Protein network-based Lasso regression model for the construction of disease-miRNA functional interactions.
There is a growing body of evidence associating microRNAs (miRNAs) with human diseases. MiRNAs are new key players in the disease paradigm demonstrating roles in several human diseases. The functional association between miRNAs and diseases remains largely unclear and far from complete. With the advent of high-throughput functional genomics techniques that infer genes and biological pathways dysregulted in diseases, it is now possible to infer functional association between diseases and biological molecules by integrating disparate biological information. Here, we first used Lasso regression model to identify miRNAs associated with disease signature as a proof of concept. Then we proposed an integrated approach that uses disease-gene associations from microarray experiments and text mining, and miRNA-gene association from computational predictions and protein networks to build functional associations network between miRNAs and diseases. The findings of the proposed model were validated against gold standard datasets using ROC analysis and results were promising (AUC=0.81). Our protein network-based approach discovered 19 new functional associations between prostate cancer and miRNAs. The new 19 associations were validated using miRNA expression data and clinical profiles and showed to act as diagnostic and prognostic prostate biomarkers. The proposed integrated approach allowed us to reconstruct functional associations between miRNAs and human diseases and uncovered functional roles of newly discovered miRNAs. Lasso regression was used to find associations between diseases and miRNAs using their gene signature. Defining miRNA gene signature by integrating the downstream effect of miRNAs demonstrated better performance than the miRNA signature alone. Integrating biological networks and multiple data to define miRNA and disease gene signature demonstrated high performance to uncover new functional associations between miRNAs and diseases.


A constraint-based approach to medical guidelines and protocols.
Medical guidelines and protocols are documents aimed at improving the quality of medical care by offering support in medical decision making in the form of management recommendations based on scientific evidence. Whereas medical guidelines are intended for nation-wide use, and thus omit medical management details that may differ among hospitals, medical protocols are aimed at local use, e.g., within hospitals, and, therefore, include more detailed information. Although a medical guideline and an associated protocol concerning the management of a particular disorder are related to each other, one question is to what extent they are different. Formal methods are applied to shed light on this issue. A Dutch medical guideline regarding the treatment of breast cancer, and a Dutch protocol based on it, are taken as an example.


[New treatments of pediatric pulmonary hypertension].
Pulmonary arterial hypertension is a serious condition, with an estimated prevalence of 4 children over a million. Symptoms of this condition are not specific, leading to a potential delay in the diagnosis. Treatment of pediatric pulmonary hypertension is currently based on adult guidelines, using new targeted therapies, separated in 3 main categories: Endothelin receptor antagonists, prostacyclin and analogues, and phosphodiesterase type 5 inhibitors. These therapies improve symptoms and survival, but neither of them can cure the condition. Various new molecules are being currently tested in children or in development, offering hope to further improve the prognosis of pulmonary arterial hypertension.


Continuous culture in combined backmix-plug-flow-tubular-loop fermentor configurations.
Several combinations of backmix, tubular-loop, and plug-flow fermentors with and without culture recycle were studied by computer simulations. The steady-state concentrations of cell mass in a continuous culture were calculated as a function of dilution rate using Monod growth kinetics. It was found theoretically and verified for one case experimentally that the maximum dilution rate, over which microbial cells were washed out from the fermentor, could be elevated well beyond the maximum specific growth rate if a particular fermentor combination was used. A combination of two backmix fermentors has been analyzed previously by Sinclair and Brown. Application of this type of fermentor combination as a seed tank for performing continuous culture of microbes in a plug-flow reactor was shown with special reference to fermentation production using the kinetics proposed by Luedeking and Piret, van Dedem and Moo-Young, and Brown and Vass.


Inter-eye osmolarity differences in patients with symptomatic and non-symptomatic dry eyes.
To analyze whether inter-eye osmo larity differences were related to dry eye symptomatology. A total of 135 participants were randomly recruited from those who visited in the Optometry Clinic of the Optometry Faculty (Universidade de Santiago de Compostela). In a single scheduled session after the recruitment, Ocular Surface Disease Index was filled out following the standard instructions and TearLab measurements were made in both the participants' eyes (10-15 min lapse). Osmolarity values were compared between the right and left eyes and the absolute inter-ocular difference (|OD-OS|) correlated with the Ocular Surface Disease Index score for the whole sample. Based on the Ocular Surface Disease Index score, the sample was divided into four symptomatic subgroups, and differences in the |OD-OS| values were calculated. The whole sample showed a statistically significant inter-eye osmolarity difference (p=0.025; |OD-OS| = 9.2 ± 9.3 mOsm/l) and the correlation between Ocular Surface Disease Index and |OD-OS| (r=0.369; p<0.001). A statistically significant difference was found in the |OD-OS| value between symptomatic subgroups (Kruskal-Wallis, p=0.003). Mann-Whitney U test showed a significant difference between asymptomatic vs. moderate (p=0.006) vs. severe symp tomatic patients (p=0.001) and between mild vs. severe symptomatic patients (p=0.045), whereas no difference on |OD-OS| was found between participants with contiguous symptomatic subgroups (all p³0.174). Tear film inter-eye osmolarity differences are significantly higher in severe dry eye disease symptoms.


Triggering of locust jump by multimodal inhibitory interneurons.
1. The locust jump is triggered by a sudden inhibition of activity in hindleg flexor tibiae motoneurons following cocontraction of the hindleg flexor and extensor tibiae muscles. The main result of this investigation was the identification of two interneurons (one for each hindleg) that monosynaptically inhibit flexor tibiae motoneurons and whose properties are all consistent with them being the trigger interneurons for initiating a jump. 2. These interneurons receive strong excitatory input from many sensory modalities (visual, auditory, tactile, and proprioceptive). Because of their multimodal response characteristics, we designated them M-neurons. A particularly strong excitatory input to each M-neuron is from both descending contralateral movement detector (DCMD) interneurons. 3. The threshold for spike initiation in the M-neurons is high (approximately 14 mV). As a consequence, input from any one sensory modality alone rarely initiates action potentials. 4. Each M-neuron is depolarized by sensory input from leg proprioceptors. We propose that proprioceptive feedback during the cocontraction phase depolarizes the M-neurons to decrease their threshold, thus enabling extrinsic sensory stimuli to generate action potentials in both M-neurons and in so doing trigger a jump. The function of the proprioceptive gating of inhibitory transmission from the various sensory systems to the flexor motoneurons (via the M-neurons) is to ensure the development of a strong isometric contraction of the extensor tibiae muscle, and thus a powerful jump in response to external stimuli. 5. Insofar as the initiation of the locust jump depends on sensory convergence onto large identified interneurons, this behavior is similar to ballistic movements in some other animals such as the crayfish tail flip and the startle response in fish. The unique feature of the locust jump is that the trigger interneurons initiate the jump only after a preceding phase (cocontraction) has been accomplished.


[2 scenarios on extension of life. Various social consequences of a higher life expectancy].
This article explores the potential consequences of an extra life extension till 2010. For this purpose the method of scenario analysis is used. Life extension is defined as an extra increase in life expectancy at birth (compared to the 'normal' demographic forecast). The optimistic scenario is based on an equal delay of both death and the prevalence of disease and disability. In the pessimistic scenario, only death is delayed, which brings more morbidity. It is stressed that the development of morbidity considerably influences the social consequences of extra life extension, such as the use older people make of the (health) care services system, and the socio-economic and the socio-cultural position of the elderly. In the optimistic scenario the pressure on care services is more or less the same as it would be according to the normal demographic forecast, although the patients/clients are older. Due to the extra increase in life expectancy the costs of social security will be much higher. The percentage of people incapable of work, the age of retirement, the position of the elderly employee in the labour force and the norms and values concerning old age differ in both scenarios.


Toutatis, a TIP5-related protein, positively regulates Pannier function during Drosophila neural development.
The GATA factor Pannier (Pnr) activates proneural expression through binding to a remote enhancer of the achaete-scute (ac-sc) complex. Chip associates both with Pnr and with the (Ac-Sc)-Daughterless heterodimer bound to the ac-sc promoters to give a proneural complex that facilitates enhancer-promoter communication during development. Using a yeast two-hybrid screening, we have identified Toutatis (Tou), which physically interacts with both Pnr and Chip. Loss-of-function and gain-of-function experiments indicate that Tou cooperates with Pnr and Chip during neural development. Tou shares functional domains with chromatin remodelling proteins, including TIP5 (termination factor TTFI-interacting protein 5) of NoRC (nucleolar remodelling complex), which mediates repression of RNA polymerase 1 transcription. In contrast, Tou acts positively to activate proneural gene expression. Moreover, we show that Iswi associates with Tou, Pnr and Chip, and is also required during Pnr-driven neural development. The results suggest that Tou and Iswi may belong to a complex that directly regulates the activity of Pnr and Chip during enhancer-promoter communication, possibly through chromatin remodelling.


Joint representation of working memory and uncertainty in human cortex.
Neural representations of visual working memory (VWM) are noisy, and thus, decisions based on VWM are inevitably subject to uncertainty. However, the mechanisms by which the brain simultaneously represents the content and uncertainty of memory remain largely unknown. Here, inspired by the theory of probabilistic population codes, we test the hypothesis that the human brain represents an item maintained in VWM as a probability distribution over stimulus feature space, thereby capturing both its content and uncertainty. We used a neural generative model to decode probability distributions over memorized locations from fMRI activation patterns. We found that the mean of the probability distribution decoded from retinotopic cortical areas predicted memory reports on a trial-by-trial basis. Moreover, in several of the same mid-dorsal stream areas, the spread of the distribution predicted subjective trial-by-trial uncertainty judgments. These results provide evidence that VWM content and uncertainty are jointly represented by probabilistic neural codes.


Comparison of interferon-gamma, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor for priming leukocyte-mediated hyphal damage of opportunistic fungal pathogens.
Proinflammatory cytokines have been proposed as adjunctive therapeutic agents to enhance the host immune response during infections caused by opportunistic fungi. The study compared the differential in vitro priming effects of interferon-gamma (IFN-gamma), granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) on hyphal damage of opportunistic fungi mediated by isolated neutrophils (polymorphonuclear leukocytes, PMNL) and buffy coat cells (polymorphonuclear leukocytes/peripheral blood mononuclear cells, PMNL/PBMC) from healthy donors. IFN-gamma (1000 U/mL) effectively primed both PMNL and PMNL/PBMC for enhanced hyphal damage of Aspergillus fumigatus, Fusarium solani, and Candida albicans. G-CSF (100 ng/mL) increased hyphal damage mediated by both PMNL and PMNL/PBMC against F. solani, and GM-CSF (100 ng/mL) augmented the antifungal activity of PMNL/PBMC against hyphal forms of both F. solani and C. albicans. IFN-gamma may be superior to G-CSF or GM-CSF for enhancing the microbicidal activity of PMNL and PMNL/PBMC against opportunistic fungi.


Nitrogen, phosphorus, and cation use efficiency in stands of regenerating tropical dry forest.
Plants on infertile soils exhibit physiological and morphological traits that support conservative internal nutrient cycling. However, potential trade-offs among use efficiencies for N, P, and cations are not well explored in species-rich habitats where multiple elements may limit plant production. We examined uptake efficiency and use efficiency of N, P, K, Ca, Mg, Al, and Na in plots of regenerating tropical dry forests spanning a gradient of soil fertility. Our aim was to determine whether plant responses to multiple elements are correlated, or whether there are trade-offs among exploitation strategies across stands varying in community composition, soil quality, and successional stage. For all elements, both uptake efficiency and use efficiency decreased as availability of the corresponding element increased. Plant responses to N, Na, and Al were uncoupled from uptake and use efficiencies for P and essential base cations, which were tightly correlated. N and P use efficiencies were associated with shifts in plant species composition along the soil fertility gradient, and there was also a trend towards increasing N use efficiency with stand age. N uptake efficiency was positively correlated with the abundance of tree species that associate with ectomycorrhizal fungi. Taken together, our results suggest that successional processes and local species composition interact to regulate plant responses to availability of multiple resources. Successional tropical dry forests appear to employ different strategies to maximize response to N vs. P and K.


Spectral diffusion: an algorithm for robust material decomposition of spectral CT data.
Clinical successes with dual energy CT, aggressive development of energy discriminating x-ray detectors, and novel, target-specific, nanoparticle contrast agents promise to establish spectral CT as a powerful functional imaging modality. Common to all of these applications is the need for a material decomposition algorithm which is robust in the presence of noise. Here, we develop such an algorithm which uses spectrally joint, piecewise constant kernel regression and the split Bregman method to iteratively solve for a material decomposition which is gradient sparse, quantitatively accurate, and minimally biased. We call this algorithm spectral diffusion because it integrates structural information from multiple spectral channels and their corresponding material decompositions within the framework of diffusion-like denoising algorithms (e.g. anisotropic diffusion, total variation, bilateral filtration). Using a 3D, digital bar phantom and a material sensitivity matrix calibrated for use with a polychromatic x-ray source, we quantify the limits of detectability (CNR = 5) afforded by spectral diffusion in the triple-energy material decomposition of iodine (3.1 mg mL(-1)), gold (0.9 mg mL(-1)), and gadolinium (2.9 mg mL(-1)) concentrations. We then apply spectral diffusion to the in vivo separation of these three materials in the mouse kidneys, liver, and spleen.


COVID-19 and Cancer Comorbidity: Therapeutic Opportunities and Challenges.
The coronavirus disease 2019 (COVID-19) is a viral disease caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that affects the respiratory system of infected individuals. COVID-19 spreads between humans through respiratory droplets produced when an infected person coughs or sneezes. The COVID-19 outbreak originated in Wuhan, China at the end of 2019. As of 29 Sept 2020, over 235 countries, areas or territories across the globe reported a total of 33,441,919 confirmed cases, and 1,003,497 confirmed deaths due to COVID-19. Individuals of all ages are at risk for infection, but in most cases disease severity is associated with age and pre-existing diseases that compromise immunity, like cancer. Numerous reports suggest that people with cancer can be at higher risk of severe illness and related deaths from COVID-19. Therefore, managing cancer care under this pandemic is challenging and requires a collaborative multidisciplinary approach for optimal care of cancer patients in hospital settings. In this comprehensive review, we discuss the impact of the COVID-19 pandemic on cancer patients, their care, and treatment. Further, this review covers the SARS-CoV-2 pandemic, genome characterization, COVID-19 pathophysiology, and associated signaling pathways in cancer, and the choice of anticancer agents as repurposed drugs for treating COVID-19.


Does monastic life predispose to the risk of Saint Anthony's fire (herpes zoster)?
The consequences of the epidemiology of varicella for zoster epidemiology are still debated. We therefore compared the frequency of herpes zoster in an adult population with virtually no varicella zoster virus (VZV) exposure with that in the general population (GP). We performed a national, multicenter, observational, exposed versus nonexposed, comparative study. The nonexposed population consisted of members of contemplative monastic orders (CMO) of the Roman Catholic Church living in 40 isolated monasteries in France. The exposed population consisted of a sample of the GP representative of the French population in terms of age group, sex, socio-occupational categories, and regions. The primary analysis population comprised 920 members of CMO (41.5% nuns; mean age, 64.2 years) and 1533 members of the GP (51.9% women; mean age, 64.6 years). The reported frequency of zoster was 16.2% among CMO and 15.1% in the GP (P = .27, adjusted for sex and age). The reported mean age of onset of zoster was 54.8 and 48.6 years, respectively (P = .06). This study failed to demonstrate an increased risk or earlier onset of zoster in members of CMO not exposed to VZV, compared with that in the GP. Although adults highly exposed to VZV could have a reduced risk of zoster, compared with the GP, our results suggest that the opposite is not true: adults not exposed to VZV are not at increased risk of zoster when compared with the GP, challenging the relevance of the assumptions and forecasts of current epidemiological models.


Antipsychotics: a real or confounding risk factor for venous thromboembolism?
In a meta-analysis of case-control studies, Zhang et al. (2011) found an increased risk of venous thromboembolic events (VTE) in patients exposed to antipsychotics (OR=2.39 [1.71-3.35]). Our updated meta-analysis including the 2 available cohort studies, recognized as a more relevant type of observational study, showed a weaker, but still strong association (OR=1.84 [1.39; 2.44]). In view of the lack of data on the confirmed risk factors for VTE in existing studies, prospective studies including adjustment for these risk factors are warranted to confirm this association and to assess the benefit/risk ratio of antipsychotics in high-risk patients.


Glyphosate and ATP binding by mononuclear Zn(II) complexes with non-symmetric ditopic polyamine ligands.
Binding of Zn(II) by the ditopic ligands L1py, L2py and L1para, composed of a cyclam unit linked to the linear polyamines 1,4,8,11-tetraazaundecane (L1py and L2para) and 1,4,7-triazaheptane (L2py) via a 2,6-dimethylpyridinyl (L1py and L2py) or a 1,4-dimethylbenzyl spacer (L2para), has been analyzed by means of potentiometric and (1)H and (13)C NMR measurements. All ligands form stable mononuclear Zn(II) complexes in a wide pH range, featuring the metal ion bound to the macrocyclic unit. The open-chain polyamine unit can easily bind several protons in aqueous solution affording protonated metal complexes at neutral and acidic pH values. These complexes behave as bifunctional receptors for the anionic substrates N-(phosphonomethyl)glycine (glyphosate or PMG) and ATP. Potentiometric, (1)H and (31)P NMR measurements show that the Zn(II) complex with L1py is the better receptor for both substrates, thanks to the simultaneous presence of a pyridine linker functionalized at its 2,6 positions and of a flexible linear tetraamine chain. In fact, these structural features allow a stronger interaction of PMG and ATP with both the protonated tetraamine moiety and the Zn(II)-cyclam core.


Functional differences in the beta gamma complexes of transducin and the inhibitory guanine nucleotide regulatory protein.
We have examined the mechanism of inhibition of adenylate cyclase using the purified alpha and beta gamma subunits of bovine brain inhibitory guanine nucleotide regulatory protein (Ni) (i.e., alpha i and beta gamma N) and bovine retinal transducin (alpha T and beta gamma T) in reconstituted phospholipid vesicle systems. The addition of beta gamma N or beta gamma T to lipid vesicles containing the pure stimulatory guanine nucleotide regulatory protein (Ns) from human erythrocytes as well as a resolved preparation of the catalytic moiety (C) of bovine caudate adenylate cyclase results in significant inhibition of guanine nucleotide stimulated cyclase activity (80-90%). The inhibition by these beta gamma subunit complexes appears to fully account for the inhibitory effects observed with holo-Ni or holotransducin. A variety of structure-function comparisons of the beta gamma N and beta gamma T complexes were performed in order to further probe the molecular mechanisms involved in the inhibitory pathway. Whereas the beta subunits of beta gamma N and beta gamma T appear to be very similar, if not identical, on the basis of comparisons of their gel electrophoretic mobility and immunological cross-reactivity, clear differences exist in the apparent structures of gamma N and gamma T. Interestingly, functional differences are observed in the effectiveness of these two beta gamma complexes to inhibit adenylate cyclase activity. Specifically, while both beta gamma N and beta gamma T are capable of effecting significant levels of inhibition of the guanine nucleotide stimulated activities, the beta gamma N complex is consistently more potent than beta gamma T in inhibiting these activities.(ABSTRACT TRUNCATED AT 250 WORDS)


Small bowel feeding and risk of pneumonia in adult critically ill patients: a systematic review and meta-analysis of randomized trials.
This systematic review and meta-analysis aimed to evaluate the effect of small bowel feeding compared with gastric feeding on the frequency of pneumonia and other patient-important outcomes in critically ill patients. We searched EMBASE, MEDLINE, clinicaltrials.gov and personal files from 1980 to Dec 2012, and conferences and proceedings from 1993 to Dec 2012 for randomized trials of adult critically ill patients in the intensive care unit (ICU) comparing small bowel feeding to gastric feeding, and evaluating risk of pneumonia, mortality, length of ICU stay, achievement of caloric requirements, duration of mechanical ventilation, vomiting, and aspiration. Independently, in duplicate, we abstracted trial characteristics, outcomes and risk of bias. We included 19 trials with 1394 patients. Small bowel feeding compared to gastric feeding was associated with reduced risk of pneumonia (risk ratio [RR] 0.70; 95% CI, 0.55, 0.90; P = 0.004; I2 = 0%) and ventilator-associated pneumonia (RR 0.68; 95% CI 0.53, 0.89; P = 0.005; I2 = 0%), with no difference in mortality (RR 1.08; 95% CI 0.90, 1.29; P = 0.43; I2 = 0%), length of ICU stay (WMD -0.57; 95%CI -1.79, 0.66; P = 0.37; I2 = 0%), duration of mechanical ventilation (WMD -1.01; 95%CI -3.37, 1.35; P = 0.40; I2 = 17%), gastrointestinal bleeding (RR 0.89; 95% CI 0.56, 1.42; P = 0.64; I2 = 0%), aspiration (RR 0.92; 95% CI 0.52, 1.65; P = 0.79; I2 = 0%), and vomiting (RR 0.91; 95% CI 0.53, 1.54; P = 0.72; I2 = 57%). The overall quality of evidence was low for pneumonia outcome. Small bowel feeding, in comparison with gastric feeding, reduces the risk of pneumonia in critically ill patients without affecting mortality, length of ICU stay or duration of mechanical ventilation. These observations are limited by variation in pneumonia definition, imprecision, risk of bias and small sample size of individual trials.


Did awarding badges increase data sharing in BMJ Open? A randomized controlled trial.
Sharing data and code are important components of reproducible research. Data sharing in research is widely discussed in the literature; however, there are no well-established evidence-based incentives that reward data sharing, nor randomized studies that demonstrate the effectiveness of data sharing policies at increasing data sharing. A simple incentive, such as an Open Data Badge, might provide the change needed to increase data sharing in health and medical research. This study was a parallel group randomized controlled trial (protocol registration: doi:10.17605/OSF.IO/PXWZQ) with two groups, control and intervention, with 80 research articles published in BMJ Open per group, with a total of 160 research articles. The intervention group received an email offer for an Open Data Badge if they shared their data along with their final publication and the control group received an email with no offer of a badge if they shared their data with their final publication. The primary outcome was the data sharing rate. Badges did not noticeably motivate researchers who published in BMJ Open to share their data; the odds of awarding badges were nearly equal in the intervention and control groups (odds ratio = 0.9, 95% CI [0.1, 9.0]). Data sharing rates were low in both groups, with just two datasets shared in each of the intervention and control groups. The global movement towards open science has made significant gains with the development of numerous data sharing policies and tools. What remains to be established is an effective incentive that motivates researchers to take up such tools to share their data.


PRAS40 signaling in tumor.
The proline-rich Akt substrate of 40 kDa (PRAS40) is a substrate of Akt and a component of the mammalian target of rapamycin complex 1 (mTORC1). Locating at the crossroad of the PI3K/Akt pathway and the mTOR pathway, PRAS40 is phosphorylated by growth factors or other stimuli, and regulates the activation of these signaling pathways in turn. PRAS40 plays an important role in metabolic disorders and multiple cancers, and the phosphorylation of PRAS40 is often associated with the tumor progression of melanoma, prostate cancer, etc. PRAS40 promotes tumorigenesis by deregulating cellular proliferation, apoptosis, senescence, metastasis, etc. Herein, we provide an overview on current understandings of PRAS40 signaling in the tumor formation and progression, which suggests that PRAS40 or phospho-PRAS40 could become a novel biomarker and therapeutic target in tumor.


Causal association between aspirin use and risk of endometrioid carcinoma: a Mendelian randomization study.
The aim of the study was to investigate the causal relationship between aspirin use and the risk of endometrial endometrioid cancer (EEC) using two-sample Mendelian randomization (TSMR) and multivariable Mendelian randomization (MVMR) study. A TSMR analysis was conducted to estimate the potential causal relationship between aspirin use and the risk of EEC using genome-wide data from Genome-wide association study (GWAS). The causal association between aspirin use and EEC was further analyzed by MVMR analysis after adjusting for various factors such as obesity, hypertension, diabetes, and infertility. The single nucleotide polymorphism (SNP) data associated with aspirin use and EEC was obtained from the GWAS catalog database. A total of six SNPs were included as instrumental variables in TSMR, which showed that taking aspirin reduced the risk of EEC [OR = 0.02, 95% CI = 0-0.28, p = 0.005, inverse variance weighted (IVW) method]. Besides, the results of the weighted median (WME) method, weighted mode, and simple mode were consistent with the results shown by the IVW method. After further using the MVMR method, the causal association of aspirin use and prevention of EEC onset remained significant after adjusting for the effects of obesity, hypertension, and diabetes (OR = 0.076, 95% CI = 0.007-0.793, p = 0.031). Sensitivity analyses, including heterogeneity, horizontal multiplicity, and leave-one-out tests, showed the reliability of the instrumental variables, proving that the results were reliable and not significantly biased. Taking aspirin can reduce the risk of EEC morbidity, and it is expected to be of great significance for the early prevention and treatment of endometrial cancer by exploring the biological mechanism of aspirin on endometrioid cancer at a deeper level.


A regional interdependence model of musculoskeletal dysfunction: research, mechanisms, and clinical implications.
The term 'regional interdependence' or RI has recently been introduced into the vernacular of physical therapy and rehabilitation literature as a clinical model of musculoskeletal assessment and intervention. The underlying premise of this model is that seemingly unrelated impairments in remote anatomical regions of the body may contribute to and be associated with a patient's primary report of symptoms. The clinical implication of this premise is that interventions directed at one region of the body will often have effects at remote and seeming unrelated areas. The formalized concept of RI is relatively new and was originally derived in an inductive manner from a variety of earlier publications and clinical observations. However, recent literature has provided additional support to the concept. The primary purpose of this article will be to further refine the operational definition for the concept of RI, examine supporting literature, discuss possible clinically relevant mechanisms, and conclude with a discussion of the implications of these findings on clinical practice and research.


Evaluation of a Gastrointestinal Pathogen Panel Immunoassay in Stool Testing of Patients with Suspected Clostridioides (Clostridium) difficile Infection.
Clostridioides (Clostridium) difficile infection (CDI) is the most common causative pathogen of health care-associated gastrointestinal infections; however, due to the overlap of clinical symptoms with those of other causes of acute gastroenteritis, the selection of the most appropriate laboratory test is difficult. From April to October 2018, 640 stool samples requested for CDI testing were examined using the mariPOC CDI and Gastro test (ArcDia), which allows the detection of C. difficile glutamate dehydrogenase (GDH) and toxin A/B, norovirus genogroups GI and GII.4, rotavirus, adenovirus, and Campylobacter spp. In parallel, the C. Diff Quik Chek Complete test (Alere) was used as a routine diagnostic assay, and C. difficile toxigenic culture was used as a reference method. The sensitivity of the mariPOC CDI and Gastro test was comparable to that of C. Diff Quik Chek Complete for the detection of GDH (96.40% [95% confidence interval {CI}, 91.81% to 98.82%] versus 95.68% [95% CI, 90.84 to 98.40%]; P = 1.00) and was higher for the detection of toxin A/B (66.67% [95% CI, 57.36 to 75.11%] versus 55.56% [95% CI, 46.08 to 64.74%]; P = 0.00). The specificity of the mariPOC CDI and Gastro test was lower than that of C. Diff Quik Chek Complete for GDH detection (95.21% [95% CI, 92.96% to 96.91%] versus 97.60% [95% CI, 95.85% to 98.76%]; P = 0.04) and comparable to that of C. Diff Quik Chek Complete for toxin A/B detection (99.24 [95% CI, 98.05% to 99.79%] versus 99.81% [95% CI, 98.94% to 100.0%]; P = 0.37). In 29 cases (4.53%), other causative agents of diarrhea were detected (Campylobacter spp. [n = 17], rotavirus [n = 7], and norovirus genogroup GII.4 [n = 5]).


Endogenous abscisic acid as a key switch for natural variation in flooding-induced shoot elongation.
Elongation of leaves and stem is a key trait for survival of terrestrial plants during shallow but prolonged floods that completely submerge the shoot. However, natural floods at different locations vary strongly in duration and depth, and, therefore, populations from these locations are subjected to different selection pressure, leading to intraspecific variation. Here, we identified the signal transduction component that causes response variation in shoot elongation among two accessions of the wetland plant Rumex palustris. These accessions differed 2-fold in petiole elongation rates upon submergence, with fast elongation found in a population from a river floodplain and slow elongation in plants from a lake bank. Fast petiole elongation under water consumes carbohydrates and depends on the (inter)action of the plant hormones ethylene, abscisic acid, and gibberellic acid. We found that carbohydrate levels and dynamics in shoots did not differ between the fast and slow elongating plants, but that the level of ethylene-regulated abscisic acid in petioles, and hence gibberellic acid responsiveness of these petioles explained the difference in shoot elongation upon submergence. Since this is the exact signal transduction level that also explains the variation in flooding-induced shoot elongation among plant species (namely, R. palustris and Rumex acetosa), we suggest that natural selection results in similar modification of regulatory pathways within and between species.


From outside to inside? Dose-dependent renal tubular damage after high-dose peptide receptor radionuclide therapy in rats measured with in vivo (99m)Tc-DMSA-SPECT and molecular imaging.
In peptide receptor radionuclide therapy (PRRT), the dose-limiting organ is, most often, the kidney. However, the precise mechanism as well as the exact localization of kidney damage during PRRT have not been fully elucidated. We studied renal damage in rats after therapy with different amounts of [(177)Lu-DOTA(0), Tyr(3)]octreotate and investigated (99m)Tc-DMSA (dimercaptosuccinic acid) as a tool to quantify renal damage after PRRT. Twenty-nine (29) rats were divided into 3 groups and injected with either 0, 278, or 555 MBq [(177)Lu-DOTA(0), Tyr(3) ]octreotate, leading to approximately 0, 46, and 92 Gy to the renal cortex. More than 100 days after therapy, kidney damage was investigated using (99m)Tc-DMSA single-photon emission computed tomography (SPECT) autoradiography, histology, and blood analyses. In vivo SPECT with (99m)Tc-DMSA resulted in high-resolution (<1.6-mm) images. The (99m)Tc-DMSA uptake in the rat kidneys was inversely related with the earlier injected activity of [(177)Lu-DOTA(0), Tyr(3)]octreotate and correlated inversely with serum creatinine values. Renal ex vivo autoradiograms showed a dose-dependent distribution pattern of (99m)Tc-DMSA. (99m)Tc-DMSA SPECT could distinguish between the rats that were injected with 278 or 555 MBq [(177)Lu-DOTA(0), Tyr(3) ]octreotate, whereas histologic damage grading of the kidneys was nearly identical for these 2 groups. Histologic analyses indicated that lower amounts of injected radioactivity caused damage mainly in the proximal tubules, whereas as well the distal tubules were damaged after high-dose radioactivity. Renal damage in rats after PRRT appeared to start in a dose-dependent manner in the proximal tubules and continued to the more distal tubules with increasing amounts of injected activity. In vivo SPECT measurement of (99m)Tc-DMSA uptake was highly accurate to grade renal tubular damage after PRRT.


Physical descriptions of the bacterial nucleoid at large scales, and their biological implications.
Recent experimental and theoretical approaches have attempted to quantify the physical organization (compaction and geometry) of the bacterial chromosome with its complement of proteins (the nucleoid). The genomic DNA exists in a complex and dynamic protein-rich state, which is highly organized at various length scales. This has implications for modulating (when not directly enabling) the core biological processes of replication, transcription and segregation. We overview the progress in this area, driven in the last few years by new scientific ideas and new interdisciplinary experimental techniques, ranging from high space- and time-resolution microscopy to high-throughput genomics employing sequencing to map different aspects of the nucleoid-related interactome. The aim of this review is to present the wide spectrum of experimental and theoretical findings coherently, from a physics viewpoint. In particular, we highlight the role that statistical and soft condensed matter physics play in describing this system of fundamental biological importance, specifically reviewing classic and more modern tools from the theory of polymers. We also discuss some attempts toward unifying interpretations of the current results, pointing to possible directions for future investigation.


[Effects of multimodal combination dialysis on Klotho protein, FGF-23 and BNP in patients with maintenance hemodialysis].
To discuss the effects of multimodal combination dialysis on Klotho protein, fibroblast growth factor-23 (FGF-23) and brain natriuretic peptide (BNP) in patients with maintenance hemodialysis (MHD). A randomized controlled trial (RCT) was conducted. 120 patients who was diagnosed with chronic renal failure (CRF) uremia receiving MHD over 3 months admitted to Blood Purification Centre of Department of Nephrology of the Second People's Hospital of Guiyang from December 2015 to December 2016 were enrolled, who were randomly divided into hemodialysis (HD) group (HD for 8 times a month), HD + hemofiltration (HF) group (HD for 8 times a month + HF once a month), and HD + HF + hemoperfusion (HP) group (HD for 8 times a month + HF for 4 times a month + HP once a month), with 40 patients in each group. Before and after treatment for 6 months and 12 months, blood was taken from venous circuit tube, the serum Klotho protein and FGF-23 levels were determined by enzyme linked immunosorbent assay (ELISA), and the serum BNP level was determined by electrochemiluminescence. 120 patients with MHD were enrolled in the final analysis without withdrawal. There were no significant differences in the levels of Klotho protein, FGF-23, or BNP before enrollment among the three groups (all P > 0.05). Compared with those before enrollment, the levels of serum Klotho protein after enrollment in three groups showed a sustained upward tendency, which were higher in HD + HF + HP group than in HD + HF group and HD group (μg/L: 2.59±0.61, 1.63±0.35, 1.13±0.26 at 6 months, F = 119.374, P = 0.000; 6.98±1.21, 3.57±1.03, 2.12±0.43 at 12 months, F = 275.675, P = 0.000); the levels of FGF-23 showed a sustained downward tendency, which were lower in HD + HF + HP group than in HD + HF group and HD group (ng/L: 69.22±38.26, 132.28±61.18, 178.50±74.64 at 6 months, F = 33.509, P = 0.000; 32.81±17.32, 87.93±43.27, 146.33±69.28 at 12 months, F = 55.466, P = 0.000); the BNP showed a similar tendency as FGF-23 (ng/L: 4 083.39±2 864.53, 7 245.69±4 643.81, 7 969.12±5 360.85 at 6 months, F = 8.758, P = 0.000; 1 521.86±894.63, 4 554.32±1 969.84, 5 013.89±2 033.64 at 12 months, F = 49.003, P = 0.000). Multimodal combination dialysis can increase the Klotho protein level, and decrease the levels of FGF-23 and BNP in MHD patients with CRF uremia.


P21-activated protein kinase 1 induces colorectal cancer metastasis involving ERK activation and phosphorylation of FAK at Ser-910.
Pak1 has been reported to be overexpressed in colorectal cancer, but the role of Pak1 in colorectal cancer remains unclear. In this study, Pak1 expression and activity were associated with aggressive behavior of colorectal cancer. Overexpression of Pak1 increased colorectal cancer cell motility and invasion, whereas down-regulation of Pak1 expression or activity reduced colorectal cancer cell migration and invasion. In addition, activated Pak1 inhibited stress fiber and focal adhesion complex formation in colorectal cancer cells and led to formation of motile phenotypes. Importantly, activated Pak1 elicited phosphorylation of FAK at Ser-910 via an ERK-dependent pathway in colorectal cancer cell lines and clinical samples. In conclusion, our results suggest that activated Pak1 regulates colorectal cancer metastasis requiring an ERK-dependent phosphorylation of FAK at Ser-910.


Longitudinal right ventricular function is a better predictor of right ventricular contribution to exercise performance than global or outflow tract ejection fraction in tetralogy of Fallot: a combined echocardiography and magnetic resonance study.
The contribution of the systolic function of the right ventricular (RV) outflow tract (RVOT) and of longitudinal shortening of the body of the right ventricle to global RV systolic function and exercise capacity in patients after tetralogy of Fallot (TOF) repair is unclear. Our aim was to characterize the functional role of the RVOT and to identify the most suitable method of assessing RV systolic function in clinical practice. The cardiac magnetic resonance (CMR) studies, echocardiograms, and medical records of 50 consecutive patients with repaired TOF who underwent CMR were reviewed. The volumes of the RVOT and of the remainder of the RV were measured separately. Echocardiographic RV strain measurements based on ultrasound speckle tracking were collected. After excluding the akinetic RVOT, RVEF was statistically higher (47.1 vs. 45.0%, P< 0.0001) but the average increase in EF was small. The correlations of fractional area change and global longitudinal strain, both by echocardiography, with global RVEF were moderate (r= 0.59, P= 0.0001 and r= 0.56, P= 0.0004, respectively). The correlation between RVEF and predicted maximal oxygen consumption (VO(2)max-predicted) was weak, regardless of whether the akinetic RVOT was included or not (r= 0.33, P= 0.049 and r= 0.36, P= 0.03, respectively). Of all imaging parameters, echocardiographic RV longitudinal strain correlated best with VO(2)max-predicted (r= 0.66, P= 0.0001). In patients following TOF repair, echocardiographic and CMR descriptors of global RV systolic function are, at best, weak predictors of exercise tolerance. Longitudinal function of the RV, measured remotely from the RVOT, may be a more important determinant of exercise performance than global RVEF in patients with aneurismal RVOTs.


Time-of-flight spectroscopy of the energy distribution of laser-ablated atoms and ions.
The growth of ultrathin films, deposited by laser ablation, crucially depends on the energy of the ablated species. Therefore, a time-of-flight (TOF) spectrometer has been constructed and measurements have been carried out in order to determine the energy distribution of laser-ablated Fe and Pt atoms and ions in the plasma created by nanosecond pulses of a frequency-doubled neodymium doped yttrium aluminum garnet laser. The experiments have been performed in ultrahigh vacuum at relatively low laser power. For measuring the spectra of the neutrals, a cross-beam electron source for postionization and electric as well as magnetic fields for repelling the ions are employed. Nevertheless, measurements of neutral particles are restricted to low plasma densities due to electrostatic shielding within the plasma, leading to an inefficient deflection of charged particles by electrostatic and magnetic fields. Test measurements have been performed by utilizing the TOF spectrometer as a pressure gauge and also by chopping the electron beam, running the TOF spectrometer as a residual gas mass spectrometer. The spectra of the laser-ablated plasmas have shown plasma conditions with a Debye length of approximately 10(-4) m, densities of 10(15)-10(16) m(-3) and ion energies up to 150 eV. Neutral spectra have shown an unexpectedly low fraction of neutrals (10(-3)-10(-4)) and hyperthermal energies up to several 10 eV, possibly contributed by recombination of ions and electrons in the plasma. Even though gas spectra had demonstrated the expected sensitivity of the TOF spectrometer for low-energy neutrals, no thermally evaporated neutral atoms could be found.


Optimizing patient derived mesenchymal stem cells as virus carriers for a phase I clinical trial in ovarian cancer.
Mesenchymal stem cells (MSC) can serve as carriers to deliver oncolytic measles virus (MV) to ovarian tumors. In preparation for a clinical trial to use MSC as MV carriers, we obtained cells from ovarian cancer patients and evaluated feasibility and safety of this approach. MSC from adipose tissues of healthy donors (hMSC) and nine ovarian cancer patients (ovMSC) were characterized for susceptibility to virus infection and tumor homing abilities. Adipose tissue (range 0.16-3.96 grams) from newly diagnosed and recurrent ovarian cancer patients yielded about 7.41×106 cells at passage 1 (range 4-9 days). Phenotype and doubling times of MSC were similar between ovarian patients and healthy controls. The time to harvest of 3.0×108 cells (clinical dose) could be achieved by day 14 (range, 9-17 days). Two of nine samples tested had an abnormal karyotype represented by trisomy 20. Despite receiving up to 1.6×109 MSC/kg, no tumors were seen in SCID beige mice and MSC did not promote the growth of SKOV3 human ovarian cancer cells in mice. The ovMSC migrated towards primary ovarian cancer samples in chemotaxis assays and to ovarian tumors in athymic mice. Using non-invasive SPECT-CT imaging, we saw rapid co-localization, within 5-8 minutes of intraperitoneal administration of MV infected MSC to the ovarian tumors. Importantly, MSC can be pre-infected with MV, stored in liquid nitrogen and thawed on the day of infusion into mice without loss of activity. MV infected MSC, but not virus alone, significantly prolonged the survival of measles immune ovarian cancer bearing animals. These studies confirmed the feasibility of using patient derived MSC as carriers for oncolytic MV therapy. We propose an approach where MSC from ovarian cancer patients will be expanded, frozen and validated to ensure compliance with the release criteria. On the treatment day, the cells will be thawed, washed, mixed with virus, briefly centrifuged and incubated for 2 hours with virus prior to infusion of the virus/MSC cocktail into patients.


Coordinate regulation of virulence and metabolic genes by the transcription factor HbhR in Mycobacterium marinum.
The heparin-binding hemagglutinin (HBHA) is a multifunctional protein involved in adherence of Mycobacterium tuberculosis to non-phagocytic cells and in the formation of intracytosolic lipid inclusions. We demonstrate that the expression of hbhA is regulated by a transcriptional repressor, named HbhR, in Mycobacterium marinum. The hbhR gene, located upstream of hbhA, was identified by screening a transposon insertion library and detailed analysis of a mutant overproducing HBHA. HbhR was found to repress both hbhA and hbhR transcription by binding to the promoter regions of both genes. Complementation restored production of HBHA. RNA-seq analyses comparing the mutant and parental strains uncovered 27 genes, including hbhA, that were repressed and 20 genes activated by HbhR. Among the former, the entire locus of genes coding for a type-VII secretion system, including esxA, esxB and pe-ppe paralogs, as well as the gene coding for PspA, present in intracellular lipid vesicles, was identified, as was katG, a gene involved in the sensitivity to isoniazid. The latter category contains genes that play a role in diverse functions, such as metabolism and resistance to oxidative conditions. Thus, HbhR appears to be a master regulator, linking the transcriptional regulation of virulence, metabolic and antibiotic sensitivity genes in M. marinum.


[The biological properties of Aerococcus antagonists, representatives of human microbiocenoses].
The paper deals with the data on biology of Aerococcus, a slightly studied group of microorganisms. Physiological-biochemical properties of Aerococcus are described, data of their distribution in nature are given. Peculiar attention is paid to the estimate of the role of Aerococcus in human microbiocenoses. As a result of the profound and all-round study of this group of microorganisms the authors have developed new bacterial drug "A-bakterin" based on the aerococcus strain. Data presented about the results of clinical tests of "A-bakterin" are presented, a possibility to use Aerococcus lysate in the elaboration of new drugs is discussed.


Cigarette Smoking and Semen Quality: A New Meta-analysis Examining the Effect of the 2010 World Health Organization Laboratory Methods for the Examination of Human Semen.
Approximately 37% of men of reproductive age smoke cigarettes, with Europe having the highest tobacco use among all the World Health Organization (WHO) regions. Toxins from tobacco smoking can potentially affect sperm development and function, with a negative effect on semen parameters. Given the high prevalence of smoking and recent changes in the WHO laboratory methods for the examination of human semen, the role of this exposure in face of new WHO methods needs to be clarified. We conducted a systematic review, followed by a meta-analysis, to determine whether cigarette smoking affects human semen parameters. PubMed, Saint Joseph's University Discover, and Google Scholar were used to identify relevant studies published after release of the latest WHO methods for laboratory evaluation of human semen. Participants were from fertility/urologic clinics and andrology laboratories. The outcome measures were semen volume, sperm concentration, motility, and morphology, the parameters usually used in clinical settings to assess fertility. Twenty studies with 5865 participants were included in the meta-analysis. Exposure to cigarette smoking was associated with reduced sperm count (mean difference [MD]: -9.72×106/ml; 95% confidence interval [CI], -13.32 to -6.12), motility (MD: -3.48%; 95% CI, -5.53 to -1.44), and morphology (MD: -1.37%; 95% CI, -2.63 to -0.11). Subgroup analyses indicated that effect size was higher in infertile men than in the general population and in moderate/heavy smokers than in mild smokers. The overall effect size on semen volume, sperm count, and motility remained similar when 2010 and earlier WHO manuals were used for semen analysis but was lower with regard to sperm morphology. Our results suggest that cigarette smoking has an overall negative effect on semen parameters. The latest WHO laboratory methods for the examination of human semen had a minimal impact on the magnitude of effect size, thus confirming the observed negative effect of smoking on conventional semen parameters. A new systematic review and meta-analysis comprising 5865 men shows that cigarette smoking is associated with reduced sperm count and motility. Deterioration of semen quality is more pronounced in moderate and heavy smokers.


A Split Staphylococcus aureus Cas9 as a Compact Genome-Editing Tool in Plants.
Split-protein methods-where a protein is split into two inactive fragments that must re-assemble to form an active protein-can be used to regulate the activity of a given protein and reduce the size of gene transcription units. Here, we show that a Staphylococcus aureus Cas9 (SaCas9) can be split, and that split-SaCas9 expressed from Agrobacterium can induce targeted mutagenesis in Nicotiana benthamiana. Since SaCas9 is smaller than the more commonly used Cas9 derived from Streptococcus pyogenes, the split-SaCas9 provides the smallest tool yet for clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) plant genome editing. Both sets of split-SaCas9 (_430N/431C and _739N/740C) exhibited genome-editing activity, and the activity of split-SaCas9_739N/740C was almost the same as that of full-length SaCas9. This result indicates that split-SaCas9_739N/740C is suitable for use in targeted mutagenesis. We also show that the split-SaCas9 fragment expressed from Tomato mosaic virus could induce targeted mutagenesis together with another fragment expressed from Agrobacterium, suggesting that a split-SaCas9 system using a plant virus vector is a promising tool for integration-free plant genome editing. Split-SaCas9 has the potential to regulate CRISPR/Cas9-mediated genome editing activity in plant cells both temporally and spatially.


Post-prandial hypoglycemia after bariatric surgery: pharmacological treatment with verapamil and acarbose.
Postprandial hypoglycemia is a common complication of bariatric surgery. It is usually caused by late dumping syndrome, but a few other causes have already been described, including insulinoma and noninsulinoma pancreatogenous hypoglycemic syndrome (NIPHS). Considering that NIPHS is a recently described syndrome and is also very rare, therapeutic approaches are still not consensual. We report the case of a 26-year-old woman who was submitted to bariatric surgery and presented episodic postprandial hypoglycemic episodes after 16 months. Fasting C-peptide, insulin, and glucose were normal. Because of the possibility of NIPHS, clinical treatment was initiated with verapamil and acarbose, leading to a significant reduction of hypoglycemic episodes and also their severity. Surgery is the most common approach to NIPHS. However, in cases of mild or moderate symptoms, it is important to consider the possibility of pharmacological treatment. This approach may result, at least for some time, in an amelioration of symptoms without the need of an aggressive procedure.


Comparative study of two new commercial echelle spectrometers equipped with intensified CCD for analysis of laser-induced breakdown spectroscopy.
The purpose of this paper is to provide the reader with comparative information about two new commercial echelle spectrometers equipped with intensified CCD (ICCD) detectors for laser-induced breakdown spectroscopy analysis. We carried out a performance comparison between two commercial ICCD/echelle spectrometers [ESA 3000 (LLA Instruments GmbH, Berlin-Adlershof, Germany) and a Mechelle 7500 (Multichannel Instruments, Stockholm, Sweden)] for the determination of the concentrations of Be, Mg, Si, Mn, Fe, and Cu in the same Al alloy samples adopting the same experimental conditions. The results show that both systems, despite their differences in terms of resolution, have similar performance in terms of sensitivity and precision of measurements for these elements in an Al alloy matrix at least for the range of wavelength 280-400 nm studied in this work.


Effect of baclofen on the acid pocket at the gastroesophageal junction.
Previous studies established that a pocket of highly acidic gastric juice is present postprandially at the gastroesophageal junction in man. The GABA-B agonist baclofen inhibits postprandial reflux events through its effects on the lower esophageal sphincter (LES). The aim of the current study was to investigate whether baclofen would affect the location and the extent of the postprandial acid pocket in healthy volunteers. Twelve healthy volunteers underwent acid pocket studies on two different occasions, at least 1 week apart. LES position was determined preprandially with pull-through manometry. Dual pH electrode and manometry probe stepwise pull-through (1 cm/minute, LES-10 to +5 cm) was performed at 30-minute intervals for 150 minutes, with administration of placebo or baclofen 40 mg after the first and ingestion of a liquid meal after the second pull-through. After placebo, a significant drop in intragastric gastric pH was present at the gastroesophageal junction after the meal, reflecting the acid pocket, and this was associated with a drop in LES pressure. Baclofen did not affect the presence of the acid pocket, but prevented the postprandial drop in LES pressure, and the extent of the acid pocket above the upper margin of the manometrically located LES was significantly decreased by baclofen (1.6 ± 0.7 vs. 0.3 ± 0.4 cm at 60 minutes, 2.2 ± 0.6 vs. 0.2 ± 0.6 at 90 minutes, and 1.5 ± 0.5 vs. 0.7 ± 0.7 cm at 120 minutes, all P < 0.05). Baclofen does not alter the intragastric acid pocket, but limits its extension into the distal esophagus, probably through an increase in postprandial LES pressure.


Neuroreflexotherapy for nonspecific low back pain: a systematic review.
Systematic review. To assess the effectiveness of neuroreflexotherapy (NRT) for low back pain (LBP). Few of the alternatives for the management of LBP have a firm base of evidence for their effectiveness. Recently, a new intervention known as NRT has been developed in Spain and has been reported to have favorable results. Searches were undertaken according to Cochrane Collaboration guidelines, and randomized controlled trials that evaluated NRT as treatment for patients with nonspecific LBP were included. A qualitative synthesis and an assessment of methodological quality were undertaken. Three randomized controlled trials were included, with 125 and 148 subjects in control and intervention groups, respectively. NRT was compared with sham in two trials and standard care in one. Individuals receiving active NRT showed significantly better outcomes for pain, mobility, disability, medication use, consumption of resources, and costs. No major side effects were reported by those receiving active NRT. NRT appears to be a safe and effective intervention for nonspecific LBP. This conclusion is limited to three trials conducted by a small number of experienced clinicians. Further trials in other settings are needed to determine whether these favorable results can be generalized.


Prevalence and mortality associated with cytomegalovirus infection in nonimmunosuppressed patients in the intensive care unit.
Cytomegalovirus is the most common viral opportunistic infection in immunocompromised patients. However, recent studies have demonstrated active cytomegalovirus infection in nonimmunosuppressed intensive care unit patients. To define the frequency and mortality rate associated with cytomegalovirus infection in nonimmunosuppressed patients in the intensive care unit. A systematic review up to October 2008 was performed. Pooled results were analyzed by fixed- and random-effects models. Cochran Q and I2 were performed for heterogeneity. Thirteen studies (n = 1258) were selected. The overall rate of active cytomegalovirus infection was 17% (95% confidence interval [CI], 11% to 24%; p < .0001; I2 = 86%). When the patients were screened for > or =5 intensive care unit days, the overall rate of infection increased to 21% (95% CI, 15% to 29%; p < .001). The infection rate for studies that used cytomegalovirus DNA/antigen for diagnosis was 20% (95% CI, 13% to 31%; p < .0001) and for studies that used culture was 12% (95% CI, 6% to 22%; p < .0001). The cytomegalovirus rate for patients with unknown serology was 7% (95% CI, 3% to 14%; p < .0001), whereas the rate for patients with positive serology was 31% (95% CI, 22% to 42%; p < .0001). The rate of infection was higher in patients with severe sepsis: 32% (95% CI, 22% to 45%; p < .0001). And in patients with high disease severity: 32% (95% CI, 23% to 42%; p < .0001). The overall mortality rate associated with active cytomegalovirus infection was 1.93 times (95% CI, 1.29 to 2.88; p = .001) as high as that without cytomegalovirus infection. Active cytomegalovirus infection occurs frequently in nonimmunosuppressed patients in intensive care, especially in those with positive cytomegalovirus serology, intensive care unit stay > or =5 days, severe sepsis, and high disease severity, in whom the rate of cytomegalovirus infection is up to 36%. Mortality rate is significantly doubled with cytomegalovirus, but a cause-effect relationship cannot be established yet. A large prospective cohort study on the patient population identified by our findings is needed to define who is at the highest risk for developing active cytomegalovirus infection and to determine its effects on mortality.


Integration of sulcal and functional information for multimodal neuronavigation.
The authors present the use of cortical sulci, segmented from magnetic resonance (MR) imaging, and functional data from functional (f)MR imaging and magnetoencephalography (MEG) in the image-guided surgical management of lesions adjacent to the sensorimotor cortex. In an initial set of 11 patients, sulci near lesions were automatically segmented from MR imaging data sets, then MEG and fMR imaging examinations were performed. Relevant functional information was preoperatively interpreted and selected from MEG and fMR imaging and subsequently transferred to the navigation system for selected sulci. A neuronavigation system consisting of a surgical microscope with enhanced reality overlay display was used. Data were displayed as contours on the cut-plane images of a stereotactic workstation and as contours on the overlay screen of the head-up display within the optical path of the right eyepiece of the surgical microscope. This method, in which both sulcal and functional mapping are used for surgery planning and neuronavigation, provides helpful information. It is a promising procedure for the treatment of patients who harbor lesions in areas around the eloquent cortex.


Timing of lowest and highest peak expiratory flow in patients with asthma: influence of anti-inflammatory treatment.
We sought to determine the optimal time for measuring peak expiratory flow rate (PEF) in patients with mild to moderate asthma, before and after treatment with inhaled beclomethasone dipropionate (BDP). After 2 weeks of observation, BDP (400 microg/d) was given to 22 patients with mild to moderate asthma. The dose of BDP (800-1200 microg/d) was increased every 2 weeks until PEF varied by no more than 20% each day. PEF was measured four times daily: on awakening, around noon, in the evening and at bedtime. Significant (P < 0.05) rhythms were detected by single cosinor analysis in all patients, both during observation and during treatment. Analysis by the population mean-cosinor method showed that the mean mesor was 378.8+/-59.1 lmin(-1), the mean amplitude was 53.9+/-13.4 lmin(-1), and the mean acrophase was at 16:26+/-0:32 before treatment. After treatment, the mean mesor was 528.0+/-61.9 l min(-1), the mean amplitude was 37.6+/-12.2 lmin(-1), and the mean acrophase was at 16:35+/-0:32. The mesor increased significantly (P<0.05), and the amplitude decreased significantly (P<0.05) after treatment. The acrophase did not change. These data indicate that PEF is lowest at 04:30 and highest at 16:30 in patients with mild to moderate asthma, both during observation and during treatment. We conclude that if one needs to assess PEF twice a day, this should ideally be done at 04:30 and 16:30, not only before but also after treatment with BDP.


A Review of Extracorporeal Blood Purification Techniques for the Treatment of Critically Ill Coronavirus Disease 2019 Patients.
In late 2019, a novel betacoronavirus, later termed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was discovered in patients with an unknown respiratory illness in Wuhan, China. SARS-CoV-2 and the disease caused by the novel coronavirus, coronavirus disease 2019 (COVID-19), spread rapidly and resulted in the World Health Organization declaring a pandemic in March 2020. In a minority of patients infected with SARS-CoV-2, severe illness develops characterized by a dysregulated immune response, acute respiratory distress syndrome, and multisystem organ failure. Despite the development of antiviral and multiple immunomodulatory therapies, outcomes of severe illness remain poor. In response, the Food and Drug Administration in the United States authorized the emergency use of several extracorporeal blood purification (EBP) devices for critically ill patients with COVID-19. Extracorporeal blood purification devices target various aspects of the host response to infection to reduce immune dysregulation. This review highlights the underlying technology, currently available literature on use in critically ill COVID-19 patients, and future studies involving four EBP platforms: 1) oXiris filter, 2) CytoSorb filter, 3) Seraph 100 Microbind blood affinity filter, and 4) the Spectra Optia Apheresis System with the Depuro D2000 Adsorption Cartridge.


3-OMD and homocysteine plasma levels in parkinsonian patients.
One main metabolizing pathway of levodopa is O-methylation to 3-O-methyldopa (3-OMD) by catechol-O-methyltransferase (COMT). Since COMT requires Mg2+ and S-adenosylmethionine as methyl donor for this transmethylating process, COMT converts S-adenosylmethionine to S-adenosylhomocysteine and subsequent homocysteine. Objective of this study was to demonstrate relations between plasma levodopa, 3-OMD and total homocysteine in treated parkinsonian subjects. We measured homocysteine, levodopa and 3-OMD by HPLC. We compared plasma homocysteine in two groups of treated parkinsonian subjects subdivided according to their 3-OMD level. Homocysteine was significantly (p = 0.002) elevated in the group with higher 3-OMD concentrations and positively (r = 0.52, p = 0.0006) correlated to 3-OMD. Homocysteine induces vascular disease. Previous studies showed an increase of ischaemic heart- and cerebrovascular disease in treated parkinsonian patients.


The Herbicide Glyphosate and Its Apparently Controversial Effect on Human Health: An Updated Clinical Perspective.
Glyphosate (G) is the most common weed-killer in the world. Every year tons and tons of G are applied on crop fields. G was first introduced in the mid 1970s and since then its usage has gradually increased to reach a peak since 2005. Now G usage is approximately 100 -fold what it was in 1970. Its impact on human health was considered benign at the beginning. But over the years, evidence of a pervasive negative effect of this pesticide on humans has been mounting. Nonetheless, G usage is allowed by government health control agencies (both in the United States and Europe), that rely upon the evidence produced by the G producer. However, the IARC (International Agency for Research on Cancer) in 2015 has stated that G is probable carcinogenic (class 2A), the second highest class in terms of risk. In this review, we explore the effect of G on human health, focusing in particular on more recent knowledge. We have attempted to untangle the controversy about the dangers of the product for human beings in view of a very recent development, when the so -called Monsanto Papers, consisting of Emails and memos from Monsanto came to light, revealing a coordinated strategy to manipulate the debate about the safety of glyphosate to the company's advantage. The story of G is a recurrent one (see the tobacco story), that seriously jeopardizes the credibility of the scientific study in the modern era.


SOD1 activity threshold and TOR signalling modulate VAP(P58S) aggregation via reactive oxygen species-induced proteasomal degradation in a Drosophila model of amyotrophic lateral sclerosis.
Familial amyotrophic lateral sclerosis (ALS) is an incurable, late-onset motor neuron disease, linked strongly to various causative genetic loci. ALS8 codes for a missense mutation, P56S, in VAMP-associated protein B (VAPB) that causes the protein to misfold and form cellular aggregates. Uncovering genes and mechanisms that affect aggregation dynamics would greatly help increase our understanding of the disease and lead to potential therapeutics. We developed a quantitative high-throughput Drosophila S2R+ cell-based kinetic assay coupled with fluorescent microscopy to score for genes involved in the modulation of aggregates of the fly orthologue, VAP(P58S), fused with GFP. A targeted RNA interference screen against 900 genes identified 150 hits that modify aggregation, including the ALS loci Sod1 and TDP43 (also known as TBPH), as well as genes belonging to the mTOR pathway. Further, a system to measure the extent of VAP(P58S) aggregation in the Drosophila larval brain was developed in order to validate the hits from the cell-based screen. In the larval brain, we find that reduction of SOD1 levels or decreased mTOR signalling reduces aggregation, presumably by increasing the levels of cellular reactive oxygen species (ROS). The mechanism of aggregate clearance is, primarily, proteasomal degradation, which appears to be triggered by an increase in ROS. We have thus uncovered an interesting interplay between SOD1, ROS and mTOR signalling that regulates the dynamics of VAP aggregation. Mechanistic processes underlying such cellular regulatory networks will lead to better understanding of the initiation and progression of ALS.This article has an associated First Person interview with the first author of the paper.


Cricoid pressure and laryngeal manipulation in 402 pre-hospital emergency anaesthetics: essential safety measure or a hindrance to rapid safe intubation?
This is the first study to look at the effects of cricoid pressure/laryngeal manipulation on the laryngeal view and intubation success in the emergency or pre-hospital environment. Cricoid pressure is applied in the hope of reducing the incidence of aspiration. However the technique has never been evaluated in a randomized trial and may adversely affect laryngeal view. In order to improve intubating conditions cricoid pressure may be released and the larynx manipulated into a more favourable position. We carried out a prospective observational study to evaluate the effects of cricoid pressure and laryngeal manipulation on laryngeal view in our physician led pre-hospital trauma service. 402 patients were included over a 16-month period. We intubated 98.8% patients on the first or second attempt. In 61 intubations (in 55 patients, 13.6%) the larynx required manipulation to facilitate intubation. In 22 intubations cricoid pressure was removed with the laryngeal view improving in 50%. Bimanual laryngeal manipulation was used in 25 intubations and the larynx better visualised in 60% of these. Backwards upwards rightwards pressure was applied to the larynx in 14 intubations and the laryngeal view improved in 64%. Two patients regurgitated when cricoid pressure was released. Both had prolonged periods of bag valve mask ventilation and difficult intubations. The results suggest that cricoid pressure should be removed if the laryngeal view obtained is not sufficient to allow immediate intubation. Further manipulation of the larynx is likely to improve the chances of successful tracheal tube placement.


Informed consent and patients with cancer: role of the nurse as advocate.
Informed consent is an ongoing process, and oncology nurses are important advocates to identify information gaps and patient concerns during this process. This article discusses the rights of research participants from a regulatory perspective. Two case scenarios are presented and discussed to describe how nurses can ensure that patients are truly informed and understand the clinical trial process.


Antifibrotic effects of a recombinant adeno-associated virus carrying small interfering RNA targeting TIMP-1 in rat liver fibrosis.
Elevated tissue inhibitor of metalloproteinase 1 (TIMP-1) expression contributes to excess production of extracellular matrix in liver fibrosis. Herein, we constructed a recombinant adeno-associated virus (rAAV) carrying siRNA of the TIMP-1 gene (rAAV/siRNA-TIMP-1) and investigated its effects on liver fibrosis in rats. Two models of rat liver fibrosis, the carbon tetrachloride and bile duct ligation models, were treated with rAAV/siRNA-TIMP-1. In the carbon tetrachloride model, rAAV/siRNA-TIMP-1 administration attenuated fibrosis severity, as determined by histologic analysis of hepatic collagen accumulation, hydroxyproline content, and concentrations of types I and III collagen in livers and sera. Levels of mRNA and active matrix metalloproteinase (MMP) 13 were elevated, whereas levels of mRNA and active MMP-2 were decreased. Moreover, a marked decrease was noted in the expression of α-smooth muscle actin, a biomarker of activated hepatic stellate cells (HSCs), and transforming growth factor-β1, critical for the development of liver fibrosis. Similarly, rAAV/siRNA-TIMP-1 treatment significantly alleviated bile duct ligation-induced liver fibrosis. Furthermore, this treatment dramatically suppressed TIMP-1 expression in HSCs from both model rats. These data indicate that the administration of rAAV/siRNA-TIMP-1 attenuated liver fibrosis by directly elevating the function of MMP-13 and diminishing activated HSCs. It also resulted in indirect decreased expression of type I collagen, MMP-2, and transforming growth factor-β1. In conclusion, rAAV/siRNA-TIMP-1 may be an effective antifibrotic gene therapy agent.


The association between late-onset fecal incontinence and obstetric anal sphincter defects.
Endoanal ultrasonographic results have demonstrated that clinically occult anal sphincter damage during vaginal delivery is common. This may or may not be associated with postpartum fecal incontinence (FI). Bayesian meta-analysis of the literature revealed that at least two thirds of obstetric sphincter disruptions are asymptomatic in the postpartum period. Women with postpartum asymptomatic sphincter damage may be at increased risk for FI with aging compared with those without sphincter injury. Case series. Tertiary referral center. After excluding patients with other possible causes of FI, the histories of 124 consecutive women with late-onset FI after vaginal delivery were analyzed. Endoanal ultrasonographic findings, pudendal nerve terminal motor latency assessment, and anal manometric results. Eighty-eight women (71%) with a median of 3 vaginal deliveries had sphincter defects on endoanal ultrasonographic results. The mean incontinence score, squeeze and resting pressures, median age at last delivery, and median duration of FI were not significantly different between patients with and without sphincter defects. Pudendal neuropathy was more frequent in patients without sphincter defects (10 [30.3%], left side; 12 [36.4%], right side) than in patients with sphincter defects (12 [14.3%] and 16 [19.3%], respectively), with the difference nearly reaching statistical significance (P =.054 and P =.059, respectively). The median age at onset of FI in patients with a sphincter defect was 61.5 years vs 68.0 years in those without a sphincter defect, which was not statistically significant (P =.08). Analysis of the current patient population revealed that 88 women (71%) with late-onset FI after vaginal delivery had an anatomical sphincter defect. Thus, FI related to anal sphincter defects is likely to occur even in an elderly population who had experienced vaginal deliveries earlier in life.


Fas and Fas-associated death domain protein regulate monocyte chemoattractant protein-1 expression by human smooth muscle cells through caspase- and calpain-dependent release of interleukin-1alpha.
We previously reported that treatment of human vascular smooth muscle cells (SMCs) with proapoptotic stimuli, including Fas ligand plus cycloheximide (FasL/Chx), or overexpression of Fas-associated death domain protein (FADD) result in increased expression of monocyte chemoattractant protein-1 (MCP-1) and other proinflammatory genes. In this study, we demonstrate that Fas/FADD-induced MCP-1 upregulation is driven by an autocrine/paracrine signaling loop in which interleukin (IL)-1alpha synthesis and release are activated through caspase- and calpain-dependent processes. Untreated SMCs contain very little IL-1alpha protein or transcript. Both were increased greatly in response to Fas/FADD activation, primarily through an autocrine/paracrine pathway in which secreted IL-1alpha stimulated additional IL-1alpha synthesis and release. Caspase 8 (Csp8) activity increased in response to FasL/Chx treatment, and Csp8 inhibitors markedly reduced IL-1alpha release and MCP-1 upregulation. In contrast, Csp8 activity was not significantly increased in response to FADD overexpression and caspase inhibitors did not effect FADD-induced MCP-1 upregulation. Both FasL/Chx treatment and FADD overexpression increased the activity of calpains. Calpain inhibitors reduced IL-1alpha release and MCP-1 upregulation in both FADD-overexpressing SMCs and FasL/Chx-treated SMCs without blocking Csp8 activity. This indicates that calpains are not required for activation of caspases and that caspase activation is not sufficient for IL-1alpha release and MCP-1 upregulation. These data suggest that calpains play a dominant role in Fas/FADD-induced IL-1alpha release and MCP-1 upregulation and that caspase activation may function to amplify the effects of calpain activation.


The Reliability of a Semi-automated Algorithm for Detection of Cortical Interruptions in Finger Joints on High Resolution CT Compared to MicroCT.
We developed a semi-automated algorithm for the detection of cortical interruptions in finger joints using high-resolution peripheral quantitative computed tomography (HR-pQCT). Here, we tested its reliability compared to microCT (µCT) as gold standard. Nineteen joints of 10 female anatomic index fingers were imaged by HR-pQCT and µCT (82 and 18 µm isotropic voxel sizes, respectively). The algorithm was applied for detection of cortical interruptions of different minimum diameters (range >0.16 to >0.50 mm). Reliability was tested at the joint level with intra-class correlation coefficient (ICC) for the number of interruptions and interruption surface, and at the level of a single interruption for matching between HR-pQCT and µCT with a fixed interruption diameter (>0.10 mm) on µCT. The positive predictive value (PPV0.10mm) and sensitivity0.10mm were evaluated. The mean number of interruptions per joint depended on the diameter cut-off and ranged from 3.4 to 53.5 on HR-pQCT and from 1.8 to 45.1 on µCT for interruptions >0.50 to >0.16 mm, respectively. Reliability at the joint level was almost perfect (ICC ≥0.81) for both the number and surface of interruptions >0.16 and >0.33 mm. As expected, the PPV0.10mm increased with increasing interruption diameter from 84.9 to 100%, for interruptions >0.16 and >0.50 mm, respectively. However, the sensitivity0.10mm decreased with increasing interruption diameter from 62.4 to 4.7%. This semi-automated algorithm for HR-pQCT in finger joints performed best for the detection of cortical interruptions with a minimum diameter of >0.16 or >0.33 mm, showing almost perfect reliability at the joint level and interruptions matched with those on µCT.


Complex cellular logic computation using ribocomputing devices.
Synthetic biology aims to develop engineering-driven approaches to the programming of cellular functions that could yield transformative technologies. Synthetic gene circuits that combine DNA, protein, and RNA components have demonstrated a range of functions such as bistability, oscillation, feedback, and logic capabilities. However, it remains challenging to scale up these circuits owing to the limited number of designable, orthogonal, high-performance parts, the empirical and often tedious composition rules, and the requirements for substantial resources for encoding and operation. Here, we report a strategy for constructing RNA-only nanodevices to evaluate complex logic in living cells. Our 'ribocomputing' systems are composed of de-novo-designed parts and operate through predictable and designable base-pairing rules, allowing the effective in silico design of computing devices with prescribed configurations and functions in complex cellular environments. These devices operate at the post-transcriptional level and use an extended RNA transcript to co-localize all circuit sensing, computation, signal transduction, and output elements in the same self-assembled molecular complex, which reduces diffusion-mediated signal losses, lowers metabolic cost, and improves circuit reliability. We demonstrate that ribocomputing devices in Escherichia coli can evaluate two-input logic with a dynamic range up to 900-fold and scale them to four-input AND, six-input OR, and a complex 12-input expression (A1 AND A2 AND NOT A1*) OR (B1 AND B2 AND NOT B2*) OR (C1 AND C2) OR (D1 AND D2) OR (E1 AND E2). Successful operation of ribocomputing devices based on programmable RNA interactions suggests that systems employing the same design principles could be implemented in other host organisms or in extracellular settings.


Hypertension and hypertension-related disease in mongolia; findings of a national knowledge, attitudes and practices study.
Mongolia has a high and increasing burden of hypertension and related disease, with cardiovascular diseases among the leading causes of death. Yet little is known about the knowledge, attitudes and practices of the Mongolian population with regards to blood pressure. With this in mind, a national Non-Communicable Diseases knowledge, attitudes and practices survey on blood pressure was implemented in late 2010. This paper reports on the findings of this research. Using a multi-stage, random cluster sampling method 3450 participant households were selected from across Mongolia. This survey was interviewer-administered and included demographic and socio-economic questions. Sample size was calculated using methods aligned with the World Health Organization STEPS surveys. One fifth of participants reported having never heard the term 'blood pressure'. This absence of health knowledge was significantly higher in men, and particularly younger men. The majority of participants recognised high blood pressure to be a threat to health, with a higher level of risk awareness among urban individuals. Education level and older age were generally associated with a heightened knowledge and risk perception. Roughly seven in ten participants were aware of the relationship between salt and blood pressure. Exploring barriers to screening, participants rated a 'lack of perceived importance' as the main deterring factor among fellow Mongolians and overall, participants perceived medication and exercise as the only interventions to be moderately effective at preventing high blood pressure. Rural populations; younger populations; men; and less educated populations, all with lower levels of knowledge and risk perception regarding hypertension, present those most vulnerable to it and the related health outcomes. This research intimates major health knowledge gaps in sub-populations within Mongolia, regarding health-risks related to hypertension.


Dynamic occlusion analysis in optical flow fields.
Optical flow can be used to locate dynamic occlusion boundaries in an image sequence. We derive an edge detection algorithm sensitive to changes in flow fields likely to be associated with occlusion. The algorithm is patterned after the Marr-Hildreth zero-crossing detectors currently used to locate boundaries in scalar fields. Zero-crossing detectors are extended to identify changes in direction and/or magnitude in a vector-valued flow field. As a result, the detector works for flow boundaries generated due to the relative motion of two overlapping surfaces, as well as the simpler case of motion parallax due to a sensor moving through an otherwise stationary environment. We then show how the approach can be extended to identify which side of a dynamic occlusion boundary corresponds to the occluding surface. The fundamental principal involved is that at an occlusion boundary, the image of the surface boundary moves with the image of the occluding surface. Such information is important in interpreting dynamic scenes. Results are demonstrated on optical flow fields automatically computed from real image sequences.


MAP9 Loss Triggers Chromosomal Instability, Initiates Colorectal Tumorigenesis, and Is Associated with Poor Survival of Patients with Colorectal Cancer.
Chromosomal instability (CIN) is a common phenomenon in colorectal cancer, but its role and underlying cause remain unknown. We have identified that mitotic regulator microtubule-associated protein 9 (MAP9) is a critical regulator of CIN in colorectal cancer. We thus studied the effect of MAP9 loss on colorectal cancer in Map9-knockout mice and in cell lines. We generated colon epithelial-specific Map9-knockout mice and evaluated colorectal cancer development. Effect of Map9 knockout on colorectal cancer progression was determined in chemical or ApcMin /+ -induced colorectal cancer. Molecular mechanism of MAP9 was determined using spectral karyotyping, microtubule assays, and whole-genome sequencing (WGS). Clinical significance of MAP9 was examined in 141 patients with CRC. Spontaneous colonic tumors (9.1%) were developed in colon epithelium-specific Map9-knockout mice at 17 months, but none was observed in wild-type littermates. Map9 deletion accelerated colorectal cancer formation both in ApcMin /+ mice and azoxymethane-treated mice, and reduced survival in ApcMin /+ mice. Mechanistically, MAP9 stabilized microtubules and mediated mitotic spindle assembly. MAP9 also maintained the spindle pole integrity and protected K-fiber from depolymerization at spindle poles. MAP9 loss induced severe mitosis failure, chromosome segregation errors, and aneuploidy, leading to transformation of normal colon epithelial cells. WGS confirmed enhanced CIN in intestinal tumors from Map9 knockout ApcMin /+ mice. In patients with colorectal cancer, MAP9 was frequently silenced and its downregulation was associated with poor survival. MAP9 is a microtubule stabilizer that contributes to spindle stability and inhibits colorectal tumorigenesis, supporting the role of MAP9 as a tumor suppressor for preventing CIN in colorectal cancer.


Analyzing visual-search observers using eye-tracking data for digital breast tomosynthesis images.
Visual-search (VS) model observers have the potential to provide reliable predictions of human-observer performance in detection-localization tasks. The purpose of this work was to examine some characteristics of human gaze on breast images with the goal of informing the design of our VS observers. Using a helmet-mounted eye-tracking system, we recorded the movement of gaze from human observers as they searched for masses in sets of 2D digital breast tomosynthesis (DBT) images. The masses in this study were of a single profile. The DBT images were extracted from image volumes reconstructed with the filtered backprojection method. Fixation times associated with observer points of interest were computed from the observer data. We used the k-mean clustering algorithm to get dwell times of gaze data. The dwell times were then compared to sets of morphological feature values extracted from the images. These features, extracted as cross correlations involving the mass profile and the test image, included the matched filter (MF), gradient MF, Laplacian MF, and adaptive MF. The adaptive MF combining four feature maps was computed using a hotelling discriminant generated from training data. For this investigation, we computed correlation coefficients between the fixation times and the feature values. We also conducted a significance test by computing p-values of correlation coefficients for five features. Of all these features, the adaptive MF provided the highest correlation coefficients for DBT images with different densities.


A Direct Algorithm for Optimization Problems With the Huber Penalty.
We present a direct (noniterative) algorithm for 1-D quadratic data fitting with neighboring intensity differences penalized by the Huber function. Applications of such an algorithm include 1-D processing of medical signals, such as smoothing of tissue time concentration curves in kinetic data analysis or sinogram preprocessing, and using it as a subproblem solver for 2-D or 3-D image restoration and reconstruction. dynamic programming was used to develop the direct algorithm. The problem was reformulated as a sequence of univariate optimization problems, for , where is the number of data points. The solution to the univariate problem at index is parameterized by the solution at , except at . Solving the univariate optimization problem at yields the solution to each problem in the sequence using back-tracking. Computational issues and memory cost are discussed in detail. Two numerical studies, tissue concentration curve smoothing and sinogram preprocessing for image reconstruction, are used to validate the direct algorithm and illustrate its practical applications. In the example of 1-D curve smoothing, the efficiency of the direct algorithm is compared with four iterative methods: the iterative coordinate descent, Nesterov's accelerated gradient descent algorithm, FISTA, and an off-the-shelf second order method. The first two methods were applied to the primal problem, the others to the dual problem. The comparisons show that the direct algorithm outperforms all other methods by a significant factor, which rapidly grows with the curvature of the Huber function. The second example, sinogram preprocessing, showed that robustness and speed of the direct algorithm are maintained over a wide range of signal variations, and that noise and streaking artifacts could be reduced with almost no increase in computation time. We also outline how the proposed 1-D solver can be used for imaging applications.


The strength of primary care in Europe: an international comparative study.
A suitable definition of primary care to capture the variety of prevailing international organisation and service-delivery models is lacking. Evaluation of strength of primary care in Europe. International comparative cross-sectional study performed in 2009-2010, involving 27 EU member states, plus Iceland, Norway, Switzerland, and Turkey. Outcome measures covered three dimensions of primary care structure: primary care governance, economic conditions of primary care, and primary care workforce development; and four dimensions of primary care service-delivery process: accessibility, comprehensiveness, continuity, and coordination of primary care. The primary care dimensions were operationalised by a total of 77 indicators for which data were collected in 31 countries. Data sources included national and international literature, governmental publications, statistical databases, and experts' consultations. Countries with relatively strong primary care are Belgium, Denmark, Estonia, Finland, Lithuania, the Netherlands, Portugal, Slovenia, Spain, and the UK. Countries either have many primary care policies and regulations in place, combined with good financial coverage and resources, and adequate primary care workforce conditions, or have consistently only few of these primary care structures in place. There is no correlation between the access, continuity, coordination, and comprehensiveness of primary care of countries. Variation is shown in the strength of primary care across Europe, indicating a discrepancy in the responsibility given to primary care in national and international policy initiatives and the needed investments in primary care to solve, for example, future shortages of workforce. Countries are consistent in their primary care focus on all important structure dimensions. Countries need to improve their primary care information infrastructure to facilitate primary care performance management.


Development of thiolated xanthan gum-stearylamine conjugate based mucoadhesive system for the delivery of biochanin-A to melanoma cells.
Recently, instead of creating new active compounds, scientists have been working to increase the bioavailability and residence time of existing drugs by modifying the characteristics of the delivery systems. In the present study, a novel mucoadhesive bioconjugate (SN-XG-SH) was synthesized by functionalizing a polysaccharide xanthan gum (XG) with cysteamine hydrochloride (CYS) and a lipid stearylamine (SN). FTIR, CHNS and 1H NMR studies confirmed the successful synthesis of SN-XG-SH. Mucoadhesion of the thiolated XG was enhanced and evaluated by different methods. Disulfide bond formation between thiolated XG and skin mucus enhances mucoadhesive behavior. The mucoadhesive bioconjugate was used to prepare nanoparticles for the delivery of hydrophobic biochanin-A (Bio-A) for the treatment of melanoma. The thiolated xanthan gum nanoparticles also demonstrated high drug entrapment efficiency, sustained drug release, and high storage stability. The drug loaded nanoparticles (Bio-A@TXNPs) significantly improved the cytotoxicity of Bio-A against human epidermoid cancer cells (A431 cells) by inducing apoptosis and changing mitochondrial membrane potential. In conclusion, thiolation of XG improves its mucoadhesive properties and prolongs the release of Bio-A. Thus, thiolated XG conjugate has a high potential for use as a bioadhesive agent in controlled and localised delivery of drugs in different skin diseases including melanoma.


Modulation of cytochrome P450 gene expression and arachidonic acid metabolism during isoproterenol-induced cardiac hypertrophy in rats.
Several cytochrome P450 (P450) enzymes have been identified in the heart, and their levels have been reported to be altered during cardiac hypertrophy. Moreover, there is a strong correlation between P450-mediated arachidonic acid metabolites and the pathogenesis of cardiac hypertrophy. Therefore, we investigated the effect of isoproterenol-induced cardiac hypertrophy on the expression of several P450 genes and their associated P450-derived metabolites of arachidonic acid. Cardiac hypertrophy was induced by seven daily i.p. injections of 5 mg/kg isoproterenol. Thereafter, the heart, lung, liver, and kidney were harvested, and the expression of different genes was determined by real-time polymerase chain reaction. Heart microsomal protein from control or isoproterenol treated rats was incubated with 50 microM arachidonic acid, and arachidonic acid metabolites were determined by liquid chromatography-electron spray ionization-mass spectrometry. Our results show that isoproterenol treatment significantly increased the heart/body weight ratio and the hypertrophic markers. In addition, there was a significant induction of CYP1A1, CYP1B1, CYP4A3, and soluble epoxide hydrolase and a significant inhibition of CYP2C11 and CYP2E1 in the hypertrophied hearts as compared with the control. CYP1A1, CYP2E1, and CYP4A3 gene expression was induced in the kidney, and CYP4A3 was induced in the liver of isoproterenol-treated rats. Isoproterenol treatment significantly reduced 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid formation and significantly increased their corresponding 8,9-, and 14,15-dihydroxyeicosatrienoic acid and the 20-hydroxyeicosatetraenoic acid metabolite. In conclusion, isoproterenol-induced cardiac hypertrophy alters arachidonic acid metabolism and its associated P450 enzymes, suggesting their role in the development and/or progression of cardiac hypertrophy.


Effect of ATP on preadipocyte migration and adipocyte differentiation by activating P2Y receptors in 3T3-L1 cells.
The effect of extracellular ATP on adipogenesis was investigated using the mouse 3T3-L1 cell line. Incubation of cells with ATP (1-100 microM) for 5 min induced actin filament reorganization and membrane ruffling mediated through P2Y receptors. Enhancement of preadipocyte migration into fat cell clusters is one of the essential processes of adipose tissue development in vivo and cell migration assays revealed that stimulation of P2Y receptors enhanced chemokinesis (migration) in a concentration dependent manner. In this cell line, growth arrest is required before initiation of differentiation and growth-arrested post-confluent cells can be converted into adipocytes by the presence of the adipogenic hormones dexamethasone, 3-isobutyl-1-methylxanthine and insulin. On the other hand, those hormones alone do not trigger differentiation in proliferating cells. ATP did not induce differentiation when applied alone to either proliferating or postconfluent cells. By contrast, proliferating cells (density <50%) preincubated with ATP for 5 min and subsequently given the adipogenic hormones in the continued presence of ATP, underwent adipocyte differentiation mediated through phospholipase C-coupled P2Y receptors. These adipocytes were found to show very similar characteristics, including morphology and intracellular triacylglycerol accumulation compared with adipocytes differentiated from post-confluent preadipocytes with those adipogenic hormones. When proliferating cells were preincubated with ATP before the addition of the adipogenic hormones, gene expression of aP2 (adipose protein 2) was markedly increased within 6 days, whereas without ATP pretreatment the expression level stayed very low. These results suggest that extracellular ATP renders preadipocytes responsive to adipogenic hormones during the growth phase.


Derivation of the propagation equations for higher order aberrations of local wavefronts.
From the literature the analytical calculation of local power and astigmatism of a wavefront after refraction and propagation is well known; it is, e.g., performed by the Coddington equation for refraction and the classical vertex correction formula for propagation. Recently the authors succeeded in extending the Coddington equation to higher order aberrations (HOA). However, equivalent analytical propagation equations for HOA do not exist. Since HOA play an increasingly important role in many fields of optics, e.g., ophthalmic optics, it is the purpose of this study to extend the propagation equations of power and astigmatism to the case of HOA (e.g., coma and spherical aberration). This is achieved by local power series expansions. In summary, with the results presented here, it is now possible to calculate analytically the aberrations of a propagated wavefront directly from the aberrations of the original wavefront containing both low-order and high-order aberrations.