Health literacy as a predictor of follow-up after an abnormal Pap smear: a prospective study.
Low literacy influences cervical cancer screening knowledge, and is a possible contributor to racial disparities in cervical cancer. To examine the hypothesis that literacy predicts patient adherence to follow-up recommendations after an abnormal Pap smear. A prospective, continuity clinic-based study. From a sample of 538 women undergoing literacy testing at the time of Pap smear screening, we studied 68 women with abnormal Pap smear diagnoses. Literacy was assessed using the Rapid Evaluation of Adult Literacy in Medicine (REALM). We also measured other proxies for literacy, including educational attainment and physician estimates of patients' literacy level. Outcome measures included on-time and 1-year follow-up and duration of time to follow-up after an abnormal Pap smear. Only one-third of the cohort adhered to follow-up recommendations. At 1 year, 25% of the women had not returned at all. Patients with inadequate literacy (as assessed by the REALM) were less likely to follow up within 1 year, although this result was not statistically significant (adjusted odds ratio [OR]=3.8, 95% confidence interval [CI]: 0.8 to 17.4). Patients subjectively assessed by their physician to have low literacy skills were significantly less likely to follow up within 1 year (adjusted OR=14, 95% CI: 3 to 65). Less than high school education (hazard ratio (HR)= 2.3; 95% CI: 1.2, 4.6) and low physician-estimated literacy level (HR=3.4, 95% CI: 1.4, 8.2), but not objective literacy level, were significant predictors of duration of time to follow-up, adjusting for recommended days to follow-up and other factors. Among women with an abnormal Pap smear, those perceived by their physician to have low literacy were significantly more likely to fail to present for follow-up.


Epileptic Seizure Detection and Experimental Treatment: A Review.
One-fourths of the patients have medication-resistant seizures and require seizure detection and treatment continuously to cope with sudden seizures. Seizures can be detected by monitoring the brain and muscle activities, heart rate, oxygen level, artificial sounds, or visual signatures through EEG, EMG, ECG, motion, or audio/video recording on the human head and body. In this article, we first discuss recent advances in seizure sensing, signal processing, time- or frequency-domain analysis, and classification algorithms to detect and classify seizure stages. Then, we show a strong potential of applying recent advancements in non-invasive brain stimulation technology to treat seizures. In particular, we explain the fundamentals of brain stimulation approaches, including (1) transcranial magnetic stimulation (TMS), (2) transcranial direct current stimulation (tDCS), (3) transcranial focused ultrasound stimulation (tFUS), and how to use them to treat seizures. Through this review, we intend to provide a broad view of both recent seizure diagnoses and treatments. Such knowledge would help fresh and experienced researchers to capture the advancements in sensing, detection, classification, and treatment seizures. Last but not least, we provide potential research directions that would attract seizure researchers/engineers in the field.


Characterization of the Fungitoxic Activity on Botrytis cinerea of N-phenyl-driman-9-carboxamides.
A total of 12 compounds were synthesized from the natural sesquiterpene (-) drimenol (compounds 4 to 15). The synthesized compounds corresponded to N-phenyl-driman-9-carboxamide derivatives, similar to some fungicides that inhibit the electron-transport chain. Their structures were characterized and confirmed by 1H NMR, 13C NMR spectroscopy, and mass spectrometry. Compounds 5 to 15 corresponded to novel compounds. The effect of the compounds on the mycelial growth of Botrytis cinerea was evaluated. Methoxylated and chlorinated compounds in the aromatic ring (compounds 6, 7, 12, and 13) exhibited the highest antifungal activity with IC50 values between 0.20 and 0.26 mM. On the other hand, the effect on conidial germination of B. cinerea of one methoxylated compound (6) and one chlorinated compound (7) was analyzed, and no inhibition was observed. Additionally, compound 7 decreased 36% the rate of oxygen consumption by germinating conidia.


Structure, dynamics, and thermodynamics of a family of potentials with tunable softness.
We investigate numerically the structure, thermodynamics, and relaxation behavior of a family of (n, 6) Lennard-Jones-like glass-forming binary mixtures interacting via pair potentials with variable softness, fixed well depth, and fixed well depth location. These constraints give rise to progressively more negative attractive tails upon softening, for separations greater than the potential energy minimum. Over the range of conditions examined, we find only modest dependence of structure on softness. In contrast, decreasing the repulsive exponent from n=12 to n=7 causes the diffusivity to increase by as much as two orders of magnitude at fixed temperature and density, and produces mechanically stable packings (inherent structures) with cohesive energies that are, on average, ∼1.7 well depths per particle larger than for the corresponding Lennard-Jones (n=12) case. The softer liquids have markedly higher entropies and lower Kauzmann temperatures than their Lennard-Jones (n=12) counterparts, and they remain diffusive down to appreciably lower temperatures. We find that softening leads to a modest increase in fragility.


Resveratrol Improves Paclitaxel-Induced Cognitive Impairment in Mice by Activating SIRT1/PGC-1α Pathway to Regulate Neuronal State and Microglia Cell Polarization.
This study aimed to investigate the effect of resveratrol (Res) on paclitaxel (PTX)-induced cognitive impairment and elucidate the underlying molecular mechanisms. Morris Water Maze (MWM) test was used to evaluate the mice's spatial learning and memory abilities. Western blotting was applied to detect protein expression of receptor-interacting protein (RIP3), mixed lineage kinase domain-like protein (MLKL), silencing information regulator 2 related enzyme 1 (SIRT1), peroxisome proliferator activated receptor coactivator-1 (PGC-1α), NADPH oxidase 2 (NOX2), NOX4, postsynaptic density zone 95 (PSD95), arginase-1 (Arg-1) and inducible nitric oxide synthase (iNOS). Immunofluorescence of RIP3, MLKL, Arg-1, Iba-1 and iNOS was conducted to observe the apoptosis of hippocampal cells and the polarization of microglia. qRT-PCR was performed to detect BDNF mRNA expressions. DHE staining was used to assess the level of oxidative stress response. Golgi-Cox staining and dendritic spine counting were applied to visualize synaptic structural plasticity. Postsynaptic density was performed by transmission electron microscope. ELISA was used to detect the contents of tumour necrosis factor alpha (TNF-α), IL-1β, IL-4, and IL-10. PTX-induced cognitive impairment model was constructed after the application of PTX, represented as longer latency to platform and less platform crossing times over the whole period in PTX group. After Res treatment, the above indicators were reversed, indicating that cognitive function was improved. Moreover, Res reduced neuronal apoptosis and oxidative stress through SIRT1/PGC-1α pathway in mice, manifesting as down-regulated expression of RIP3, MLKL, NOX2 and NOX4. Meanwhile, Res increased the density of dendritic spines and the expression of PSD95 and BDNF, thereby ameliorating the PTX induced synaptic damage. Besides, M2 microglia was in the majority, eliciting the expression of anti-inflammatory cytokines IL-4 and IL-10 after Res treatment in PTX+Res group, while immunofluorescence images results demonstrated an decrease in the proportion of M2 microglia a following SIRT1 inhibitor EX-527. Res improves PTX-induced cognitive impairment in mice by activating SIRT1/PGC-1α pathways to regulate neuronal state and microglia cell polarization.


Nanotherapeutics in angiogenesis: synthesis and in vivo assessment of drug efficacy and biocompatibility in zebrafish embryos.
Carbon nanotubes have shown broad potential in biomedical applications, given their unique mechanical, optical, and chemical properties. In this pilot study, carbon nanotubes have been explored as multimodal drug delivery vectors that facilitate antiangiogenic therapy in zebrafish embryos. Three different agents, ie, an antiangiogenic binding site (cyclic arginine-glycin-easpartic acid), an antiangiogenic drug (thalidomide), and a tracking dye (rhodamine), were conjugated onto single-walled carbon nanotubes (SWCNT). The biodistribution, efficacy, and biocompatibility of these triple functionalized SWCNT were tested in mammalian cells and validated in transparent zebrafish embryos. Accumulation of SWCNT-associated nanoconjugates in blastoderm cells facilitated drug delivery applications. Mammalian cell xenograft assays demonstrated that these antiangiogenic SWCNT nanoconjugates specifically inhibited ectopic angiogenesis in the engrafted zebrafish embryos. This study highlights the potential of using SWCNT for generating efficient nanotherapeutics.


From meiosis to postmeiotic events: alignment and recognition of homologous chromosomes in meiosis.
Recombination of homologous chromosomes is essential for correct reductional segregation of homologous chromosomes, which characterizes meiosis. To accomplish homologous recombination, chromosomes must find their homologous partners and pair with them within the spatial constraints of the nucleus. Although various mechanisms have developed in different organisms, two major steps are involved in the process of pairing: first, alignment of homologous chromosomes to bring them close to each other for recognition; and second, recognition of the homologous partner of each chromosome so that they can form an intimate pair. Here, we discuss the various mechanisms used for alignment and recognition of homologous chromosomes in meiosis.


Inhibition of proliferation of human leukaemic cell populations by deferoxamine.
Deferoxamine is a hydroxylamine which binds ferric ions to form a highly stable complex. Since iron is thought to be required at a critical stage for cell proliferation, we investigated the effect of deferoxamine on the proliferative activity of human leukaemic cell populations in vitro by means of 3 permanent cell lines, HL60, U937 and 8402. We found deferoxamine to be a potent inhibitor of DNA synthesis and proliferation of leukaemic cells, acting by accumulating treated cells at the early S phase of the cell cycle. Suppression of leukaemic proliferation was obtained at deferoxamine concentrations in the range usually achieved in the treatment of patients for iron overload. Deferoxamine might therefore warrant further investigation as a potentially useful agent for leukaemia chemotherapy.


Distribution and function of hyaluronan binding protein involved in hyaluronan depolymerization (HYBID, KIAA1199) in the mouse central nervous system.
HYBID (HYaluronan Binding Protein Involved in hyaluronan [HA] Depolymerization, KIAA1199) is one of the HA binding proteins that is involved in the depolymerization of HA. HYBID mRNA is highly expressed in the brain, however, the role of HYBID in the brain remains unclear. In this study, we bred Hybid knock-out (KO) mice and evaluated the function of Hybid in the central nervous system. Hybid mRNA was expressed in the brain, especially in the hippocampus and cerebellum, in wild-type mice. Hybid KO mice demonstrated decreased mnemonic ability in novel object recognition and Morris water maze tests. The average molecular mass of hippocampal HA increased in KO mice, accompanied by a significant increase in the total HA amount. Hybid KO mice did not differ in behavior from wild-type mice in the open field test, evaluation of acoustic startle responses, or drug-induced seizure test. In real-time PCR, Hyal1 and Hyal2 mRNA levels, which code hyaluronidases 1 and 2, respectively, did not differ between the Hybid KO and wild-type mouse brain. These results indicate that Hybid plays a key role in memory function in the brain.


Understanding coronary artery bypass transit time flow curves: role of bypass graft compliance.
Low mean bypass graft flow (Q) and high pulsatility index (PI) measured by the transit time flow measurement method are not specific for anastomotic stenosis, but occur with competitive flow and poor coronary run-off. We hypothesized that graft compliance is responsible for these changes and that flow measured at the proximal end of the coronary bypass can be viewed as a sum of the graft capacitive flow and flow that passes through the distal anastomosis. Transit time flow measurements (TTFMs) of 15 left internal thoracic artery (LITA) to LAD bypass grafts and 10 saphenous vein grafts (SVGs) to either the right coronary artery (RCA) or posterior descending artery (PDA) were analysed. The TTFM was performed on the proximal and distal end of the graft, and proximally with distal occlusion of the graft. Low mean bypass graft flow PI and diastolic filling (DF) measured distally and proximally were compared, and graft compliance was estimated. Diastolic filling was higher distally in every single case (LITA-LAD: distal DF 76 ± 12% vs proximal 66 ± 13%, P = 0.005; SVG-RCA/PDA: distal 72 ± 15% vs proximal 63 ± 12%, P = 0.018). There were no significant differences in Q and PI. Subtracting the distal from the proximal flow gave a result identical to the proximal TTFM in distally occluded grafts, confirming the presence of graft capacitive flow. Graft compliance estimated from the flow of distally occluded grafts was 0.99 ± 0.47 μl/mmHg for LITA grafts and 0.78 ± 0.42 μl/mmHg for SVG grafts. The study confirmed that the TTFM measured at the proximal end of the coronary bypass could be viewed as a sum of graft capacitive flow and the flow that passes through the distal anastomosis. Graft capacitive flow increases the systolic and decreases the diastolic TTFM when measured at the proximal end of the graft. It explains the higher DF when the TTFM is measured at the distal end of the graft and the increase in the PI at the proximal end when Q decreases. As the influence of graft capacitive flow on the PI in low Q can be eliminated by performing the TTFM at the distal end of the graft, we believe that the value of PI is clinically irrelevant.


The risk of partner aggression research: impact of laboratory couples conflict protocols on participants.
The impact of male-to-female intimate partner violence (IPV) research on participants is unknown. A measure of impact was given to participants in an IPV study to assess systematically the impact of completing questionnaires, engaging in conflict conversations, and being interviewed individually about anger escalation and de-escalation during the conversations. Participants completed a six-question, Likert-scaled impact measure. Both male and female participants rated the impact of the study as helpful to them personally and to their relationships. Female participants rated different segments of the study as more helpful to themselves and their relationships, while male participants did not find any segment of the study to have a different impact than other segments.


Postformal thinking and creativity among late adolescents: a post-Piagetian approach.
This study investigated the relationship between cognitive development levels and creative performance among late adolescents from a post-Piagetian perspective. Participants were 386 college students, ranging in age from 19 to 26 years. The Social Paradigm Belief Scale was employed to measure the three cognitive styles of late adolescence: formal, relativistic, and dialectical thinking. The Divergent Thinking Test (DTT) was used to measure creative performance. Dialectical and relativistic thinking were positively correlated with creative performance, whereas formal thinking was negatively correlated. Planned contrasts revealed that postformal thinkers scored higher than formal thinkers in all dimensions of creativity, and additional MANOVA analysis exhibited a similar pattern. Multiple discriminant analysis showed that the linear combination of the six dimensions of creativity recognized in the DTT discriminated between formal and postformal thinkers, which supported our findings about the relationship between postformal thinking and creativity. Future research directions and implications for creativity pedagogy are discussed.


Direct measurement of oxidative metabolism in the living brain by microdialysis: a review.
This review summarizes microdialysis studies that address the question of which compounds serve as energy sources in the brain. Microdialysis was used to introduce 14C-labeled glucose, lactate, pyruvate, glutamate, glutamine, and acetate into the interstitial fluid of the brain to observe their metabolism to 14CO2. Although glucose uptake from the systemic system supplies the carbon source for these compounds, compounds synthesized from glucose by the brain are subject to recycling including complete metabolism to CO2. Therefore, the brain utilizes multiple compounds in its domain to provide the energy needed to fulfill its function. The physiological conditions controlling metabolism and the contribution of compartmentation into different brain regions, cell types, and subcellular spaces are still unresolved. The aconitase inhibitor fluorocitrate, with a lower inhibition threshold in glial cells, was used to identify the proportion of lactate and glucose that was oxidized in glial cells versus neurons. The fluorocitrate data suggest that glial and neuronal cells are capable of utilizing both lactate and glucose for energy metabolism.


The crisis of September 11: the emergency response of Ontario hospitals and other health system partners.
The horrific events of September 11, 2001, have caused all individuals and institutions to step back and evaluate their ability to respond to a crisis of previously unimaginable proportions. A media search and incident review of Ontario Ministry of Health and Long-Term Care records confirms that no event in collective memory has had the potential to yield so many hospital patients. This article describes the legislative framework and process by which the ministry either leads or supports an emergency response. Within this context, the authors analyze the early preparations of the ministry and the Ontario hospital system as they readied to accept unknown numbers of patients from the attacks on the World Trade Center in New York City and the Pentagon in Washington, DC. While the focus of the article is on hospitals, the authors also consider the readiness actions taken by the system as a whole, including emergency services, CritiCall and the Ontario Hospital Association. The role of support agencies in helping Ontario's hospitals respond to the crisis is also examined. Whether the preparations undertaken and the commitments made by Ontario's hospitals and other health system partners would have been sufficient remains untested at this time. However, a careful review of emergency response strategies in order to identify any planning gaps is only prudent. This analysis concludes with a discussion of what has been learned and some thoughts on how those lessons can assist the ministry and our hospitals to remain prepared.


Solving a Higgs optimization problem with quantum annealing for machine learning.
The discovery of Higgs-boson decays in a background of standard-model processes was assisted by machine learning methods. The classifiers used to separate signals such as these from background are trained using highly unerring but not completely perfect simulations of the physical processes involved, often resulting in incorrect labelling of background processes or signals (label noise) and systematic errors. Here we use quantum and classical annealing (probabilistic techniques for approximating the global maximum or minimum of a given function) to solve a Higgs-signal-versus-background machine learning optimization problem, mapped to a problem of finding the ground state of a corresponding Ising spin model. We build a set of weak classifiers based on the kinematic observables of the Higgs decay photons, which we then use to construct a strong classifier. This strong classifier is highly resilient against overtraining and against errors in the correlations of the physical observables in the training data. We show that the resulting quantum and classical annealing-based classifier systems perform comparably to the state-of-the-art machine learning methods that are currently used in particle physics. However, in contrast to these methods, the annealing-based classifiers are simple functions of directly interpretable experimental parameters with clear physical meaning. The annealer-trained classifiers use the excited states in the vicinity of the ground state and demonstrate some advantage over traditional machine learning methods for small training datasets. Given the relative simplicity of the algorithm and its robustness to error, this technique may find application in other areas of experimental particle physics, such as real-time decision making in event-selection problems and classification in neutrino physics.


Replacement of the descending aorta: recent outcomes of open surgery performed with partial cardiopulmonary bypass.
Surgical replacement is our standard treatment for descending aortic aneurysm, despite the advent of thoracic endoprostheses. We retrospectively analyzed outcomes of descending aortic replacement performed with partial cardiopulmonary bypass. Since 1994, a total of 113 patients in our institution (mean age 68 +/- 12 years, n = 75 male) have undergone graft replacement of the descending aorta for nondissecting aneurysm. There were 16 emergency cases (14.2%). All operations were performed through left thoracotomy with partial cardiopulmonary bypass with segmental clamping. Since 1998, preoperative magnetic resonance angiography has been performed to detect the Adamkiewicz artery in elective cases. Motor evoked potentials are now measured intraoperatively. Early mortalities were 5.3% overall (6/113), 1.0% (1/97) in elective cases, and 31.3% (5/16) in emergency cases. Rates of spinal cord dysfunction were 2.7% overall (3/113), 1.0% (1/97) in elective cases, and 12.5% (2/16) in emergency cases. Stroke rates were 7.1% overall (8/113), 4.1% (4/97) in elective cases, and 25.0% (4/16) in emergency cases. Rates of respiratory failure were 9.7% overall (11/113), 9.2% (9/97) in elective cases, and 12.5% (2/16) in emergency cases. No patient underwent reoperation for the same lesion as a result of repair problems in the follow-up period. Kaplan-Meier overall survival estimates were 92.2% at 3 years, 90.6% at 5 years, and 70.2% at 10 years. Although it is more invasive than stent graft repair, descending aorta replacement performed with partial cardiopulmonary bypass involves a risk comparable to that associated with thoracic endoprosthesis placement.


Mortality Rate in a Cohort of People Living With HIV in Rural Tanzania After Accounting for Unseen Deaths Among Those Lost to Follow-up.
Mortality assessment in cohorts with high numbers of persons lost to follow-up (LTFU) is challenging in settings with limited civil registration systems. We aimed to assess mortality in a clinical cohort (the Kilombero and Ulanga Antiretroviral Cohort (KIULARCO)) of human immunodeficiency virus (HIV)-infected persons in rural Tanzania, accounting for unseen deaths among participants LTFU. We included adults enrolled in 2005-2015 and traced a nonrandom sample of those LTFU. We estimated mortality using Kaplan-Meier methods 1) with routinely captured data (method A), 2) crudely incorporating tracing data (method B), 3) weighting using tracing data to crudely correct for unobserved deaths among participants LTFU (method C), and 4) weighting using tracing data accounting for participant characteristics (method D). We investigated associated factors using proportional hazards models. Among 7,460 adults, 646 (9%) died, 883 (12%) transferred to other clinics, and 2,911 (39%) were LTFU. Of 2,010 (69%) traced participants, 325 (16%) were found: 131 (40%) had died and 130 (40%) had transferred. Five-year mortality estimates derived using the 4 methods were 13.1% (A), 16.2% (B), 36.8% (C), and 35.1% (D), respectively. Higher mortality was associated with male sex, referral as a hospital inpatient, living close to the index clinic, lower body mass index, more advanced World Health Organization HIV clinical stage, lower CD4 cell count, and less time since initiation of antiretroviral therapy. Adjusting for unseen deaths among participants LTFU approximately doubled the 5-year mortality estimates. Our approach is applicable to other cohort studies adopting targeted tracing.


Vancomycin-resistant enterococcal colonisation of hospitalised patients in Auckland.
To assess the prevalence of vancomycin-resistant enterococcal colonisation of hospitalised patients in five selected Auckland hospitals. Faeces specimens submitted to the Microbiology Laboratories at Auckland and Middlemore Hospitals for Clostridium difficile toxin assay were screened for the presence of vancomycin-resistant enterococci (VRE). VRE were cultured from two of 686 patients, giving a colonisation rate of 0.3% in those patients who had a faeces sample submitted for C. difficile toxin assay (95% CI 0 to 0.7%). Both isolates were Enterococcus faecalis; susceptible to ampicillin, resistant to vancomycin and of the vanA genotype. This is the first screening study in New Zealand that has identified patients with VRE colonisation. While VRE are still rarely isolated in this country, rates of colonisation and infection may be increasing. Hospitals need to be aware of the likely emergence of VRE and be prepared to implement strategies to limit their spread.


Release of elements from some gold alloys and amalgams in corrosion.
The release of Au, Ag, Cu and Zn elements from six commercially available gold alloys and three amalgam alloys was studied. The polarizing electropotential system with modified Fusayama solution was used. The cycle process was repeated 500 times between +/- 1000 mV during a period of 5 h 22 min. During the process samples of solution were analyzed in order to follow the release of elements. Results revealed rapid release of Zn from most alloys, release of Ag from most alloys and release of Au from two alloys. Also, rapid release of Cu was found from amalgams but not from gold alloys. Release of Ag from gold alloys showed very good passivation up to 3 h, after which it was released in varying amounts.


Reduced transaminase B (IlvE) activity caused by the lack of yjgF is dependent on the status of threonine deaminase (IlvA) in Salmonella enterica serovar Typhimurium.
The YjgF/YER057c/UK114 family is a highly conserved class of proteins that is represented in the three domains of life. Thus far, a biochemical function demonstrated for these proteins in vivo or in vitro has yet to be defined. In several organisms, strains lacking a YjgF homolog have a defect in branched-chain amino acid biosynthesis. This study probes the connection between yjgF and isoleucine biosynthesis in Salmonella enterica. In strains lacking yjgF the specific activity of transaminase B, catalyzing the last step in the synthesis of isoleucine, was reduced. In the absence of yjgF, transaminase B activity could be restored by inhibiting threonine deaminase, the first enzymatic step in isoleucine biosynthesis. Strains lacking yjgF showed an increased sensitivity to sulfometruron methyl, a potent inhibitor of acetolactate synthase. Based on work described here and structural reports in the literature, we suggest a working model in which YjgF has a role in protecting the cell from toxic effects of imbalanced ketoacid pools.


Increased connective tissue extracellular matrix in the op/op model of osteopetrosis.
Mice that are homozygous for the recessive osteopetrosis spontaneous mutation (op/op) develop severe osteopetrosis due to a defect in the production of macrophage colony-stimulating factor (M-CSF) and a deficiency in monocyte-derived osteoclasts. Our study describes a novel soft tissue finding in an osteopetrosis (B6C3Fe a/a-Csf1(op)/J) mouse model. Tissues were obtained from B6C3Fe a/a-Csf1(op)/J mice and age-matched wild-type mice, processed for hematoxylin and eosin sections, and comprehensive light microscopic tissue evaluation was performed. Mutant mice had characteristic traits of op/op deficiency including missing incisors and domed skulls. Histologically, the bone marrow cavity was effaced by interweaving thick bony trabeculae consistent with osteopetrosis. An increase in a finely granular, basophilic interstitial extracellular matrix (ECM) was observed in the subcutaneous connective tissue of the op/op mice when compared with controls. Histochemically, the ECM was negative with periodic acid Schiff and stained dark blue with alcian blue at a pH of 2.5, indicating that it is composed primarily of nonsulfated glycosaminoglycans (GAGs). This work suggests an increased ECM that is composed mainly of GAGs located in the subcutaneous tissue in op/op mice. This increase in ECM may be related to altered matrix production or turnover because of changes in M-CSF production.


Identification of novel MECOM gene fusion and personalized therapeutic targets through integrative clinical sequencing in secondary acute myeloid leukemia in a patient with severe congenital neutropenia: a case report and literature review.
Severe congenital neutropenia (SCN) is a rare hematologic disorder characterized by defective myelopoiesis and a high incidence of malignant transformation to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). SCN patients who develop MDS/AML have excessive toxicities to traditional chemotherapy, and safer therapies are needed to improve overall survival in this population. In this report, we outline the use of a prospective integrative clinical sequencing trial (PEDS-MIONCOSEQ) in a patient with SCN and AML to help identify oncogenic targets for less toxic agents. Integrative sequencing identified two somatic cis-mutations in the colony stimulating factor 3 receptor (CSF3R) gene, a p.T640N mutation in the transmembrane region and a p.Q768* truncation mutation in the cytoplasmic domain. A somatic mutation p.H105Y, in the runt homology domain (RHD) of runt-related transcription factor 1 (RUNX1), was also identified. In addition, sequencing discovered a unique in-frame EIF4A2-MECOM (MDS1 and ectopic viral integration site 1 complex) chromosomal translocation with high MECOM expression. His mutations in CSF3R served as potential targets for tyrosine kinase inhibition and therefore provided an avenue to avoid more harmful therapy. This study highlights the utility of integrative clinical sequencing in SCN patients who develop leukemia and outlines a strategy on how to approach these patients in a future clinical sequencing trial to improve historically poor outcomes. A thorough review of leukemia in SCN and the role of CSF3R mutations in oncologic therapy are provided to support a new strategy on how to approach MDS/AML in SCN.


Characterization of a cluster of CTCF-binding sites in a protocadherin regulatory region.
The mammalian clustered protocadherin (Pcdh) locus contains more than 50 highly-similar genes arrayed in tandem. These Pcdh genes are organized into three closely-linked clusters (Pcdhα, Pcdhβ, and Pcdhγ). The encoded PCDH proteins play critical roles in neuronal diversity, single cell identity, and synaptic connectivity. Recent studies revealed that directional CTCF (CCCTC-binding factor) binding to CBS (CTCF-binding site) determines the specific interaction between enhancers and promoters, and the three Pcdhβγ clusters form two CCDs (CTCF/cohesin- mediated chromatin domain) which is important for gene regulation. Here, we characterized a regulatory region, which contains several HSs (DNase I hypersensitive sites), downstream of the Pcdhβ clusters. Specifically, CTCF ChIP-Seq (Chromatin immunoprecipitation-sequencing) experiments revealed several peaks in the Pcdhβγ regulatory regions. In addition, we performed comprehensive EMSA (Electrophoresis mobility shift assay) experiments and identified exact 42-bp CBS sites for each CTCF peak. Interestingly, we found that single CTCF peaks can contain two CBS sites. Finally, genome-wide computational analyses revealed many CBS sites close to chromatin marks of regulatory elements, such as enhancers and promoters. We propose that CTCF may mediate specific interactions between enhancers and promoters to form active transcription hub for gene expression.


A single arm prospective feasibility study evaluating wound closure with a unique wearable device that provides intermittent plantar compression and offloading in the treatment of non-healing diabetic foot ulcers.
The incidence and economic burden of diabetic foot ulcers continues to rise throughout the world. In this prospective study, a unique device designed to offload the wound, enhance circulation and monitor patient compliance was evaluated for safety and efficacy. The device provides offloading and intermittent plantar compression to improve the pedal flow of oxygenated blood and support wound healing while recording patient use. Ten patients with non-healing diabetic foot ulcers UTgrade 1A/Wagner grade 1 were treated weekly for up to 12 weeks. The primary endpoint was complete wound closure at 12 weeks, and secondary endpoints included healing time, percent area reduction and changes in pain using the visual analogue pain scale. Eight out of ten wounds healed within 12 weeks(80%), and the mean healing time was 41 days(95% CI:24.3-58.3). The percent area reduction was 75(SD:53.9). The baseline visual analogue pain scale was 4.5(2.9) as compared with 3.3(3.4) at end of study. No device-related or serious adverse events were reported. This unique intermediate plantar compression and offloading device may be considered as an alternative for safe and effective for treatment of non-healing diabetic foot ulcers. During treatment, wound healing was significantly accelerated, and pain was improved. Larger randomised controlled trials are underway to validate these early findings.


The contribution of apparent and inherent usability to a user's satisfaction in a searching and browsing task on the Web.
Previous research found that apparent and inherent usability had big influences on user's acceptance of computer systems. This research extended these findings to the area of user's satisfaction. The study investigated the impact of inherent and apparent usability on user's satisfaction of Web page designs while the two main tasks on the World Wide Web, searching and browsing, were performed. The results indicated that inherent usability was the main factor contributing to user's satisfaction in both searching and browsing. General principles and specific recommendations for the design and evaluation of Web page designs are derived from these findings.


Photoinduced electron transfer from carbon nanotubes to fullerenes: C60versus C70.
Hybrid carbon materials are found to exhibit novel optoelectronic properties at their interfaces, but the related interfacial carrier dynamics is rarely explored theoretically. In this contribution, we have employed density functional theory (DFT) and DFT-based nonadiabatic dynamics methods to explore photoinduced interfacial electron transfer processes at interfaces between a single-walled carbon nanotube with chiral index (6,5) and C60 or C70 (C60@CNT65 and C70@CNT65). We have found that with low E11 excitation, electron transfer takes place from CNT65 to C60 and C70 in both heterojunctions. This process is ultrafast and completed within about 200 fs, which is consistent with recent experiments. Differently, high E22 excitation does not induce electron injection to C60 in C60@CNT65; instead, "hot" electrons produced within CNT65 will be trapped in its higher conduction band for a while because of slow inter-band relaxation. By contrast, in C70@CNT65, high E22 excitation still can lead to ultrafast electron transfer to C70, but only a comparable amount of electrons are transferred (ca. 30%). Interestingly, electrons either remaining on CNT65 or transferred to C70 are trapped in the higher conduction band for a while, similarly, due to slow inter-band relaxation. The present results could be useful to guide the design of excellent interfaces of mixed-dimensional hybrid carbon materials for various optoelectronic applications.


Ministerial Resolution No. 392-88-SA/DM, 24 October 1988.
This Resolution sets forth the Regulations on the organization and functions of the Peruvian National Maternal-Child Institute, created by Supreme Decree No. 022-87-SA. The following are among the functions of the Institute: 1) to propose a policy of maternal-perinatal care; 2) to encourage and realize basic, clinical, and operative research, developing technologies appropriate to the national maternal-perinatal health situation; 3) to disseminate to all levels scientific results in the maternal-perinatal area; 4) to coordinate and develop specialized training programs in maternal-perinatal health directed at health personnel and the community; 5) to contribute to the improvement and training of all personnel participating in activities aimed at gynecological, obstetrical, and perinatal care; 6) to intensify the training of specialists required for the care of women and childbirth; 7) to facilitate the decentralization of maternal-child care in order to achieve specialized care; 8) to propose rules and procedures for maternal-perinatal care; 9) to advise the High Directorate of the Ministry of Health with respect to maternal-child care; 10) to coordinate, support, and evaluate activities carried out by public and other institutions directed at maternal-perinatal health care; and 11) to increase and improve the quality of institutional care services for women of child-bearing age, pregnant women, child-birth, and the recently born, with the priority of developing care of greater sophistication. Further provisions of the Resolution set forth the organization, interinstitutional relations, and resources of the Institute, among other things.


Understanding Reaction Networks through Controlled Approach to Equilibrium Experiments Using Transient Methods.
We report a combined experimental/theoretical approach to studying heterogeneous gas/solid catalytic processes using low-pressure pulse response experiments achieving a controlled approach to equilibrium that combined with quantum mechanics (QM)-based computational analysis provides information needed to reconstruct the role of the different surface reaction steps. We demonstrate this approach using model catalysts for ammonia synthesis/decomposition. Polycrystalline iron and cobalt are studied via low-pressure TAP (temporal analysis of products) pulse response, with the results interpreted through reaction free energies calculated using QM on Fe-BCC(110), Fe-BCC(111), and Co-FCC(111) facets. In TAP experiments, simultaneous pulsing of ammonia and deuterium creates a condition where the participation of reactants and products can be distinguished in both forward and reverse reaction steps. This establishes a balance between competitive reactions for D* surface species that is used to observe the influence of steps leading to nitrogen formation as the nitrogen product remains far from equilibrium. The approach to equilibrium is further controlled by introducing delay timing between NH3 and D2 which allows time for surface reactions to evolve before being driven in the reverse direction from the gas phase. The resulting isotopic product distributions for NH2D, NHD2, and HD at different temperatures and delay times and NH3/D2 pulsing order reveal the role of the N2 formation barrier in controlling the surface concentration of NHx* species, as well as providing information on the surface lifetimes of key reaction intermediates. Conclusions derived for monometallic materials are used to interpret experimental results on a more complex and active CoFe bimetallic catalyst.


Treatment of acute silicoproteinosis by whole-lung lavage.
Acute silicoproteinosis is a rare disease that occurs following a heavy inhalational exposure to silica dusts. Clinically, it resembles pulmonary alveolar proteinosis (PAP); silica exposure is thought to be a cause of secondary PAP. We describe a patient with biopsy-confirmed acute silicoproteinosis whose course was complicated by acute hypoxemic respiratory failure requiring mechanical ventilation. Without clinical improvement despite antibiotic and steroid treatment, the patient was scheduled for whole-lung lavage under general anesthesia. Anesthetic challenges included double-lumen tube placement and single-lung ventilation in a hypoxic patient, facilitating lung lavage, and protecting the contralateral lung from catastrophic spillage.


Narrative review of the mechanism of natural products and scar formation in wound repair.
Wound healing is a complex and multifactorial response to the disruption of the normal anatomy and function of skin tissue, which mainly includes four progressive stages: hemostasis, inflammation, proliferation and remodeling. Wound healing is a complex process, and multiple conditions can lead to impaired wound healing and, consequently, scar formation. Natural products discovered and applied for a long time have always been the source of new drugs. With the deepening of research, the role of natural products in promoting wound repair has gradually been a focus. Some natural products and compound drugs are effective in promoting skin wound healing and in reducing adverse reactions after wound healing. This article reviews the mechanism of natural products and some compound drugs in healing skin wounds from the following aspects: related cellular effects during wound repair and scar formation, regulation of growth factors, extracellular matrix (ECM), and collagen metabolism. Proteolysis by proteolytic enzymes, such as plasmin, matrix metalloproteinases, and their activators and inhibitors, plays a critical role in wound repair. Some keratinocytes often express some matrix metalloproteinases and plasminogen activators, thus promoting the hydrolysis of components such as fibrin in blood clots to facilitate migration. In this paper, we review recent studies on the role and mechanism of some natural products on scar formation found in wound repair. We aim to provide a basis for the in-depth study of the intrinsic mechanism of natural products in repairing wounds and a reference for further development of drugs for wound repair with better efficacy and fewer side effects.


[Higher prevalence of depression in patients with rheumatoid arthritis--a systematic review].
Chronic pain patients frequently suffer from depression. This systematic review finds that patients suffering from rheumatoid arthritis (RA) have a higher prevalence of depression than controls without RA. Depression is related to pain intensity, passive coping strategies and disability. For patients this may result in a decreased quality of life and a shorter lifespan. For society it results in increased health costs.


Impact of long- and short-range fibre depletion on the cognitive deficits of fronto-temporal dementia.
Recent studies suggest a framework where white-matter (WM) atrophy plays an important role in fronto-temporal dementia (FTD) pathophysiology. However, these studies often overlook the fact that WM tracts bridging different brain regions may have different vulnerabilities to the disease and the relative contribution of grey-matter (GM) atrophy to this WM model, resulting in a less comprehensive understanding of the relationship between clinical symptoms and pathology. Using a common factor analysis to extract a semantic and an executive factor, we aimed to test the relative contribution of WM and GM of specific tracts in predicting cognition in the Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI). We found that semantic symptoms were mainly dependent on short-range WM fibre disruption, while damage to long-range WM fibres was preferentially associated to executive dysfunction with the GM contribution to cognition being predominant for local processing. These results support the importance of the disruption of specific WM tracts to the core cognitive symptoms associated with FTD. As large-scale WM tracts, which are particularly vulnerable to vascular disease, were highly associated with executive dysfunction, our findings highlight the importance of controlling for risk factors associated with deep WM disease, such as vascular risk factors, in patients with FTD in order not to potentiate underlying executive dysfunction.


Tianwang Buxin Granules Influence the Intestinal Flora in Perimenopausal Insomnia.
The subjects included 13 PI patients from the Hubei Provincial Hospital of TCM, Hubei University of TCM, and Wuhan Traditional Chinese Medicine Hospital, and the corresponding noninsomniac spouses of the patients were selected as controls. TWBXG was continuously administered for 4 weeks. The feces of PI patients and their noninsomniac spouses before and after treatment with TWBXG were collected. The intestinal flora composition of each group was detected by metagenomic sequencing, and the efficacy of TWBXG was evaluated by the PSQI scale. Compared with the control group, the model group showed an increase in the abundance of Roseburia faecis, Ruminococcus, Prevotella copri, Fusicatenibacter saccharivorans, and Blautia obeum, while those of Bacteroides, fecal Bacteroidetes, and Faecalibacterium prausnitzii were decreased. Compared with pretreatment, the PSQI score was significantly reduced (P < 0.05), the abundance of Bacteroides, fecal Bacteroidetes, and Faecalibacterium prausnitzii increased, and that of Roseburia faecis, Ruminococcus, Prevotella copri, Fusicatenibacter saccharivorans, and Blautia obeum decreased after treatment. However, there was still a certain gap in the abundance of related flora in the treatment group compared with the control. PI is associated with disturbances in the intestinal flora and is mainly related to the disorders of Roseburia faecis, Ruminococcus, Prevotella copri, Fusicatenibacter saccharivorans, Blautia obeum, Bacteroides, fecal Bacteroidetes, and Faecalibacterium prausnitzii. TWBXG can effectively treat PI, and its effect may be achieved by regulating the disordered intestinal flora. Clinical Trials. The study was registered in the Chinese clinical trial registry and approved by the World Health Organization clinical trial registration platform (Effects of the modified Tianwang Buxin granule and modified Tianwang Buxin decoction pieces on insomnia: a randomized, controlled trial, ChiCTR-IPR-17011549).


YB-1, the E2F pathway, and regulation of tumor cell growth.
Y-box binding factor 1 (YB-1) has been associated with prognosis in many tumor types. Reduced YB-1 expression inhibits tumor cell growth, but the mechanism is unclear. YB-1 mRNA levels were compared with tumor grade and histology using microarray data from 771 breast cancer patients and with disease-free survival and distant metastasis-free survival using data from 375 of those patients who did not receive adjuvant therapy. Microarrays were further searched for genes that had correlated expression with YB-1 mRNA. Small interfering RNA (siRNA) was used to study the effects of reduced YB-1 expression on growth of three tumor cell lines (MCF-7 breast, HCT116 colon, and A549 lung cancer cells), on tumorigenesis by A549 cells in nude mice, and on global transcription in the three cancer cell lines. Reporter gene assays were used to determine whether YB-1 siRNAs affected the expression of E2F1, and chromatin immunoprecipitation was used to determine whether YB-1 bound to various E2F promoters as well as E2F1-regulated promoters. All P values were from two-sided tests. YB-1 levels were elevated in more aggressive tumors and were strongly associated with poor disease-free survival and distant metastasis-free survival. YB-1 expression was often associated with the expression of genes with E2F sites in their promoters. Cells expressing YB-1 siRNA grew substantially more slowly than control cells and formed tumors less readily in nude mice. Transcripts that were altered in cancer cell lines with YB-1 siRNA included 32 genes that are components of prognostic gene expression signatures. YB-1 regulated expression of an E2F1 promoter-reporter construct in A549 cells (eg, relative E2F1 promoter activity with control siRNA = 4.04; with YB-1 siRNA = 1.40, difference= -2.64, 95% confidence interval = -3.57 to -1.71, P < .001) and bound to the promoters of several well-defined E2F1 target genes. YB-1 expression is associated with the activity of E2F transcription factors and may control tumor cell growth by this mechanism.


Tachycardia in hyperthyroidism: Not so common.
The commonly held association of hyperthyroidism with sinus tachycardia and widened pulse pressure (PP) has not been reassessed in decades despite patients with hyperthyroidism in current practice not always present with these signs. The study objective was to assess prevalence and variability of sinus tachycardia and widened PP in present day among individuals with different degrees of hyperthyroidism. Data was collected retrospectively from 248 adult patients in an outpatient setting with biochemical evidence of hyperthyroidism, recorded heart rate (HR) and blood pressure (BP) who were not treated with medications that can influence these parameters. Mean age was 42.0 ± 14.2 years with 66.9% being female. Median free thyroxine (fT4) level was 3.49 (IQR 2.42-4.58) ng/dL and thyroid stimulating hormone (TSH) 0.02 (IQR 0.01-0.03) mIU/L. Tachycardia, defined as HR >100 bpm, was present in 28.2%. In the lowest and highest fT4 quartiles, tachycardia was present in 16.4% and 38.7% respectively. Using logistic regression, tachycardia was associated with higher fT4 and diastolic BP. More lenient outcome of tachycardia with HR >90 bpm was seen in 47.2%. Widened PP, defined as >50 mmHg, was observed in 64.1% of patients and correlated with higher fT4 and BP. Tachycardia is not a common feature of hyperthyroidism today. The relatively infrequent finding of tachycardia in this study compared to older studies may reflect differences in the way medicine is practiced today. The increased ordering of thyroid function tests most likely unmasked cases of mild or asymptomatic thyrotoxicosis. A widened PP was a more prevalent clinical finding in this study.


Long Noncoding RNA ROR Regulates Proliferation, Invasion, and Stemness of Gastric Cancer Stem Cell.
Gastric cancer remains an incurable malignance and the second leading cause of cancer death globally. Recent progress in gastric cancer research has demonstrated the crucial roles of cancer stem cells (CSCs) in the development, metastasis, and drug resistance of this disease. Various studies have highlighted the role of long noncoding RNAs (lncRNAs) in the pathogenesis of gastric cancer. In this study, through fluorescence-activated cell sorting, we isolated gastric CSCs (GCSCs) from MKN-45 cells and demonstrated for the first time that lncRNA ROR was highly expressed in CD133+ GCSCs. Overexpression of lncRNA ROR significantly increased, but knockdown of lncRNA ROR inhibited the proliferation and invasion of GCSCs. Most importantly, lncRNA ROR led to upregulation of several key stemness transcriptional factors, such as OCT4, SOX2, and NANOG, as well as CD133 GCSC. Our data demonstrated that lncRNA ROR was associated with core stemness transcriptional factors and the pluripotent state of GCSCs. These results further improved our understanding of the functional cross talking network during development of GCSCs and may provide novel target for the diagnostics and therapeutics of gastric cancer.


Epigenetic changes by DNA methylation in chronic and intermittent hypoxia.
DNA methylation of cytosine residues is a well-studied epigenetic change, which regulates gene transcription by altering accessibility for transcription factors. Hypoxia is a pervasive stimulus that affects many physiological processes. The circulatory and respiratory systems adapt to chronic sustained hypoxia, such as that encountered during a high-altitude sojourn. Many people living at sea level experience chronic intermittent hypoxia (IH) due to sleep apnea, which leads to cardiovascular and respiratory maladaptation. This article presents a brief update on emerging evidence suggesting that changes in DNA methylation contribute to pathologies caused by chronic IH and potentially mediate adaptations to chronic sustained hypoxia by affecting the hypoxia-inducible factor (HIF) signaling pathway.


Age greater than 60 years portends a worse prognosis in patients with papillary thyroid cancer: should there be three age categories for staging?
Age is an important prognostic factor in papillary thyroid cancer (PTC), with better survival observed in patients < 45 years of age, regardless of stage. Although the impact of increasing age on PTC-related survival is well-known, previous studies have focused on survival relative to age 45 years only. As the number of patients entering their 7th decade of life increases, PTC-related survival in this demographic becomes increasingly important. Survival in patients ≥ 60 years specifically compared to other groups has not previously been examined. We sought to determine whether age ≥ 60 years is an adverse prognostic factor for disease-specific survival and recurrence in patients with PTC. The California Cancer Registry database was linked to inpatient and ambulatory patient records from the Office of Statewide Health Planning and Development for the years 2000-2011. This linked database was queried for patients diagnosed with papillary thyroid cancer and treated with surgery. We then identified prognostic factors related to both 5-year and 10-year disease-specific survival and disease-free survival in patients ≤ 45, 45-59, and ≥ 60 years. Multivariable Cox proportional hazard models were created to test the effect of age ≥ 60 on disease-specific and disease-free survival, controlling for clinical, treatment, and demographic factors. The final cohort included 15,675 patients. Of the group, 46.3% were between 18 and 44 years of age, 33.6% were 45-59 years, and 20.1% were ≥ 60. Univariate analysis showed that compared to other groups, patients ≥ 60 were more likely to be male (p < 0.001), present with tumors > 5 cm (p < 0.001), more likely to have metastatic disease (p < 0.001), less likely to receive radioactive iodine (p < 0.001), and more likely to receive external beam radiation therapy (p < 0.001). In multivariable Cox proportional hazards models for 5 and 10-year disease-free survival, age ≥ 60 was associated with higher risk of disease at 5 and 10-years (HR 2.3 and 1.9 respectively, p < 0.001). Similar results were observed for 5 and 10-year disease-specific survival (HR 38.0 and 30.0 respectively, p < 0.001) after controlling for gender, race, co-morbidity, stage, surgical procedure, radioactive iodine, insurance, and hospital volume. Patients ≥ 60 years of age have worse DSS and DFS after a diagnosis of PTC, across all stages of disease. Given that patients over the age of 45 years have progressively worse survival as they age, these data support having three age groups, 18-44 years of age, 45-59 years, and ≥ 60 as an independent predictor of survival and recurrence to current staging guidelines.


Do you know this syndrome?
Keratitis-ichthyosis-deafness (KID) syndrome is a rare congenital ectodermal dysplasia affecting skin, the corneal epithelium and inner ear. Clinical signs consist of erythrokeratodermal plaques on the face and skin folds, usually present from birth, as well as severe and bilateral sensorineural hearing loss and corneal vascularization associated with slow-progressing keratitis which follows skin and hearing changes at puberty. In view of symptoms of deafness, blindness, skin infections and the risk of malignant degeneration, early diagnosis of the syndrome is essential, together with clinical follow-up and genetic counseling.


Performance of imaging modalities in diagnosis of liver metastases from colorectal cancer: a systematic review and meta-analysis.
Surgery of liver metastases can be effective, and the appropriate selection of surgical candidates relies first on imaging. Different techniques are available, but information on their relative performance is unclear. The aim of this overview is to assess the imaging modality performance in the diagnosis of colorectal cancer (CRC) liver metastases. MEDLINE and EMBASE were searched for articles published from January 2000 to August 2008. Eligible trials had to be conducted on patients with diagnosis/suspicion of CRC liver metastases, comparing more than two modalities among MRI, computed tomography (CT), positron emission tomography using fluoro-18-deoxyglucose (FDG-PET), ultrasonography (US). Pooled estimates of sensitivity, specificity were calculated and pair-wise comparisons were performed. Of 6030 screened articles, 25 were eligible. Sensitivity and specificity on a per-patient basis for US, CT, MRI, and FDG-PET were 63.0% and 97.6%, 74.8% and 95.6%, 81.1% and 97.2, and 93.8% and 98.7%, respectively. On a per-lesion basis, sensitivity was 86.3%, 82.6%, 86.3%, and 86.0%, respectively. Specificity was reported in few studies. MRI showed a better sensitivity than CT in per-patient (odds ratio [OR]: 0.69; 95% confidence interval [CI]: 0.47-0.99; P = 0.05) and in per-lesion analysis (OR: 0.66; 95% CI: 0.55-0.80; P < 0.0001). In per-lesion analysis, the difference was higher when liver-specific contrast agents were administered. Available evidence supports the MRI use for the detection of CRC liver metastases.


Attitudes towards people with mental illness. Effects of a training program for secondary school students.
This article reports a control study on the influence of a training program on attitude change towards people with mental illness. One hundred and seventeen students from 13 schools formed school-based mental health clubs, which composed the treatment group. They were given a mental health training program at different schools. The comparison group consisted of 102 secondary school students who had received no intervention. Students of both groups were assessed before the commencement, at the last session, and seven months after completion of the program with an OMICC (Opinion about Mental Illness in Chinese Community) scale developed by the authors. The study revealed significant positive changes, which could last a longer period of time, in specific attitudes on separatism and stigmatization of people with mental illness among students after the training program.


Assessing uncertainties in crop and pasture ensemble model simulations of productivity and N2 O emissions.
Simulation models are extensively used to predict agricultural productivity and greenhouse gas emissions. However, the uncertainties of (reduced) model ensemble simulations have not been assessed systematically for variables affecting food security and climate change mitigation, within multi-species agricultural contexts. We report an international model comparison and benchmarking exercise, showing the potential of multi-model ensembles to predict productivity and nitrous oxide (N2 O) emissions for wheat, maize, rice and temperate grasslands. Using a multi-stage modelling protocol, from blind simulations (stage 1) to partial (stages 2-4) and full calibration (stage 5), 24 process-based biogeochemical models were assessed individually or as an ensemble against long-term experimental data from four temperate grassland and five arable crop rotation sites spanning four continents. Comparisons were performed by reference to the experimental uncertainties of observed yields and N2 O emissions. Results showed that across sites and crop/grassland types, 23%-40% of the uncalibrated individual models were within two standard deviations (SD) of observed yields, while 42 (rice) to 96% (grasslands) of the models were within 1 SD of observed N2 O emissions. At stage 1, ensembles formed by the three lowest prediction model errors predicted both yields and N2 O emissions within experimental uncertainties for 44% and 33% of the crop and grassland growth cycles, respectively. Partial model calibration (stages 2-4) markedly reduced prediction errors of the full model ensemble E-median for crop grain yields (from 36% at stage 1 down to 4% on average) and grassland productivity (from 44% to 27%) and to a lesser and more variable extent for N2 O emissions. Yield-scaled N2 O emissions (N2 O emissions divided by crop yields) were ranked accurately by three-model ensembles across crop species and field sites. The potential of using process-based model ensembles to predict jointly productivity and N2 O emissions at field scale is discussed.


Michael Balint's Word Trail: The 'Ocnophil', the 'Philobat' and Creative Dyads.
In this paper, I discuss how Michael Balint arrived at the concepts of 'ocnophil' and 'philobat', which refer to two kinds of object relations. I look at the correspondence between Balint and the classical scholar David Eichholz. The two crafted these words together in a passionate exchange of letters. By recognizing the importance of creative dyads in psychoanalysis, we gain more insight into the creation of psychoanalytic knowledge beyond the frame of individual authorship. I read the collaboration between Balint and Eichholz in its historical and theoretical context, particularly in relation to the Budapest School of psychoanalysis, where intellectual collaborations had an important place. The Budapest School was Michael Balint's first home, and it shaped his epistemic and psychoanalytic style. Balint constructed his psychoanalytic theories in a spirit of openness, maintaining a commitment to conversations between psychoanalysis and other disciplines.


Single frequency Ti:sapphire laser with continuous frequency-tuning and low intensity noise by means of the additional intracavity nonlinear loss.
A single frequency Ti:sapphire (Ti:S) laser with continuous frequency-tuning and low intensity noise is presented, in which an extra nonlinear (NL) loss crystal is placed inside the resonator instead of the traditional etalon locking system. When a NL crystal is inserted into a home-made Ti:S laser resonator, the single frequency laser of 1.27 W at 795 nm with a continuous frequency-tuning range of 48 GHz is realized under the pump level of 11.27 W and the intensity noise at the lower frequencies is successfully suppressed.


Investigation of a new arthrographic contrast agent: Iotrol.
A new nonionic dimer (Iotrol; Schering AG) and diatrizoate meglumine-diatrizoate sodium (Renografin-60; Squibb) were compared as arthrographic agents by injecting these substances into the knees of rabbits. Three experienced arthrographers judged the image quality produced by Iotrol to be superior to that of Renografin-60. Following animal sacrifice, histologic examination of the synovium revealed a significant difference in the inflammatory response evoked by the contrast agents: Iotrol caused less inflammation. In a second group of rabbits, methylprednisolone was subcutaneously injected 24 hours before the arthrographic studies. The methylprednisolone significantly reduced the inflammation in the Renografin-60 subgroup when compared with the nonmedicated counterparts. No significant effect was noted in a like comparison with Iotrol. In addition, the administration of methylprednisolone led to a deterioration of the radiographic images. Based upon our data, we believe Iotrol is superior to Renografin-60 as an arthrographic agent.


Cholinesterase inhibitor effects on extracellular acetylcholine in rat cortex.
A microdialysis technique was used to sample acetylcholine (ACh) from the cerebral cortex of conscious rats. We thus investigated the effects of systemically administered cholinesterase inhibitors (ChEI) such as physostigmine (300 micrograms/kg), heptylphysostigmine (5 mg/kg) and tetrahydroaminoacridine (tacrine, 5 mg/kg) on extracellular ACh levels. Baseline quantities of extracellular ACh could be detected, even in the absence of ChEI. Acetylcholine levels increased to 1100% over baseline within 30 min of physostigmine administration and returned to control levels after 1.25 hr. Heptylphysostigmine elicited a maximal increase of 1000% within 1.5 hr, and the effect persisted up to 9.5 hr. A 500% increase was observed 1.5 hr after tacrine administration, and ACh returned to control levels after 4 hr. Although the ACh effects observed in this study correlated with previously determined levels of acetylcholinesterase (AChE) inhibition, we conclude that measures of cortical AChE activity alone are not sufficient to predict extracellular ACh levels following systemic ChEI administration.


Conformational dynamics of the human serotonin transporter during substrate and drug binding.
The serotonin transporter (SERT), a member of the neurotransmitter:sodium symporter family, is responsible for termination of serotonergic signaling by re-uptake of serotonin (5-HT) into the presynaptic neuron. Its key role in synaptic transmission makes it a major drug target, e.g. for the treatment of depression, anxiety and post-traumatic stress. Here, we apply hydrogen-deuterium exchange mass spectrometry to probe the conformational dynamics of human SERT in the absence and presence of known substrates and targeted drugs. Our results reveal significant changes in dynamics in regions TM1, EL3, EL4, and TM12 upon binding co-transported ions (Na+/K+) and ligand-mediated changes in TM1, EL3 and EL4 upon binding 5-HT, the drugs S-citalopram, cocaine and ibogaine. Our results provide a comprehensive direct view of the conformational response of SERT upon binding both biologically relevant substrate/ions and ligands of pharmaceutical interest, thus advancing our understanding of the structure-function relationship in SERT.


Extracting rules: early and late mismatch negativity to tone patterns.
The auditory processing of physical stimulus features can be measured by the mismatch negativity. Past studies have shown that higher-order stimulus features also elicit a mismatch negativity. In some studies, a second component, termed late mismatch negativity, has been observed; yet the functional significance of this component remains unclear. We tested two-tone-pattern stimuli following an abstract rule in healthy adults. As expected, the tone pattern elicited a significant mismatch negativity peaking at 146 ms but a significant late mismatch negativity at around 340 ms was also observed. These findings show that the violation of an abstract rule elicits an early and late mismatch negativity. The late mismatch negativity might be triggered on the basis of auditory rule extraction processes and reflect a transfer of rules to the long-term memory.


Surgical treatment of aortic regurgitation due to Takayasu arteritis: long-term morbidity and mortality.
The goal of this retrospective study was to determine the late outcome of surgical treatment for aortic valve regurgitation due to Takayasu arteritis and correlate it with evidence of inflammation on pathological examination. Ninety consecutive patients who underwent surgery for aortic valve regurgitation due to Takayasu arteritis between 1979 and 2003 were studied. Intraoperative pathological specimens of the aortic wall from 69 patients were retrospectively examined for inflammation. Aortic valve replacement was performed in 63 patients (group A) and composite graft repair in 27 patients (group B). The aortic root diameter was 39.9+/-9.5 mm in group A and 54.4+/-13.6 mm in group B (P<0.0001). Preoperative steroid therapy was performed in 40 patients (44.4%). Hospital mortality was 4.8% (3/63) in group A and 7.4% (2/27) in group B. The overall 15-year survival rate was 76.1%. Detachment of the valve or graft occurred in 11.1% (7/63) of group A and in 3.7% (1/27) of group B patients (P=0.43). Late dilatation (>50 mm) of the residual ascending aorta occurred in 11.1% (7/63) of group A and in 3.7% (1/27) of group B patients (P=0.43). Active inflammation was confirmed in intraoperative pathological specimens of 10 patients, and detachment of the valve or graft occurred in 4 of these patients. Univariate analysis of background variables revealed active inflammation to be a risk factor for detachment (P=0.0001; risk ratio 55). Late dilatation of the ascending aorta after aortic valve replacement is a clinically important finding. Active inflammation could be related to valve or graft detachment.


[Retrosternal gastric bypass in the palliative treatment of advanced carcinoma of the thoracic esophagus].
Palliative substernal gastric bypass was performed in 20 patients with far-advanced, obstructing carcinoma of the thoracic esophagus between the years 1978 and 1982. In 18 patients the thoracic esophagus was bypassed using the stomach brought to the neck by substernal route for anastomosis to the proximal end of the divided cervical esophagus. The thoracic esophagus was completely excluded in 10 patients; the tumor-bearing segment of the esophagus excluded formed a small and asymptomatic mucocele with time. The Kirschner-Ong technique with the additional step of Roux-en-Y jejunal anastomosis to the intra-abdominal esophagus was used to provide drainage of esophageal secretions in 8 patients with tracheoesophageal invasion or impingement, for fear of imminent esophagorespiratory fistula; in three of these patients a radiation therapy was subsequently administered. In two patients an isoperistaltic gastric tube formed from the greater curvature and brought to the neck substernally was used for esophageal bypass. Anastomotic leakage occurred in 3 patients (15%). The thirty day operative mortality was 10 per cent (2/20) and the mean survival time was 10 months. The palliation afforded was excellent in all survivors with restoration of the ability to swallow a normal diet until the time of death. The authors believe that a simple one-stage bypass of the esophagus using the stomach substernally is an effective alternative to esophageal intubation, prolonged radiation therapy or colon bypass in achieving palliation with an acceptable morbidity and mortality in a high risk patient group.


From gestational chronodisruption to noncommunicable diseases: Pathophysiological mechanisms of programming of adult diseases, and the potential therapeutic role of melatonin.
During gestation, the developing fetus relies on precise maternal circadian signals for optimal growth and preparation for extrauterine life. These signals regulate the daily delivery of oxygen, nutrients, hormones, and other biophysical factors while synchronizing fetal rhythms with the external photoperiod. However, modern lifestyle factors such as light pollution and shift work can induce gestational chronodisruption, leading to the desynchronization of maternal and fetal circadian rhythms. Such disruptions have been associated with adverse effects on cardiovascular, neurodevelopmental, metabolic, and endocrine functions in the fetus, increasing the susceptibility to noncommunicable diseases (NCDs) in adult life. This aligns with the Developmental Origins of Health and Disease theory, suggesting that early-life exposures can significantly influence health outcomes later in life. The consequences of gestational chronodisruption also extend into adulthood. Environmental factors like diet and stress can exacerbate the adverse effects of these disruptions, underscoring the importance of maintaining a healthy circadian rhythm across the lifespan to prevent NCDs and mitigate the impact of gestational chronodisruption on aging. Research efforts are currently aimed at identifying potential interventions to prevent or mitigate the effects of gestational chronodisruption. Melatonin supplementation during pregnancy emerges as a promising intervention, although further investigation is required to fully understand the precise mechanisms involved and to develop effective strategies for promoting health and preventing NCDs in individuals affected by gestational chronodisruption.


Mutations in the su(s) gene affect RNA processing in Drosophila melanogaster.
We have studied the effect of mutations in the suppressor of sable [su(s)] gene on P element-induced yellow alleles. Two independent mutations tested, y76d28 and y1#7, contain a 1.1-kilobase (kb) P element inserted in the 5' transcribed untranslated portion of the yellow gene. Sequences responsible for the y1#7 mutation are inserted in the same transcriptional orientation as yellow and cannot be processed by splicing, and this mutation is not suppressed by su(s) mutations. P element sequences are located in a transcriptional orientation opposite to that of the yellow gene in y76d28; these sequences can be spliced from a composite P element-yellow mRNA, resulting in low accumulation of a functional 1.9-kb yellow transcript. The levels of both the putative precursor P element-yellow RNA and the 1.9-kb yellow transcript increase in y76d28 su(s) flies, suggesting that mutations in su(s) do not affect the efficiency of splicing of the P element sequences. Analysis of y76d28 cDNAs isolated from flies carrying a wild-type or mutant su(s) gene demonstrates that the choice of splice junctions to process P element sequences is unchanged in these different backgrounds, suggesting that mutations in su(s) do not affect the selection of donor and acceptor splice sites. We propose that the su(s) protein functions to control the stability of unprocessed RNA during the splicing reaction.


Solvent electrostriction-driven peptide folding revealed by quasi-Gaussian entropy theory and molecular dynamics simulation.
A quantitative understanding of the complex relationship between microscopic structure and the thermodynamics driving peptide and protein folding is a major goal of biophysical chemistry. Here, we present a methodology comprising the use of an extended quasi-Gaussian entropy theory parametrized using molecular dynamics simulation that provides a complete description of the thermodynamics of peptide conformational states. The strategy is applied to analyze the conformational thermodynamics of MR121-GSGSW, a peptide well characterized in experimental studies. The results demonstrate that the extended state of the peptide possesses the lowest partial molar entropy. The origin of this entropy decrease is found to be in the increase of the density and orientational order of the hydration water molecules around the peptide, induced by the "unfolding". While such a reduction of the configurational entropy is usually associated with the hydrophobic effect, it is here found to be mainly due to the interaction of the solute charges with the solvent, that is, electrostriction.


[A study of the initial suppressor function of lymphocytes].
The new method for analysis of initial suppressor lymphocyte function in newly isolated monocultures is based on quantitative cytofluorometric analysis of early mitogen-induced activation of B lymphocytes in the presence of prednisolone that switches off a T lymphocyte immunoregulatory effect. Suppressor lymphocytes monitor B lymphocyte exit into proliferative pool and early processes of nuclear chromatin activation. The levels of initial suppressor lymphocyte function and lymphocytic proliferative activity are in inverse correlation. Suppressor lymphocyte function has been essentially reduced in rheumatoid arthritis patients as against normal subjects. A reduction as low as 70 percent of the normal value (recorded in 1/3 of the patients) is compensated with unchanged regulatory control over B cells, and reduction as low as 40 percent of the normal value (in 2/3 of the patients) is characterized by loss of regulatory control and B cell hyperactivation.


α-Synuclein increases β-amyloid secretion by promoting β-/γ-secretase processing of APP.
α-Synuclein misfolding and aggregation is often accompanied by β-amyloid deposition in some neurodegenerative diseases. We hypothesised that α-synuclein promotes β-amyloid production from APP. β-Amyloid levels and APP amyloidogenic processing were investigated in neuronal cell lines stably overexpressing wildtype and mutant α-synuclein. γ-Secretase activity and β-secretase expression were also measured. We show that α-synuclein expression induces β-amyloid secretion and amyloidogenic processing of APP in neuronal cell lines. Certain mutations of α-synuclein potentiate APP amyloidogenic processing. γ-Secretase activity was not enhanced by wildtype α-synuclein expression, however β-secretase protein levels were induced. Furthermore, a correlation between α-synuclein and β-secretase protein was seen in rat brain striata. Iron chelation abolishes the effect of α-synuclein on neuronal cell β-amyloid secretion, whereas overexpression of the ferrireductase enzyme Steap3 is robustly pro-amyloidogenic. We propose that α-synuclein promotes β-amyloid formation by modulating β-cleavage of APP, and that this is potentially mediated by the levels of reduced iron and oxidative stress.


Callus cultures for phytometabolism studies: phytometabolites of 3-trifluoromethylphenol in Lemnaceae plants and callus cultures.
Plant callus cultures have the potential to advance phytoremediation science by allowing study of cellular phytometabolism in absence of sorption, translocation, microbial degradation, and other phytoremediation processes; however, studies demonstrating the applicability of results from callus cultures to whole plants are limited. The aim of this study was to evaluate the feasability and applicability of using callus cultures to study phytometabolism. This aim was accomplished through evaluation of induction and growth of Lemnaceae callus cultures and comparison of phytometabolism in callus cultures and whole plants. Four out of eight published methods for callus culture of Lemnaceae successfully induced callus cultures that exhibited doubling times of 1.7 to 23 wks. Callus cultures and whole plants of Landoltia punctata and Lemna minor metabolized 3-trifluoromethylphenol (3-TFMP) through conjugation with glucopyranoside, malonyl-glucopyranoside, and glucopyranosyl-apiofuranoside. However, concentrations of metabolites were approximately 10 times less in callus cultures than in plants. While results demonstrated applicability of callus cultures results to whole plants, the low success rate of callus induction procedures, length of time required to produce substantial callus mass, and the low accumulation of metabolites in callus cultures may limit the feasibility of callus cultures for assessing phytometabolism.


Does the recommended lymphocyte cytokinesis-block micronucleus assay for human biomonitoring actually detect DNA damage induced by occupational and environmental exposure to genotoxic chemicals?
This commentary challenges the paradigm that the cytokinesis-block micronucleus assay (CBMN assay) with cultured human lymphocytes, as it is performed currently, is a sensitive and useful tool for detecting genotoxic effects in populations exposed occupationally or environmentally to genotoxic chemicals. Based on the principle of the assay and the available data, increased micronucleus (MN) frequencies in binucleated cells (BNC) are mainly due to MN produced in vitro during the cultivation period (i.e. MN produced in vivo do not substantially contribute to the MN frequency measured in BNC). The sensitivity of the assay for the detection of induced MN in BNC after an in vivo exposure to a genotoxic chemical is limited because cytochalasin B (Cyt-B) is added relatively late during the culture period and, therefore, the BNC that are scored do not always represent cells that have completed one cell cycle only. Furthermore, this delay means that damaged cells can be eliminated by apoptosis and/or that DNA damage induced in vivo can be repaired prior to the production of a MN in the presence of Cyt-B. A comparison with the in vitro CBMN assay used for genotoxicity testing leads to the conclusion that it is highly unlikely that DNA damage induced in vivo is the cause for increased MN frequencies in BNC after occupational or environmental exposure to genotoxic chemicals. This commentary casts doubt on the usefulness of the CBMN assay as an indicator of genotoxicity in human biomonitoring and questions the relevance of many published data for hazard identification and risk assessment. Thus, it seems worthwhile to reconsider the use of the CBMN assay as presently conducted for the detection of genotoxic exposure in human biomonitoring.


A modified surgical technique for reconstruction of an acute acromioclavicular joint dislocation.
We report a modified surgical technique for reconstruction of coracoclavicular and acromioclavicular ligaments after acute dislocation of acromioclavicular joint using suture anchors. We have repaired 3 consecutive type III acromioclavicular dislocations with good results. This technique is simple and safe and allows anatomical reconstruction of the ligaments in acute dislocations.


Construction of a dual affinity tagged allele of the Rb1 tumor suppressor gene in the mouse.
Loss of Rb1 tumor suppressor gene function is involved in the genesis of most human cancers. Novel therapies targeting Rb1 have been slow to develop because of our incomplete understanding of its molecular mechanisms of action. Rb1 protein (pRb) binds a host of cellular genes and proteins, and these molecular interactions mediate its various functions. Given the potential complexity of these molecular interactions and the lack of established methods for pRb purification, it has been difficult to systematically identify gene and protein interactions relevant to tumor suppression in different tissues in vivo. To address this limitation, we have generated a dual affinity tagged Rb1 allele in the mouse. The tagged allele functions as wild type and the encoded protein can be purified by tandem affinity chromatography. This allele will facilitate identification and characterization of native pRb molecular interactions in any tissue accessible in the mouse.


A comparison of chincap and maxillary protraction appliances in the treatment of skeletal Class III malocclusions.
The purpose of this retrospective investigation was to compare cephalometrically the treatment effects of chincap and maxillary protraction appliances in subjects with a Class III skeletal malocclusion with a combination of an underdeveloped maxilla and prominent mandible. Twenty-four patients were divided into two groups according to the treatment type; the chincap group (mean age 11.03 years, n = 12) and the Delaire type maxillary protraction appliance group (mean age 10.72 years, n = 12). In both groups, a significant increase in ANB, molar relationship, and overjet showed the effect of the appliances in the treatment of Class III malocclusions. In comparing the two groups, the maxilla was displaced more anteriorly and the molar relationship correction was greater in the maxillary protraction appliance group (P < 0.05). Angular and dimensional parameters for lower incisor/NB and nasolabial angle showed significant differences between the groups (P < 0.05).


Muscle dysmorphia: a new syndrome in weightlifters.
AUTHOR:e-mail address please Recently more men have reported a desire for larger, more muscular bodies. Muscle dysmorphia (MD) is a new syndrome in which individuals (usually men), although highly muscular, have a pathological belief that they are of very small musculature. As more men are motivated to take up training with weights in order to develop greater musculature, more cases of MD are likely to be encountered. A greater understanding and awareness of the syndrome are therefore needed. Therefore the aim of this study was to investigate perceptions of physical self in male weightlifters, one group with MD (n = 24) and one without (n = 30). Between group comparisons were made using the multidimensional body-self relations questionnaire. The findings confirm the nature of the disorder in that those with MD syndrome have poorer body image and are less happy with their bodies. Moreover, in addition to a desire for greater muscularity, they are very concerned not to gain fat. The results also suggest that future research into perceptions of specific body parts and health is warranted.


Disulphide-reduced superoxide dismutase-1 in CNS of transgenic amyotrophic lateral sclerosis models.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease afflicting the voluntary motor system. More than 100 different mutations in the ubiquitously expressed enzyme superoxide dismutase-1 (SOD1) have been associated with the disease. To search for the nature of the cytotoxicity of mutant SOD1s, amounts, enzymic activities and structural properties of the protein as well as the CNS histopathology were examined in multiple transgenic murine models. In order to generate the ALS phenotype within the short lifespan of the mouse, more than 20-fold increased rates of synthesis of mutant SOD1s appear to be required. The organs of transgenic mice expressing human wild-type SOD1 or either of the G93A and D90A mutant proteins showed high steady-state protein levels. The major proportion of these SOD1s in the CNS were inactive due to insufficient Cu charging and all contained subfractions with a reduced C57-C146 intrasubunit disulphide bond. Both G85R and the truncated G127insTGGG mutant showed low steady-state protein levels, lacked enzyme activity and had no C57-C146 disulphide bond. These mutants were also enriched in the CNS relative to other organs, suggesting inefficient recognition and degradation of misfolded disulphide-reduced SOD1 in susceptible tissues. In end-stage disease, despite 35-fold differences in levels of mutant SOD1s, similar amounts of detergent-resistant aggregates accumulated in the spinal cord. Small granular as well as larger more diffuse human SOD1 (hSOD1)-inclusions developed in all strains, the latter more pronounced in those with high hSOD1 levels. Widespread vacuolizations were seen in the strains with high levels of hSOD1 but not those with low, suggesting these alterations to be artefacts related to high hSOD1 levels and not to the ALS-causing cytotoxicity. The findings suggest that the motoneuron degeneration could be due to long-term exposure to misfolded aggregation-prone disulphide-reduced SOD1, which constitutes minute subfractions of the stable mutants and larger proportions of the unstable mutants.


[Analysis of heart rate variability during the head-up tilt test in patients with vasovagal syncope].
Changes of the autonomous nervous tonus are considered the most important factor in the pathogenesis of vasovagal syncope. In order to investigate changes of the autonomous tonus the authors examined in patients with vasovagal syncope the variability during the head-up tilt test (HUT). In 35 patients with assumed vasovagal syncope the authors used a passive HUT (45 mins., 60 degrees) and subsequently nitroglycerin-stimulated HUT (0.4 mg s.l, 15 mins.). The heart rate variability was evaluated before the onset of the test in a horizontal position, immediately after tilting the patient (0 min.), during the 5th, 10th, 15th minute of the passive test, during the 5th minute of the nitroglycerin test, during the appearance of symptoms and after termination of the test in a horizontal position. They compared the results between a group of 20 patients with positive HUT (13 men, 36 years) and in 15 patients with a negative HUT (7 men, 32 years). The parameters of heart rate variability were during the development of the syncope (mean 6.4 mins. after administration of NTG) as compared with corresponding values in patients with negative HUT (during the 5th minute after administration of NTG) as follows: RR interval 759.6 +/- 248.1 ms vs. 552.1 +/- 88.7 ms (p = 0.01), SDNN 44.8 +/- 49.6 vs. 29.9 +/- 18.3 (p = 0.001), RMSSD 31.8 +/- 34.9 vs. 15.2 +/- 10.2 (p = 0.03), LF 4.44 +/- 0.66 lnms2 vs. 4.38 +/- 0.53 lnms2 (p = 0.82), HF 4.44 +/- 0.57 lnms2 vs. 4.39 +/- 0.45 lnms2 (p = 0.82), LF/HF 0.99 +/- 0.03 vs. 0.99 +/- 0.02 (p = 0.90). On development of the first presyncopal manifestations the statistical parameters of heart rate variability in patients with positive HUT were significantly higher as compared with patients with negative HUT, which suggests an increase of the parasympathetic autonomous tonus during the development of the vasovagal syncope.


Molecular mechanism of Epimedium in the treatment of vascular dementia based on network pharmacology and molecular docking.
Backgroud: Vascular dementia is the second most common cause of dementia after Alzheimer's disease, accounting for an estimated 15% of cases. Recently, Epimedium has attracted great attention for its potential neuroprotective benefit. However, the direct role and mechanism of Epimedium on vascular dementia still lack systematic research. To systematically explore the possible pharmacological mechanism of Epimedium for the treatment of vascular dementia, network pharmacology, molecular docking, combined with experiment validation were conducted. Methods: The bioactive compounds and targets of Epimedium were obtained from the TCMSP database. The potential targets of vascular dementia were identified from the DrugBank, OMIM, Genecards, Therapeutic Target Database, and DisGeNET databases. GO and KEGG pathway analyses were performed. Molecular docking was applied to validate the interaction between active components and hub targets. The bilateral common carotid artery occlusion (BCCAO) method was used for construction of a vascular dementia model in mice. The effects of Epimedium on learning and memory ability were examined by behavioral tests. The mechanisms of the cerebral protective effects of Epimedium were evaluated by WB, RT-PCR, and immunofluorescence. Results: A total of 23 Epimedium active ingredients, and 71 intersecting targets of Epimedium against vascular dementia were obtained. The top five hub targets AKT1, TNF, IL1β, IL6, and MMP9 were identified, and molecular docking showed good binding. GO enrichment showed a total of 602 enrichment results, with 458 (80.56%) key targets mainly focused on biological processes (BP). The response to hypoxia, positive regulation of nitric oxide biosynthetic process, aging, inflammatory response, cellular response to lipopolysaccharide, negative regulation of apoptotic process were well ranked. KEGG pathway enrichment analysis identified the TNF signaling pathway as an important pathway, with the MAPK/extracellular signal-regulated kinase (ERK) and NF-κB signaling pathways as the key pathways involved. Consistently, in vivo experiments showed that Epimedium treatment improved learning and memory functions in mice with vascular dementia. In addition, Epimedium attenuated the activation of microglia and astrocytes in the hippocampal region after BCCAO. RT-qPCR and Western blot analysis showed that Epimedium not only affected the expression of AKT, TNF, IL1β, IL6, and MMP9, but also suppressed the TNF signaling pathway. Conclusion: Epimedium may exert a protective effect against vascular dementia through the alleviation of oxidative stress, neuroinflammation, BBB dysfunction, apoptosis through TNF signaling pathway. This study explored the mechanism of Epimedium on vascular dementia systematically through network pharmacological and in vivo experiment approach, which provides insight into the treatment of vascular dementia.


A New Methodology for a Retrofitted Self-tuned Controller with Open-Source FPGA.
Servo systems are feedback control systems characterized by position, speed, and/or acceleration outputs. Nowadays, industrial advances make the electronic stages in these systems obsolete compared to the mechanical elements, which generates a recurring problem in technological, commercial and industrial applications. This article presents a methodology for the development of an open-architecture controller that is based on reconfigurable hardware under the open source concept for servo applications. The most outstanding contribution of this paper is the implementation of a Genetic Algorithm for online self tuning with a focus on both high-quality servo control and reduction of vibrations during the positioning of a linear motion system. The proposed techniques have been validated on a real platform and form a novel, effective approach as compared to the conventional tuning methods that employ empirical or analytical solutions and cannot improve their parameter set. The controller was elaborated from the Graphical User Interface to the logical implementation while using free tools. This approach also allows for modification and updates to be made easily, thereby reducing the susceptibility to obsolescence. A comparison of the logical implementation with the manufacturer software was also conducted in order to test the performance of free tools in FPGAs. The Graphical User Interface developed in Python presents features, such as speed profiling, controller auto-tuning, measurement of main parameters, and monitoring of servo system vibrations.


Factors associated with metachronous metastases and survival in locally advanced and recurrent rectal cancer.
Better understanding of the impact of metachronous metastases in locally advanced and recurrent rectal cancer may improve decision-making. The aim of this study was to investigate factors influencing metachronous metastasis and its impact on survival in patients who have a beyond total mesorectal excision (bTME) operation. This was a retrospective study of consecutive patients who had bTME surgery for locally advanced and recurrent rectal cancer at a tertiary referral centre between January 2006 and December 2016. The primary outcome was overall survival. Cox proportional hazards regression analyses were performed. The influence of metachronous metastases on survival was investigated. Of 220 included patients, 171 were treated for locally advanced primary tumours and 49 for recurrent rectal cancer. Some 90·0 per cent had a complete resection with negative margins. Median follow-up was 26·0 (range 1·5-119·6) months. The 5-year overall survival rate was 71·1 per cent. Local recurrence and metachronous metastasis rates were 11·8 and 22·2 per cent respectively. Patients with metachronous metastases had a worse overall survival than patients without metastases (median 52·9 months versus estimated mean 109·4 months respectively; hazard ratio (HR) 6·73, 95 per cent c.i. 3·23 to 14·00). Advancing pT category (HR 2·01, 1·35 to 2·98), pN category (HR 2·43, 1·65 to 3·59), vascular invasion (HR 2·20, 1·22 to 3·97) and increasing numbers of positive lymph nodes (HR 1·19, 1·07 to 1·16) increased the risk of metachronous metastasis. Nine of 17 patients (53 per cent) with curatively treated synchronous metastases at presentation developed metachronous metastases, compared with 40 of 203 (19·7 per cent) without synchronous metastases (P = 0·002). Corresponding median length of disease-free survival was 17·5 versus 90·8 months (P < 0·001). As metachronous metastases impact negatively on survival after bTME surgery, factors associated with metachronous metastases may serve as selection tools when determining suitability for treatment with curative intent.


[The Dutch College of General Practitioners' practice guidelines, "Examination of the neonate": response from the perspective of general practice medicine].
With the publication of the Dutch College of General Practitioners' practice guideline 'Examination of the neonate', a discussion which has lasted several decades has been brought to an end. Up to now a second neonatal examination by the general practitioner on the third, fourth or fifth day after a midwife-assisted birth was recommended. The arguments in support of this recommendation were based on the following: (a) the limited expertise of midwives in the past, (b) the experience that general practitioners had in examining children, although this experience was not specifically related to the defects for which neonates should be checked, and (c) the government bodies' wish to restrict the number of hospital deliveries by giving greater structure to the organisation of midwife care, which in practice, did not lead to large changes. Based on three studies, the practice guideline recommends that a second examination is of no added value.


Monitoring stimulus-evoked hemodynamic response during deep brain stimulation with single fiber spectroscopy.
Deep brain stimulation (DBS) is a revolutionary treatment for movement disorders. Measuring DBS-induced hemodynamic responses may be useful for surgical guidance of DBS electrode implantation as well as to study the mechanism and assess therapeutic effects of DBS. In this study, we evaluated the performance of a single fiber spectroscopic (SFS) system for measuring hemodynamic response in different cortical layers in a DBS animal model. We showed that SFS is capable of measuring minute relative changes in oxygen saturation and blood volume fraction in-vivo at a sampling rate of 22-33 Hz. During stimulation, blood volume fraction increased, while oxygen saturation showed both increases and decreases at different cortical depths across animals. In addition, we showed the potential of using SFS for measuring other physiological parameters, for example, heart rate, and respiratory rate.


The nanopore electrode.
The fabrication and electrochemical characterization of truncated cone-shaped nanopore electrodes are reported. A nanopore electrode is a Pt disk electrode embedded at the bottom of a conical pore, the circular orifice of the pore having nanometer dimensions. The electrochemical properties of nanopore electrodes with orifice radii of 39 and 74 nm are presented. Both the steady-state and transient voltammetric behavior of the nanopore electrode are reported and compared to predictions obtained using finite-element simulations. The truncated cone-shaped pore electrode possesses a unique transport property-the steady-state flux of molecules into a deep pore is limited by the restriction near the pore orifice, and thus, the steady-state current is independent of the pore depth. This characteristic is potentially useful in studying transport through nanometer-scale orifices.