Seasonal photosynthetic responses of European oaks to drought and elevated daytime temperature.
Oaks are commonly considered as drought- and heat-tolerant trees that might benefit from a warmer and drier climate. Their tolerance to drought has been frequently studied in the past, whereas studies dealing with elevated temperature or its combination with drought are very limited in number. In this study we investigated seasonal photosynthetic patterns in three European oak species (Quercus robur, Q. petraea, Q. pubescens) exposed in lysimeter-based open-top chambers (OTC) to elevated daytime temperature, drought and their combination. Stomatal and non-stomatal traits of photosynthesis were followed over an entire growing season and related to changes in daytime temperature, soil moisture and pre-dawn leaf water potential (Ψ(PD) ). Elevated daytime temperature enhanced net photosynthesis (P(N) ) in a season-dependent manner, with higher mid-summer rates than in controls exposed to ambient temperature. Drought imposed in early and mid-summer reduced the soil moisture content and caused a gradual decline in Ψ(PD) , stomatal conductance (g(S) ) and P(N) . Drought effects on Ψ(PD) and P(N) were exacerbated when drought was combined with elevated daytime temperature. In general, P(N) tended to be more affected by low soil moisture content or low Ψ(PD) in Q. robur than in Q. petraea and Q. pubescens. Non-stomatal limitations may have contributed to the drought-induced decline of P(N) in Q. robur, as indicated by a down-regulation of PSII photochemistry (F(V) /F(M) ) and decreased chlorophyll content. Taken together, our findings show that European oaks may benefit from elevated temperature, but detrimental effects can be expected when elevated temperature occurs simultaneously with drought.


Stable gelatin-based phantom materials with tunable x-ray attenuation properties and 3D printability for x-ray imaging.
We report a novel method for developing gelatin-based phantom materials for transmission x-ray imaging with high stability at room temperature and tunable x-ray attenuation properties. This is achieved by efficiently cross-linking gelatin in a glycerin solution with only 10% water by volume and systematically decreasing their x-ray attenuation coefficients by doping with microbubbles that are originally designed to be used as lightweight additives for paints and crack fillers. For demonstration, we mimic breast glandular and adipose tissues by using such gelatin materials and also study the feasibility of 3D printing them based on the extrusion-based technique. Results from x-ray spectroscopy (15-45 keV) show the materials to have stable x-ray attenuation properties of glandular and adipose tissues over a period of two months. Micro-CT analysis of independently prepared samples shows the materials to be uniform and easy to reproduce with minimum variability in attenuation values. These materials can be used to 3D print realistic phantoms that mimic x-ray properties of various biological tissues.


Disruption of T cell development and repertoire selection by calcineurin inhibition in vivo.
The microbial products FK506 and CsA are potent immunosuppressive agents that prevent early transcriptional events in TcR-mediated activation. Their mode of action is dependent upon the inhibition of calcineurin, a serine/threonine phosphatase positioned within the calcium-dependent signaling pathway. TcR-mediated activation of thymocytes constitutes an important prerequisite for their development and selection to mature T cells. Disruption of the cross-talk between thymic APC and thymocytes results in the loss of normal T cell ontogeny. To study the role of calcineurin in T cell maturation and repertoire selection in vivo, mice were treated with either FK506 or CsA. Administration of either drug inhibited the progression of CD4+CD8+ positive thymocytes to mature single positive T cells. Furthermore, both drugs disrupted the process of negative thymic selection, causing an increased frequency of self-reactive cells among the few positively selected T cells. These effects correlated directly with the degree of inhibition of in vivo calcineurin enzyme activity. Blocking calcineurin activity appears to disrupt positive thymic selection and to prevent the deletion of self-reactive thymocytes.


Lateral effects in pattern vision.
There is a large literature on lateral effects in pattern vision but no consensus about them or comprehensive model of them. This paper reviews the literature with a focus on the effects of parallel context in the central fovea. It describes seven experiments that measure detection and discrimination thresholds in annular and Gabor-pattern contexts at different separations. It presents a model of these effects, which is an elaboration of Foley's (1994) model. The model describes the results well, and it shows that lateral context affects the response to the target by both multiplicative excitation and additive inhibition. Both lateral effects extend for several wavelengths beyond the target. They vary in relative strength, producing near suppression and far enhancement of the response to the target. The model describes the detection and discrimination results well, and it also describes the results of experiments on lateral effects on perceived contrast. The model is consistent with the physiology of V1 cells.


Agmatine-conjugated cytidine in a tRNA anticodon is essential for AUA decoding in archaea.
A modified base at the first (wobble) position of some tRNA anticodons is critical for deciphering the genetic code. In eukaryotes and eubacteria, AUA codons are decoded by tRNAsIle with modified bases pseudouridine (and/or inosine) and lysidine, respectively. The mechanism by which archaeal species translate AUA codons is unclear. We describe a polyamine-conjugated modified base, 2-agmatinylcytidine (agm(2)C or agmatidine), at the wobble position of archaeal tRNA(Ile) that decodes AUA codons specifically. We demonstrate that archaeal cells use agmatine to synthesize agm(2)C of tRNA(Ile). We also identified a new enzyme, tRNA(Ile)-agm(2)C synthetase (TiaS), that catalyzes agm(2)C formation in the presence of agmatine and ATP. Although agm(2)C is chemically similar to lysidine, TiaS constitutes a distinct class of enzyme from tRNA(Ile)-lysidine synthetase (TilS), suggesting that the decoding systems evolved convergently across domains.


Dynamic enlargement and mobilization of lipid droplets in pluripotent cells coordinate morphogenesis during mouse peri-implantation development.
Mammalian pre-implantation embryos accumulate substantial lipids, which are stored in lipid droplets (LDs). Despite the fundamental roles of lipids in many cellular functions, the significance of building-up LDs for the developing embryo remains unclear. Here we report that the accumulation and mobilization of LDs upon implantation are causal in the morphogenesis of the pluripotent epiblast and generation of the pro-amniotic cavity in mouse embryos, a critical step for all subsequent development. We show that the CIDEA protein, found abundantly in adipocytes, enhances lipid storage in blastocysts and pluripotent stem cells by promoting LD enlargement through fusion. The LD-stored lipids are mobilized into lysosomes at the onset of lumenogenesis, but without CIDEA are prematurely degraded by cytosolic lipases. Loss of lipid storage or inactivation of lipophagy leads to the aberrant formation of multiple cavities within disorganised epithelial structures. Thus, our study reveals an unexpected role for LDs in orchestrating tissue remodelling and uncovers underappreciated facets of lipid metabolism in peri-implantation development.


Molecular Transformation of Crude Oil Contaminated Soil after Bioelectrochemical Degradation Revealed by FT-ICR Mass Spectrometry.
Bioremediation is a low-cost approach for crude oil spill remediation, but it is often limited by electron acceptor availability. In addition, the biodegradation products of crude oil contaminants are complex, and transformation pathways are difficult to decipher. This study demonstrates that bioelectrochemical systems (BESs) can be effective in crude oil degradation by integrating biological and electrochemical pathways, and more importantly, it provides the first understanding on the daughter products of bioelectrochemical hydrocarbon degradation. Using electrospray ionization (ESI) Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) and two-dimensional gas chromatography (GC × GC), the results showed that the active BES reactor improved the total petroleum hydrocarbon (TPH) degradation by ∼70% than open circuit control reactors. After separating the daughter products into nine fractions (MA1-MA9) according to the molecular weight (m/z 200-1000) by modified aminopropyl silica (MAPS) fractionation, we found that active BES remediation resulted in 50% more polar, oxygen-containing naphthenic (NAP) acids. The MA4 fraction (centered at ∼550 Da) increased by 47%, and MA5 and MA7 fractions with higher molucular weight increased by a maximum of ∼7- and 9-fold, respectively. These results are in accordance with the variation of bulk elemental compositions in O2 species, where daughter transformation products doubled relative to parent oil extract. The contribution of newly generated NAP acids was mainly from higher-order oxygen species (O5-O6) with increased hydrophobicity in conjunction with a decreased abundance in lower-order oxygen species (O1). Overall, the study suggests that n-alkane degradation occurred via β-oxidation to oxygenated transformation products with lower molecular weight, such as n-alcohols in O1 class and subsequently to n-fatty acids in O2 class.


Young People Who Meaningfully Improve Are More Likely to Mutually Agree to End Treatment.
Objective: Symptom improvement is often examined as an indicator of a good outcome of accessing mental health services. However, there is little evidence of whether symptom improvement is associated with other indicators of a good outcome, such as a mutual agreement to end treatment. The aim of this study was to examine whether young people accessing mental health services who meaningfully improved were more likely to mutually agree to end treatment. Methods: Multilevel multinomial regression analysis controlling for age, gender, ethnicity, and referral source was conducted on N = 8,995 episodes of care [Female = 5,469, 61%; meanAge = 13.66 (SD = 2.87) years] using anonymised administrative data from young people's mental health services. Results: Compared to young people with no change in mental health difficulties, those showing positive meaningful changes in mental health difficulties were less likely to have case closure due to non-mutual agreement (Odds Ratio or OR = 0.58, 95% Confidence Interval or CI = 0.50-0.61). Similarly, they were less likely to transfer (OR = 0.61, 95% CI = 0.49-0.74) or end treatment for other reasons (OR = 0.59, 95% CI = 0.50-0.70) than by case closure due to mutual agreement. Conclusion: The findings suggest that young people accessing mental health services whose symptoms meaningfully improve are more likely to mutually agree to end treatment, adding to the evidence that symptom improvement may be appropriate to examine as an indicator of a good outcome of accessing mental health services.


The PAMPA datasets: a metagenomic survey of microbial communities in Argentinean pampean soils.
Soil is among the most diverse and complex environments in the world. Soil microorganisms play an essential role in biogeochemical cycles and affect plant growth and crop production. However, our knowledge of the relationship between species-assemblies and soil ecosystem processes is still very limited. The aim of this study was to generate a comprehensive metagenomic survey to evaluate the effect of high-input agricultural practices on soil microbial communities. We collected soil samples from three different areas in the Argentinean Pampean region under three different types of land uses and two soil sources (bulk and rhizospheric). We extracted total DNA from all samples and also synthetized cDNA from rhizospheric samples. Using 454-FLX technology, we generated 112 16S ribosomal DNA and 14 16S ribosomal RNA amplicon libraries totaling 1.3 M reads and 36 shotgun metagenome libraries totaling 17.8 million reads (7.7 GB). Our preliminary results suggested that water availability could be the primary driver that defined microbial assemblages over land use and soil source. However, when water was not a limiting resource (annual precipitation >800 mm) land use was a primary driver. This was the first metagenomic study of soil conducted in Argentina and our datasets are among the few large soil datasets publicly available. The detailed analysis of these data will provide a step forward in our understanding of how soil microbiomes respond to high-input agricultural systems, and they will serve as a useful comparison with other soil metagenomic studies worldwide.


Early Ambulation Decreases Length of Hospital Stay, Perioperative Complications and Improves Functional Outcomes in Elderly Patients Undergoing Surgery for Correction of Adult Degenerative Scoliosis.
Ambispective cohort review. To examine the effects of early mobilization on patient outcomes, complications profile, and 30-day readmission rates. Prolonged immobilization after surgery can result in functional decline and an increased risk of hospital-associated complications. We conducted an ambispective study of 125 elderly patients (>65 years) undergoing elective spinal surgery for correction of adult degenerative scoliosis. We identified all unplanned readmissions within 30 days of discharge. Unplanned readmissions were defined to have occurred as a result of either a surgical or a nonsurgical complication. "Days of immobility" was defined as the number of days until a patient moved out of bed beyond a chair. Patients in the top and bottom quartiles were dichotomized into "early ambulators" and "late ambulators", respectively. Early ambulators were ambulatory within 24 hours of surgery, whereas late ambulators were ambulatory at a minimum of 48 hours after surgery. Complication rates, duration of hospital stay, and 30-day readmission rates were compared between early ambulators and late ambulators. Baseline characteristics were similar between both cohorts. Compared with patients with a longer duration of immobility (i.e., late ambulators), the prevalence of at least one perioperative complication was significantly lower in the early ambulators cohort (30% vs. 54%, P = 0.06). The length of inhospital stay was 34% shorter in the early ambulators cohort (5.33 days vs. 8.11 days, P = 0.01). Functional independence was superior in the early ambulators cohort, with the majority of patients discharged directly home after surgery compared with late ambulators (71.2% vs. 22.0%, P = 0.01). Early ambulation after surgery significantly reduces the incidence of perioperative complications, shortens duration of inhospital stay, and contributes to improved perioperative functional status in elderly patients. Even a delay of 24 hours to ambulation is associated with higher complication rates and inferior functional outcomes. 3.


Sonophore-enhanced nanoemulsions for optoacoustic imaging of cancer.
Optoacoustic imaging offers the promise of high spatial resolution and, at the same time, penetration depths well beyond the conventional optical imaging technologies, advantages that would be favorable for a variety of clinical applications. However, similar to optical fluorescence imaging, exogenous contrast agents, known as sonophores, need to be developed for molecularly targeted optoacoustic imaging. Despite numerous optoacoustic contrast agents that have been reported, there is a need for more rational design of sonophores. Here, using a library screening approach, we systematically identified and evaluated twelve commercially available near-infrared (690-900 nm) and highly absorbing dyes for multi-spectral optoacoustic tomography (MSOT). In order to achieve more accurate spectral deconvolution and precise data quantification, we sought five practical mathematical methods, namely direct classical least squares based on UV-Vis (UV/Vis-DCLS) or optoacoustic (OA-DCLS) spectra, non-negative LS (NN-LS), independent component analysis (ICA) and principal component analysis (PCA). We found that OA-DCLS is the most suitable method, allowing easy implementation and sufficient accuracy for routine analysis. Here, we demonstrate for the first time that our biocompatible nanoemulsions (NEs), in combination with near-infrared and highly absorbing dyes, enable non-invasive in vivo MSOT detection of tumors. Specifically, we found that NE-IRDye QC1 offers excellent optoacoustic performance and detection compared to related near-infrared NEs. We demonstrate that when loaded with low fluorescent or dark quencher dyes, NEs represent a flexible and new class of exogenous sonophores suitable for non-invasive pre-clinical optoacoustic imaging.


Predicting response to epidermal growth factor receptor-targeted therapy in colorectal cancer.
The discovery over 20 years ago by the Nobel Laureate Stanley Cohen of epidermal growth factor and its receptor, followed by the recognition that this receptor is overexpressed in multiple cancer types, has been of phenomenal significance. From these events the 'Holy Grail' of targeted therapy has looked increasingly realistic. Over the last 5 years this work has come of age with the licensing of multiple agents targeting this important mitogenic pathway in multiple tumor types. However, these agents and the technology behind them, while impressive, have resulted in lower clinical response rates than anticipated. In this review we will focus on the epidermal growth factor receptor-targeted therapies in colorectal cancer, why our expectations from these therapies have not yet been fulfilled and how we may predict those cancers that are likely to respond or be resistant to these therapies through a greater appreciation of the intricacy, diversity and dynamism of cellular signaling mechanisms.


Selective delay activity in the medial prefrontal cortex of the rat: contribution of sensorimotor information and contingency.
The medial prefrontal cortex (mPFC) plays a critical role in the organization of goal-directed behaviors and in the learning of reinforcement contingencies. Given these observations, it was hypothesized that mPFC neurons may store associations between sequentially paired stimuli when both stimuli contribute to the prediction of reward. To test this hypothesis, neural-ensemble spiking activity was recorded as rats performed a paired-associate discrimination task. Rats were trained to associate sequentially presented stimuli with probabilistic reward. In one condition, both elements of the stimulus sequence provided information about reward delivery. In another condition, only the first stimulus contributed to the prediction. As hypothesized, stimulus-selective, prospective delay activity was observed during sequences in which both elements contributed to the prediction of reward. Unexpectedly, selective delay responses were associated with slight variations in head position and thus not necessarily generated by intrinsic mnemonic processes. Interestingly, the sensitivity of neurons to head position was greatest during intervals when reward delivery was certain. These results suggest that a significant portion of delay activity in the rat mPFC reflects task-relevant sensorimotor activity, possibly related to enhancing stimulus detection, rather than stimulus-stimulus associations. These observations agree with recent evidence that suggests that prefrontal neurons are particularly responsive during the performance of action sequences related to the acquisition of reward. These results also indicate that considerable attention must be given to the monitoring and analysis of sensorimotor variables during delay tasks because slight changes in position can produce activity in the mPFC that erroneously appears to be driven by intrinsic mechanisms.


Down-regulating humoral immune responses: implications for organ transplantation.
Alloantibody can be a major barrier to successful organ transplantation; however, therapy to control antibody production or to alter its impact on the allograft remains limited. The goal of this review is to examine the regulatory steps that are involved in the generation of alloreactive B cells, with a specific emphasis on how known mechanisms relate to clinical situations in transplant recipients. Thus, we will examine the process of activation of mature, naïve B cells and how this relates to de novo antibody production. The role of long-lived plasma cells in persistent antibody production and the factors regulating their longevity will be explored. The regulation of memory B cells and their possible roles in alloimmunity also will be assessed. Finally, we will review current therapeutic approaches aimed at controlling alloantibody and assess their efficacy. By examining the pathways to antibody production mechanistically, we hope to identify important gaps in our current knowledge and gain insight into possible new therapeutic approaches to overcoming antibody in transplant patients.


Convergent evolution of complex regulatory landscapes and pleiotropy at Hox loci.
Hox genes are required during the morphogenesis of both vertebrate digits and external genitals. We investigated whether transcription in such distinct contexts involves a shared enhancer-containing landscape. We show that the same regulatory topology is used, yet with some tissue-specific enhancer-promoter interactions, suggesting the hijacking of a regulatory backbone from one context to the other. In addition, comparable organizations are observed at both HoxA and HoxD clusters, which separated through genome duplication in an ancestral invertebrate animal. We propose that this convergent regulatory evolution was triggered by the preexistence of some chromatin architecture, thus facilitating the subsequent recruitment of the appropriate transcription factors. Such regulatory topologies may have both favored and constrained the evolution of pleiotropic developmental loci in vertebrates.


Demonstration of iodine K-edge imaging by use of an energy-discrimination X-ray computed tomography system with a cadmium telluride detector.
An energy-discrimination K-edge X-ray computed tomography (CT) system is useful for increasing the contrast resolution of a target region by utilizing contrast media. The CT system has a cadmium telluride (CdTe) detector, and a projection curve is obtained by linear scanning with use of the CdTe detector in conjunction with an X-stage. An object is rotated by a rotation step angle with use of a turntable between the linear scans. Thus, CT is carried out by repetition of the linear scanning and the rotation of an object. Penetrating X-ray photons from the object are detected by the CdTe detector, and event signals of X-ray photons are produced with use of charge-sensitive and shaping amplifiers. Both the photon energy and the energy width are selected by use of a multi-channel analyzer, and the number of photons is counted by a counter card. For performing energy discrimination, a low-dose-rate X-ray generator for photon counting was developed; the maximum tube voltage and the minimum tube current were 110 kV and 1.0 microA, respectively. In energy-discrimination CT, the tube voltage and the current were 60 kV and 20.0 microA, respectively, and the X-ray intensity was 0.735 microGy/s at 1.0 m from the source and with a tube voltage of 60 kV. Demonstration of enhanced iodine K-edge X-ray CT was carried out by selection of photons with energies just beyond the iodine K-edge energy of 33.2 keV.


"Tears in my eyes 'cause somebody finally understood": client perceptions of practitioners following brain injury.
The purpose of this study was to identify practitioner qualities and traits that clients with brain injury see as important. An opportunistic sample of 51 participants with brain injury was interviewed about perceptions of service access and effectiveness. An interview guide was used to gather data for this phenomenological qualitative study. Four interviewers individually conducted audiotaped interviews, which were then transcribed. Coding and theme development were completed using HyperRESEARCH software. Three themes regarding practitioner qualities emerged from the data: (a) roles of the provider, (b) perceived helpfulness of services, and (c) personal characteristics of the providers. Beneficial provider roles included advocate, friend, mentor, and team member. Perceptions of helpfulness of the services included relevance, meaningfulness, practical application, skill development potential, and whether periodic feedback on progress was provided. Personal characteristics of the provider valued by the participants were clear and honest communicator, supportive, respectful, good listener, and understanding. Practitioners need to pay increased attention to the perceptions of care and services of clients with brain injury. The current study closely supports previous research related to quality of care in the medical and community arenas and offers some additional suggestions to professionals who work with persons with brain injury, including learning how to time giving information to clients and how to understand client concerns without being prescriptive. Future research in this area needs to focus on and describe providers who demonstrate an ability-through their willingness to don a variety of roles, their helpful services, and their personal characteristics-to meet the unique needs of clients with brain injury.


Gender-Typed and Gender-Segregated Play Among Tanzanian Hadza and Congolese BaYaka Hunter-Gatherer Children and Adolescents.
Few data exist on gender-typed and gender-segregated play in hunter-gatherer societies, despite their unique demographic and cultural features which may influence children's gendered play. Using naturalistic observations of Hadza (N = 46, 41% female) and BaYaka (N = 65, 48% female) hunter-gatherer 3- to 18-year-olds from Tanzania and the Republic of Congo, we showed that access to playmates was negatively associated with playing in mixed-gender groups. Young boys did not engage in more rough-and-tumble play than girls, but adolescent boys participated in this type of play more than adolescent girls. Children were also more likely to participate in work-themed play which conformed to gender norms within their society. Findings are discussed within the context of gendered division of labor, child autonomy, and demography.


IRF5 regulates airway macrophage metabolic responses.
Interferon regulatory factor 5 (IRF5) is a master regulator of macrophage phenotype and a key transcription factor involved in expression of proinflammatory cytokine responses to microbial and viral infection. Here, we show that IRF5 controls cellular and metabolic responses. By integrating ChIP sequencing (ChIP-Seq) and assay for transposase-accessible chromatin using sequencing (ATAC)-seq data sets, we found that IRF5 directly regulates metabolic genes such as hexokinase-2 (Hk2). The interaction of IRF5 and metabolic genes had a functional consequence, as Irf5-/- airway macrophages but not bone marrow-derived macrophages (BMDMs) were characterized by a quiescent metabolic phenotype at baseline and had reduced ability to utilize oxidative phosphorylation after Toll-like receptor (TLR)-3 activation, in comparison to controls, ex vivo. In a murine model of influenza infection, IRF5 deficiency had no effect on viral load in comparison to wild-type controls but controlled metabolic responses to viral infection, as IRF5 deficiency led to reduced expression of Sirt6 and Hk2. Together, our data indicate that IRF5 is a key component of AM metabolic responses following influenza infection and TLR-3 activation.


Lung function and blood markers of nutritional status in non-COPD aging men with smoking history: a cross-sectional study.
Cigarette smoking and advanced age are well known as risk factors for chronic obstructive pulmonary disease (COPD), and nutritional abnormalities are important in patients with COPD. However, little is known about the nutritional status in non-COPD aging men with smoking history. We therefore investigated whether reduced lung function is associated with lower blood markers of nutritional status in those men. This association was examined in a cross-sectional study of 65 Japanese male current or former smokers aged 50 to 80 years: 48 without COPD (non-COPD group), divided into tertiles according to forced expiratory volume in one second as percent of forced vital capacity (FEV(1)/FVC), and 17 with COPD (COPD group). After adjustment for potential confounders, lower FEV(1)/FVC was significantly associated with lower red blood cell count (RBCc), hemoglobin, and total protein (TP); not with total energy intake. The difference in adjusted RBCc and TP among the non-COPD group tertiles was greater than that between the bottom tertile in the non-COPD group and the COPD group. In non-COPD aging men with smoking history, trends toward reduced nutritional status and anemia may independently emerge in blood components along with decreased lung function even before COPD onset.


The cardiovascular effects of amodiaquine and structurally related antimalarials: An individual patient data meta-analysis.
Amodiaquine is a 4-aminoquinoline antimalarial similar to chloroquine that is used extensively for the treatment and prevention of malaria. Data on the cardiovascular effects of amodiaquine are scarce, although transient effects on cardiac electrophysiology (electrocardiographic QT interval prolongation and sinus bradycardia) have been observed. We conducted an individual patient data meta-analysis to characterise the cardiovascular effects of amodiaquine and thereby support development of risk minimisation measures to improve the safety of this important antimalarial. Studies of amodiaquine for the treatment or prevention of malaria were identified from a systematic review. Heart rates and QT intervals with study-specific heart rate correction (QTcS) were compared within studies and individual patient data pooled for multivariable linear mixed effects regression. The meta-analysis included 2,681 patients from 4 randomised controlled trials evaluating artemisinin-based combination therapies (ACTs) containing amodiaquine (n = 725), lumefantrine (n = 499), piperaquine (n = 716), and pyronaridine (n = 566), as well as monotherapy with chloroquine (n = 175) for uncomplicated malaria. Amodiaquine prolonged QTcS (mean = 16.9 ms, 95% CI: 15.0 to 18.8) less than chloroquine (21.9 ms, 18.3 to 25.6, p = 0.0069) and piperaquine (19.2 ms, 15.8 to 20.5, p = 0.0495), but more than lumefantrine (5.6 ms, 2.9 to 8.2, p < 0.001) and pyronaridine (-1.2 ms, -3.6 to +1.3, p < 0.001). In individuals aged ≥12 years, amodiaquine reduced heart rate (mean reduction = 15.2 beats per minute [bpm], 95% CI: 13.4 to 17.0) more than piperaquine (10.5 bpm, 7.7 to 13.3, p = 0.0013), lumefantrine (9.3 bpm, 6.4 to 12.2, p < 0.001), pyronaridine (6.6 bpm, 4.0 to 9.3, p < 0.001), and chloroquine (5.9 bpm, 3.2 to 8.5, p < 0.001) and was associated with a higher risk of potentially symptomatic sinus bradycardia (≤50 bpm) than lumefantrine (risk difference: 14.8%, 95% CI: 5.4 to 24.3, p = 0.0021) and chloroquine (risk difference: 8.0%, 95% CI: 4.0 to 12.0, p < 0.001). The effect of amodiaquine on the heart rate of children aged <12 years compared with other antimalarials was not clinically significant. Study limitations include the unavailability of individual patient-level adverse event data for most included participants, but no serious complications were documented. While caution is advised in the use of amodiaquine in patients aged ≥12 years with concomitant use of heart rate-reducing medications, serious cardiac conduction disorders, or risk factors for torsade de pointes, there have been no serious cardiovascular events reported after amodiaquine in widespread use over 7 decades. Amodiaquine and structurally related antimalarials in the World Health Organization (WHO)-recommended dose regimens alone or in ACTs are safe for the treatment and prevention of malaria.


Neural Mechanisms of Reward Prediction Error in Autism Spectrum Disorder.
Few studies have explored neural mechanisms of reward learning in ASD despite evidence of behavioral impairments of predictive abilities in ASD. To investigate the neural correlates of reward prediction errors in ASD, 16 adults with ASD and 14 typically developing controls performed a prediction error task during fMRI scanning. Results revealed greater activation in the ASD group in the left paracingulate gyrus during signed prediction errors and the left insula and right frontal pole during thresholded unsigned prediction errors. Findings support atypical neural processing of reward prediction errors in ASD in frontostriatal regions critical for prediction coding and reward learning. Results provide a neural basis for impairments in reward learning that may contribute to traits common in ASD (e.g., intolerance of unpredictability).


Intraarterial protein delivery via intimally-adherent bilayer hydrogels.
Arterial structure plays an important role in drug delivery from intraarterial depots. The internal elastic lamina forms a major diffusive resistance to the transport of macromolecular drugs from intimally-adherent hydrogel depots to the arterial media. The objectives of this study were to develop an approach by which to form a bilayer hydrogel depot with a higher permeability intimally-adherent layer, containing the drug, and a lower permeability luminal layer, and to evaluate ex vivo whether this luminal layer could enhance the delivery of a protein to the arterial media. Sequential interfacial photopolymerization of polyethyleneglycol diacrylate precursors (molecular weight 4000 for the luminal layer, 10,000 for the intimal layer) with eosin Y and triethanolamine as an initiation system was employed to form these bilayer hydrogels. Horseradish peroxidase was used as a model protein, and delivery to the arterial media was measured in rat carotid arteries ex vivo. The lower permeability luminal layer served to enhance delivery of the model protein into the arterial media for delivery periods at least up to 72 h. Thus, it was possible to compensate for the diffusional resistance of the internal elastic lamina on the one side of the hydrogel depot with a second diffusional resistance on the other side of the hydrogel.


Control of actin polymerization in live and permeabilized fibroblasts.
We have investigated the spatial control of actin polymerization in fibroblasts using rhodamine-labeled muscle actin in; (a) microinjection experiments to follow actin dynamics in intact cells, and (b) incubation with permeabilized cells to study incorporation sites. Rhodamine-actin was microinjected into NIH-3T3 cells which were then fixed and stained with fluorescein-phalloidin to visualize total actin filaments. The incorporation of newly polymerized actin was assayed using rhodamine/fluorescein ratio-imaging. The results indicated initial incorporation of the injected actin near the tip and subsequent transport towards the base of lamellipodia at rates greater than 4.5 microns/min. Furthermore, both fluorescein- and rhodamine-intensity profiles across lamellipodia revealed a decreasing density of actin filaments from tip to base. From this observation and the presence of centripetal flux of polymerized actin we infer that the actin cytoskeleton partially disassembles before it reaches the base of the lamellipodium. In permeabilized cells we found that, in agreement with the injection studies, rhodamine-actin incorporated predominantly in a narrow strip of less than 1-microns wide, located at the tip of lamellipodia. The critical concentration for the rhodamine-actin incorporation (0.15 microM) and its inhibition by CapZ, a barbed-end capping protein, indicated that the nucleation sites for actin polymerization most likely consist of free barbed ends of actin filaments. Because any potential monomer-sequestering system is bypassed by addition of exogenous rhodamine-actin to the permeabilized cells, these observations indicate that the localization of actin incorporation in intact cells is determined, at least in part, by the presence of specific elongation and/or nucleation sites at the tips of lamellipodia and not solely by localized desequestration of subunits. We propose that the availability of the incorporation sites at the tips of lamellipodia is because of capping activities which preferentially inhibit barbed-end incorporation elsewhere in the cell, but leave barbed ends at the tips of lamellipodia free to add subunits.


The Family and Medical Leave Act. Final rule.
This Final Rule amends certain regulations of the Family and Medical Leave Act of 1993 (the FMLA or the Act) to implement amendments to the military leave provisions of the Act made by the National Defense Authorization Act for Fiscal Year 2010, which extends the availability of FMLA leave to family members of members of the Regular Armed Forces for qualifying exigencies arising out of the servicemember's deployment; defines those deployments covered under these provisions; extends FMLA military caregiver leave for family members of current servicemembers to include an injury or illness that existed prior to service and was aggravated in the line of duty on active duty; and extends FMLA military caregiver leave to family members of certain veterans with serious injuries or illnesses. This Final Rule also amends the regulations to implement the Airline Flight Crew Technical Corrections Act, which establishes eligibility requirements specifically for airline flight crewmembers and flight attendants for FMLA leave and authorizes the Department to issue regulations regarding the calculation of leave for such employees as well as special recordkeeping requirements for their employers. In addition, the Final Rule includes clarifying changes concerning the calculation of intermittent or reduced schedule FMLA leave; reorganization of certain sections to enhance clarity; the removal of the forms from the regulations; and technical corrections to the current regulations.


Identification of beta-tubulin isoforms as tumor antigens in neuroblastoma.
There is currently substantial interest in the identification of human tumor antigens for diagnosis and immunotherapy of cancer. We have implemented a proteomic approach for the identification of tumor proteins that elicit a humoral response in cancer patients, which we have applied to neuroblastoma. Proteins from neuroblastoma tumors and cell lines were separated by two-dimensional PAGE and transferred to poly(vinylidene difluoride) membranes. Sera from 23 newly diagnosed patients with neuroblastoma, from 12 newly diagnosed children with other solid tumors, and from 13 normal individuals were screened for IgG and IgM autoantibodies against neuroblastoma proteins by means of Western blot analysis. Sera from 11 patients with neuroblastoma and from 1 patient with a primitive neuroectodermal tumor, but none of the other controls exhibited IgG-based reactivity against a protein constellation with an estimated Mr 50,000. NH2-terminal sequence and mass spectrometric analysis identified the major constituents of this constellation as beta-tubulin isoforms I and III. The IgG antibodies were additionally characterized to be of the subclass IgG1. Neuroblastoma patient sera that contained anti-beta-tubulin IgG antibodies also contained IgM antibodies specific against the full-length beta-tubulin molecule and against COOH-terminal beta-tubulin cleavage products. Neuroblastoma patient sera that reacted with beta-tubulin I and III isoforms in neuroblastoma tissues did not react with beta-tubulin I and III isoforms found in normal brain tissue. Our findings indicate the occurrence of beta-tubulin peptides in neuroblastoma, which are immunogenic. The occurrence of immunogenic peptides in neuroblastoma may have utility in diagnosis and in immunotherapy of this aggressive childhood tumor.


The World Health Organization Adult Attention-Deficit/Hyperactivity Disorder Self-Report Screening Scale for DSM-5.
Recognition that adult attention-deficit/hyperactivity disorder (ADHD) is common, seriously impairing, and usually undiagnosed has led to the development of adult ADHD screening scales for use in community, workplace, and primary care settings. However, these scales are all calibrated to DSM-IV criteria, which are narrower than the recently developed DSM-5 criteria. To update for DSM-5 criteria and improve the operating characteristics of the widely used World Health Organization Adult ADHD Self-Report Scale (ASRS) for screening. Probability subsamples of participants in 2 general population surveys (2001-2003 household survey [n = 119] and 2004-2005 managed care subscriber survey [n = 218]) who completed the full 29-question self-report ASRS, with both subsamples over-sampling ASRS-screened positives, were blindly administered a semistructured research diagnostic interview for DSM-5 adult ADHD. In 2016, the Risk-Calibrated Supersparse Linear Integer Model, a novel machine-learning algorithm designed to create screening scales with optimal integer weights and limited numbers of screening questions, was applied to the pooled data to create a DSM-5 version of the ASRS screening scale. The accuracy of the new scale was then confirmed in an independent 2011-2012 clinical sample of patients seeking evaluation at the New York University Langone Medical Center Adult ADHD Program (NYU Langone) and 2015-2016 primary care controls (n = 300). Data analysis was conducted from April 4, 2016, to September 22, 2016. The sensitivity, specificity, area under the curve (AUC), and positive predictive value (PPV) of the revised ASRS. Of the total 637 participants, 44 (37.0%) household survey respondents, 51 (23.4%) managed care respondents, and 173 (57.7%) NYU Langone respondents met DSM-5 criteria for adult ADHD in the semistructured diagnostic interview. Of the respondents who met DSM-5 criteria for adult ADHD, 123 were male (45.9%); mean (SD) age was 33.1 (11.4) years. A 6-question screening scale was found to be optimal in distinguishing cases from noncases in the first 2 samples. Operating characteristics were excellent at the diagnostic threshold in the weighted (to the 8.2% DSM-5/Adult ADHD Clinical Diagnostic Scale population prevalence) data (sensitivity, 91.4%; specificity, 96.0%; AUC, 0.94; PPV, 67.3%). Operating characteristics were similar despite a much higher prevalence (57.7%) when the scale was applied to the NYU Langone clinical sample (sensitivity, 91.9%; specificity, 74.0%; AUC, 0.83; PPV, 82.8%). The new ADHD screening scale is short, easily scored, detects the vast majority of general population cases at a threshold that also has high specificity and PPV, and could be used as a screening tool in specialty treatment settings.


Green tea polyphenol extract attenuates inflammation in interleukin-2-deficient mice, a model of autoimmunity.
Green tea polyphenols (GrTP) have been previously shown to decrease endotoxin-induced tumor necrosis factor-alpha production and lethality in mice. Our present studies demonstrate that GrTP inhibit inflammatory responses and may be useful in treating chronic inflammatory states, such as inflammatory bowel disease. In this preliminary study, we examined whether GrTP decrease disease activity in interleukin-2-deficient (IL-2(-/-) mice. Eight-week old IL-2(-/-) C57BL/6J mice who were fed nonpurified diet were randomly assigned to receive water with GrTP (5 g/L) or water alone (control) for up to 6 wk. After 1 wk, explant colon and lamina propria lymphocyte (LPL) cultures were established from a subgroup of mice and supernatants collected. Culture supernatants from GrTP-treated mice showed decreased spontaneous interferon-gamma and tumor necrosis factor-alpha secretion compared with that of controls. At 6 wk, the GrTP group had less severe colitis as demonstrated by lower histologic scores and wet colon weights. This was associated with lower plasma levels of serum amyloid A, increased weight gain and improved hematocrits. These results show that GrTP attenuated inflammation in IL-2(-/-) mice and suggest a role for GrTP in treating chronic inflammatory diseases such as inflammatory bowel disease.


First Complete Genome Sequence of Haematobacter massiliensis OT1 (Chromosome and Multiple Plasmids), Isolated from Human Skin.
Haematobacter massiliensis OT1 was isolated from human skin. This strain can catabolize 4-hydroxybenzoate. Here, we present the first complete whole-genome sequence of this species, which has one chromosome (2,467 kbp) and nine plasmids (total of 1,765 kbp). The analysis of the H. massiliensis OT1 genome indicated a potential for autotrophic growth.


Targeting the sheddase activity of ADAM17 by an anti-ADAM17 antibody D1(A12) inhibits head and neck squamous cell carcinoma cell proliferation and motility via blockage of bradykinin induced HERs transactivation.
A disintegrin and metalloproteinase 17 (ADAM17) regulates key cellular processes including proliferation and migration through the shedding of a diverse array of substrates such as epidermal growth factor receptor (EGFR) ligands. ADAM17 is implicated in the pathogenesis of many diseases including rheumatoid arthritis and cancers such as head and neck squamous cell carcinoma (HNSCC). As a central mediator of cellular events, overexpressed EGFR is a validated molecular target in HNSCC. However, EGFR inhibition constantly leads to tumour resistance. One possible mechanism of resistance is the activation of alternative EGFR family receptors and downstream pathways via the release of their ligands. Here, we report that treating human HNSCC cells in vitro with a human anti-ADAM17 inhibitory antibody, D1(A12), suppresses proliferation and motility in the absence or presence of the EGFR tyrosine kinase inhibitor (TKI) gefitinib. Treatment with D1(A12) decreases both the endogenous and the bradykinin (BK)-stimulated shedding of HER ligands, accompanied by a reduction in the phosphorylation of HER receptors and downstream signalling pathways including STAT3, AKT and ERK. Knockdown of ADAM17, but not ADAM10, also suppresses HNSCC cell proliferation and migration. Furthermore, we show that heregulin (HRG) and heparin-binding epidermal growth factor like growth factor (HB-EGF) predominantly participate in proliferation and migration, respectively. Taken together, these results demonstrate that D1(A12)-mediated inhibition of cell proliferation, motility, phosphorylation of HER receptors and downstream signalling is achieved via reduced shedding of ADAM17 ligands. These findings underscore the importance of ADAM17 and suggest that D1(A12) might be an effective targeted agent for treating EGFR TKI-resistant HNSCC.


Higher Levels of ANGPTL5 in the Circulation of Subjects With Obesity and Type 2 Diabetes Are Associated With Insulin Resistance.
Objective: The family of angiopoietin-like proteins (ANGPTLs) is composed of eight ANGPTLs members that are involved in regulating various metabolic processes and have been implicated in type 2 diabetes (T2D) and obesity. ANGPTL5 is an understudied member of this family that has been suggested to regulate triglyceride metabolism with a potential role in obesity. This study was designed to investigate the expression levels of ANGPTL5 protein in the circulation of subjects with obesity and T2D. Methods: A total of 204 subjects were enrolled in this cross-sectional study, of which 95 had diagnosed T2D and 109 did not (non-T2D). Within the non-T2D group, 39 subjects were obese (BMI ≥ 30 Kg/m2) and 70 were not (BMI < 30 Kg/m2). Among subjects with T2D, 61 were obese and 34 were non-obese. Circulating ANGPTL5 plasma levels were measured by enzyme-linked immunosorbent assay (ELISA). Results: In this study, we showed that ANGPTL5 levels were higher in the plasma of subjects with T2D [mean ± standard error of the mean (SEM): 5.78 ± 2.70 ng/mL] compared with individuals without T2D (mean ± SEM: 4.42 ± 2.22 ng/mL; P < 0.001). Obese and non-T2D subjects had significantly higher levels of ANGPTL5 (mean ± SEM: 5.115 ± 0.366 ng/mL) compared with non-obese, non-T2D subjects (mean ± SEM: 4.02 ± 0.271 ng/mL; P = 0.003). Similarly, among subjects with diagnosed T2D, those who were obese had higher ANGPTL5 plasma levels than non-obese subjects, although this difference did not reach statistical significance (P = 0.088). Correlation analyses revealed that ANGPTL5 levels positively associated with fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), triglycerides (TGL), and insulin resistance as measured by HOMA-IR. Conclusion: our data shows for the first time that circulating ANGPTL5 levels were higher in obese individuals and those with T2D. Further analysis will be required to better understand the interaction between ANGPTL5 and other metabolic related biomarkers to shed more light on its role in diabetes and obesity.


Loneliness and implicit attention to social threat: A high-performance electrical neuroimaging study.
Prior research has suggested that loneliness is associated with an implicit hypervigilance to social threats-an assumption in line with the evolutionary model of loneliness that indicates feeling socially isolated (or on the social perimeter) leads to increased attention and surveillance of the social world and an unwitting focus on self-preservation. Little is known, however, about the temporal dynamics for social threat (vs. nonsocial threat) in the lonely brains. We used high-density electrical neuroimaging and a behavioral task including social and nonsocial threat (and neutral) pictures to investigate the brain dynamics of implicit processing for social threat vs. nonsocial threat stimuli in lonely participants (N = 10), compared to nonlonely individuals (N = 9). The present study provides evidence that social threat images are differentiated from nonsocial threat stimuli more quickly in the lonely (~116 ms after stimulus onset) than nonlonely (~252 ms after stimulus onset) brains. That speed of threat processing in lonely individuals is in accord with the evolutionary model of loneliness. Brain source estimates expanded these results by suggesting that lonely (but not nonlonely) individuals showed early recruitment of brain areas involved in attention and self-representation.


Antiproteinuric effect predicts renal protection by angiotensin-converting enzyme inhibition in rats with established adriamycin nephrosis.
1. The mechanism of renal protection by angiotensin-converting enzyme inhibition is still the subject of debate. Inhibition of proteinuria might play a role. If so, a good antiproteinuric response to angiotensin-converting enzyme inhibition should predict subsequent protection against renal structural damage. This hypothesis has not been tested in models where treatment is started after the renal disease is well established, i.e. models that mimic the clinical situation. 2. We therefore investigated this hypothesis in 96 male Wistar rats with established adriamycin nephrosis. Reduction of proteinuria was achieved by lisinopril (0, 2, 5 and 10 mg day-1 kg-1) on two different sodium diets (0.3% and 0.05% NaCl). Therapy started 6 weeks after adriamycin (at stable proteinuria) and was continued for 6 weeks. 3. Lisinopril reduced blood pressure by 32 +/- 4% and proteinuria by an average of 72 +/- 7%, with stabilization after 2 weeks. Considerable interindividual differences in antiproteinuric response was found. Glomerulosclerosis score was reduced by 15 +/- 5%. All the effects of angiotensin-converting enzyme inhibitors were enhanced by sodium depletion, but sodium depletion in itself did not affect blood pressure (124 +/- 4 mmHg), proteinuria (664 +/- 68 mg/day) or glomerulosclerosis score (30 +/- 5%). Interestingly, the more proteinuria was reduced initially in an individual rat, the less sclerosis was found in the long term in that rat. 4. In conclusion, angiotensin-converting enzyme inhibition lowers proteinuria and prevents glomerulosclerosis in established adriamycin nephrosis. These effects are enhanced by sodium depletion. The individual short-term antiproteinuric effect predicts the protection against ultimate glomerular damage. This is consistent with the hypothesis that reduction of proteinuria is a mechanism by which angiotensin-converting enzyme inhibitors exert renoprotection.


Clinical characteristics, prognosis, and seropositivity to the anti-aquaporin-4 antibody in Korean patients with longitudinally extensive transverse myelitis.
Longitudinally extensive transverse myelitis (LETM) is a syndrome with extensive spinal cord lesions spanning three or more vertebral segments on spinal cord MRI. Although many reports have indicated that LETM is a characteristic feature of neuoromyelitis optica (NMO) in Western countries, the clinical characteristics and risk for development of NMO in Korean patients with LETM is not clear. We retrospectively investigated the clinical, laboratory, radiological features, and prognosis of Korean patients with a first-ever episode of idiopathic LETM. Patients were classified into four subgroups, depending on their clinical course: monophasic LETM, recurrent LETM, NMO, and classic multiple sclerosis (MS). We compared various clinical, laboratory, and radiological features between groups. Of 20 patients with first-ever LETM, 15 (75%) were men, and 13 (65%) experienced clinical relapse over a mean follow-up period of 58 months. Three of 20 patients (two with NMO, one with recurrent myelitis) were seropositive for anti-AQP4 antibodies. The predominance of men in the monophasic and recurrent LETM groups compared to the NMO group was remarkable. In conclusion, Korean patients with LETM are predominantly male and have low seropositivity for anti-AQP4 antibody, which distinguishes them from LETM patients in Western countries. Patients with LETM and seropositivity for anti-AQP4 antibody have a high risk of relapse. The male predominance and the relatively low seropositive rate for anti-AQP4 suggests that rather than being a limited form of NMO, recurrent LETM is a new clinical entity in Koreans.


Changes in prefrontal cortex and paralimbic activity in depression following two weeks of daily left prefrontal TMS.
Twenty-two depressed adults were scanned with perfusion single-photon computed emission tomography before and after 2 weeks of left perfrontal transcranial magnetic stimulation (TMS) in a parallel design, double-blind treatment study. At medication-free baseline, across all subjects, blood flow in the bilateral medial temporal lobes, left prefrontal cortex, and caudate significantly declined with increased depression severity. Also at baseline, depressed adults who responded to TMS, compared with nonresponders, showed increased inferior frontal lobe activity. Following treatment, there was an even greater difference in inferior frontal blood flow in responders compared with nonresponders, and the negative baseline correlations between depression severity and limbic and prefrontal blood flow disappeared. These results suggest that in depressed adults, 10 days of prefrontal TMS affects prefrontal and paralimbic activity, which may explain its antidepressant effects.


Identification of amino acids in the N-methyl-D-aspartate receptor NR1 subunit that contribute to the glycine binding site.
The mammalian N-methyl-D-aspartate (NMDA) receptor complex is though to consist of an NR1 subunit in combination with one or more of the four NR2 subunits (A, B, C, and D). When corresponding cDNAs are expressed in Xenopus oocytes, ion channels with the characteristic profile of NMDA receptors are formed. The receptor is unique in requiring two coagonists, glutamate and glycine, for activation of the channel. We have used site-directed mutagenesis to study amino acids in the human NR1 subunit that contribute to the glycine binding site of the NMDA receptor without affecting the agonist site for glutamate. Mutations to D481 and K483 produced receptors with up to 160-fold lower affinities for glycine, as well as other agonists and partial agonists, without affecting maximum current size or the degree of agonist efficacy. The D481A mutation also led to 40-50-fold lower affinities for two structurally diverse glycine site antagonists. From these data we propose that the carboxyl group of this aspartate interacts with the amino moiety of glycine and the equivalent group contained in other agonists and antagonists.


Use of Indocyanine Green Angiography to Identify the Superficial Temporal Artery and Vein in Forehead Flaps for Facial Reconstruction.
The superficial temporal artery (STA) frontal branch flap is susceptible to venous congestion because of its unpredictable and variable outflow. The authors applied indocyanine green angiogra-phy in identifying the superficial temporal vessels to help surgeons with proper flap designs to avoid severe complications. A retrospective review from 2015 to 2020 was conducted. All the patients who underwent indocyanine green angiography before forehead flap transfer for facial defect reconstruction were reviewed. The STA and vein were observed using indocyanine green angiography preoperatively. The relationship between the artery and vein was investigated. The venous anatomy was analyzed to guide the pedicle design. The survival of the flap and complications were assessed. A total of 12 patients were identified and included in this study. Indocyanine green angiography allows clear visualization of the detailed anatomy of the STA and vein. The frontal branch of the vein had great variations and generally diverged from the arterial branch. The tiny venae comitantes provided sufficient drainage for 2 small forehead flaps. The frontal branch of the vein entered the forehead and was used as the outflow channel in 4 patients. The parietal branch of the vein, which consistently gave off secondary tributaries to the superior forehead, was included in the pedicle in 6 patients. All flaps survived without complications. indocyanine green angiography provided accurate localization of the superficial temporal vessels. This technique may be helpful in the precise planning forehead flap surgeries and in avoiding the risk of venous congestion.


Motivation in medical education: how theory can inform our practice.
Medical educators seek to understand and facilitate learners' motivations to acquire the skills, knowledge, values, and attitudes that will prepare them for life-times of learning and providing care to their patients and communities. Yet faculty are often challenged by experiences with learners who appear unmotivated, or who seem to value goals other than those the faculty espouse. Understanding what motivates learners may help educators appreciate the complex environment in which motivations are formed, and the sometimes-hidden influences upon motivation that may explain learners' attitudes and behaviors. In this brief essay, the author discusses some of the current theories about motivation and describes how they might relate to the education of physicians. She also explores the too-frequent disparities between medical schools' stated goals for learners and what is actually taught or rewarded by faculty. Although motivation is multifaceted, involving learners and the entire learning environment, there are strategies that may be used to strengthen students' motivations to achieve important goals.


Reputational concerns with altruistic providers.
We study a model of reputational concerns when doctors differ in their degree of altruism and they can signal their altruism by their (observable) quality. When reputational concerns are high, following the introduction or enhancement of public reporting, the less altruistic (bad) doctor mimics the more altruistic (good) doctor. Otherwise, either a separating or a semi-separating equilibrium arises: the bad doctor mimics the good doctor with probability less than one. Pay-for-performance incentive schemes are unlikely to induce crowding out, unless some dimensions of quality are unobservable. Under the pooling equilibrium a purchaser can implement the first-best quality by appropriately choosing a simple payment scheme with a fixed price per unit of quality provided. This is not the case under the separating equilibrium. Therefore, policies that enhance public reporting complement pay-for-performance schemes.


Dural arteriovenous fistula of the anterior condylar confluence and hypoglossal canal mimicking a jugular foramen tumor.
The anterior condylar confluence (ACC) is located on the external orifice of the canal of the hypoglossal nerve and provides multiple connections with the dural venous sinuses of the posterior fossa, internal jugular vein, and the vertebral venous plexus. Dural arteriovenous fistulas (DAVFs) of the ACC and hypoglossal canal (anterior condylar vein) are extremely rare. The authors present a case involving an ACC DAVF and hypoglossal canal that mimicked a hypervascular jugular bulb tumor. This 53-year-old man presented with right hypoglossal nerve palsy. A right pulsatile tinnitus had resolved several months previously. Magnetic resonance imaging demonstrated an enhancing right-sided jugular foramen lesion involving the hypoglossal canal. Cerebral angiography revealed a hypervascular lesion at the jugular bulb, with early venous drainage into the extracranial vertebral venous plexus. This was thought to represent either a glomus jugulare tumor or a DAVF. The patient underwent preoperative transarterial embolization followed by surgical exploration via a far-lateral transcondylar approach. At surgery, a DAVF was identified draining into the ACC and hypoglossal canal. The fistula was surgically obliterated, and this was confirmed on postoperative angiography. The patient's hypoglossal nerve palsy resolved. Dural arteriovenous fistulas of the ACC and hypoglossal canal are rare lesions that can present with isolated hypoglossal nerve palsies. They should be included in the differential diagnosis of hypervascular jugular bulb lesions. The authors review the anatomy of the ACC and discuss the literature on DAVFs involving the hypoglossal canal.


A new maximum color contrast sensitivity test for detecting early changes of visual function in age-related macular degeneration.
To determine the association between age-related macular degeneration (AMD) and color perception established by the Farnsworth-Munsell 100 hue (F-M 100) and maximum color contrast sensitivity (MCCS) tests. We performed a case-control study, which comprised of 100 patients with AMD and 100 healthy controls. To test visual acuity (VA), a typical Snellen chart was used. The computerized F-M 100 and MCCS programs were used for color discrimination. The results of VA, and the F-M 100 and MCCS tests in the healthy controls were statistically significantly better than in the patients with AMD (1.0 vs. 0.82±0.16, P=0.005; 87.39±24.11 vs. 185.39±74.43, P=0.005; 1.33±1.17 vs. 1.96±0.46, P=0.005, respectively). When VA was 1.0 in patients with AMD, the total error scores of the F-M 100 test and MCCS test compared with healthy persons were even worse (166.09±66.57 vs. 87.39±24.11, P=0.002; 1.67±0.92 vs. 1.33±1.17, P=0.001, respectively). Analysis of the results of patients with AMD compared to healthy controls showed the highest error score in the blue color range. The results of the color contrast sensitivity test decreased by half in patients with AMD compared with ophthalmologically healthy patients when they performed the F-M 100 test and by one and half when they performed a MCCS test in the blue color range.


A registry-based randomized trial comparing radial and femoral approaches in women undergoing percutaneous coronary intervention: the SAFE-PCI for Women (Study of Access Site for Enhancement of PCI for Women) trial.
This study sought to determine the effect of radial access on outcomes in women undergoing percutaneous coronary intervention (PCI) using a registry-based randomized trial. Women are at increased risk of bleeding and vascular complications after PCI. The role of radial access in women is unclear. Women undergoing cardiac catheterization or PCI were randomized to radial or femoral arterial access. Data from the CathPCI Registry and trial-specific data were merged into a final study database. The primary efficacy endpoint was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding or vascular complications requiring intervention. The primary feasibility endpoint was access site crossover. The primary analysis cohort was the subgroup undergoing PCI; sensitivity analyses were conducted in the total randomized population. The trial was stopped early for a lower than expected event rate. A total of 1,787 women (691 undergoing PCI) were randomized at 60 sites. There was no significant difference in the primary efficacy endpoint between radial or femoral access among women undergoing PCI (radial 1.2% vs. 2.9% femoral, odds ratio [OR]: 0.39; 95% confidence interval [CI]: 0.12 to 1.27); among women undergoing cardiac catheterization or PCI, radial access significantly reduced bleeding and vascular complications (0.6% vs. 1.7%; OR: 0.32; 95% CI: 0.12 to 0.90). Access site crossover was significantly higher among women assigned to radial access (PCI cohort: 6.1% vs. 1.7%; OR: 3.65; 95% CI: 1.45 to 9.17); total randomized cohort: (6.7% vs. 1.9%; OR: 3.70; 95% CI: 2.14 to 6.40). More women preferred radial access. In this pragmatic trial, which was terminated early, the radial approach did not significantly reduce bleeding or vascular complications in women undergoing PCI. Access site crossover occurred more often in women assigned to radial access. (SAFE-PCI for Women; NCT01406236).


Compact and Computationally Efficient Representation of Deep Neural Networks.
At the core of any inference procedure, deep neural networks are dot product operations, which are the component that requires the highest computational resources. For instance, deep neural networks, such as VGG-16, require up to 15-G operations in order to perform the dot products present in a single forward pass, which results in significant energy consumption and thus limits their use in resource-limited environments, e.g., on embedded devices or smartphones. One common approach to reduce the complexity of the inference is to prune and quantize the weight matrices of the neural network. Usually, this results in matrices whose entropy values are low, as measured relative to the empirical probability mass distribution of its elements. In order to efficiently exploit such matrices, one usually relies on, inter alia, sparse matrix representations. However, most of these common matrix storage formats make strong statistical assumptions about the distribution of the elements; therefore, cannot efficiently represent the entire set of matrices that exhibit low-entropy statistics (thus, the entire set of compressed neural network weight matrices). In this paper, we address this issue and present new efficient representations for matrices with low-entropy statistics. Alike sparse matrix data structures, these formats exploit the statistical properties of the data in order to reduce the size and execution complexity. Moreover, we show that the proposed data structures can not only be regarded as a generalization of sparse formats but are also more energy and time efficient under practically relevant assumptions. Finally, we test the storage requirements and execution performance of the proposed formats on compressed neural networks and compare them to dense and sparse representations. We experimentally show that we are able to attain up to ×42 compression ratios, ×5 speed ups, and ×90 energy savings when we lossless convert the state-of-the-art networks, such as AlexNet, VGG-16, ResNet152, and DenseNet, into the new data structures and benchmark their respective dot product.


PRO: confronting resistance to rule-based medicine is essential to improving outcomes.
The past 20 years have seen two great changes in the practice of medicine: the widespread adoption of evidence-based medicine, and the increasing challenge of managing complex multimorbid patients. Both these developments have resulted in clinical rules and protocols becoming ever more abundant and increasingly critical to delivering safe and effective patient care. These evidence-based clinical rules perform at least as well as expert opinion, and the increasing volume and quality of available clinical data suggests their performance could continue to improve. This article considers why clinicians deviate from effective rules, highlighting key issues such as the persisting culture of heroism, institutional inertia, deference to authority and personal heuristics. We argue that better rules can be created, and that clinical improvements will follow if there is a 'common knowledge' of these rules. Furthermore, we argue that there is a ceiling to the effectiveness of any rule, even one as simple as ensuring hand hygiene, unless individuals are held accountable for transgressions.


Passive immunization against Cryptococcus neoformans with an isotype-switch family of monoclonal antibodies reactive with cryptococcal polysaccharide.
The in vivo properties of an immunoglobulin isotype-switch family of monoclonal antibodies specific for the polysaccharide capsule of Cryptococcus neoformans were examined in a murine model of cryptococcosis. Subclass-switch variants were isolated by sequential sublining of an immunoglobulin G subclass 1 (IgG1)-secreting cell line. Antibodies of the IgG1, IgG2a, and IgG2b isotypes with identical reactivities with cryptococcal polysaccharide were prepared. The antibodies had the distinct biological properties associated with the heavy chains of each respective isotype. The antibodies were used prophylactically or therapeutically in an attempt to alter the course of cryptococcal infection in mice. Survival of mice and a tissue census of the numbers of viable cryptococci in the lung, spleen, and brain were used as indicators of efficacy. Passive immunization with the IgG2a and IgG2b antibodies effected a reduction in the numbers of cryptococci in lung and spleen. Passive immunization with the IgG1 antibody was markedly less effective. Passive immunization had little or no effect on the numbers of cryptococci in brain tissue, regardless of the immunoglobulin isotype. Despite apparent efficacy with regard to reduction in the numbers of yeast cells in the lung and spleen, the results showed no improvement in survival from murine cryptococcosis. Our results indicate that passive immunization produces a modest effect on the course of murine cryptococcosis in tissues other than brain. However, under the experimental conditions used, such treatment does not have a measurable impact on the ultimate outcome of the infection.


Topography of the northern hemisphere of Mercury from MESSENGER laser altimetry.
Laser altimetry by the MESSENGER spacecraft has yielded a topographic model of the northern hemisphere of Mercury. The dynamic range of elevations is considerably smaller than those of Mars or the Moon. The most prominent feature is an extensive lowland at high northern latitudes that hosts the volcanic northern plains. Within this lowland is a broad topographic rise that experienced uplift after plains emplacement. The interior of the 1500-km-diameter Caloris impact basin has been modified so that part of the basin floor now stands higher than the rim. The elevated portion of the floor of Caloris appears to be part of a quasi-linear rise that extends for approximately half the planetary circumference at mid-latitudes. Collectively, these features imply that long-wavelength changes to Mercury's topography occurred after the earliest phases of the planet's geological history.


Mitochondrial fusion directs cardiomyocyte differentiation via calcineurin and Notch signaling.
Mitochondrial morphology is crucial for tissue homeostasis, but its role in cell differentiation is unclear. We found that mitochondrial fusion was required for proper cardiomyocyte development. Ablation of mitochondrial fusion proteins Mitofusin 1 and 2 in the embryonic mouse heart, or gene-trapping of Mitofusin 2 or Optic atrophy 1 in mouse embryonic stem cells (ESCs), arrested mouse heart development and impaired differentiation of ESCs into cardiomyocytes. Gene expression profiling revealed decreased levels of transcription factors transforming growth factor-β/bone morphogenetic protein, serum response factor, GATA4, and myocyte enhancer factor 2, linked to increased Ca(2+)-dependent calcineurin activity and Notch1 signaling that impaired ESC differentiation. Orchestration of cardiomyocyte differentiation by mitochondrial morphology reveals how mitochondria, Ca(2+), and calcineurin interact to regulate Notch1 signaling.


Tumor-specific cytotoxic T lymphocyte responses against chondrosarcoma with HLA haplotype loss restricted by the remaining HLA class I allele.
Although loss of HLA expression by malignant cells has also been demonstrated, it has not been clarified how the loss of HLA expression observed in vitro actually results in immune escape. We demonstrated two major findings: (i) a part of chromosome 6 coding for HLA haplotypes was deleted from the genome of chondrosarcoma cell line, OUMS-27; furthermore, immunohistostaining for HLA-A11 showed that the original chondrosarcoma tissue lost the expression of HLA-A11, implicating that HLA haplotype loss was already present in the original tumor tissue and (2) HLA class I-restricted and autologous tumor-specific cytotoxic T cells (CTL) were generated from peripheral blood lymphocytes of the patient with chondrosarcoma, from whom OUMS-27 originated. This CTL line was maintained by weekly stimulation with OUMS-27, and lysed OUMS-27 in an HLA-A24 dependent manner but did not either K562 or autologous (EBV)-transformed B cells. These observations indicated that OUMS-27 and its original tumor are still immunogenic and can present antigen peptides with the remaining HLA-A24, even if HLA expression is partially lost. Tumor specific immunotherapy can be applied to the treatment of malignancies, even if HLA expression is partially lost.


Regeneration of adult rat sensory and motor neuron axons through chimeric peroneal nerve grafts containing donor Schwann cells engineered to express different neurotrophic factors.
Large peripheral nerve (PN) defects require bridging substrates to restore tissue continuity and permit the regrowth of sensory and motor axons. We previously showed that cell-free PN segments repopulated ex vivo with Schwann cells (SCs) transduced with lentiviral vectors (LV) to express different growth factors (BDNF, CNTF or NT-3) supported the regeneration of axons across a 1 cm peroneal nerve defect (Godinho et al., 2013). Graft morphology, the number of regrown axons, the ratio of myelinated to unmyelinated axons, and hindlimb locomotor function differed depending on the growth factor engineered into SCs. Here we extend these observations, adding more LVs (expressing GDNF or NGF) and characterising regenerating sensory and motor neurons after injection of the retrograde tracer Fluorogold (FG) into peroneal nerve distal to grafts, 10 weeks after surgery. Counts were also made in rats with intact nerves and in animals receiving autografts, acellular grafts, or grafts containing LV-GFP transduced SCs. Counts and analysis of FG positive (+) DRG neurons were made from lumbar (L5) ganglia. Graft groups contained fewer labeled sensory neurons than non-operated controls, but this decrease was only significant in the LV-GDNF group. These grafts had a complex fascicular morphology that may have resulted in axon trapping. The proportion of FG+ sensory neurons immunopositive for calcitonin-gene related peptide (CGRP) varied between groups, there being a significantly higher percentage in autografts and most neurotrophic factor groups compared to the LV-CNTF, LV-GFP and acellular groups. Furthermore, the proportion of regenerating isolectin B4+ neurons was significantly greater in the LV-NT-3 group compared to other groups, including autografts and non-lesion controls. Immunohistochemical analysis of longitudinal graft sections revealed that all grafts contained a reduced number of choline acetyltransferase (ChAT) positive axons, but this decrease was significant only in the GDNF and NT-3 graft groups. We also assessed the number and phenotype of regrowing lumbar FG+ motor neurons in non-lesioned animals, and in rats with autografts, acellular grafts, or in grafts containing SCs expressing GFP, CNTF, NGF or NT-3. The overall number of FG+ motor neurons per section was similar in all groups; however in tissue immunostained for NeuN (expressed in α- but not γ-motor neurons) the proportion of NeuN negative FG+ neurons ranged from about 40-50% in all groups except the NT-3 group, where the percentage was 82%, significantly more than the SC-GFP group. Immunostaining for the vesicular glutamate transporter VGLUT-1 revealed occasional proprioceptive terminals in 'contact' with regenerating FG+ α-motor neurons in PN grafted animals, the acellular group having the lowest counts. In sum, while all graft types supported sensory and motor axon regrowth, there appeared to be axon trapping in SC-GDNF grafts, and data from the SC-NT-3 group revealed greater regeneration of sensory CGRP+ and IB4+ neurons, preferential regeneration of γ-motor neurons and perhaps partial restoration of monosynaptic sensorimotor relays.


Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing.
Thiopurine methyltransferase (TPMT) activity exhibits monogenic co-dominant inheritance, with ethnic differences in the frequency of occurrence of variant alleles. With conventional thiopurine doses, homozygous TPMT-deficient patients (~1 in 178 to 1 in 3,736 individuals with two nonfunctional TPMT alleles) experience severe myelosuppression, 30-60% of individuals who are heterozygotes (~3-14% of the population) show moderate toxicity, and homozygous wild-type individuals (~86-97% of the population) show lower active thioguanine nucleolides and less myelosuppression. We provide dosing recommendations (updates at http://www.pharmgkb.org) for azathioprine, mercaptopurine (MP), and thioguanine based on TPMT genotype.


Substrate recognition and hydrolysis by a family 50 exo-β-agarase, Aga50D, from the marine bacterium Saccharophagus degradans.
The bacteria that metabolize agarose use multiple enzymes of complementary specificities to hydrolyze the glycosidic linkages in agarose, a linear polymer comprising the repeating disaccharide subunit of neoagarobiose (3,6-anhydro-l-galactose-α-(1,3)-d-galactose) that are β-(1,4)-linked. Here we present the crystal structure of a glycoside hydrolase family 50 exo-β-agarase, Aga50D, from the marine microbe Saccharophagus degradans. This enzyme catalyzes a critical step in the metabolism of agarose by S. degradans through cleaving agarose oligomers into neoagarobiose products that can be further processed into monomers. The crystal structure of Aga50D to 1.9 Å resolution reveals a (β/α)8-barrel fold that is elaborated with a β-sandwich domain and extensive loops. The structures of catalytically inactivated Aga50D in complex with non-hydrolyzed neoagarotetraose (2.05 Å resolution) and neoagarooctaose (2.30 Å resolution) provide views of Michaelis complexes for a β-agarase. In these structures, the d-galactose residue in the -1 subsite is distorted into a (1)S3 skew boat conformation. The relative positioning of the putative catalytic residues are most consistent with a retaining catalytic mechanism. Additionally, the neoagarooctaose complex showed that this extended substrate made substantial interactions with the β-sandwich domain, which resembles a carbohydrate-binding module, thus creating additional plus (+) subsites and funneling the polymeric substrate through the tunnel-shaped active site. A synthesis of these results in combination with an additional neoagarobiose product complex suggests a potential exo-processive mode of action of Aga50D on the agarose double helix.


Anodal transcranial direct current stimulation applied over the supplementary motor area delays spontaneous antiphase-to-in-phase transitions.
Coordinated bimanual oscillatory movements often involve one of two intrinsically stable phasing relationships characterized as in-phase (symmetrical) or antiphase (asymmetrical). The in-phase mode is typically more stable than antiphase, and if movement frequency is increasing during antiphase movements, a spontaneous transition to the in-phase pattern occurs. There is converging neurophysiological evidence that the supplementary motor area (SMA) plays a critical role in the successful performance of these patterns, especially during antiphase movements. We investigated whether modulating the excitability of the SMA via offline transcranial direct current stimulation (tDCS) would delay the onset of anti-to-in-phase transitions. Participants completed two sessions (separated by ∼48 h), each consisting of a pre- and post-tDCS block in which they performed metronome-paced trials of rhythmic in- and antiphase bimanual supination-pronation movements as target oscillation frequency was systematically increased. Anodal or cathodal tDCS was applied over the SMA between the pre- and post-tDCS blocks in each session. Following anodal tDCS, participants performed the antiphase pattern with increased accuracy and stability and were able to maintain the coordination pattern at a higher oscillation frequency. Antiphase performance was unchanged following cathodal tDCS, and neither tDCS polarity affected the in-phase mode. Our findings suggest increased SMA excitability induced by anodal tDCS can improve antiphase performance and adds to the accumulating evidence of the pivotal role of the SMA in interlimb coordination.


Genome Wide Identification and Functional Prediction of Long Non-Coding RNAs Responsive to Sclerotinia sclerotiorum Infection in Brassica napus.
Sclerotinia stem rot caused by Sclerotinia sclerotiorum affects canola production worldwide. Emerging evidence suggests that long non-coding RNAs (lncRNAs) play important roles in the regulation of gene expression in plants, in response to both abiotic and biotic stress. So far, identification of lncRNAs has been limited to a few model plant species, and their roles in mediating responses to biotic stresses are yet to be characterized in Brassica napus. The present study reports the identification of novel lncRNAs responsive to S. sclerotiorum infection in B. napus at two time points after infection (24 hpi and 48 hpi) using a stranded RNA-Sequencing technique and a detection pipeline for lncRNAs. Of the total 3,181 lncRNA candidates, 2,821 lncRNAs were intergenic, 111 were natural antisense transcripts, 76 possessed exonic overlap with the reference coding transcripts while the remaining 173 represented novel lnc- isoforms. Forty one lncRNAs were identified as the precursors for microRNAs (miRNAs) including miR156, miR169 and miR394, with significant roles in mediating plant responses to fungal phytopathogens. A total of 931 differentially expressed lncRNAs were identified in response to S. sclerotiorum infection and the expression of 12 such lncRNAs was further validated using qRT-PCR. B. napus antisense lncRNA, TCONS_00000966, having 90% overlap with a plant defensin gene, showed significant induction at both infection stages, suggesting its involvement in the transcriptional regulation of defense responsive genes under S. sclerotiorum infection. Additionally, nine lncRNAs showed overlap with cis-regulatory regions of differentially expressed genes of B. napus. Quantitative RT-PCR verification of a set of S. sclerotiorum responsive sense/antisense transcript pairs revealed contrasting expression patterns, supporting the hypothesis that steric clashes of transcriptional machinery may lead to inactivation of sense promoter. Our findings highlight the potential contributions of lncRNAs in regulating expression of plant genes that respond to biotic stress.


Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) results from a progressive decline in lung function, which is thought to be the consequence of airway inflammation. We hypothesized that antiinflammatory therapy with inhaled corticosteroids would slow this decline. We enrolled 1116 persons with COPD whose forced expiratory volume in one second (FEV1) was 30 to 90 percent of the predicted value in a 10-center, placebo-controlled, randomized trial of inhaled triamcinolone acetonide administered at a dose of 600 microg twice daily. The primary outcome measure was the rate of decline in FEV1 after the administration of a bronchodilator. The secondary outcome measures included respiratory symptoms, use of health care services, and airway reactivity. In a substudy of 412 participants, we measured bone density in the lumbar spine and femur at base line and one and three years after the beginning of treatment. The mean duration of follow-up was 40 months. The rate of decline in the FEV1 after bronchodilator use was similar in the 559 participants in the triamcinolone group and the 557 participants in the placebo group (44.2+/-2.9 vs. 47.0+/-3.0 ml per year, P= 0.50). Members of the triamcinolone group had fewer respiratory symptoms during the course of the study (21.1 per 100 person-years vs. 28.2 per 100 person-years, P=0.005) and had fewer visits to a physician because of a respiratory illness (1.2 per 100 person-years vs. 2.1 per 100 person-years, P=0.03). Those taking triamcinolone also had lower airway reactivity in response to methacholine challenge at 9 months and 33 months (P=0.02 for both comparisons). After three years, the bone density of the lumbar spine and the femur was significantly lower in the triamcinolone group (P < or = 0.007). Inhaled triamcinolone does not slow the rate of decline in lung function in people with COPD, but it improves airway reactivity and respiratory symptoms and decreases the use of health care services for respiratory problems. These benefits should be weighed against the potential long-term adverse effects of triamcinolone on bone mineral density.


Collapse of Anopheles darlingi populations in Suriname after introduction of insecticide-treated nets (ITNs); malaria down to near elimination level.
A longitudinal study of malaria vectors was carried out in three villages in Suriname between 2006 and 2010. During 13,392 man hours of collections, 3,180 mosquitoes were collected, of which 33.7% were anophelines. Of these, Anopheles darlingi accounted for 88.1%, and An. nuneztovari accounted for 11.1%. The highest mean An. darlingi human biting rate (HBR) observed per survey was 1.43 bites/man per hour outdoor and 1.09 bites/man per hour indoor; 2 An. darlingi of the 683 tested were infected with Plasmodium falciparum. The anopheline HBR decreased to zero after the onset of malaria intervention activities, including insecticide-treated net (ITN) distribution, in 2006. Malaria transmission decreased to pre-elimination levels. It is concluded that the combination of ITN and climatic events has led to the collapse of malaria vector populations in the study sites in the interior of the country. The results are discussed in relation to the stability of malaria transmission in areas with low-density human populations.


HFE gene mutations increase the risk of coronary heart disease in women.
The purpose of the present study is to examine HFE gene mutations in relation to newly diagnosed (incident) coronary heart disease (CHD). In a population-based follow-up study of 7,983 individuals aged 55 years and older, we compared the risk of incident CHD between HFE carriers and non-carriers, overall and stratified by sex and smoking status. HFE mutations were significantly associated with an increased risk of incident CHD in women but not in men (hazard ratio [HR] for women = 1.7, 95% confidence interval [CI] 1.2-2.4 versus HR for men = 0.9, 95% CI 0.7-1.2). This increased CHD risk associated with HFE mutations in women was statistically significant in never smokers (HR = 1.8, 95% CI 1.1-2.8) and current smokers (HR = 3.1, 95% CI 1.4-7.1), but not in former smokers (HR = 1.3, 95% CI 0.7-2.4). HFE mutations are associated with increased risk of incident CHD in women.


Characteristics of healthy vascular ageing in pooled population-based cohort studies: the global Metabolic syndrome and Artery REsearch Consortium.
Arterial ageing is characterized by increasing arterial stiffness as measured by pulse wave velocity (PWV). This process is enhanced in participants with early vascular ageing (EVA), but slowed in participants with healthy vascular ageing (HVA). We aimed to describe characteristics of EVA and HVA in a transcontinental study including 11 cohorts. In all, 18 490 participants from the global MARE Consortium, free of cardiovascular disease, participated with data on PWV and cardiometabolic risk factors. We defined HVA as the lowest 10% and EVA as the highest 10% of the standardized PWV distribution, adjusted for age intervals. HVA individuals were compared with the 90% of non-HVA individuals with ANCOVA, adjusted for age, sex and hypertension. The 1723 HVA participants were at the same age as the rest of the population, more likely women (59.4 vs 57.0%), and with significantly lower levels of established cardiovascular risk factors (blood pressure, lipids, glucose). Similarly, the prevalence rate of obesity, diabetes mellitus, hypertension and the metabolic syndrome was lower in the HVA participants. In the presence of similar levels of cardiovascular risk factors, HVA participants in the 50-64 years of age group presented lower PWV 5.8 (SD 0.5) vs. 7.4 (1.4) m/s (P < 0.0001) than control individuals in the 35-49 years of age group, corresponding to an estimated difference in chronological age of 14 years. Participants with healthy vascular ageing (HVA), belonging to the lowest end of the PWV distribution, are in general characterized by an up to 14 years estimated younger biological (vascular) age than those with higher PWV values, and have lower levels of risk factors.


Enhancing Interpretability in Factor Analysis by Means of Mathematical Optimization.
Exploratory Factor Analysis (EFA) is a widely used statistical technique to discover the structure of latent unobserved variables, called factors, from a set of observed variables. EFA exploits the property of rotation invariance of the factor model to enhance factors' interpretability by building a sparse loading matrix. In this paper, we propose an optimization-based procedure to give meaning to the factors arising in EFA by means of an additional set of variables, called explanatory variables, which may include in particular the set of observed variables. A goodness-of-fit criterion is introduced which quantifies the quality of the interpretation given this way. Our methodology also exploits the rotational invariance of EFA to obtain the best orthogonal rotation of the factors, in terms of the goodness-of-fit, but making them match to some of the explanatory variables, thus going beyond traditional rotation methods. Therefore, our approach allows the analyst to interpret the factors not only in terms of the observed variables, but in terms of a broader set of variables. Our experimental results demonstrate how our approach enhances interpretability in EFA, first in an empirical dataset, concerning volumes of reservoirs in California, and second in a synthetic data example.


Does bromocriptine improve glycemic control of obese type-2 diabetics?
Various oral hypoglycemic agents have already been administered to type-2 diabetic patients to normalize their plasma glucose concentrations but they have not had complete and sustained success. In recent years, bromocriptine has been tried with controversial results. In present study, the effect of bromocriptine on glycemic control was evaluated in obese type-2 diabetic patients. In a double-blind placebo-controlled clinical trial, 40 obese patients with type-2 diabetes (aged 32-70 years) were randomly allocated to the two treatment groups. The first group received bromocriptine (2.5 mg daily) for a total of 3 months. The second group received placebo. They had been uncontrolled on fixed doses of glibenclamide or its combination with metformin in the 3 months before enrolling in the study. The fasting plasma glucose (FPG) level and glycosylated hemoglobin (HbA1) were measured and body mass index (BMI) was calculated before and 1, 2 and 3 months after treatment. The FPG level decreased in the bromocriptine-treated group from 10.59 +/- 0.42 to 9.06 +/- 0.41 mmol/l (mean +/- SEM; p < 0.01), whereas in the placebo group it was not changed, 10.69 +/- 0.52 and 10.6 +/- 0.57 mmol/l, respectively. The HbA1 concentration was reduced in the bromocriptine-treated group from 9.9 +/- 0.3 to 9.5 +/-0.2% (p = 0.06), whereas it increased in the placebo-treated group from 10.2 +/- 0.3 to 11.3 +/- 0.6% (p < 0.05). The differences in HbA1 (1.8%, p < 0.01) and FPG (1.55 mmol/l, p < 0.05) levels between the bromocriptine and placebo groups at 3 months were significant. No changes in body weight or BMI occurred during the study in either placebo- or bromocriptine-treated group. The data further support the contention that bromocriptine improves glycemic control in obese type-2 diabetic patients, although the mechanism of action remains to be determined.


Real-time coherence holography.
Coherence holography capable of real-time recording and reconstruction is proposed and experimentally demonstrated with a generic Leith-type coherence hologram. The coherence hologram is optically generated in real-time using a Mach-Zehnder interferometer and reconstructed using a Sagnac radial shearing interferometer. With this method one can create an optical field distribution with a desired spatial coherence function, and visualize the coherence function in real-time as the contrast and phase variations in an interference fringe pattern. The reconstructed image of the complex coherence function has been quantified with the Fourier transform method of fringe-pattern analysis.


The coordination of centrosome reproduction with nuclear events of the cell cycle in the sea urchin zygote.
Centrosomes repeatedly reproduce in sea urchin zygotes arrested in S phase, whether cyclin-dependent kinase 1-cyclin B (Cdk1-B) activity remains at prefertilization levels or rises to mitotic values. In contrast, when zygotes are arrested in mitosis using cyclin B Delta-90, anaphase occurs at the normal time, yet centrosomes do not reproduce. Together, these results reveal the cell cycle stage specificity for centrosome reproduction and demonstrate that neither the level nor the cycling of Cdk1-B activity coordinate centrosome reproduction with nuclear events. In addition, the proteolytic events of the metaphase-anaphase transition do not control when centrosomes duplicate. When we block protein synthesis at first prophase, the zygotes divide and arrest before second S phase. Both blastomeres contain just two complete centrosomes, which indicates that the cytoplasmic conditions between mitosis and S phase support centrosome reproduction. However, the fact that these daughter centrosomes do not reproduce again under such supportive conditions suggests that they are lacking a component required for reproduction. The repeated reproduction of centrosomes during S phase arrest points to the existence of a necessary "licensing" event that restores this component to daughter centrosomes during S phase, preparing them to reproduce in the next cell cycle.


An increased high-density lipoprotein cholesterol/apolipoprotein A-I ratio is associated with increased cardiovascular and all-cause mortality.
High-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (Apo A-I) are key cardiovascular risk factors, but whether the ratio of HDL-C/Apo A-I concentrations affects risk of cardiovascular disease (CVD) and other diseases is uncertain. To investigate whether HDL-C and Apo A-I concentrations and the ratio of HDL-C/Apo A-I affect risk of death from CVD, cancer and all causes. Data were analysed from an occupational cohort of 263,340 people between 2002 and 2009. Cox proportional hazards models were used to estimate HRs (and 95% CIs) for mortality using the sex-specific lowest quartiles of HDL-C, Apo A-I concentrations and HDL-C/Apo A-I ratio as the reference groups. 1012 participants died (median follow-up 4.2 years). There were no significant associations between HDL quartiles and all mortality outcomes. In contrast, there was a positive trend for the association across increasing HDL/Apo A-I ratio quartiles and mortality from CVD, cancer and all cause (p values for trends across quartiles=0.016, 0.001 and <0.001, respectively). The adjusted HRs for highest HDL/Apo A-I ratio quartile versus the lowest were 2.37 (95% CI 0.89 to 6.37) (CVD); 2.32 (95% CI 1.34 to 4.03) (cancer) and 1.87 (95% CI 1.32 to 2.66) (all-cause mortality). These data show for the first time that an increased HDL-C/Apo A-I ratio may be a shared risk factor for CVD, cancer and all-cause mortality.


Effects of neuroleptic treatment on symptoms of schizophrenia and plasma homovanillic acid concentrations.
Measurement of plasma concentrations of the dopamine metabolite, homovanillic acid, is an indirect tool to assess changes in dopamine turnover in schizophrenic patients. Plasma homovanillic acid concentrations have been reported to decrease during neuroleptic treatment, with the decrement correlating with symptomatic improvement in symptoms of schizophrenia. The present study tested the hypothesis that neuroleptic drugs decrease plasma homovanillic acid concentrations in those schizophrenic patients who improve with administration of neuroleptic drugs but not in patients who fail to display a treatment response. Twenty schizophrenic men who remained drug free for at least 2 weeks were treated with 20 mg/d of haloperidol for 5 weeks. Symptoms and plasma homovanillic acid concentrations were assessed on the last drug-free day and weekly for 5 weeks. Mean plasma homovanillic acid concentrations decreased in the group of patients who responded to neuroleptic treatment and did not change in the group of patients who did not improve. These findings suggest that there may be a qualitative distinction between responders and nonresponders to dopamine antagonists.