Low RMRratio as a Surrogate Marker for Energy Deficiency, the Choice of Predictive Equation Vital for Correctly Identifying Male and Female Ballet Dancers at Risk.
Ballet dancers are reported to have an increased risk for energy deficiency with or without disordered eating behavior. A low ratio between measured (m) and predicted (p) resting metabolic rate (RMRratio < 0.90) is a recognized surrogate marker for energy deficiency. We aimed to evaluate the prevalence of suppressed RMR using different methods to calculate pRMR and to explore associations with additional markers of energy deficiency. Female (n = 20) and male (n = 20) professional ballet dancers, 19-35 years of age, were enrolled. mRMR was assessed by respiratory calorimetry (ventilated open hood). pRMR was determined using the Cunningham and Harris-Benedict equations, and different tissue compartments derived from whole-body dual-energy X-ray absorptiometry assessment. The protocol further included assessment of body composition and bone mineral density, blood pressure, disordered eating (Eating Disorder Inventory-3), and for females, the Low Energy Availability in Females Questionnaire. The prevalence of suppressed RMR was generally high but also clearly dependent on the method used to calculate pRMR, ranging from 25% to 80% in males and 35% to 100% in females. Five percent had low bone mineral density, whereas 10% had disordered eating and 25% had hypotension. Forty percent of females had elevated Low Energy Availability in Females Questionnaire score and 50% were underweight. Suppressed RMR was associated with elevated Low Energy Availability in Females Questionnaire score in females and with higher training volume in males. In conclusion, professional ballet dancers are at risk for energy deficiency. The number of identified dancers at risk varies greatly depending on the method used to predict RMR when using RMRratio as a marker for energy deficiency.


Methylglyoxal: (active agent of manuka honey) in vitro activity against bacterial biofilms.
Pseudomonas aeruginosa (PA) and Staphylococcus aureus (SA) biofilms are associated with poor chronic rhinosinusitis (CRS) disease control following surgery. Manuka honey (MH) has been shown to be both an effective in vitro treatment agent for SA and PA biofilms and nontoxic to sinonasal respiratory mucosa. Methylglyoxal (MGO) has been reported to be the major antibacterial agent in MH. The effect of this agent against SA and PA biofilms has yet to be reported. Our objective was to determine the in vitro effect of MGO against biofilms of SA and PA, via in vitro testing of MGO against bacterial biofilms. An established biofilm model was used to determine the effective concentration (EC) of MGO against 10 isolates of methicillin-resistant SA (MRSA) and PA. The EC of MGO was also determined against planktonic (free-swimming) MRSA and PA. For MRSA, the EC against planktonic organisms was a concentration of 0.08 mg/mL to 0.3 mg/mL whereas against the biofilm MRSA isolates, the EC ranged from 0.5 mg/mL to 3.6 mg/mL. For PA, the EC against planktonic organisms was a concentration of 0.15 mg/mL to 1.2 mg/mL for planktonic organisms whereas against the biofilm PA isolates, the EC ranged from 1.8 mg/mL to 7.3 mg/mL. MGO, a component of MH, is an effective antimicrobial agent against both planktonic and biofilm MRSA and PA organisms in vitro.


The unitary event underlying multiquantal EPSCs at a hair cell's ribbon synapse.
EPSCs at the synapses of sensory receptors and of some CNS neurons include large events thought to represent the synchronous release of the neurotransmitter contained in several synaptic vesicles by a process known as multiquantal release. However, determination of the unitary, quantal size underlying such putatively multiquantal events has proven difficult at hair cell synapses, hindering confirmation that large EPSCs are in fact multiquantal. Here, we address this issue by performing presynaptic membrane capacitance measurements together with paired recordings at the ribbon synapses of adult hair cells. These simultaneous presynaptic and postsynaptic assays of exocytosis, together with electron microscopic estimates of single vesicle capacitance, allow us to estimate a single vesicle EPSC charge of approximately -45 fC, a value in close agreement with the mean postsynaptic charge transfer of uniformly small EPSCs recorded during periods of presynaptic hyperpolarization. By thus establishing the magnitude of the fundamental quantal event at this peripheral sensory synapse, we provide evidence that the majority of spontaneous and evoked EPSCs are multiquantal. Furthermore, we show that the prevalence of uniquantal versus multiquantal events is Ca2+ dependent. Paired recordings also reveal a tight correlation between membrane capacitance increase and evoked EPSC charge, indicating that glutamate release during prolonged hair cell depolarization does not significantly saturate or desensitize postsynaptic AMPA receptors. We propose that the large EPSCs reflect the highly synchronized release of multiple vesicles at single presynaptic ribbon-type active zones through a compound or coordinated vesicle fusion mechanism.


Structural insights into the interaction of the nuclear exosome helicase Mtr4 with the preribosomal protein Nop53.
The nuclear exosome and the associated RNA helicase Mtr4 participate in the processing of several ribonucleoprotein particles (RNP), including the maturation of the large ribosomal subunit (60S). S. cerevisiae Mtr4 interacts directly with Nop53, a ribosomal biogenesis factor present in late pre-60S particles containing precursors of the 5.8S rRNA. The Mtr4-Nop53 interaction plays a pivotal role in the maturation of the 5.8S rRNA, providing a physical link between the nuclear exosome and the pre-60S RNP. An analogous interaction between Mtr4 and another ribosome biogenesis factor, Utp18, directs the exosome to an earlier preribosomal particle. Nop53 and Utp18 contain a similar Mtr4-binding motif known as the arch-interacting motif (AIM). Here, we report the 3.2 Å resolution crystal structure of S. cerevisiae Mtr4 bound to the interacting region of Nop53, revealing how the KOW domain of the helicase recognizes the AIM sequence of Nop53 with a network of hydrophobic and electrostatic interactions. The AIM-interacting residues are conserved in Mtr4 and are not present in the related cytoplasmic helicase Ski2, rationalizing the specificity and versatility of Mtr4 in the recognition of different AIM-containing proteins. Using nuclear magnetic resonance (NMR), we show that the KOW domain of Mtr4 can simultaneously bind an AIM-containing protein and a structured RNA at adjacent surfaces, suggesting how it can dock onto RNPs. The KOW domains of exosome-associated helicases thus appear to have evolved from the KOW domains of ribosomal proteins and to function as RNP-binding modules in the context of the nuclear exosome.


Bacteriophage resistance mechanisms.
Phages are now acknowledged as the most abundant microorganisms on the planet and are also possibly the most diversified. This diversity is mostly driven by their dynamic adaptation when facing selective pressure such as phage resistance mechanisms, which are widespread in bacterial hosts. When infecting bacterial cells, phages face a range of antiviral mechanisms, and they have evolved multiple tactics to avoid, circumvent or subvert these mechanisms in order to thrive in most environments. In this Review, we highlight the most important antiviral mechanisms of bacteria as well as the counter-attacks used by phages to evade these systems.


Role of the medial prefrontal cortex in impaired decision making in juvenile attention-deficit/hyperactivity disorder.
Attention-deficit/hyperactivity disorder (ADHD) has been associated with deficient decision making and learning. Models of ADHD have suggested that these deficits could be caused by impaired reward prediction errors (RPEs). Reward prediction errors are signals that indicate violations of expectations and are known to be encoded by the dopaminergic system. However, the precise learning and decision-making deficits and their neurobiological correlates in ADHD are not well known. To determine the impaired decision-making and learning mechanisms in juvenile ADHD using advanced computational models, as well as the related neural RPE processes using multimodal neuroimaging. Twenty adolescents with ADHD and 20 healthy adolescents serving as controls (aged 12-16 years) were examined using a probabilistic reversal learning task while simultaneous functional magnetic resonance imaging and electroencephalogram were recorded. Learning and decision making were investigated by contrasting a hierarchical Bayesian model with an advanced reinforcement learning model and by comparing the model parameters. The neural correlates of RPEs were studied in functional magnetic resonance imaging and electroencephalogram. Adolescents with ADHD showed more simplistic learning as reflected by the reinforcement learning model (exceedance probability, Px = .92) and had increased exploratory behavior compared with healthy controls (mean [SD] decision steepness parameter β: ADHD, 4.83 [2.97]; controls, 6.04 [2.53]; P = .02). The functional magnetic resonance imaging analysis revealed impaired RPE processing in the medial prefrontal cortex during cue as well as during outcome presentation (P < .05, family-wise error correction). The outcome-related impairment in the medial prefrontal cortex could be attributed to deficient processing at 200 to 400 milliseconds after feedback presentation as reflected by reduced feedback-related negativity (ADHD, 0.61 [3.90] μV; controls, -1.68 [2.52] μV; P = .04). The combination of computational modeling of behavior and multimodal neuroimaging revealed that impaired decision making and learning mechanisms in adolescents with ADHD are driven by impaired RPE processing in the medial prefrontal cortex. This novel, combined approach furthers the understanding of the pathomechanisms in ADHD and may advance treatment strategies.


Current and emerging roles of functional imaging in radiation therapy.
The advent of functional imaging facilitates the acquisition of patient-specific tumor characteristics, including its metabolic state and regional oxygen tension. Recent advances promote incorporating this information with data obtained from current imaging techniques, such as MRI and CT, to manage various malignancies. Functional imaging's vital roles progressively evolved to include: aiding in diagnosis, improving radiation treatment planning, differentiating tumor volume from surrounding normal tissues which enables dose escalation to the former while improving sparing of the latter, adapting radiation therapy regimens according to a tumor's response to initial treatment, and assessing radiation therapy response and toxicity. This review explores functional imaging in radiation oncology in the context of these five applications, as well as its comparison to, and integration with, existing imaging modalities. In parallel with advances in functional imaging and understanding of tumor microbiology, the emergence of diverse tracers provides a plethora of options to distinguish and manage malignancies on the basis of specific metabolic processes and changing microenvironmental cues. Current limitations, potential concerns, and future innovations of functional imaging are also discussed.


Stress and disease progression in multiple sclerosis and its animal models.
Since the first description of multiple sclerosis (MS) by Charcot, stress has been hypothesized to be a potential trigger of relapses. In recent years, data from observational studies in MS patients have provided some support for an association between stress and MS relapses. Furthermore, studies employing the MS animal model experimental autoimmune encephalomyelitis have shown that certain stressors can exacerbate the disease if administered prior to disease induction. Several lines of research have explored the 2 major stress response systems--the hypothalamic-pituitary-adrenal axis and the autonomic nervous system--and their relation to disease course in MS and experimental autoimmune encephalomyelitis. These studies provide evidence that insensitivity of the immune system to signals from these systems may play a role in inflammatory events. These findings can be integrated into a biological model of stress response system alterations in MS.


Dose-dependent osteogenic effect of octacalcium phosphate on mouse bone marrow stromal cells.
Octacalcium phosphate (OCP) has been advocated to be a precursor of biological apatite crystals in bones and teeth. Our previous studies showed that synthetic OCP stimulates bone regeneration, followed by the progressive conversion of OCP into hydroxyapatite (HA), when implanted in bone defects. However, the precise mechanism to induce the osteogenic phenotype in osteoblasts by OCP has not been identified. The present study was designed to investigate whether the physicochemical aspect, specific to and derived from the structural properties of OCP, influences the function of an osteoblastic cell line, mouse bone marrow stromal ST-2 cells. Different amounts of synthetic OCP and synthetic sintered ceramic HA were coated onto 48-well tissue culture plates. The amounts of OCP and HA were controlled to strengthen their intrinsic physicochemical properties, in which the milieu around the crystals will be modified during the culture. The roughness of the OCP coatings was independent of the amount of coating. Chemical analyses of the supernatants of the OCP coatings revealed that the concentration of Ca2+ decreased with increasing amounts of OCP, while the concentration of inorganic phosphate increased markedly, most probably through OCP--apatite conversion. ST-2 cells were cultured on the OCP or HA coatings up to day 21. The OCP coating caused a significant decrease in cell attachment and in the initial stage of proliferation, dependent upon the amount of coating. On the other hand, OCP enhanced the expression of osteogenic markers, including type I collagen, alkaline phosphatase, and osterix. However, HA did not alter the expression of these markers in ST-2 cells cultured on different amounts of HA coating. These results demonstrated that OCP is capable of inducing the differentiation of stromal cells into osteoblastic cells, especially differentiation into early stage osteoblastic cells, prior to reaching the stage of mature osteoblastic cell lineage.


The Antibody Light-Chain Linker Regulates Domain Orientation and Amyloidogenicity.
The antibody light chain (LC) consists of two domains and is essential for antigen binding in mature immunoglobulins. The two domains are connected by a highly conserved linker that comprises the structurally important Arg108 residue. In antibody light chain (AL) amyloidosis, a severe protein amyloid disease, the LC and its N-terminal variable domain (VL) convert to fibrils deposited in the tissues causing organ failure. Understanding the factors shaping the architecture of the LC is important for basic science, biotechnology and for deciphering the principles that lead to fibril formation. In this study, we examined the structure and properties of LC variants with a mutated or extended linker. We show that under destabilizing conditions, the linker modulates the amyloidogenicity of the LC. The fibril formation propensity of LC linker variants and their susceptibility to proteolysis directly correlate implying an interplay between the two LC domains. Using NMR and residual dipolar coupling-based simulations, we found that the linker residue Arg108 is a key factor regulating the relative orientation of the VL and CL domains, keeping them in a bent and dense, but still flexible conformation. Thus, inter-domain contacts and the relative orientation of VL and CL to each other are of major importance for maintaining the structural integrity of the full-length LC.


The state of minimally invasive pancreaticoduodenectomy in Chinese mainland: A systematic literature review.
The development of Minimally invasive pancreaticoduodenectomy (MIPD) in Chinese mainland has been extremely quick. However, the safety and oncologic outcomes remain controversial. This review evaluates the current status of MIPD in Chinese mainland. A systematic literature search was performed using: Pubmed, Web of Sci, CNKI, Wanfang Data and Sinomed databases to filter all studies published up to and including June 2019 using key words "pancreaticoduodenectomy," or "Whipple operation" combined with "laparoscopy," or "laparoscopic," or "robotic," or "da Vinci," or "minimally invasive," or "hand-assisted". This systematic review included 39 articles that documented 2,653 MIPDs in Chinese mainland. The weighted average operative time was 370.6 min, and the weighted average blood loss was 278.0 mL. The overall morbidity was 31.9%, which Clavien-Dindo ≥ 3 complications accounted for 13.4%. Pancreatic fistula, delayed gastric emptying, bile leak and postoperative hemorrhage were reported in 20.9%, 5.5%, 3.5% and 6.0% of patients respectively. The average lengh of hospital stay was 16.1 days. The overall surgical mortality was 1.7%. The mean number of harvested lymph nodes was 13.5, and the rate of positive margin was 5.3%. Based on Chinese national condition, the operative volume of MIPD in Chinese mainland is the leading position in the world, and compared with some large international meta-analysis, no inferior perioperative and short-term oncological outcomes were observed in MIPD of Chinese mainland. However, research on survival analysis and phased learning curve outcomes is needed urgently before the innovative techniques are widely accepted.


Salience of emotional displays of danger and contagion in faces is enhanced when progesterone levels are raised.
Findings from previous studies of hormone-mediated behavior in women suggest that raised progesterone level increases the probability of behaviors that will reduce the likelihood of disruption to fetal development during pregnancy (e.g. increased avoidance of sources of contagion). Here, we tested women's (N=52) sensitivity to potential cues to nearby sources of contagion (disgusted facial expressions with averted gaze) and nearby physical threat (fearful facial expressions with averted gaze) at two points in the menstrual cycle differing in progesterone level. Women demonstrated a greater tendency to perceive fearful and disgusted expressions with averted gaze as more intense than those with direct gaze when their progesterone level was relatively high. By contrast, change in progesterone level was not associated with any change in perceptions of happy expressions with direct and averted gaze, indicating that our findings for disgusted and fearful expressions were not due to a general response bias. Collectively, our findings suggest women are more sensitive to facial cues signalling nearby contagion and physical threat when raised progesterone level prepares the body for pregnancy.


Cholinergic innervation in neuritic plaques.
Although several studies of Alzheimer's disease suggest that the frequency of neuritic plaques in the cerebral cortex is correlated with the severity of dementia and with reduction in presynaptic cholinergic markers in the cortex, the relationship between cholinergic cortical innervation and the pathogenesis of plaques is unknown. The hypothesis was tested that the neurites in the plaque consist, in part, of presynaptic cholinergic axons, many of which arise from neurons in the basal forebrain. This hypothesis was tested by analyzing the character and distribution of plaques in monkeys, aged 4 to 31 years, with staining for acetylcholin-esterase and also with Congo red and silver stains. Immature and mature plaques were rich in acetylcholinesterase. As the plaques matured, the amount of amyloid increased, and the number of neurites and the activity of acetylcholinesterase decreased. End-stage amyloid-rich plaques lacked acetylcholinesterase. These observations indicate that changes in cortical cholinergic innervation are an important feature in the pathogenesis and evolution of the neuritic plaque.


WE-C-217BCD-01: Development of an Integrated Multimodal Imaging System (IMIS) for Surgical Guidance.
To develop an intraoperative multimodal imaging system (IMIS) for surgical guidance, combining gamma ray scintigraphy with a video camera system for simultaneous real-time visible and near infrared fluorescence (NIRf) imaging. The gamma camera component has been tested in a pilot human study for intraoperative SLN biopsy in melanoma patients. To characterize the optical components, the spatial resolution of the visible light video camera, the depth-dependent visualization by the NIRf system of targets containing indocyanine green (ICG) and the excitation radiation rejection of the NIRf system were evaluated in bench-top tests. Spatial resolution was quantified using a USAF test pattern and NIRf performance was evaluated using phantoms containing fluorescent targets in mixtures of fat-emulsion (Intralipid) and india ink to simulate optical transport in human tissue. The visible/NIRf system was also used to image a live anaesthetized mouse model of breast cancer. Intraoperatively the SiPM gamma camera detected 100% of positive lymph nodes. The visible light camera system contrast transfer function is >10% up to 3.2 1p/mm. The NIRf image SNR when imaging a 9.9 mm diameter lesion containing a 20 μM ICG concentration is > 2 for lesion depths up to 8 mm. The current combination of excitation and emission filters results in nearly complete rejection of backscattered light, resulting in a leakage count rate less than 1% of the system dark count rate. The optical component of the IMIS system demonstrates high spatial resolution, excellent rejection of background excitation radiation, and good target SNR for realistic tracer concentration and target depth. It is capable of accurately coregistered video rate visible/NIRf imaging.


An Egsnrc investigation of the P(TP) correction factor for ion chambers in kilovoltage X rays.
As part of the standard practice for obtaining consistent ion chamber measurements with cavities open to the surrounding atmosphere, the raw measured response is corrected to the response at a reference temperature and pressure using the standard temperature-pressure correction factor (P(TP)). In this study, the EGSnrc Monte Carlo code was used to investigate the validity of the P(TP) correction factor for kilovoltage x rays incident on various geometrically distinct ion chambers. The calculated P(TP)-corrected chamber response deviated by over 2% relative to expected values for a 40 kV spectrum incident on a graphite thimble chamber at an air density typical of Mexico City. The relative deviation from the expected response was much worse for a large spherical graphite chamber, exceeding 16% at an air density of 0.6 kg/m3 (approximately 0.5 atm at 22 degrees C) for the same beam energy. The breakdown of the P(TP) correction factor was also observed for a 26 kV mammography spectrum incident on two mammography chambers. For 60Co beams, the P(TP) correction factor behaved as expected. For day-to-day variations in pressure, only a negligible of the P(TP) correction factor was observed with low x-ray energies. Factors contributing to the breakdown of the P(TP) correction factor at low x-ray energies and large pressure variations, such as the range of electrons, the material of the wall, the chamber dimensions and air-photon interactions, are discussed in depth.


Zebrafish response to a robotic replica in three dimensions.
As zebrafish emerge as a species of choice for the investigation of biological processes, a number of experimental protocols are being developed to study their social behaviour. While live stimuli may elicit varying response in focal subjects owing to idiosyncrasies, tiredness and circadian rhythms, video stimuli suffer from the absence of physical input and rely only on two-dimensional projections. Robotics has been recently proposed as an alternative approach to generate physical, customizable, effective and consistent stimuli for behavioural phenotyping. Here, we contribute to this field of investigation through a novel four-degree-of-freedom robotics-based platform to manoeuvre a biologically inspired three-dimensionally printed replica. The platform enables three-dimensional motions as well as body oscillations to mimic zebrafish locomotion. In a series of experiments, we demonstrate the differential role of the visual stimuli associated with the biologically inspired replica and its three-dimensional motion. Three-dimensional tracking and information-theoretic tools are complemented to quantify the interaction between zebrafish and the robotic stimulus. Live subjects displayed a robust attraction towards the moving replica, and such attraction was lost when controlling for its visual appearance or motion. This effort is expected to aid zebrafish behavioural phenotyping, by offering a novel approach to generate physical stimuli moving in three dimensions.


Enhancing the use and quality of colorectal cancer screening.
To conduct a systematic review of the use and quality (including underuse, overuse, and misuse) of appropriate colorectal cancer (CRC) screening, including factors associated with screening, effective interventions to improve screening rates, current capacity, and monitoring and tracking the use and quality. Trends in the use and quality of CRC screening tests is also presented. We searched MEDLINE, the Cochrane Library, and the Cochrane Central Trials Registry, supplemented by handsearches, for studies published in English from January 1998 through September 2009. We used standard Evidence-based Practice Center methods of dual review of abstracts, full text articles, abstractions, quality rating, and quality grading. We resolved disagreements by consensus. We found multiple problems of underuse, overuse, and misuse of CRC screening. We identified a total of 116 articles for inclusion into the systematic review, including a total of 72 studies qualified for inclusion for key question (KQ) 2, 21 for KQ 3, 12 for KQ 4, and 8 for KQ 5. A number of patient-level factors are associated with lower screening rates, including having low income or less education, being uninsured or of Hispanic or Asian descent, not being acculturated into the United States, and having less or reduced access to care. Being insured, of higher income or education, and non-Hispanic white, participating in other cancer screenings, having a family history of CRC or personal history of another cancer, as well as receiving a physician recommendation to be screened, are associated with higher screening rates. Interventions that effectively increased CRC screening with high strength of evidence include patient reminders, one-on-one interactions, eliminating structural barriers, and system-level changes. The largest magnitude of improvement came from one-on-one interactions and eliminating barriers. Purely educational small-media interventions do not improve screening rates. Evidence is mixed for decision aids, although certain designs may be effective. No studies tested interventions to reduce overuse or misuse of CRC screening. We found no studies that assessed monitoring systems for underuse, overuse, and misuse of CRC screening. Modeling studies, using various assumptions, show that if the United States were to adopt a colonoscopy-only approach to CRC screening and everyone were to agree to be screened in this way, it is likely that colonoscopy capacity would need to be substantially increased. Both CRC screening and patient-physician discussions of CRC screening are underused, and important problems of overuse and misuse also exist. Some interventions hold promise for improvement. The research priority is to design and test interventions to increase screening and CRC screening discussions, building on the effective approaches identified in this review, and tailored to specific population needs. In addition, new interventions to reduce overuse and misuse should be designed and tested, along with studies of ongoing monitoring systems that are linked to feedback and continued improvement efforts.


Motor Cortical Network Plasticity in Patients With Recurrent Brain Tumors.
Objective: The adult brain's potential for plastic reorganization is an important mechanism for the preservation and restoration of function in patients with primary glial neoplasm. Patients with recurrent brain tumors requiring multiple interventions over time present an opportunity to examine brain reorganization. Magnetoencephalography (MEG) is a noninvasive imaging modality that can be used for motor cortical network mapping which, when performed at regular intervals, offers insight into this process of reorganization. Utilizing MEG-based motor mapping, we sought to characterize the reorganization of motor cortical networks over time in a cohort of 78 patients with recurrent glioma. Methods: MEG-based motor cortical maps were obtained by measuring event-related desynchronization (ERD) in ß-band frequency during unilateral index finger flexion. Each patient presented at our Department at least on two occasions for tumor resection due to tumor recurrence, and MEG-based motor mapping was performed as part of preoperative assessment before each surgical resection. Whole-brain activation patterns from first to second MEG scan (obtained before first and second surgery) were compared. Additionally, we calculated distances of activation peaks, which represent the location of the primary motor cortex (MC), to determine the magnitude of movement in motor eloquent areas between the first and second MEG scan. We also explored which demographic, anatomic, and pathological factors influence these shifts. Results: The whole-brain activation motor maps showed a subtle movement of the primary MC from first to second timepoint, as was confirmed by the determination of motor activation peaks. The shift of ipsilesional MC was directly correlated with a frontal-parietal tumor location (p < 0.001), presence of motor deficits (p = 0.021), and with a longer period between MEG scans (p = 0.048). Also, a disengagement of wide areas in the contralesional (ipsilateral to finger movement) hemisphere at the second time point was observed. Conclusions: MEG imaging is a sensitive method for depicting the plasticity of the motor cortical network. Although the location of the primary MC undergoes only subtle changes, appreciable shifts can occur in the setting of a stronger and longer impairment of the tumor on the MC. The ipsilateral hemisphere may serve as a reservoir for functional recovery.


Structural neuroimaging studies in major depressive disorder. Meta-analysis and comparison with bipolar disorder.
Although differences in clinical characteristics exist between major depressive disorder (MDD) and bipolar disorder (BD), consistent structural brain abnormalities that distinguish the disorders have not been identified. To investigate structural brain changes in MDD using meta-analysis of primary studies; assess the effects of medication, demographic, and clinical variables; and compare the findings with those of a meta-analysis of studies on BD. The MEDLINE, EMBASE, and PsycINFO databases were searched for studies from January 1, 1980, to February 2, 2010. Two hundred twenty-five studies that used magnetic resonance imaging or x-ray computed tomography to compare brain structure in patients with MDD with that of controls were included in an online database, and 143 that measured common brain structures were selected for meta-analysis. Twenty-five variables, including demographic and clinical data, were extracted from each study, when available. For the meta-analysis, mean structure size and standard deviation were extracted for continuous variables, and the proportion of patients and controls with an abnormality in brain structure was extracted for categorical variables. Compared with the structure of a healthy brain, MDD was associated with lateral ventricle enlargement; larger cerebrospinal fluid volume; and smaller volumes of the basal ganglia, thalamus, hippocampus, frontal lobe, orbitofrontal cortex, and gyrus rectus. Patients during depressive episodes had significantly smaller hippocampal volume than patients during remission. Compared with BD patients, those with MDD had reduced rates of deep white matter hyperintensities, increased corpus callosum cross-sectional area, and smaller hippocampus and basal ganglia. Both disorders were associated with increased lateral ventricle volume and increased rates of subcortical gray matter hyperintensities compared with healthy controls. The meta-analyses revealed structural brain abnormalities in MDD that are distinct from those observed in BD. These findings may aid investigators attempting to discriminate mood disorders using structural magnetic resonance imaging data.


A clinically viable index for quantifying denture plaque.
A denture plaque index using the dye disclosing method was evaluated in 24 patients with Type II denture stomatitis and 17 control subjects with healthy palatal mucosa. Patients with denture stomatitis had statistically significantly higher plaque scores than did controls, indicating a quantitative increase in denture plaque in patients with denture stomatitis. When this plaque index was tested by two examiners for intraexaminer and interexaminer reproducibility, it yielded a 92% to 96% reproducibility. The plaque index used in this study seems to satisfy the criteria for an ideal clinical index: It is simple, reliable, reproducible, and economical and can be carried out in the shortest possible time in a clinical setting.


Cerebral blood flow laterality derived from arterial spin labeling as a biomarker for assessing the disease severity of parkinson's disease.
To evaluate cerebral blood flow (CBF) laterality derived from arterial spin labeling (ASL) in early-stage Parkinson's disease (PD) patients compared with those with advanced stages. Thirty-eight patients with PD (21 patients in early stages, 17 patients in advanced stages) were retrospectively studied. The CBF maps derived from 3T ASL data were co-registered to the corresponding 3DT1WI using SPM 12 software. Caudate nucleus (CN), putamen (PT), globus pallidus (GP), and thalamus (TH) were manually traced on the representative axial slices of 3DT1WI. CBF of the CN, PT, GP, and TH was measured using corresponding pixels on the co-registered CBF maps. A laterality index (LI) was calculated as the ratio of the contralateral CBF to primary affected side CBF. Each LI was compared between early and advanced stages of PD using the Mann-Whitney U-test. The LIs were also compared between each stage of PD. In the CN, the LIs were significantly higher in early stages (mean LI ± SD, 95% confidence interval = 1.06 ± 0.14, 1.00-1.13) than in advanced stages (0.94 ± 0.14, 0.87-1.01; P < 0.05). We also observed a tendency toward decreased LIs with disease severity (1.10 ± 0.14, 0.99-1.21 for Hoehn and Yahr stage I; 1.04 ± 0.14, 0.92-1.12 for stage II; 0.96 ± 0.11, 0.89-1.10 for stage III; 0.93 ± 0.17, 0.81-1.05 for stage IV). The evaluation of CBF laterality pattern in the CN using ASL may be useful for assessing the disease severity of PD patients. 3 J. MAGN. RESON. IMAGING 2017;45:1821-1826.


[Knowledge about their disease and treatment among patients with rheumatoid arthritis].
The transfer of information in the physician-patient relationship is important, especially in chronic diseases such as Rheumatoid Arthritis (RA), since it influences the perception and behavior that the patient has about his or her illness. To evaluate the level of knowledge and concern of their illness and treatment and their relationship with functional disability, perception of the pain and global assessment of disease activity, in patients with RA. Cross sectional study of 104 patients (mean age 56 years, 100 women) with RA. Demographic and clinical variables were registered. The knowledge about their illness and requirement of further information and concern about aspects of the illness and treatment, were assessed. Physical functioning was measured using the Health Assessment Questionnaire (HAQ). A visual analogue (VAS) and Likert scales were used for a global assessment of disease activity. Sixty percent of patients had only primary school studies. The median evolution of the illness was 14 years. Ninety eight percent knew their diagnosis and 91% required further information. There was a high degree of concern about the disease and treatment. The average HAQ score was 0.9. There was a statistically significant relationship between HAQ score and pain VAS (r =0.41, p <0.01). There was a moderate agreement between the global assessment of disease activity made by patients and physicians (Kappa =0.499; p =0.000). Even though patients with RA are informed about their disease, they require further information. Their highest concern is about the functional consequences of RA and they perceive a higher activity of the disease than their treating physicians.


Pesticide exposures and multiple myeloma in Iowa men.
A population-based case-control study of 173 White men with multiple myeloma (MM) and 650 controls was conducted in Iowa (United States), an area with a large farming population, to evaluate the association between MM, agricultural risk factors, and exposure to individual pesticides. A slight nonsignificantly elevated risk for MM was seen among farmers (odds ratio [OR] = 1.2, 95 percent confidence interval [CI] = 0.8-1.7). Although slight excesses were observed, there were no significant associations between MM and handling either classes of pesticides or specific pesticides. Thus, this study found little evidence to suggest an association between risk of MM and farming or pesticides.


Anxiety and depression are risk factors rather than consequences of functional somatic symptoms in a general population of adolescents: the TRAILS study.
It is well known that functional somatic symptoms (FSS) are associated with anxiety and depression. However, evidence is lacking about how they are related to FSS. The aim of this study was to clarify these relationships and examine whether anxiety and depression are distinctly related to FSS. We hypothesized that anxiety contributes to the development of FSS and that depression is a consequence of FSS. FSS, anxiety, and depression were measured in adolescents (N = 2230, 51% women) by subscales of the Youth Self-Report during three assessment waves (adolescents successively aged: 10-12, 12-14, and 14-17) and by corresponding subscales of the Child Behavior Checklist. Using structural equation models, we combined trait and state models of FSS with those of anxiety and depression, respectively. We identified which relationships (contemporaneous and two-year lagged) significantly connected the states of FSS with the states of anxiety and depression. Trait variables were all highly interrelated (r = .54-.63). Contrary to our hypothesis, both state anxiety (beta = .35) and state depression (beta = .45) had a strong contemporaneous effect on state FSS. In turn, state FSS had a weak two-year lagged effect on state anxiety (beta = .11) and an even weaker effect on state depression (beta = .06). While the effect of anxiety and depression on FSS is strong and immediate, FSS exert a weaker and delayed influence on anxiety and depression. Further research should be done to detect the exact ways in which anxiety and depression lead to FSS, and FSS lead to anxiety and depression.


Codling Moth Wing Morphology Changes Due to Insecticide Resistance.
The codling moth (CM) (Cydia pomonella L.) is the most important apple pest in Croatia and Europe. Owing to its economic importance, it is a highly controlled species and the intense selection pressure the species is under has likely caused it to change its phenotype in response. Intensive application of chemical-based insecticide treatments for the control of CM has led to resistance development. In this study, the forewing morphologies of 294 CM (11 populations) were investigated using geometric morphometric procedures based on the venation patterns of 18 landmarks. Finite element method (FEM) was also used to further investigate the dispersal capabilities of moths by modelling wing deformation versus wind speed. Three treatments were investigated and comprised populations from integrated and ecological (susceptible) orchards and laboratory-reared non-resistant populations. Forewing shape differences were found among the three treatment populations investigated. Across all three population treatments, the movement of landmarks 1, 7, 8, 9, and 12 drove the wing shape differences found. A reliable pattern of differences in forewing shape as related to control practice type was observed. FEM revealed that as wind speed (m/s-1) increased, so too did wing deformation (mm) for CM from each of the three treatments modelled. CM from the ecological orchards displayed the least deformation followed by integrated then laboratory-reared CM, which had the highest wing deformation at the highest wind speeds. This study presents an affordable and accessible technique that reliably demonstrates wing shape differences, and thus its use as a population biomarker to detect resistance should be further investigated.


Similarity of the yeast RAD51 filament to the bacterial RecA filament.
The RAD51 protein functions in the processes of DNA repair and in mitotic and meiotic genetic recombination in the yeast Saccharomyces cerevisiae. The protein has adenosine triphosphate-dependent DNA binding activities similar to those of the Escherichia coli RecA protein, and the two proteins have 30 percent sequence homology. RAD51 polymerized on double-stranded DNA to form a helical filament nearly identical in low-resolution, three-dimensional structure to that formed by RecA. Like RecA, RAD51 also appears to force DNA into a conformation of approximately a 5.1-angstrom rise per base pair and 18.6 base pairs per turn. As in other protein families, its structural conservation appears to be stronger than its sequence conservation. Both the structure of the protein polymer formed by RecA and the DNA conformation induced by RecA appear to be general properties of a class of recombination proteins found in prokaryotes as well as eukaryotes.


Blood and urinary measures of hydration status during progressive acute dehydration.
To determine whether: a) plasma osmolarity (Posm) is sensitive to small incremental changes in hydration status, b) urine specific gravity (Usg) can accurately identify a state of euhydration, c) Usg is a sensitive indicator of a change in hydration status, and d) Usg correlates with Posm. Euhydrated (Posm = 288 +/- 4 mOsm.L-1) subjects (N = 12) were dehydrated by 5% of their body weight via exercise in the heat (40 degrees C, 20% RH). Posm, urine osmolarity (Uosm), and Usg were measured at 1%, 3%, and 5% dehydration, and 30 and 60 min of recovery (rec). Subjects consumed water in recovery equal to their loss of body weight. Posm increased incrementally with each successive increase in percent body weight loss (%BWL). Usg was not significantly different from baseline until 3% BML. Uosm was not significantly different from baseline until 5% BWL. Usg correlated moderately (r = 0.46, P > 0.10) with Posm but reasonably well (r = 0.68, P < 0.02) with Uosm. Posm accurately identifies a state of euhydration and is sensitive to changes in hydration status during acute dehydration and rehydration. Usg and Uosm are also sensitive to changes in hydration status but lag behind during periods of rapid body fluid turnover and therefore correlate only moderately with Posm during acute dehydration.


Oxidant trade-offs in immunity: an experimental test in a lizard.
Immune system functioning and maintenance entails costs which may limit investment into other processes such as reproduction. Yet, the proximate mechanisms and 'currencies' mediating the costs of immune responses remain elusive. In vertebrates, up-regulation of the innate immune system is associated with rapid phagocytic production of pro-oxidant molecules (so-called 'oxidative burst' responses). Oxidative burst responses are intended to eliminate pathogens but may also constitute an immunopathological risk as they may induce oxidative damage to self cells. To minimize the risk of infection and, at the same time, damage to self, oxidative burst activity must be carefully balanced. The current levels of pro- and antioxidants (i.e. the individual oxidative state) is likely to be a critical factor affecting this balance, but this has not yet been evaluated. Here, we perform an experiment on wild-caught painted dragon lizards (Ctenophorus pictus) to examine how the strength of immune-stimulated oxidative burst responses of phagocytes in whole blood relates to individual oxidative status under control conditions and during an in vivo immune challenge with Escherichia coli lipopolysaccharide (LPS). Under control conditions, oxidative burst responses were not predicted by the oxidative status of the lizards. LPS-injected individuals showed a strong increase in pro-oxidant levels and a strong decrease in antioxidant levels compared to control individuals demonstrating a shift in the pro-/antioxidant balance. Oxidative burst responses in LPS-injected lizards were positively related to post-challenge extracellular pro-oxidants (reflecting the level of cell activation) and negatively related to pre-challenge levels of mitochondrial superoxide (suggesting an immunoregulatory effect of this pro-oxidant). LPS-challenged males had higher oxidative burst responses than females, and in females oxidative burst responses seemed to depend more strongly on antioxidant status than in males. Our results confirm the idea that oxidative state may constrain the activity of the innate immune system. These constraints may have important consequences for the way selection acts on pro-oxidant generating processes.


Germline Genetic Variants in TEK, ANGPT1, ANGPT2, MMP9, FGF2 and VEGFA Are Associated with Pathologic Complete Response to Bevacizumab in Breast Cancer Patients.
We previously reported improved pathologic complete response (pCR) in a prospective phase II study using neoadjuvant bevacizumab in combination with chemotherapy compared to chemotherapy alone in breast cancer patients (41% vs. 25%, p = 0.0291). In this study, we queried germline single-nucleotide polymorphisms (SNPs) in angiogenesis-related genes for their impact on pCR and overall survival (OS). DNA for genotyping was available from 34 subjects who received bevacizumab in addition to chemotherapy and 29 subjects who did not. Using Illumina® technology, we queried 504 SNPs with a minor allele frequency (MAF) of at least 5%, located in 10 angiogenesis-related genes, for their effect on pCR via logistic regression with an additive-inheritance model while adjusting for race and bevacizumab treatment. SNPs that showed significant associations with pCR were selected for additional characterization. After adjusting for race and tumor type, patients who had bevacizumab added to their neoadjuvant therapy were found to experience a significantly improved rate of pCR compared to patients who did not (adjusted OR 8.40, 95% CI 1.90-37.1). When patients were analyzed for SNP effects via logistic regression with race and bevacizumab treatment included as covariates, two SNPs in angiopoietin 1 (ANGPT1), six in ANGPT2, three in fibroblast growth factor 2 (FGF2), four in matrix metalloproteinase 9 (MMP9), three in tyrosine kinase, endothelial (TEK) and two in vascular endothelial growth factor A (VEGFA) were associated with pCR (P<0.05). However, when overall survival was considered, there was no difference between treatment groups or between genotypes. Genetic variability in TEK, ANGPT1, ANGPT2, FGF2, MMP9 and VEGFA is associated with pCR in bevacizumab-treated patients. Consistent with other studies, adding bevacizumab to standard chemotherapy did not impact OS, likely due to other factors and thus, while SNPs in TEK, ANGPT1, ANGPT2, FGF2, MMP9 and VEGFA were associated with pCR, they were not predictive of OS in this patient population. ClinicalTrials.gov NCT00203502.


Choline PET and PET/CT in Primary Diagnosis and Staging of Prostate Cancer.
PET and PET/CT using [(11)C]- and [(18)F]-labelled choline derivates is increasingly being used for imaging of primary and recurrent prostate cancer. While PET and PET/CT with [(11)C]- and [(18)F]-labelled choline derivates in patients suffering from biochemical recurrence of prostate cancer has been examined in many studies that demonstrate an increasing importance, its role in the primary staging of prostate cancer is still a matter of debate.Morphological and functional imaging techniques such as CT, MRI and TRUS have demonstrated only limited accuracy for the diagnosis of primary prostate cancer. Molecular imaging with PET and PET/CT could potentially increase accuracy to localize primary prostate cancer. A considerable number of studies have examined the value of PET/CT with [(11)C]- and [(18)F]- labelled choline derivates for the diagnosis of primary prostate cancer with mixed results. Primary prostate cancer can only be detected with moderate sensitivity using [(11)C]- and [(18)F]choline PET and PET/CT. The detection rate depends on the tumour configuration. Detection is also limited by a considerable number of microcarcinomas that cannot be detected due to partial volume effects. Therefore small and in part rind-like tumours can often not be visualized. Furthermore, the differentiation between benign changes like prostatitis, high-grade intraepithelial neoplasia (HGPIN) or prostatic hyperplasia is not always possible. Therefore, at the present time, the routine use of PET/CT with [(11)C]- and [(18)F]-labelled choline derivates cannot be recommended as a first-line screening procedure for primary prostate cancer in men at risk. A potential application of choline PET and PET/CT may be to increase the detection rate of clinically suspected prostate cancer with multiple negative prostate biopsies, for example in preparation of a focused re-biopsy and may play a role in patient stratification with respect to primary surgery and radiation therapy in the future.


If these data could talk.
In the last few decades, data-driven methods have come to dominate many fields of scientific inquiry. Open data and open-source software have enabled the rapid implementation of novel methods to manage and analyze the growing flood of data. However, it has become apparent that many scientific fields exhibit distressingly low rates of reproducibility. Although there are many dimensions to this issue, we believe that there is a lack of formalism used when describing end-to-end published results, from the data source to the analysis to the final published results. Even when authors do their best to make their research and data accessible, this lack of formalism reduces the clarity and efficiency of reporting, which contributes to issues of reproducibility. Data provenance aids both reproducibility through systematic and formal records of the relationships among data sources, processes, datasets, publications and researchers.


A multimode analysis of the gas-phase photoelectron spectra in oligoacenes.
We present a multimode vibrational analysis of the gas-phase ultraviolet photoelectron spectra of the first ionization in anthracene, tetracene, and pentacene, using electron-vibration constants computed at the density functional theory level. The first ionization of each molecule exhibits a high-frequency vibronic structure; it is shown that this regularly spaced feature is actually the consequence of the collective action of several vibrational modes rather than the result of the interaction with a single mode. We interpret this feature in terms of the missing mode effect. We also discuss the vibronic coupling constants and relaxation energies obtained from the fit of the photoelectron spectra with the linear vibronic model.


Mode and tempo of molecular evolution in the nematode caenorhabditis: cytochrome oxidase II and calmodulin sequences.
Through direct sequencing methods, the mitochondrial gene for cytochrome oxidase subunit two (CO II) and the single-copy nuclear gene for calmodulin were compared among strains of Caenorhabidits elegans and two other Caenorhabditis species (C. remanei and C. briggsae). In addition the CO II sequence was determined from a distantly related nematode, Steinernema intermedii. Among the 11 strains of C. elegans tested, there are four types of CO II gene, arising from two major lineages. Levels of intraspecific difference in the CO II gene are low (less than 2.0%) compared to the extraordinary divergence between congeneric species, which is about 50% when corrected for multiple hits. Concordant with the increase in divergence between taxa is a change in the pattern of substitution from a strong transition bias (24 transitions compared to two transversions) within species to a substitution pattern that appears to reflect the base composition of the mitochondrial genome when more divergent nematodes are compared. The base composition of the Caenorhabditis CO II gene is strongly biased toward A + T at all three positions of codons and appears to constrain the amino acid composition of the protein. Both the CO II and calmodulin genes show extreme conservation of amino acid sequences. When the accumulation of changes at silent sites in the two genes is compared among strains, it becomes evident that the mitochondrial gene is changing faster than the nuclear gene.


Individualizing the risks and benefits of postmenopausal hormone therapy.
The objective was to develop an individualized risk-benefit model quantifying the impact of combined use of estrogen and progestogen on chronic diseases. The study population consisted of women, aged 40+, prescribed postmenopausal hormone therapy (HT) in the UK General Practice Research Database (N > 200,000). Individualized risks of fracture, colorectal cancer, diabetes mellitus, myocardial infarction, deep venous thrombosis/pulmonary embolism, breast cancer, and stroke were estimated using Cox regression. Relative rates from the Women's Health Initiative trial were used to estimate attributable risks (ie, excess risks) in a risk-benefit simulation model. Risks and benefits increased with age and length of HT use. HT use for 5 years initiated at age 45 increased the absolute risk of myocardial infarction by 0.04% and breast cancer by 0.3% and reduced the risk of hip fracture by 0.03%. Comparably, 5-year HT use started at age 75 led to increases in the risks of myocardial infarction and breast cancer (+0.4% and +0.2%, respectively) and reduced that of hip fracture (-0.9%). There was considerable heterogeneity in the risks and benefits of HT. In most of the younger HT users, the frequency of risks exceeded that of the benefits, although the absolute excess risks were small. In HT users aged 70+, 62.4% experienced more benefits than risks, whereas 37.6% experienced more risks than benefits. The frequency of beneficial and adverse effects of HT on chronic diseases was low in younger women, whereas the ratio of these risks and benefits varied substantially among the older users. However, the study could not asses the effects of HT on menopausal symptoms and quality of life, benefits more likely to be observed among younger women.


On magnitudes in memory: An internal clock account of space-time interaction.
Traditionally, research on time perception has diverged into a representational approach that focuses on the interaction between time and non-temporal magnitude information like spatial distance, and a mechanistic approach that emphasizes the workings and timecourse of components within an internal clock. We combined these approaches in order to identify the locus of space-time interaction effects in the mechanistic framework of the internal clock model. In three experiments, we contrasted the effects of spatial distance (a long- vs. short-distance line) on time perception with those of visual flicker (a flickering vs. static stimulus) in a duration reproduction paradigm. We found that both a flickering stimulus and a long-distance line lengthened reproduced time when presented during time encoding. However, when presented during time reproduction, a flickering stimulus shortened reproduced time but a long-distance line had no effect. The results thus show that, while visual flickers affects duration accumulation itself, spatial distance instead biases the memory of the accumulated duration. These findings are consistent with a clock-magnitude account of space-time interaction whereby both temporal duration and spatial distance are represented as mental magnitudes that can interfere with each other while being kept in memory, and places the locus of interaction between temporal and non-temporal magnitude dimensions at the memory maintenance stage of the internal clock model.


Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation.
Contemporary clinical risk stratification schemata for predicting stroke and thromboembolism (TE) in patients with atrial fibrillation (AF) are largely derived from risk factors identified from trial cohorts. Thus, many potential risk factors have not been included. We refined the 2006 Birmingham/National Institute for Health and Clinical Excellence (NICE) stroke risk stratification schema into a risk factor-based approach by reclassifying and/or incorporating additional new risk factors where relevant. This schema was then compared with existing stroke risk stratification schema in a real-world cohort of patients with AF (n = 1,084) from the Euro Heart Survey for AF. Risk categorization differed widely between the different schemes compared. Patients classified as high risk ranged from 10.2% with the Framingham schema to 75.7% with the Birmingham 2009 schema. The classic CHADS(2) (Congestive heart failure, Hypertension, Age > 75, Diabetes, prior Stroke/transient ischemic attack) schema categorized the largest proportion (61.9%) into the intermediate-risk strata, whereas the Birmingham 2009 schema classified 15.1% into this category. The Birmingham 2009 schema classified only 9.2% as low risk, whereas the Framingham scheme categorized 48.3% as low risk. Calculated C-statistics suggested modest predictive value of all schema for TE. The Birmingham 2009 schema fared marginally better (C-statistic, 0.606) than CHADS(2). However, those classified as low risk by the Birmingham 2009 and NICE schema were truly low risk with no TE events recorded, whereas TE events occurred in 1.4% of low-risk CHADS(2) subjects. When expressed as a scoring system, the Birmingham 2009 schema (CHA(2)DS(2)-VASc acronym) showed an increase in TE rate with increasing scores (P value for trend = .003). Our novel, simple stroke risk stratification schema, based on a risk factor approach, provides some improvement in predictive value for TE over the CHADS(2) schema, with low event rates in low-risk subjects and the classification of only a small proportion of subjects into the intermediate-risk category. This schema could improve our approach to stroke risk stratification in patients with AF.


The PKCθ pathway participates in the aberrant accumulation of Fra-1 protein in invasive ER-negative breast cancer cells.
Fra-1 is aberrantly expressed in a large number of cancer cells and tissues, and emerging evidence suggests an important role for this Fos family protein in both oncogenesis and the progression or maintenance of many tumour types. Here, we show that the concentration of Fra-1 is high in invasive oestrogen receptor (ER)-negative (ER-) breast cancer cell lines, regardless of their Ras pathway status. All of the ER- cells express high levels of activated PKCθ, and the inhibition of PKCθ activity using RNA interference or the expression of a dominant-negative mutant results in a dramatic reduction in Fra-1 abundance. Conversely, the ectopic expression of constitutively active PKCθ leads to Fra-1 phosphorylation and accumulation in poorly invasive ER+ cells. This accumulation is due to the stabilisation of the Fra-1 protein through PKCθ signalling, whereas other members of the PKC family are ineffective. Both Ste20-related proline-alanine-rich kinase (SPAK) and ERK1/2, whose activities are upregulated by PKCθ, participate in PKCθ-driven Fra-1 stabilisation. Interestingly, their relative contributions appear to be different depending on the cell line studied. ERK1/2 signalling has a major role in ER- MDA-MB-231 cells, whereas Fra-1 accumulation occurs mainly through SPAK signalling in ER- BT549 cells. Fra-1 mutational analysis shows that the phosphorylation of S265, T223 and T230 is critical for PKCθ-driven Fra-1 stabilisation. Phosphorylation of the protein was confirmed using specific antisera against Fra-1 phosphorylated on T223 or S265. In addition, Fra-1 participates in PKCθ-induced cell invasion and is necessary for PKCθ-induced cell migration. In summary, we identified PKCθ signalling as an important regulator of Fra-1 accumulation in ER- breast cancer cells. Moreover, our results suggest that PKCθ could participate in progression of some breast cancers and could be a new therapeutic target.


Nurse satisfaction and the implementation of minimum nurse staffing regulations.
In 1999, California passed the first legislation in the United States to establish minimum staffing levels for licensed nurses in hospitals. Implementation of the regulation began in 2004. This article examines whether nurses who work in hospitals in California have perceived improvements in their working conditions. A statewide sample survey of registered nurses is used, and the survey data are linked with regional data to learn whether changes in satisfaction are associated with the degree to which regional employers were expected to increase nurse staffing when the ratios were implemented. Nurse satisfaction improved between 2004 and 2006, particularly with the adequacy of RN staff, time for patient education, benefits, and clerical support. There was a significant increase in overall job satisfaction between 2004 and 2006. However, improvements in satisfaction with the adequacy of RN staff were not associated with the degree to which regional hospitals were expected to increase staffing.


Inappropriate initial treatment of secondary intra-abdominal infections leads to increased risk of clinical failure and costs.
The objective of this population-based, retrospective cohort study was to investigate the incidence and initial antibiotic treatment of secondary intra-abdominal infections (sIAI) and to assess whether inappropriate initial antibiotic therapy affects patient outcomes. All patients hospitalized for sIAI (1995-1998) were identified in the PHARMO Record Linkage System, a patient-centric database including pharmacy dispensing records from community pharmacies linked to hospitalization records in the Netherlands. Complementary in-hospital antibiotic drug use was obtained from the computerized inpatient pharmacy files. The patient outcomes considered were switch to second-line antibiotic treatment, re-operation, and death. In addition, a composite variable clinical failure was constructed based on the above-mentioned outcomes. Furthermore, the effect of clinical failure on length of hospital stay and costs of hospitalization was assessed. Associations between appropriateness of initial antibiotic treatment and outcomes were estimated using multivariate logistic and linear regression models. In the source population of 228,000 persons, 175 cases were classified as sIAI (mean age 49.3 +/- 24.5, 50.9% male) resulting in an incidence of 2.3/10,000 person-years [95% confidence interval (CI) 2.0, 2.7]. Initial antibiotic treatment was appropriate for 84% of the cases. The risk of clinical failure was 17.1%. Inappropriate initial antibiotic treatment increased the risk of clinical failure 3.4-fold (95% CI 1.3, 9.1). Length of hospital stay and costs of hospitalization were significantly increased for patients with clinical failure. Inappropriate choice of initial antibiotic therapy in sIAI patients leads to more clinical failure resulting in a longer hospital stay and higher costs of hospitalization compared with appropriate initial antibiotic therapy.


Functional characterization and developmental regulation of mouse telomerase RNA.
Telomerase synthesizes telomeric DNA repeats onto chromosome ends de novo. The mouse telomerase RNA component was cloned and contained only 65 percent sequence identity with the human telomerase RNA. Alteration of the template region in vivo generated altered telomerase products. The shorter template regions of the mouse and other rodent telomerase RNAs could account for the shorter distribution of products (processivity) generated by the mouse enzyme relative to the human telomerase. Amounts of telomerase RNA increased in immortal cells derived from primary mouse fibroblasts. RNA was detected in all newborn mouse tissues tested but was decreased during postnatal development.


Cerebral infarcts associated with migraine: clinical features, risk factors and follow-up.
There have been few reports concerning the characteristics of cerebral infarction associated with migraine (CIAM), and especially about the subsequent fate of these patients. We studied 14 patients (9 female) with CIAM. In all these patients the onset of cerebral infarction was accompanied by a unilateral throbbing headache, in 8 also with a gradual build-up of neurological deficits. No other cause of cerebral infarction could be found in these patients. Twelve patients had had previous attacks of migraine, with auras in 6. The nature of the neurological deficit was similar to previous auras in only 3 of these patients. The 2 patients without a history of migraine both developed migraine attacks afterwards. During the same period we also studied 14 patients (8 female) with a cerebral infarct of unknown origin (CIUO). The infarct involved the occipital lobe in 11 of the 14 patients with CIAM, whereas this occurred in 4 patients with CIUO [relative risk (RR): 2.8; 95% confidence interval (CI): 1.2-6.6]. Patients with CIAM had risk factors for atherosclerosis significantly less often than patients with CIUO (RR: 0.1; 95% CI: 0.02-0.9). The functional outcome of patients with CIAM was better than in patients with CIUO: all 14 patients with CIAM were independent in their daily activities, compared with 9 patients with CIUO (RR: 1.6; 95% CI: 1.1-2.3). No patient in either group had a recurrent stroke during a median follow-up period of 5.8 years. In conclusion, CIAM is a stroke entity causing mostly infarcts in the occipital lobe; vascular risk factors are uncommon and prognosis is generally good.


Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer.
The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals.


Community context and pCO2 impact the transcriptome of the "helper" bacterium Alteromonas in co-culture with picocyanobacteria.
Many microbial photoautotrophs depend on heterotrophic bacteria for accomplishing essential functions. Environmental changes, however, could alter or eliminate such interactions. We investigated the effects of changing pCO2 on gene transcription in co-cultures of 3 strains of picocyanobacteria (Synechococcus strains CC9311 and WH8102 and Prochlorococcus strain MIT9312) paired with the 'helper' bacterium Alteromonas macleodii EZ55. Co-culture with cyanobacteria resulted in a much higher number of up- and down-regulated genes in EZ55 than pCO2 by itself. Pathway analysis revealed significantly different transcription of genes involved in carbohydrate metabolism, stress response, and chemotaxis, with different patterns of up- or down-regulation in co-culture with different cyanobacterial strains. Gene transcription patterns of organic and inorganic nutrient transporter and catabolism genes in EZ55 suggested resources available in the culture media were altered under elevated (800 ppm) pCO2 conditions. Altogether, changing transcription patterns were consistent with the possibility that the composition of cyanobacterial excretions changed under the two pCO2 regimes, causing extensive ecophysiological changes in both members of the co-cultures. Additionally, significant downregulation of oxidative stress genes in MIT9312/EZ55 cocultures at 800 ppm pCO2 were consistent with a link between the predicted reduced availability of photorespiratory byproducts (i.e., glycolate/2PG) under this condition and observed reductions in internal oxidative stress loads for EZ55, providing a possible explanation for the previously observed lack of "help" provided by EZ55 to MIT9312 under elevated pCO2. If similar broad alterations in microbial ecophysiology occur in the ocean as atmospheric pCO2 increases, they could lead to substantially altered ecosystem functioning and community composition.


Major surgery within the first 3 months of life and subsequent biobehavioral pain responses to immunization at later age: a case comparison study.
Pain exposure during early infancy affects the pain perception beyond infancy into childhood. The objective of this study was to examine whether major surgery within the first 3 months of life in combination with preemptive analgesia alters pain responses to immunization at 14 or 45 months and to assess whether these alterations are greater in toddlers with a larger number of negative hospital experiences. Two groups of 50 toddlers each were compared: index group and control group. All index toddlers had participated within the first 3 months of their life in a randomized, clinical trial that evaluated the efficacy of preemptive morphine administration for postoperative analgesia. The controls were matched by type of immunization and community health care pediatrician. Pain reactions were recorded at routine immunization at either 14 (measles-mumps-rubella immunization) or 45 months (diphtheria-tetanus-trivalent polio immunization) of age. Outcome measures were facial reaction, coded by the Maximum Discriminative Facial Movement Coding System; heart rate (HR); and cortisol saliva concentration. Negative hospital experiences included number of operations requiring postoperative morphine administration, cumulative Therapeutic Intervention Scoring System scores, and length of stay in the intensive care unit or total hospitalization days. No differences were found between the index and control groups in the facial display of pain, anger, or sadness or in physiologic parameters such as HR and cortisol concentrations. Intragroup analyses of the index group showed that after measles-mumps-rubella vaccination, the number of negative hospital experiences correlated positively with the facial responsiveness and negatively with HR responses. No effect was seen after diphtheria-tetanus-trivalent polio immunization. Major surgery in combination with preemptive analgesia within the first months of life does not alter pain response to subsequent pain exposure in childhood. Greater exposure to early hospitalization influences the pain responses after prolonged time. These responses, however, diminish after a prolonged period of nonexposure.


Mental health and juvenile justice: moving toward more effective systems of care.
This issue brief discusses the mental health needs of youth who are involved with the juvenile justice system, how they come into contact with the system, and the evidence of the availability and quality of mental health services for such youth. The paper also explores public policy options for avoiding dependence on the juvenile justice system as a last resort for treating youth with mental disorders.


Patient safety and blood transfusion: new solutions.
Current risk from transfusion is largely because of noninfectious hazards and defects in the overall process of delivering safe transfusion therapy. Safe transfusion therapy depends on a complex process that requires integration and coordination among multiple hospital services including laboratory medicine, nursing, anesthesia, surgery, clerical support, and transportation. The multidisciplinary hospital transfusion committee has been traditionally charged with oversight of transfusion safety. However, in recent years, this committee may have been neglected in many institutions. Resurgence in hospital oversight of patient safety and transfusion efficacy is an important strategy for change. A new position, the transfusion safety officer (TSO), has been developed in some nations to specifically identify, resolve, and monitor organizational weakness leading to unsafe transfusion practice. New technology is becoming increasingly available to improve the performance of sample labeling and the bedside clerical check. Several technology solutions are in various stages of development and include wireless handheld portable digital assistants, advanced bar coding, radiofrequency identification, and imbedded chip technology. Technology-based solutions for transfusion safety will depend on the larger issue of the technology for patient identification. Devices for transfusion safety hold exciting promise but need to undergo clinical trials to show effectiveness and ease of use. Technology solutions will likely require integration with delivery of pharmaceuticals to be financially acceptable to hospitals.


N-terminal pro-B-type natriuretic peptide: a potential marker of fetal heart failure in hemolytic disease.
The hemolysis of red blood cells due to isoimmunisation results in fetal anaemia and hypoxia leading to fetal heart failure. An assessment of N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a routine practice in adult heart failure. No studies on this marker have been reported in fetal heart failure. The aim of the current study was to investigate changes in fetal NT-proBNP serum concentrations before and after intrauterine transfusions and to assess its value as a marker of fetal heart failure. Therapy of Rh immunisations was performed in 14 fetuses with 61 intrauterine transfusions. Hemoglobin concentration, red blood cells count, hematocrit and NT-proBNP concentrations were assessed in samples taken before and after each transfusion. An increase in the concentrations of blood parameters was strongly correlated with a decrease in the concentration of NT-proBNP. NT-proBNP concentrations were the greatest with the smallest Hb (4.0-5.9 g/dl), hematocrit and red blood cell (RBC) concentrations, respectively. An increase in Hb concentration by 1mg/dl and the RBC count by 1M/µl resulted in a corresponding decrease in NT-proBNP concentration by 659.0 and 2 007.1 pg/ml, respectively. The NT-proBNP concentrations decreased significantly following 52 transfusions. The fetal serum concentration of NT-proBNP appears to be a satisfactory marker for heart failure in fetuses inflicted with severe anaemia caused by hemolytic disease. Intrauterine therapy decreases the severity of anaemia and reduces the fetal heart failure index. There appears to be a strong inverse correlation between the pre-transfusion NT-proBNP concentration and morphological parameters.


Hepatocyte growth factor expression in the developing myocardium: evidence for a role in the regulation of the mesenchymal cell phenotype and urokinase expression.
During development of the heart, the endocardium of the developing cushion tissue transforms into mesenchymal cells that rapidly invade the underlying extracellular matrix. This invasive process, along with subsequent proliferation and differentiation of the mesenchyme, are essential for the normal formation of valvular and septal structures. Several factors have been identified that appear to initiate and/or control this transformation process, including the growth factor TGF-beta. In these studies we have investigated whether hepatocyte growth factor/scatter factor (HGF/SF) may also be involved in some aspects of this transformation process. Using an immunohistochemical approach we have detected a spatially restricted localization of HGF/SF to the myocardial cells of the cushion tissue. HGF was detected in extracts of the developing heart, and the presence of the active form correlated with the onset of the transformation process and the elevation of urokinase activity. The endocardial-derived mesenchymal cells of the cushion tissue were found to express the c-met HGF receptor. Isolated endocardial cells responded to the addition of HGF with increases in motility, proliferation, and urokinase production. The results from these studies suggest that HGF may function as a myocardial-derived mediator of the epithelial-mesenchymal transformation by inducing and/or maintaining the mesenchymal cell phenotype. The increase in urokinase expression by the cushion tissue cells, in response to HGF, may facilitate the invasive abilities of these cells and also provide a means of maintaining high levels of active HGF required for the stimulation of cell proliferation and migration.


Epidermal growth factor regulates the exchange rate of guanine nucleotides on p21ras in fibroblasts.
Treatment of intact Rat-1 fibroblasts with epidermal growth factor (EGF) leads to rapid activation of cellular ras-encoded proteins. By using the bacterial toxin streptolysin O to permeabilize these cells, it was shown that the low basal rate at which guanine nucleotides bind to, and dissociate from, ras-encoded protein in quiescent fibroblasts was greatly accelerated by EGF treatment. Nucleotide binding to other proteins was not affected. Stimulation of nucleotide exchange on ras-encoded protein required tyrosine kinase but not phospholipase activity. EGF had no effect on total GTPase-activating protein activity. Regulation of ras-encoded protein in Rat-1 fibroblasts is therefore mediated by stimulation, either directly or indirectly, of ras-encoded protein-specific guanine nucleotide exchange factors by the EGF receptor tyrosine kinase.


Extended Use of Full-Thickness Skin Grafts, Employing Variable Donor Sites.
Full-thickness skin graft (FTSG) is a very versatile tool regularly used in small sizes. With the established knowledge of the graft take through the margins as well as wound bed, we extended the use of the FTSG for reconstruction of large-sized defects with satisfactory results. We presented our experience in wound reconstruction using FTSG in 28 patients. We selected cases with graft size equal to or more than 130 cm2. Seven patients had chronic but healthy granulating wounds and 21 patients had fresh raw areas. Sizes of FTSG used varied between 130 to 452 cm2 of outstretched skin at donor sites. We used subgluteal skin crease in most of cases, though groin, upper medial thigh and medial arm aspects were also used. There was no difference in graft take between fresh and chronic wound sites. Almost complete graft take was the rule in all cases apart from mild epidermal skin peeling in four cases and small spots of graft necrosis in three cases. Primary wound healing at donor sites was the rule with scar hypertrophy in six cases necessitating scar conservative care for few months. Use of FTSG for reconstructing raw areas in acute and chronic wounds has to be safely reconsidered regardless of wound size. It's still a sound and reliable tool which can decrease the necessity of complex flap coverage. Subgluteal skin crease is relatively a new donor site to be considered for large grafts with primary direct closure.


Long-term testosterone replacement therapy reduces fatigue in men with hypogonadism.
Testosterone replacement therapy (TRT) is one of the main lines of treatment for men with hypogonadism. This study sought to evaluate the influence of TRT in men with late-onset hypogonadism (LOH), regarding fatigue, coronary artery disease (CAD), carotid intima-media thickness (CIMT) and cardiovascular risk. This study compared men with LOH already on TRT for >1 year to newly diagnosed men with LOH who recently started TRT (controls). We included men aged >18 years with clinical manifestations of testosterone deficiency and testosterone levels of <300 ng/dL documented in two separate occasions. A total of 33 patients were included in the study group and 30 in the control group. Mean age was 49.1 years (±11.5) in those already under TRT for >1 year and 45 (±12.2) years in the control group (p=0.18). CAD was present in 14 (46.7%) patients in the control group and in 3 (9.1%) in the study group (p<0.001). TRT >1 year was not associated with lower rates of CAD in multivariable analysis. Fatigue Severity Score was significantly higher in the control group (39.2±15.0), compared to TRT >1 year (23.5±8.1; p<0.001). In a multivariable analysis adjusted for age and hypertension, TRT >1 year was associated with a 14.8-point decrease in Fatigue Severity Score (p<0.001). Overall, there were no differences between the study group and the control group regarding cardiovascular risk (p=0.31). TRT for >1 year was associated with significantly lower fatigue scores. No differences were observed regarding CIMT, CAD and cardiovascular risk according to the WHO-ISH scale.


Future perspectives in melanoma research : Meeting report from the "Melanoma Bridge". Napoli, December 1st-4th 2015.
The sixth "Melanoma Bridge Meeting" took place in Naples, Italy, December 1st-4th, 2015. The four sessions at this meeting were focused on: (1) molecular and immune advances; (2) combination therapies; (3) news in immunotherapy; and 4) tumor microenvironment and biomarkers. Recent advances in tumor biology and immunology has led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS) of cancer patients. Immunotherapies in particular have emerged as highly successful approaches to treat patients with cancer including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), bladder cancer, and Hodgkin's disease. Specifically, many clinical successes have been using checkpoint receptor blockade, including T cell inhibitory receptors such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death-1 (PD-1) and its ligand PD-L1. Despite demonstrated successes, responses to immunotherapy interventions occur only in a minority of patients. Attempts are being made to improve responses to immunotherapy by developing biomarkers. Optimizing biomarkers for immunotherapy could help properly select patients for treatment and help to monitor response, progression and resistance that are critical challenges for the immuno-oncology (IO) field. Importantly, biomarkers could help to design rational combination therapies. In addition, biomarkers may help to define mechanism of action of different agents, dose selection and to sequence drug combinations. However, biomarkers and assays development to guide cancer immunotherapy is highly challenging for several reasons: (i) multiplicity of immunotherapy agents with different mechanisms of action including immunotherapies that target activating and inhibitory T cell receptors (e.g., CTLA-4, PD-1, etc.); adoptive T cell therapies that include tissue infiltrating lymphocytes (TILs), chimeric antigen receptors (CARs), and T cell receptor (TCR) modified T cells; (ii) tumor heterogeneity including changes in antigenic profiles over time and location in individual patient; and (iii) a variety of immune-suppressive mechanisms in the tumor microenvironment (TME) including T regulatory cells (Treg), myeloid derived suppressor cells (MDSC) and immunosuppressive cytokines. In addition, complex interaction of tumor-immune system further increases the level of difficulties in the process of biomarkers development and their validation for clinical use. Recent clinical trial results have highlighted the potential for combination therapies that include immunomodulating agents such as anti-PD-1 and anti-CTLA-4. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors on T cells and other approaches such as adoptive cell transfer are tested for clinical efficacy in melanoma as well. These agents are also being tested in combination with targeted therapies to improve upon shorter-term responses thus far seen with targeted therapy. Various locoregional interventions that demonstrate promising results in treatment of advanced melanoma are also integrated with immunotherapy agents and the combinations with cytotoxic chemotherapy and inhibitors of angiogenesis are changing the evolving landscape of therapeutic options and are being evaluated to prevent or delay resistance and to further improve survival rates for melanoma patients' population. This meeting's specific focus was on advances in immunotherapy and combination therapy for melanoma. The importance of understanding of melanoma genomic background for development of novel therapies and biomarkers for clinical application to predict the treatment response was an integral part of the meeting. The overall emphasis on biomarkers supports novel concepts toward integrating biomarkers into personalized-medicine approach for treatment of patients with melanoma across the entire spectrum of disease stage. Translation of the knowledge gained from the biology of tumor microenvironment across different tumors represents a bridge to impact on prognosis and response to therapy in melanoma. We also discussed the requirements for pre-analytical and analytical as well as clinical validation process as applied to biomarkers for cancer immunotherapy. The concept of the fit-for-purpose marker validation has been introduced to address the challenges and strategies for analytical and clinical validation design for specific assays.


Phylogenetic affinity of arbuscular mycorrhizal symbionts in Psilotum nudum.
Many lineages of land plants (from lycopsids to angiosperms) have non-photosynthetic life cycle phases that involve obligate mycoheterotrophic arbuscular mycorrhizal (AM) associations where the plant host gains organic carbon through glomalean symbionts. Our goal was to isolate and phylogenetically identify the AM fungi associated with both the autotrophic and underground mycoheterotrophic life cycle phases of Psilotum nudum. Phylogenetic analyses recovered 11 fungal phylotypes in four diverse clades of Glomus A that form AM associations with P. nudum mycoheterotrophic gametophytes and autotrophic sporophytes, and angiosperm roots found in the same greenhouse pots. The correspondence of identities of AM symbionts in P. nudum sporophytes, gametophytes and neighboring angiosperms provides compelling evidence that photosynthetic heterospecific and conspecific plants can serve as the ultimate sources of fixed carbon for mycoheterotrophic gametophytes of P. nudum, and that the transfer of carbon occurs via shared fungal networks. Moreover, broader phylogenetic analyses suggest greenhouse Psilotum populations, like field-surveyed populations of mycoheterotrophic plants, form AM associations with restricted clades of Glomus A. The phylogenetic affinities and distribution of Glomus A symbionts indicate that P. nudum greenhouse populations have the potential to be exploited as an experimental system to further study the physiology, ecology and evolution of mycoheterotrophic AM associations.


Dietary intake of cadmium, chromium, copper, manganese, selenium and zinc in a Northern Italy community.
This study provides the dietary intakes of six trace elements (cadmium, chromium, copper, manganese, selenium and zinc), generally characterized by both nutritional and toxicological features depending on their exposure. Being diet the most relevant source of exposure to trace elements in non-professionally exposed subjects, we measured content of these trace elements in foods composing the typical Italian diet using inductively coupled plasma-mass spectrometry, and assessing dietary habits using a validated semi-quantitative food frequency questionnaire we eventually estimated dietary daily intake of trace elements in a Northern Italian community. In the 890 analyzed food samples, the main contributors to cadmium intake are cereals, vegetables and sweets, while cereals, beverages and vegetable are to primary source of manganese. The primary contributors for copper are cereals, fresh fruits and vegetables, while for chromium are beverages, cereals and meat. The main source of selenium intake are cereals and meat, followed by fish, seafood and milk and dairy products, while of zinc intake are meat, cereals, milk and dairy products. In our Italian population sample, the estimated median (interquartile range) dietary daily intakes are 5.00 (3.17-7.65), 56.70 (36.08-86.70) and 66.53 (40.04-101.32) μg/day for cadmium, chromium and selenium, and corresponding figures are 0.98 (0.61-1.49), 2.34 (1.46-3.52) and 8.50 (5.21-12.48) mg/day for copper, manganese and zinc. The estimated intakes are generally within the average intake reported in other European populations, and in such cases well above the daily dietary intakes recommended by national international agencies, avoiding the risk of excess or deficiency. The present estimated intake data can be used to examine a specific trace element of interest and would afford enhanced health protection from those trace elements characterized by both nutritional and toxicological effects.


Cost-effectiveness of everolimus-eluting versus bare-metal stents in ST-segment elevation myocardial infarction: An analysis from the EXAMINATION randomized controlled trial.
Use of everolimus-eluting stents (EES) has proven to be clinically effective and safe in patients with ST-segment elevation myocardial infarction but it remains unclear whether it is cost-effective compared to bare-metal stents (BMS) in the long-term. We sought to assess the cost-effectiveness of EES versus BMS based on the 5-year results of the EXAMINATION trial, from a Spanish health service perspective. Decision analysis of the use of EES versus BMS was based on the patient-level clinical outcome data of the EXAMINATION trial. The analysis adopted a lifelong time horizon, assuming that long-term survival was independent of the initial treatment strategy after the end of follow-up. Life-expectancy, health-state utility scores and unit costs were extracted from published literature and publicly available sources. Non-parametric bootstrapping was combined with probabilistic sensitivity analysis to co-assess the impact of patient-level variation and parameter uncertainty. The main outcomes were total costs and quality-adjusted life-years. The incremental cost-effectiveness ratio was expressed as cost per quality-adjusted life-years gained. Costs and effects were discounted at 3%. The model predicted an average survival time in patients receiving EES and BMS of 10.52 and 10.38 undiscounted years, respectively. Over the life-long time horizon, the EES strategy was €430 more costly than BMS (€8,305 vs. €7,874), but went along with incremental gains of 0.10 quality-adjusted life-years. This resulted in an average incremental cost-effectiveness ratio over all simulations of €3,948 per quality-adjusted life-years gained and was below a willingness-to-pay threshold of €25,000 per quality-adjusted life-years gained in 86.9% of simulation runs. Despite higher total costs relative to BMS, EES appeared to be a cost-effective therapy for ST-segment elevation myocardial infarction patients due to their incremental effectiveness. Predicted incremental cost-effectiveness ratios were below generally acceptable threshold values.


Upper extremity deep vein thrombosis in hospitalized patients: a descriptive study.
Increasingly, there is a focus on the prevention of hospital-acquired conditions including venous thromboembolism. Many studies have evaluated pulmonary embolism and lower extremity deep vein thrombosis, but less is known about upper extremity deep vein thrombosis (UEDVT) in hospitalized patients. The objective of this study was to describe UEDVT incidence, associated risks, outcomes, and management in our institution. Using an information technology tool, we reviewed records of all symptomatic adult inpatients diagnosed with UEDVT at an academic tertiary center between September 2011 and November 2012. Fifty inpatients were diagnosed with 76 UEDVTs. Their mean age was 49 years; 70% were men. Sixteen percent had a history of venous thromboembolism; 20% had a history of malignancy. The mean length of stay (LOS) was 24.6 days (range, 2-91 days); 50% were transferred from outside hospitals. Thirty-eight percent of UEDVTs were in internal jugular veins, 21% in axillary veins, and 25% in brachial veins. Forty-four percent of patients had UEDVT associated with central venous catheters (CVCs). During hospitalization, 78% were fully anticoagulated; 75% of survivors at discharge. Only 38% were discharged to self-care; 10% died during hospitalization. Patients with UEDVT were more likely to have CVCs, malignancy, and severe infection. Many patients were transferred critically ill with prolonged LOS and high in-hospital mortality. Most UEDVTs were treated even in the absence of concurrent lower extremity deep vein thrombosis or pulmonary embolism. Additional research is needed to modify risks and optimize outcomes. Journal of Hospital Medicine 2014;9:48-53. © 2013 Society of Hospital Medicine.


Loss of Tumour Suppressor TMEM127 Drives RET-mediated Transformation Through Disrupted Membrane Dynamics.
Internalization from the cell membrane and endosomal trafficking of receptor tyrosine kinases (RTK) are important regulators of signaling in normal cells that can frequently be disrupted in cancer. The adrenal tumour pheochromocytoma (PCC) can be caused by activating mutations of the RET receptor tyrosine kinase, or inactivation of TMEM127, a transmembrane tumour suppressor implicated in trafficking of endosomal cargos. However, the role of aberrant receptor trafficking in PCC is not well understood. Here, we show that loss of TMEM127 causes wildtype RET protein accumulation on the cell surface, where increased receptor density facilitates constitutive ligand-independent activity and downstream signaling, driving cell proliferation. Loss of TMEM127 altered normal cell membrane organization and recruitment and stabilization of membrane protein complexes, impaired assembly, and maturation of clathrin coated pits, and reduced internalization and degradation of cell surface RET. In addition to RTKs, TMEM127 depletion also promoted surface accumulation of several other transmembrane proteins, suggesting it may cause global defects in surface protein activity and function. Together, our data identify TMEM127 as an important determinant of membrane organization, including membrane protein diffusability and protein complex assembly, and provide a novel paradigm for oncogenesis in PCC where altered membrane dynamics promotes cell surface accumulation and constitutive activity of growth factor receptors to drive aberrant signaling and promote transformation.