/dl and metastasis to only 1 organ were independent prognostic factors that affected the OS of the patients who received CT2. Patients who had only 1 metastastic organ, a good PS and a serum albumin level >3.5 g/dl at the beginning of CT2 demonstrated prolonged survival compared to patients who did not exhibit these 3 factors (9.5 vs. 4.3 months, p < 0.005). CT2 should be considered for patients with advanced BTC, especially for those who have only 1 metastatic organ and remain in generally good medical condition after the failure of CT1.