The effect of a lifestyle intervention in obese pregnant women on gestational metabolic profiles: findings from the UK Pregnancies Better Eating and Activity Trial (UPBEAT) randomised controlled trial.
Pregnancy is associated with widespread change in metabolism, which may be more marked in obese women. Whether lifestyle interventions in obese pregnant women improve pregnancy metabolic profiles remains unknown. Our objectives were to determine the magnitude of change in metabolic measures during obese pregnancy, to indirectly compare these to similar profiles in a general pregnant population, and to determine the impact of a lifestyle intervention on change in metabolic measures in obese pregnant women. Data from a randomised controlled trial of 1158 obese (BMI ≥ 30 kg/m2) pregnant women recruited from six UK inner-city obstetric departments were used. Women were randomised to either the UPBEAT intervention, a tailored complex lifestyle intervention focused on improving diet and physical activity, or standard antenatal care (control group). UPBEAT has been shown to improve diet and physical activity during pregnancy and up to 6-months postnatally in obese women and to reduce offspring adiposity at 6-months; it did not affect risk of gestational diabetes (the primary outcome). Change in the concentrations of 158 metabolic measures (129 lipids, 9 glycerides and phospholipids, and 20 low-molecular weight metabolites), quantified three times during pregnancy, were compared using multilevel models. The role of chance was assessed with a false discovery rate of 5% adjusted p values. All very low-density lipoprotein (VLDL) particles increased by 1.5-3 standard deviation units (SD) whereas intermediate density lipoprotein and specific (large, medium and small) LDL particles increased by 1-2 SD, between 16 and 36 weeks' gestation. Triglycerides increased by 2-3 SD, with more modest changes in other metabolites. Indirect comparisons suggest that the magnitudes of change across pregnancy in these obese women were 2- to 3-fold larger than in unselected women (n = 4260 in cross-sectional and 583 in longitudinal analyses) from an independent, previously published, study. The intervention reduced the rate of increase in extremely large, very large, large and medium VLDL particles, particularly those containing triglycerides. There are marked changes in lipids and lipoproteins and more modest changes in other metabolites across pregnancy in obese women, with some evidence that this is more marked than in unselected pregnant women. The UPBEAT lifestyle intervention may contribute to a healthier metabolic profile in obese pregnant women, but our results require replication. UPBEAT was registered with Current Controlled Trials, ISRCTN89971375 , on July 23, 2008 (prior to recruitment).


Effects of Aluminum Hydroxide and Layered Double Hydroxide on Asphalt Fire Resistance.
When a fire occurs in a tunnel, the instantaneous high temperature and smoke cause great danger to people. Therefore, the asphalt pavement material in the tunnel must have sufficient fire resistance. In this study, the effects of aluminum hydroxide and layered double hydroxide on the fire resistance of styrene-butadiene-styrene (SBS) polymer-modified asphalt was investigated. The fire resistance of the asphalt was evaluated by using a limiting oxygen index (LOI). The impact of aluminum hydroxide (ATH), layered double hydroxide (LDHs), and mixed flame retardant (MFR) on LOI was studied. The synergistic fire resistance mechanism of ATH and LDHs in asphalt binder was analyzed by using an integrated thermal analyzer‒mass spectrometry combined system (TG-DSC-MS) and Fourier transform infrared spectrometer (FTIR). The experimental results indicated that the main active temperature range of these flame retardants was 221⁻483 °C. The main components of smoke were methane, hydroxyl, water, carbon monoxide, aldehyde, carbon dioxide, etc. The addition of flame retardants could inhibit the production of methane, carbon monoxide, and aldehyde. Moreover, due to the good synergistic effects of ATH and LDHs, 20 wt % MFR had the best fire resistance.


Food security in the Baltic Republics.
Food insecurity has become an important issue in many countries of the former Soviet Union following the transition to a market economy. This study examined three aspects of food security in the Baltic Republics: reasons for choosing foods; level of dependence on home-grown or raised foods; and use of home-grown vegetables. Cross-sectional surveys. Data from surveys conducted in Estonia, Latvia and Lithuania in the summer of 1997 were used to describe the three aspects of food security and their socio-economic correlates (using descriptive statistics and logistic regression). Representative samples of adults were selected in each country (Estonia, Latvia, Lithuania, ). Cost was the most commonly reported reason for choosing foods, particularly in Lithuania (67%) and Latvia (60%) (Estonia 41%), and especially among people with lower income levels. In each country, large proportions of respondents depended partially or entirely on home-grown or raised foods (Latvia 47%, Lithuania 42%, Estonia 32%) or used home-grown vegetables frequently (Lithuania 66%, Latvia 53%, Estonia 29%); this was particularly the case in rural areas. The issue of food security needs to be examined further in the Baltic Republics and other transitional economies as increased access to safe, healthy foods for all could help improve dietary intake and reduce the high mortality from non-communicable diseases. Access to affordable, high-quality fresh foods by different social groups should be monitored and the potential contribution of home-grown and raised foods to reduce food poverty should be explored further.


Modulation of apoptosis by starvation: morphological and biochemical study of rat intestinal mucosa.
Morphology at light and electron microscopic levels, expression and activation of transglutaminase and DNA fragmentation at internucleosomal sites were used as markers to study the effect of starvation on the apoptosis of small intestinal epithelial cells. The cells entering apoptotic programme in well-fed animals undergo many morphological changes in apical cytoplasm involving alterations in actin cytoskeleton organisation which may cause a discharge of microvilli. Some free floating cells in the intestinal lumen show characteristics of apoptotic cell death, e.g. shrinkage of cell and peripheral condensation of chromatin, while mitochondria and lysosomes remain unchanged. Apoptotic bodies are also seen in scanning electron micrographs. During progressive starvation, epithelial cells do not enter the apoptotic cell death programme. Biochemical markers for apoptosis such as increased transglutaminase activity and DNA fragmentation are clearly discernible in normally fed animals. The percentage of cells labelled immunohistochemically by antibody against transglutaminase decreased during starvation while DNA fragmentation was absent. The exact mechanism for suppressing apoptosis in intestinal cells under starvation is not known. However, the data presented here support the existence of such a regulatory process.


Human Escherichia coli isolates from hemocultures: Septicemia linked to urogenital tract infections is caused by isolates harboring more virulence genes than bacteraemia linked to other conditions.
Escherichia coli is the most common cause of bloodstream infections and community-acquired sepsis. The main aim of this study was to determine virulence characteristics of E. coli isolates from hemocultures of patients with a primary disease of urogenital tract, digestive system, a neoplastic blood disease, or other conditions. Results from a set of 314 E. coli isolates from hemocultures were compared to data from a previously published analysis of 1283 fecal commensal E. coli isolates. Genetic profiling of the 314 E. coli isolates involved determination of phylogenetic group (A, B1, B2, D, C, E, and F), identification of 21 virulence factors, as well as 30 bacteriocin-encoding determinants. Pulsed-field gel electrophoresis was used to analyze clonal character of the hemoculture-derived isolates. The E. coli isolates from hemocultures belonged mainly to phylogenetic groups B2 (59.9%) and D (21.0%), and less frequently to phylogroups A (10.2%) and B1 (5.7%). Commonly detected virulence factors included adhesins (fimA 92.0%, pap 47.1%, and sfa 26.8%), and iron-uptake encoding genes (fyuA 87.9%, fepC 79.6%, aer 70.7%, iucC 68.2%, and ireA 13.7%), followed by colibactin (pks island 31.5%), and cytotoxic necrotizing factor (cnf1 11.1%). A higher frequency of microcin producers (and microcin M determinant) and a lower frequency of colicin Ib and microcin B17 was found in hemoculture-derived isolates compared to commensal fecal isolates. E. coli isolates from hemocultures harbored more virulence genes compared to fecal E. coli isolates. In addition, hemoculture E. coli isolates from patients with primary diagnosis related to urogenital tract were clearly different and more virulence genes were detected in these isolates compared to both fecal isolates and hemoculture-derived isolates from patients with blood and gastrointestinal diseases.


Room scatter effects in Total Skin Electron Irradiation: Monte Carlo simulation study.
Total Skin Electron Irradiation (TSEI) is a complex technique which usually involves the use of large electron fields and the dual-field approach. In this situation, many electrons scattered from the treatment room floor are produced. However, no investigations of the effect of scattered electrons in TSEI treatments have been reported. The purpose of this work was to study the contribution of floor scattered electrons to skin dose during TSEI treatment using Monte Carlo (MC) simulations. All MC simulations were performed with the EGSnrc code. Influence of beam energy, dual-field angle, and floor material on the contribution of floor scatter was investigated. Spectrum of the scattered electrons was calculated. Measurements of dose profile were performed in order to verify MC calculations. Floor scatter dependency on the floor material was observed (at 20 cm from the floor, scatter contribution was about 21%, 18%, 15%, and 12% for iron, concrete, PVC, and water, respectively). Although total dose profiles exhibited slight variation as functions of beam energy and dual-field angle, no dependence of the floor scatter contribution on the beam energy or dual-field angle was found. The spectrum of the scattered electrons was almost uniform between a few hundred KeV to 4 MeV, and then decreased linearly to 6 MeV. For the TSEI technique, dose contribution due to the electrons scattered from the room floor may be clinically significant and should be taken into account during design and commissioning phases. MC calculations can be used for this task.


André-Thomas (1867-1963), Initiator of Neonatal Neurology.
After a brilliant career as a clinician and anatomopathologist, André-Thomas (1868-1963) spent the last 30 years of his life validating the components of neurological examinations of newborns and infants. This novel approach was developed through long examinations of several hundreds of normal and sick children, notably those with anencephaly. By combining his vast knowledge of physiology with the results of his experimental work, André-Thomas built the foundations of a speciality that did not exist before his time: neuropaediatrics. His Études neurologiques (neurological studies), medical in nature but also very literary, echoing his illustrious predecessors of the 19th century, made him a transmitter of knowledge, a man of transition, from the anatomoclinical method of the 19th century to the standardised investigation techniques of the 20th century.


Development of different electrophysiological mechanisms for muscarinic inhibition of atria and ventricles.
The negative inotropic effect of acetylcholine (ACh) in atrial muscle can be accounted for by a decrease of a voltage- and time-dependent slow inward current (Isi) carried by Ca2+/Na+ and an increase of outward time-dependent current carried by K+ (IK1) through inwardly rectifying channels. The negative inotropic effect of ACh in ventricular muscle is associated with a reduction of Isi; there is no important effect of ACh on IK1 in ventricular muscle. Because atrial and ventricular muscles display IK1 that is sensitive to Ba2+ and have similar numbers of muscarinic receptor sites, it is concluded that ventricular muscle lacks a metabolic link between the muscarinic receptor and inwardly rectifying K+ channels. Although there is much evidence for cyclic nucleotides as the mediator between muscarinic receptors and Isi channels, cyclic nucleotides do not seem to connect these receptors with inwardly rectifying K+ channels. According to this hypothesis, identification of a metabolic link between muscarinic receptors and IK1 channels should be demonstrable in atrial but not ventricular muscle.


Aerosol delivery during mechanical ventilation.
Aerosols can be delivered during mechanical ventilation using either a nebulizer or MDI. The MDI is the most efficient method of aerosol delivery, whereas the greatest absolute amount of drug delivery is with the nebulizer.


Short-term effects of deoxynivalenol, T-2 toxin, fumonisin B1 or ochratoxin on lipid peroxidation and glutathione redox system and its regulatory genes in common carp (Cyprinus carpio L.) liver.
The effects of a single oral dose of 1.82 mg kg-1 bw of T-2 and HT-2 toxin (T-2), 1.75 mg kg-1 bw deoxynivalenol (DON) and 15-acetyl DON, 1.96 mg kg-1 bw fumonisin B1 (FB1) or 1.85 mg kg-1 bw ochratoxin A (OTA) were investigated in common carp juveniles on lipid peroxidation, the parameters of the glutathione redox system including the expression of their encoding genes in a short-term (24 h) experiment. Markers of the initiation phase of lipid peroxidation, conjugated dienes, and trienes, were slightly affected by DON and OTA treatment at 16-h sampling. The termination marker, malondialdehyde, concentration increased only as an effect of FB1. Glutathione content and glutathione peroxidase activity showed significantly higher levels in the T-2 and FB1 groups at 8 h, and in the DON and FB1 groups at 16 h. The expression of glutathione peroxidase genes (gpx4a, gpx4b) showed a dual response. Downregulation of gpxa was observed at 8 h, as the effect of DON, FB1, and OTA, but an upregulation in the T-2 group. At 16 h gpx4a upregulated as an effect of DON, T-2, and FB1, and at 24 h in the DON and T-2 groups. Expression of gpx4b downregulated at 8 h, except in the T-2 group, and upregulation observed as an effect of T-2 at 24 h. The lack of an increase in the expression of nrf2, except as the effect of DON at 8 h, and a decrease in the keap1 expression suggests that the antioxidant defence system was activated at gene and protein levels through Keap1-Nrf2 independent pathways.


Graft incorporation after acetabular and femoral impaction grafting with washed irradiated allograft and autologous marrow.
Rates of around 40% incorporation have been described when chips of irradiated cancellous allograft with retained fat were impacted with the Exeter technique. We report the results of acetabular and femoral impaction bone grafting during revision hip arthroplasty using washed irradiated allograft with autologous marrow. Eighty-five consecutive patients underwent acetabular and or femoral revision arthroplasty. Evidence of graft cortication and trabeculation was recorded on successive postoperative radiographs, over a mean period of 44 months. Ninety-six percent (49/51) and 90% (53/59) of patients showed incorporation in acetabular and femoral grafts, respectively. This was usually apparent by 6 months postoperatively. We conclude that the addition of autologous marrow to irradiated bone allograft during impaction grafting is a cheap and highly effective way of achieving graft incorporation.


Impact of blood pressure perturbations on arterial stiffness.
Although the associations between chronic levels of arterial stiffness and blood pressure (BP) have been fairly well studied, it is not clear whether and how much arterial stiffness is influenced by acute perturbations in BP. The primary aim of this study was to determine magnitudes of BP dependence of various measures of arterial stiffness during acute BP perturbation maneuvers. Fifty apparently healthy subjects, including 25 young (20-40 yr) and 25 older adults (60-80 yr), were studied. A variety of BP perturbations, including head-up tilt, head-down tilt, mental stress, isometric handgrip exercise, and cold pressor test, were used to encompass BP changes induced by physical, mental, and/or mechanical stimuli. When each index of arterial stiffness was plotted with mean BP, all arterial stiffness indices, including cardio-ankle vascular index or CAVI (r = 0.50), carotid-femoral pulse wave velocity or cfPWV (r = 0.51), brachial-ankle pulse wave velocity or baPWV (r = 0.61), arterial compliance (r = -0.42), elastic modulus (r = 0.52), arterial distensibility (r = -0.32), β-stiffness index (r = 0.19), and Young's modulus (r = 0.35) were related to mean BP (all P < 0.01). Changes in CAVI, cfPWV, baPWV, and elastic modulus were significantly associated with changes in mean BP in the pooled conditions, while changes in arterial compliance, arterial distensibility, β-stiffness index, and Young's modulus were not. In conclusion, this study demonstrated that BP changes in response to various forms of pressor stimuli were associated with the corresponding changes in arterial stiffness indices and that the strengths of associations with BP varied widely depending on what arterial stiffness indices were examined.


Modified envelope glycoproteins to retarget retroviral vectors.
A conceptual breakthrough in gene therapy would be gene transfer vector that could be systemically applied, allowing targeted gene transfer into a predetermined cell type. The host range of a retroviral vector is determined by the interaction of the viral envelope glycoprotein (Env) and the retrovirus receptor on the surface of the host cell. In this review, we describe the current efforts to engineer targeted envelope glycoproteins, which can be incorporated into retroviral particles and are capable of delivering genes in a highly specific manner.


Bayesian bivariate survival analysis using the power variance function copula.
Copula models have become increasingly popular for modelling the dependence structure in multivariate survival data. The two-parameter Archimedean family of Power Variance Function (PVF) copulas includes the Clayton, Positive Stable (Gumbel) and Inverse Gaussian copulas as special or limiting cases, thus offers a unified approach to fitting these important copulas. Two-stage frequentist procedures for estimating the marginal distributions and the PVF copula have been suggested by Andersen (Lifetime Data Anal 11:333-350, 2005), Massonnet et al. (J Stat Plann Inference 139(11):3865-3877, 2009) and Prenen et al. (J R Stat Soc Ser B 79(2):483-505, 2017) which first estimate the marginal distributions and conditional on these in a second step to estimate the PVF copula parameters. Here we explore an one-stage Bayesian approach that simultaneously estimates the marginal and the PVF copula parameters. For the marginal distributions, we consider both parametric as well as semiparametric models. We propose a new method to simulate uniform pairs with PVF dependence structure based on conditional sampling for copulas and on numerical approximation to solve a target equation. In a simulation study, small sample properties of the Bayesian estimators are explored. We illustrate the usefulness of the methodology using data on times to appendectomy for adult twins in the Australian NH&MRC Twin registry. Parameters of the marginal distributions and the PVF copula are simultaneously estimated in a parametric as well as a semiparametric approach where the marginal distributions are modelled using Weibull and piecewise exponential distributions, respectively.


Microbial uptake by the respiratory epithelium: outcomes for host and pathogen.
Intracellular occupancy of the respiratory epithelium is a useful pathogenic strategy facilitating microbial replication and evasion of professional phagocytes or circulating antimicrobial drugs. A less appreciated but growing body of evidence indicates that the airway epithelium also plays a crucial role in host defence against inhaled pathogens, by promoting ingestion and quelling of microorganisms, processes that become subverted to favour pathogen activities and promote respiratory disease. To achieve a deeper understanding of beneficial and deleterious activities of respiratory epithelia during antimicrobial defence, we have comprehensively surveyed all current knowledge on airway epithelial uptake of bacterial and fungal pathogens. We find that microbial uptake by airway epithelial cells (AECs) is a common feature of respiratory host-microbe interactions whose stepwise execution, and impacts upon the host, vary by pathogen. Amidst the diversity of underlying mechanisms and disease outcomes, we identify four key infection scenarios and use best-characterised host-pathogen interactions as prototypical examples of each. The emergent view is one in which effi-ciency of AEC-mediated pathogen clearance correlates directly with severity of disease outcome, therefore highlighting an important unmet need to broaden our understanding of the antimicrobial properties of respiratory epithelia and associated drivers of pathogen entry and intracellular fate.


Long-Distance Coherent Propagation of High-Velocity Antiferromagnetic Spin Waves.
We report on coherent propagation of antiferromagnetic (AFM) spin waves over a long distance (∼10 μm) at room temperature in a canted AFM α-Fe_{2}O_{3} owing to the Dzyaloshinskii-Moriya interaction (DMI). Unprecedented high group velocities (up to 22.5 km/s) are characterized by microwave transmission using all-electrical spin wave spectroscopy. We derive analytically AFM spin-wave dispersion in the presence of the DMI which accounts for our experimental results. The AFM spin waves excited by nanometric coplanar waveguides have large wave vectors in the exchange regime and follow a quasilinear dispersion relation. Fitting of experimental data with our theoretical model yields an AFM exchange stiffness length of 1.7 Å. Our results provide key insights on AFM spin dynamics and demonstrate high-speed functionality for AFM magnonics.


A general strategy for photoelectrochemical immunoassay using an enzyme label combined with a CdS quantum dot/TiO₂ nanoparticle composite electrode.
Photoelectrochemical (PEC) immunoassay has received increasing attention owing to its good analytical performance and attractive potential for future protein assay. This Letter represents a novel and general strategy for elegant PEC immunoassay of the important cardiac marker troponin T (cTnT) at neutral conditions. Specifically, we first developed an efficient CdS quantum dots (QDs)/TiO2 nanoparticles (NPs) photoelectrode, on the basis of which an exquisite β-galactosidase (β-Gal) catalytic system was integrated with sandwich immunobinding for probing cTnT. In pH 7.4, β-Gal could catalyze the conversion of p-aminophenyl galactopyranoside (PAPG) to p-aminophenol (PAP), which could be easily photo-oxidized to p-quinone imine (PQI). Because the resulting photocurrent was directly related with the target concentration, an innovative PEC immunoassay could be realized for cTnT detection. The neutral operating condition of this protocol would greatly contribute to its wide applicability for protein assay. This work provides the first PEC immunoassay toward cardiac marker and, more significantly, opens a different perspective for future PEC immunoassay development through a general sensing protocol.


[Age characteristics of central hemodynamics from radiocardiography data].
A study was made of the central hemodynamics in practically healthy persons aged 20 to 90 using radiocardiography. The results have shown that cardiac discharge decreases regularly with age, the time of the greater circulation and general peripheral resistance increase, the volume of the circulating pulmonary blood decreases in the presence of its practically unchanged general volume. The authors present data on the main indices of the central hemodynamics in men and women of various age groups.


Measurement bias detection through Bayesian factor analysis.
Measurement bias has been defined as a violation of measurement invariance. Potential violators-variables that possibly violate measurement invariance-can be investigated through restricted factor analysis (RFA). The purpose of the present paper is to investigate a Bayesian approach to estimate RFA models with interaction effects, in order to detect uniform and nonuniform measurement bias. Because modeling nonuniform bias requires an interaction term, it is more complicated than modeling uniform bias. The Bayesian approach seems especially suited for such complex models. In a simulation study we vary the type of bias (uniform, nonuniform), the type of violator (observed continuous, observed dichotomous, latent continuous), and the correlation between the trait and the violator (0.0, 0.5). For each condition, 100 sets of data are generated and analyzed. We examine the accuracy of the parameter estimates and the performance of two bias detection procedures, based on the DIC fit statistic, in Bayesian RFA. Results show that the accuracy of the estimated parameters is satisfactory. Bias detection rates are high in all conditions with an observed violator, and still satisfactory in all other conditions.


Vector scattering from one-dimensional periodic perfectly conducting surface: transverse magnetic polarization.
Based on the Rayleigh hypothesis and Floquet's theorem, a vector method for studying electromagnetic wave scattering from a one-dimensional periodic conducting surface with tapered transverse magnetic (TM) wave incidence is presented. The fields are represented by vectors instead of scalars so that the vector behavior of scattering (such as cross polarization) can be naturally explored. The new formulation opens a wide range of applications of the method, concerning not only gratings used in TM polarization but also conical diffraction, crossed gratings, two-dimensional problems, photonic band gaps, nonlinear optics, etc. The numerical results are consistent with the T-matrix method in the particular case in which the plane of incidence is perpendicular to the generators of the surface. For the general case in which the plane of incidence is not perpendicular to generators of the surface, the proposed method obtains significant results that reveal cross-polarized and anisotropic characteristics in the scattering while the energy balance is kept satisfactory. This straightforward approach is much more efficient than the T-matrix; thus it is suitable to extend to other more involved periodic scattering problems.


An exploration of parental awareness, knowledge, and concerns related to COVID-19.
COVID-19 rapidly spread worldwide with high morbidity and mortality. In this study, we aimed to detect parental concerns along with their awareness of and attitudes towards COVID-19 among patients admitted to our inpatient and outpatient clinics. This study was conducted at a children's hospital with 141 parents of children who were patients in the inpatient and outpatient clinics. Parents were asked to complete an anonymous questionnaire and psychiatric scales that included the Beck Depression Inventory, Beck Anxiety Inventory (BAI), and Impact of Events Scale-Revised form (IES-R). The study sample consisted of 141 parents, of which 59 were parents of inpatients and 82 were parents of outpatients. The most known COVID-19 symptoms were fever, difficulty in breathing, and cough, respectively. The most preferred precaution was "staying at home." We found a significant positive correlation between the number of precautions and BAI score (R = .169, P = .046). Inpatients' parents IES-R scores were significantly higher than outpatients' parents IES-R scores. Parents were found to be aware of the COVID-19 pandemic regardless of education status and family income. Participants' IES-R scores revealed significant differences in terms of COVID-19 impact on psychological health between the parents of inpatient and outpatient children; inpatients' parents were more concerned about COVID-19.


A group for the adult daughters of mentally ill mothers: looking backwards and forwards.
A closed time-limited therapy group was conducted for four women who had all been raised by mentally ill mothers. Themes recurring frequently included hatred of self and mother, current lack of extended family support, current parenting difficulties, ongoing stigma and isolation. All group members perceived themselves as troubled despite others' perceptions of them as resilient. The results for the individuals treated are outlined using clinical material, as statistical analysis was not undertaken. All were able to cease individual therapy. Conclusions focus on the benefits of such a group process of recognition and affirmation of the profound consequences of a mother's mental illness on her daughters and thence to grandchildren. The possibility of primary prevention using techniques from infant-parent and child-group therapy is discussed.


Mathematical modeling of mitochondrial adenine nucleotide translocase.
We have developed a mathematical model of adenine nucleotide translocase (ANT) function on the basis of the structural and kinetic properties of the transporter. The model takes into account the effect of membrane potential, pH, and magnesium concentration on ATP and ADP exchange velocity. The parameters of the model have been estimated from experimental data. A satisfactory model should take into account the influence of the electric potential difference on both ternary complex formation and translocation processes. To describe the dependence of translocation constants on electric potential we have supposed that ANT molecules carry charged groups. These groups are shifted during the translocation. Using the model we have evaluated the translocator efficiency and predicted the behavior of ANT under physiological conditions.


Evolution of drug resistance in Mycobacterium tuberculosis: a review on the molecular determinants of resistance and implications for personalized care.
Drug-resistant TB (DR-TB) remains a significant challenge in TB treatment and control programmes worldwide. Advances in sequencing technology have significantly increased our understanding of the mechanisms of resistance to anti-TB drugs. This review provides an update on advances in our understanding of drug resistance mechanisms to new, existing drugs and repurposed agents. Recent advances in WGS technology hold promise as a tool for rapid diagnosis and clinical management of TB. Although the standard approach to WGS of Mycobacterium tuberculosis is slow due to the requirement for organism culture, recent attempts to sequence directly from clinical specimens have improved the potential to diagnose and detect resistance within days. The introduction of new databases may be helpful, such as the Relational Sequencing TB Data Platform, which contains a collection of whole-genome sequences highlighting key drug resistance mutations and clinical outcomes. Taken together, these advances will help devise better molecular diagnostics for more effective DR-TB management enabling personalized treatment, and will facilitate the development of new drugs aimed at improving outcomes of patients with this disease.


Short course of oral prednisolone on disappearance of lesion and seizure recurrence in patients of solitary cysticercal granuloma with single small enhancing CT lesion: an open label randomized prospective study.
To evaluate the effect of a short course of oral prednisolone on disappearance of lesion and seizure recurrence in newly diagnosed patients with single small enhancing CT lesion. In this open-label, randomized, prospective follow-up study, 100 patients of new-onset seizures and a cysticercus granuloma presenting as single enhancing computed tomography detected lesion were randomly divided in two groups to receive either antiepileptic monotherapy (Group A) or antiepileptic drugs with oral prednisolone in a dose of 1 mg/kg body weight for 7 days and tapering off dose in next 3 days (Group B). Repeat CT scan was performed on 8th-12th week to know radiological state of lesion. The patients were followed up for 1 year for seizure recurrence. The majority of patients were in second decade. Male: female ratio 1.56:1. Mean number of seizure episodes was 4.33 +/- 3.50 in group A and 4.23 +/- 3.97 in group B. Partial seizure were the most common presentation (85%). 72% patients presented with single seizure or seizure in cluster. Solitary ring lesion was the commonest (69%) CT finding, most of them were located in parietal lobe (52%). Follow up CT scan showed complete resolution of lesion in 60.86% of total [group A (n = 47), 32 patients, 68.08%; group B (n = 45), 24 patients, 53.33%]. Significant difference in group A and B regarding lesion resolution was observed (chi2 = 5.926, d.f. = 1) p < 0.05. Clinical follow up showed seizure recurrence in group A - 5 patients (10.63%), in group B - 12 patients (26.66%). Statistically significant higher number of seizure recurrences were noted in group B as compared to group A (chi2 = 3.93, d.f. = 1) p < 0.05. Short-term oral prednisolone along with antiepileptic drugs helps in rapid resolution of single small enhancing lesions in patient with newly diagnosed seizure disorder with good clinical outcome.


Chronic cystoisosporiasis in an immunocompetent adult: A case report.
Cystoisosporiasis is an intestinal infectious disease caused by a coccidian protozoa, Cystoisospora belli (C. belli). It can cause prolonged and refractory diarrhea most commonly in immunocompromised patients, while immunocompetent individuals usually exhibit no symptoms or self-limited diarrhea. We herein report a case of chronic cystoisosporiasis in an immunocompetent patient. A 62-year-old man, who had been first diagnosed with cystoisosporiasis 15 years ago and had been treated with oral administration of trimethoprim-sulfamethoxazole (TMP-SMX), complained of persistent watery diarrhea. He was negative for anti-human immunodeficiency virus antibody and anti-human T-cell leukemia virus type 1 (HTLV-1) antibody. Biopsy specimens from the duodenum revealed oocysts in the atrophic absorptive epithelium and protozoa were detected through stool examination, indicating the recurrence of cystoisosporiasis. Capsule endoscopy showed diffuse atrophic mucosa with white villi in the entire small intestine. We diagnosed him with chronic cystoisosporiasis that occurred in an immunocompetent adult. Since oral administration of TMP-SMX and ciprofloxacin were ineffective, the intravenous administration of TMP-SMX was initiated. Intravenous TMP-SMX exhibited a significant improvement. This case indicates that even immunocompetent individuals may develop recurrent and refractory cystoisosporiasis. Furthermore, intravenous treatment of antibiotic agents should be considered when the impaired absorptive ability from the small intestine is suspected.


Inter-organ signalling by HRG-7 promotes systemic haem homeostasis.
Growing evidence in vertebrates predicts that cellular haem levels in animals are maintained not only by a cell's internal capacity for haem synthesis in a cell-autonomous manner, but also by an inter-organ haem trafficking network through cell-non-autonomous regulation. Using Caenorhabditis elegans, a genetically and optically amenable animal model for visualizing haem-dependent signalling, we show that HRG-7, a protein with homology to aspartic proteases, mediates inter-organ signalling between the intestine and extra-intestinal tissues. Intestinal HRG-7 functions as a secreted signalling factor during haem starvation in extra-intestinal tissues and is regulated through a DBL-1, homologous to BMP5, dependent signal from neurons. Given the evidence that vertebrate homologues exist for each of the components of the HRG-7-mediated signalling pathway, it is conceivable that the cell-non-autonomous signalling framework that we uncovered in C. elegans may have functional relevance for inter-organ regulation of iron and haem metabolism in humans.


Misfit and functional loading of craniofacial implants.
This study sought to develop an understanding of the magnitude and types of loads generated on craniofacial implants supporting an auricular prosthesis. Strain gauges were used to measure the in vitro and in vivo misfit loads generated when connecting auricular-style superstructures to implants and the in vivo functional load generated during the removal and insertion of the auricular prostheses. In addition, the vertical misfit of the 11 custom-built two-implant superstructures used in the in vitro study was measured. Superstructures used in the in vitro study that were considered clinically passive still had considerable preloads. In addition, the calibrated loads, which would result from the vertical misfit alone, did not account for the magnitude of the generated preloads. The clinical definition of misfit based on vertical distortion of the superstructure did not quantify the resulting misfit load. Measured in vivo functional loads were smaller than the misfit loads.


Scleral wound healing with cross-link technique using riboflavin and ultraviolet A on rabbit eyes.
The aim of study was to evaluate the cross-link using riboflavin and ultraviolet A (UVA) for improving scleral wound healing. This was an experimental study involving four New Zealand rabbits (eight eyes). Therapy procedure was chosen for the right eye and control procedure for the left one. UVA irradiation of 365 nm with a surface irradiance of 3 mW/cm2 and a photosensitizer of riboflavin drops were applied for 30 minutes on the right eye at 2 mm from the limbus. Sclerotomy incision was performed at 2 mm from the limbus in both right (on the cross-link-treated area) and left eye. Then, 30 days after surgery, a morphological analysis and histological staining with hematoxylin-eosin and picrosirius red were performed, and the sclerotomy cicatrization of right and left eyes was compared. The variables investigated were as follows: sclerotomy incision pictures and measurements were made using the ImageJ Software. Scleral thickness was measured (employing the anterior optical coherence tomography and the digital caliper). Collagen fiber density stained with picrosirius red staining was measured using the Image Pro Plus software. The morphological analysis showed that in all samples, the right eye presented sclerotomy closure, and in two eyes, among them, there were no visible edges of the sclerotomies incision. The left eye presented sclerotomy closure and incision edges. The Image Pro demonstrated a higher density of collagen fibers in the right eye when compared to the one. The statistical analysis was significant when compared to the collagen fiber density in the treated eyes with the control eyes. The cross-link procedure resulted in a better sclerotomy wound healing.


Improving big citizen science data: Moving beyond haphazard sampling.
Citizen science is mainstream: millions of people contribute data to a growing array of citizen science projects annually, forming massive datasets that will drive research for years to come. Many citizen science projects implement a "leaderboard" framework, ranking the contributions based on number of records or species, encouraging further participation. But is every data point equally "valuable?" Citizen scientists collect data with distinct spatial and temporal biases, leading to unfortunate gaps and redundancies, which create statistical and informational problems for downstream analyses. Up to this point, the haphazard structure of the data has been seen as an unfortunate but unchangeable aspect of citizen science data. However, we argue here that this issue can actually be addressed: we provide a very simple, tractable framework that could be adapted by broadscale citizen science projects to allow citizen scientists to optimize the marginal value of their efforts, increasing the overall collective knowledge.


A Case Report of Enteric Fever Caused by Consumption of Lettuce.
When Salmonella enterica serotype Typhi (S. Typhi) is present in the water, food supply, or both, it leads to the rapid development of typhoid fever. Because lettuce is an ideal host for S. Typhi's survival, lettuce grown in animal manure can be the probable source of typhoid fever. Prompt identification and proper antibiotic treatment can lessen the burden of typhoid fever on the public health system. A male farmer, age 29, was admitted to our hospital with a serious major complaint of abdominal pain, lack of appetite, and runny diarrhea. The newly hospitalized patient had a 2-week history of high-grade fever, abdominal pain, loss of appetite, watery diarrhea, back pain, and generalized body aches. Blood culture is the most accurate test for the diagnosis of typhoid fever. Blood culture was positive and showed sensitivity to ciprofloxacin and other drugs. To cure the typhoid, 500 mg of ciprofloxacin was administered twice daily for 7 days. Pathogenic components, species that are infected, and host immunity all play a role in typhoid fever pathogenesis. Typhoid fever is common in underdeveloped countries due to tainted food or hazardous water sources. This report's main goals are to draw attention to the significance of food safety procedures and to the potential dangers of consuming raw vegetables.


Immunocytochemical detection of prolactin binding sites in fine needle aspiration smears of breast lesions.
Specific prolactin (PRL) binding sites were demonstrated in the fine needle aspiration cytology (FNAC) specimens from 68 patients with benign and malignant diseases of the breast using highly sensitive technique of DNP hapten sandwich staining procedure and antibody against human PRL. In 16 patients, immunocytochemical staining was also carried out on paraffin embedded sections of corresponding lesions. FNAC specimens included 52 neoplasms and 16 non-proliferative and proliferative benign breast disease. The reaction varied in different lesions, being maximum (72%) in malignant tumours and 60 per cent in benign tumours. However, benign breast disease showed a reaction that varied with the lesion. The technique was found to be simple, sensitive and economical for demonstrating specific PRL binding sites in cytology specimens of breast lesions.


Reciprocal relationship between psychosocial work stress and quality of life: the role of gender and education from the longitudinal study of the Survey of Health, Ageing and Retirement in Europe.
To investigate the reciprocal relationship between psychosocial work stress and quality of life (QoL) and to examine whether the relationship can be moderated by gender or education. Longitudinal, population-based study. The Survey of Health, Ageing and Retirement in Europe (SHARE). The study population was derived from the SHARE, and there were 2006 participants with good QoL at baseline, 1109 with high job control and 1072 with high job reward, respectively, who were followed up for 2 years to detect incidence of poor QoL, low job control and low job reward. Logistic regression models were employed to explore the reciprocal relationship between psychological work stress and QoL. Stratification analyses by gender and education were performed. Participants with low reward (OR=1.53, 95% CI 1.26 to 1.88) and low control (OR=1.40, 95% CI 1.14 to 1.71) at baseline were at higher risk of poor QoL over the 2-year follow-up. The combination of low reward and low control further increased the risk (OR=1.90, 95% CI 1.46 to 2.48). Stratified analyses revealed that these associations were more pronounced among those who had high levels of education. Further, individuals with poor QoL were at significantly higher risk of having low reward (OR=2.14, 95% CI 1.55 to 2.96) but not low control (OR=1.33, 95% CI0.98 to 1.79) at the 2-year follow-up, especially among those who had medium levels of education. No gender differences were found. There is a reciprocal relationship between psychological work stress and poor QoL. Education may play an important role in the relationship.


Association between a restriction fragment length polymorphism at the liver/islet cell (GluT 2) glucose transporter and familial type 2 (non-insulin-dependent) diabetes mellitus.
Patients with Type 2 (non-insulin-dependent) diabetes mellitus and a strong family history of the disease may represent a sub-group where genetic factors play a preeminent role in transmission of the disease. A defect in the liver/islet cell glucose transporter (GluT 2) could explain many of the pathophysiological features of the disease. In order to test the hypothesis that genetic variation at the GluT 2 locus contributes genetic susceptibility to Type 2 diabetes, 60 unrelated Caucasian diabetic patients with at least one affected sibling were genotyped for a Taq 1 restriction fragment length polymorphism marker. Hybridisation with a cDNA GluT 2 probe identified two alleles of sizes 13 kilobase (T1) and 19 kilobase (T2). The allele frequencies in the diabetic group with a family history were significantly different from those in a racially-matched control population of 122 subjects with no personal or family history of the disease (diabetic patients T1 = 0.96, T2 = 0.04, control subjects T1 = 0.89, T2 = 0.11, p less than 0.03). However, when the study was repeated with 54 diabetic patients with indeterminate family history, statistical significance was not reached although the allele frequencies showed a similar trend. The findings of this study support the hypothesis that a genetic variant of the liver/islet cell glucose transporter may contribute to familial susceptibility in Type 2 diabetes.


Effect of Guanidinium Chloride Concentration on the Renaturation of Denatured Lysozyme.
The effect of guanidinium chloride (GdmCl) on the renaturation of denatured-reduced chicken egg white lysozyme was studied. It was found that the renaturation yield was significantly related to the GdmCl concentration, that is, the GdmCl concentration required to obtain a high renaturation yield increased with the increase of the denatured lysozyme concentration. When denatured lysozyme concentrations were lower than 0.21 g/L, the presence of 0.7 mol/L GdmCl resulted in the complete renaturation of lysozyme, while higher GdmCl concentration, i.e., 1.0--1.5 mol/L, was needed to yield more than 95% renaturation of 0.6--1.05 g/L of the denatured lysozyme. In addition, lysozyme renaturation rate decreased with increasing GdmCl concentration. Therefore, it is considered that optimizing GdmCl concentration is the key step to enhance the renaturation yield of denatured proteins.


Recent advances in molecular biomarkers for patients with hepatocellular carcinoma.
Introduction: Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide and recurrence rate after curative resection remains high. To improve HCC prognosis, novel sensitive biomarkers and targeted molecular therapies are needed. Accumulation of multiple genetic aberrations caused by pathologically derived liver damage results in HCC carcinogenesis. Elucidating the genes associated with tumorigenesis and progression of HCC may lead to the development of early detection and prognosis markers and to the identification of therapeutic targets. Areas covered: We review recently reported (January 2017-March 2019) HCC-associated molecules, including protein-coding genes, microRNAs, long non-coding RNAs, and methylated gene promoters. Expert opinion: The molecules reviewed have the potential to be clinical biomarkers and therapeutic targets for HCC. The accumulation and understanding of genetic and epigenetic data are essential to improve the management of HCC patients.


That which does not degrade you makes you stronger: infectivity of poliovirus depends on vesicle acidification.
Several years ago, an explosion of research into pathogens and autophagy showed that viruses have a wide variety of relationships to this conserved homeostatic pathway. Often, autophagy acts as a host defense mechanism, degrading viruses before they can escape the host cell, and, as such, autophagy is suppressed or avoided by those viruses. A subset of viruses, however, induces and subverts the autophagic machinery to promote their own replication. Many of these viruses inhibit the degradative step in the autophagic pathway, presumably to prevent degradation of cytosolic virions before they exit the cell. Recently, we published a study showing that poliovirus (PV), a well-studied model virus, induces true autophagic degradation. The remainder of our study provided surprising clues about the role of autophagy in promoting virus production. The purpose of this punctum is to discuss the significance of our findings to a general understanding of the autophagic pathway and its relationship to a common class of cellular pathogens.


Electrochemical promotion of organic waste fermentation: Research advances and prospects.
The current methods of treating organic waste suffer from limited resource usage and low product value. Research and development of value-added products emerges as an unavoidable trend for future growth. Electro-fermentation (EF) is a technique employed to stimulate cell proliferation, expedite microbial metabolism, and enhance the production of value-added products by administering minute voltages or currents in the fermentation system. This method represents a novel research direction lying at the crossroads of electrochemistry and biology. This article documents the current progress of EF for a range of value-added products, including gaseous fuels, organic acids, and other organics. It also presents novel value-added products, such as 1,3-propanediol, 3-hydroxypropionic acid, succinic acid, acrylic acid, and lysine. The latest research trends suggest a focus on EF for cogeneration of value-added products, studying microbial community structure and electroactive bacteria, exploring electron transfer mechanisms in EF systems, developing effective methods for nutrient recovery of nitrogen and phosphorus, optimizing EF conditions, and utilizing biosensors and artificial neural networks in this area. In this paper, an analysis is conducted on the challenges that currently exist regarding the selection of conductive materials, optimization of electrode materials, and development of bioelectrochemical system (BES) coupling processes in EF systems. The aim is to provide a reference for the development of more efficient, advanced, and value-added EF technologies. Overall, this paper aims to provide references and ideas for the development of more efficient and advanced EF technology.


Indeterminate colitis: a distinctive clinical pattern of inflammatory bowel disease in children.
Inflammatory bowel diseases such as Crohn disease and ulcerative colitis are frequently clinical conditions in children. Another clinical entity, indeterminate colitis, is considered a subgroup of pediatric inflammatory bowel disease. It is generally characterized by early onset in the first years of life, and clinical behavior is rapidly progressive to pancolitis. The definition of indeterminate colitis has changed over the years, but it is usually used to identify severe colitis with overlapping features of ulcerative colitis and Crohn disease. Ileal pouch-anal anastomosis is the surgical treatment of choice for patients with ulcerative colitis, but increased rates of complications have been found in indeterminate colitis. Therefore, it is better to be cautious in patients with indeterminate colitis who present with severe attacks and require surgery.


EHFPI: a database and analysis resource of essential host factors for pathogenic infection.
High-throughput screening and computational technology has greatly changed the face of microbiology in better understanding pathogen-host interactions. Genome-wide RNA interference (RNAi) screens have given rise to a new class of host genes designated as Essential Host Factors (EHFs), whose knockdown effects significantly influence pathogenic infections. Therefore, we present the first release of a manually-curated bioinformatics database and analysis resource EHFPI (Essential Host Factors for Pathogenic Infection, http://biotech.bmi.ac.cn/ehfpi). EHFPI captures detailed article, screen, pathogen and phenotype annotation information for a total of 4634 EHF genes of 25 clinically important pathogenic species. Notably, EHFPI also provides six powerful and data-integrative analysis tools, i.e. EHF Overlap Analysis, EHF-pathogen Network Analysis, Gene Enrichment Analysis, Pathogen Interacting Proteins (PIPs) Analysis, Drug Target Analysis and GWAS Candidate Gene Analysis, which advance the comprehensive understanding of the biological roles of EHF genes, as in diverse perspectives of protein-protein interaction network, drug targets and diseases/traits. The EHFPI web interface provides appropriate tools that allow efficient query of EHF data and visualization of custom-made analysis results. EHFPI data and tools shall keep available without charge and serve the microbiology, biomedicine and pharmaceutics research communities, to finally facilitate the development of diagnostics, prophylactics and therapeutics for human pathogens.


Frequency dependence of MR relaxation times. I. Paramagnetic ions.
T1 and T2 of paramagnetic ions in free and chelated form were measured over the range of clinical magnetic resonance imaging field strengths (0.02-1.5 T). T1 values agreed with published data; however, to our knowledge, the field dependence of T2 has not been systematically studied before Mn2+, Cr3+, and Fe3+ all showed T2 reduction at high field strengths, although reduction due to Fe3+ was minimal. This is believed to be due to "contact" interactions, which have been previously noted for manganese. No such T2 reduction was seen in the chelates, except that dysprosium chelate (but not free ion) showed an anomalous decrease in T2 at high field strengths, which may possibly be explained by a dephasing effect caused by the large magnetic moment of Dy3+.


Evaluation of Immunostimulatory Potential of Branded and US-Generic Enoxaparins in an In Vitro Human Immune System Model.
Low-molecular-weight heparins (LMWHs) have several positive therapeutic effects and can also form immunostimulatory complexes with plasma proteins, such as platelet factor 4 (PF4). We compared the innate response and functional profiles of branded and US-generic enoxaparins from 2 manufacturers in either native or PF4-bound forms in an in vitro model of human immunity. In an analysis of 2 product lots from each manufacturer and multiple separate batches of protein-heparin complexes, branded enoxaparin was shown to be consistently nonstimulatory for innate responses, whereas US-generic enoxaparins generated variable immunostimulatory profiles depending on the enoxaparin lot used to prepare the PF4-LMWH complexes. Production of tissue factor pathway inhibitor (TFPI), a physiologic heparin-induced inhibitor of tissue factor-induced coagulation that was used as a functional readout of biological activity of enoxaparins in these assays, was heightened in the presence of branded enoxaparin complexes, but its levels were variable in cultures treated with complexes containing US-generic enoxaparins. Analytical analyses suggest that the heightened immunostimulatory potential of some of the US-generic enoxaparin product lots could be tied to their capacity to form ultra-large and/or more stable complexes with PF4 than the other LMWHs included in this study. Although these distinct biological and analytical profiles might be related to the composition and/or consistency of branded and US-generic enoxaparins included in our data set, further studies are warranted to elucidate the pathophysiological relevance of these in vitro findings.


Divergent effects on phagocytosis by macrophage-derived oxygen radicals.
Clearance of senescent cells from damaged tissue is a crucial step to successfully resolve an inflammatory response. Poor clearance has been attributed to defects in neutrophil apoptosis, a process that is regulated in part by reactive oxygen species (ROS) produced by activated neutrophils. Using ROS-deficient and wild-type macrophages treated with extracellular ROS scavengers we demonstrate that macrophage-derived ROS also influence phagocytosis and do so by direct and indirect mechanisms.


Radial dysplasia with localized cutis aplasia congenita.
We describe four cases of distal radial epiphyseal dysplasia associated with a localized area of cutis aplasia congenita over the dorsum of the distal forearm. The cutis aplasia was diagnosed at birth in all cases, but the radial dysplasia was not recognized until presentation to our orthopaedic department between the ages of 5 and 10 years. This association, the long-term implications and the requirement for follow-up until skeletal maturity have not previously been described. We emphasize the importance of continued monitoring of these patients as the effects of radial dysplasia did not become obvious for several years, and the potential benefit from achieving early skin cover with grafting rather than allowing healing by secondary intention is discussed. It is important to increase awareness of this condition so that early orthopaedic and plastic surgical opinions can be sought, in order to reduce the disabling effect on the underlying radius. In this way it may be possible to elucidate the cause and manage the condition satisfactorily at an earlier stage.


cDNA microarray analysis after laser microdissection in proliferating islets of partially pancreatectomized mice.
With islet transplantation having grown in popularity since the introduction of the Edmonton protocol, how to secure an unlimited source of islets has become an urgent problem. To resolve this problem, techniques to induce or proliferate islets are urgently required. To achieve this goal, gene expression analysis using a cDNA microarray in islets of partially pancreatectomized mice, in which the remaining islets regenerate and proliferate with insulin secretion and glucose responsiveness, provides us with valuable information. However, those experiments have two critical problems: first, how to selectively collect the regenerating or proliferating islets, and second, the shortage of total RNA extracted from one islet for a microarray analysis. A useful system was thus designed which combined laser microdissection, cDNA amplification by SMART PCR, which can maintain the relative expression profile of transcripts throughout reactions, and a cDNA microarray. Furthermore, this system is expected to contribute to future studies regarding not only islet regeneration but also the function of the islet itself, and this system may also be applicable to many other types of endocrine tissue. In this review, the details of this system are presented and discussed.


Identifying Mechanisms of Behavior Change in Psychosocial Alcohol Treatment Trials: Improving the Quality of Evidence from Mediational Analyses.
In recent years, a shift has occurred from identifying variables that mediate the effects of psychosocial interventions for problematic alcohol use to trying to identify effective mechanisms of behavior change (MOBCs) that lead to better drinking-related and other outcomes. Although implementing interventions targeting specific MOBCs has considerable conceptual and intuitive appeal, it is important that strong empirical evidence be available that supports such implementation. One aim of this article is to consider some prior mediational analyses of the effects of alcohol-focused psychosocial treatments to illustrate findings and the types of evidence that typically have been presented. A second aim is to consider methodological approaches, specifically certain statistical analyses of observational data and experimental designs, that could provide more rigorous evidence regarding the causal effects of mechanisms of change (mediators) in producing desired drinking-related outcomes. Prior analyses that have examined the association of a mediator with an outcome, or the relationship between a mediator and an outcome with assigned treatment controlled, do not provide strong evidence regarding the causal effects of mediators on outcomes. Unfortunately, experimental designs that directly manipulate mediators seem difficult to apply in the alcohol treatment field as an approach to examine mediator/MOBC effects. To produce more compelling evidence, we need to investigate interventions that target a specific MOBC and then capitalize on random assignment to intervention/control conditions by using principal stratification or instrumental variable analyses to identify the effects of intervention-induced mediator change on outcomes.


Formation of a hexagonal lattice structure by an R-form lipopolysaccharide of Klebsiella: effect of various divalent cations on the lattice formation.
The R-form lipopolysaccharide from Klebsiella pneumoniae strain LEN-111 (O3-:K1-), from which cationic material had been removed by electrodialysis, was previously shown to form a hexagonal lattice structure with the lattice constant of 14 to 15 nm when suspended in 50 mM tris(hydroxymethyl)aminomethane buffer at pH 8.5 containing 10 mM Mg2+. Under this experimental condition, effects of other divalent metal cations on the hexagonal assembly of the electrodialyzed LPS were compared with that of Mg2+. The Zn2+, Hg2+, Cu2+, and Ni2+ could produce essentially the same hexagonal lattice structure with the lattice constant of 14.5 to 15.0 nm as that formed with Mg2+. The Cd2+, Co2+, and Fe2+ produced the hexagonal lattice structure with the lattice constant of 15.5 to 16.0 nm, and Ba2+, Sr2+, and Ca2+ produced that with the lattice constant of 18 to 19 nm. In addition, the hexagonal lattice structures formed with the latter three cations were less orderly than those formed with the other cations. When the higher concentrations of Ba2+, Sr2+, and Ca2+ were used, the lattice constants were not shortened. The length of lattice constants of the hexagonal lattice structures formed with the divalent cations did not relate to the quantity of the cations bound to the LPS. Among the divalent cations tested, Hg2+ was bound to the LPS in the smallest amount (its atomic ratio to P, 0.07), and Zn2+ and Fe2+ were bound in very large amounts (their atomic ratios to P, 2.94 and 8.28, respectively).


Leydig cell differentiation during the reproductive cycle of the seasonal breeder Camelus dromedarius: an ultrastructural analysis.
Spermatogenesis and Leydig cell development in the dromedary were analyzed at the ultrastructural level and correlated with fluctuations of testosterone synthesis during the mating and nonmating seasons. It was found that (1) spermatogenesis and diameter of the seminiferous tubules are dissociated from seasonal fluctuations of testosterone synthesis as they remain similar throughout the year; (2) the volume of the interstitial tissue and the rate of testosterone synthesis are correlated since both increase during the mating season and both diminish during the nonmating season; (3) during the mating season, reduction of the tubular smooth endoplasmic reticulum (SER) and proliferation of condensed SER correspond to the relatively high rate of testosterone synthesis by the 4-ene pathway; (4) during the mating season there is a drastic reduction of the SER and proliferation of myelin figures within the Leydig cells which disrupt at the end of their differentiation. During the nonmating season, testosterone synthesis is probably impaired only at the final stage of differentiation of the Leydig cell.


Surgical Repair of Congenital Coronary Artery Fistula With Giant Aneurysm.
A 67-year-old man with a 3-year history of dyspnea on exertion arrived to our institution with discontinuous palpitations and short breath. He was diagnosed with congenital coronary artery fistula (CAF). Angiography revealed 3 giant aneurysmal formations and coronary artery calcification. We report a case of successful repair of CAF with a giant coronary aneurysm by closing the orifice and resecting the aneurysm and reconstructing the left coronary artery. The surgical procedure included closure from within a vessel dilated by aneurysm and excision of the aneurysm. We were able to completely obliterate the fistula and preserve the normal blood flow through the coronary arteries post operation. The postoperative course was eventful, but the patient was discharged home. The patient was doing well at his 28-month follow-up visit.


Apical periodontitis associates with cardiovascular diseases: a cross-sectional study from Sweden.
Periodontal disease associates with systemic diseases but corresponding links regarding apical periodontitis (AP) are not so clear. Hence our aim was to study association between AP and the prevalence of systemic diseases in a study population from Sweden. The subjects were 150 patients from a randomly selected epidemiological sample of 1676 individuals. 120 accepted to participate and their basic and clinical examination data were available for these secondary analyses where dental radiographs were used to record signs for endodontic treatments and AP. Periapical Index and modified Total Dental Index scores were calculated from the x-rays to classify the severity of AP and dental infection burden, respectively. Demographic and hospital record data were collected from the Swedish National Statistics Center. T-test, chi-square and univariate analysis of covariance (ANCOVA) and regressions analyses were used for statistics. Of the 120 patients 41% had AP and 61% had received endodontic treatments of which 52% were radiographically unsatisfactory. AP patients were older and half of them were smokers. AP and periodontitis often appeared in the same patient (32.5%). From all hospital diagnoses, cardiovascular diseases (CVD) were most common, showing 20.4% prevalence in AP patients. Regression analyses, controlled for age, gender, income, smoking and periodontitis, showed AP to associate with CVD with odds ratio 3.83 (95% confidence interval 1.18-12.40; p = 0.025). The results confirmed our hypothesis by showing that AP statistically associated with cardiovascular diseases. The finding that subjects with AP also often had periodontitis indicates an increased oral inflammatory burden.


Skeletal analysis of craniofacial asymmetries in plagiocephaly (unilateral coronal synostosis).
Why do the craniofacial bones grow asymmetrically in patients with plagiocephaly (unilateral coronal synostosis)? We obtained three-dimensional skeletal replicas of two patients with the condition and analysed the deformities of the facial bones. From this analysis we deduced that the asymmetric deformation of the facial bones in these patients was caused by a combination of three rotations: rotation of the calvaria toward the affected side because of premature synostosis of the coronal and sphenofrontal sutures; rotation of the facial bones on the horizontal plane toward the unaffected side caused by anterior displacement of the TM (temporomandibular)-joint on the affected side; and downward rotation of the facial bones toward the unaffected side caused by inferior displacement of the TM-joint on the affected side.


Toward endoscopes with no distal optics: video-rate scanning microscopy through a fiber bundle.
We report a step toward scanning endomicroscopy without distal optics. The focusing of the beam at the distal end of a fiber bundle is achieved by imposing a parabolic phase profile across the exit face with the aid of a spatial light modulator. We achieve video-rate images by galvanometric scanning of the phase tilt at the proximal end. The approach is made possible by the bundle, designed to have very low coupling between cores.


Study of rickettsioses in Slovakia. II. Infestation of fleas and mites in mole nests in some localities in Central Slovakia with C. burneti and Rickettsiae belonging to the spotted fever (SF) group.
Fleas and mites obtained from 115 mole nests in Central Slovakia from an area where Q fever and rickettsiosis due to rickettsie of the SF occur, from the border of this area and apart from it, were tested for infestation with rickettsiae by the method of isolation of rickettsiae on chick embryo yolk sacs, by the method of detection of rickettsiae on smears from the arthropods using immunofluorescence, by the method of exposure of albino mice and Apodemus flavicollis to mole nests and by the method of inoculation of suspension from the arthropods to albino mice. In the latter two methods, infestation of the arthropods was assessed according to the formation of antibodies in the mice. It has been found that fleas and mites in all three areas under test are infected with C. burneti and with rickettsia of the SF group. C. burneti was currently detected in the focus of rickettsioses and in the localities situated in its borders while only one case was observed apart from the focus. Rickettsiae of the SF group were found in fleas and mites in all areas tested showing no greater percentual differences. The method of detection of rickettsia in smears from the arthropods using the immunofluorescence technique and antibody response in mice inoculated with infected arthropods was found to be the most effective in these studies. On the basis of the obtained results the authors believe that mites and fleas living in mole nests participate in the circulation of both species of rickettsiae in nature in the transfer of rickettsiae among small mammals. The question whether these arthropods are a reservoir, a biological or a mechanical vector, still remains open.


Linear approximations of global behaviors in nonlinear systems with moderate or strong noise.
While many physical or chemical systems can be modeled by nonlinear Langevin equations (LEs), dynamical analysis of these systems is challenging in the cases of moderate and strong noise. Here we develop a linear approximation scheme, which can transform an often intractable LE into a linear set of binomial moment equations (BMEs). This scheme provides a feasible way to capture nonlinear behaviors in the sense of probability distribution and is effective even when the noise is moderate or big. Based on BMEs, we further develop a noise reduction technique, which can effectively handle tough cases where traditional small-noise theories are inapplicable. The overall method not only provides an approximation-based paradigm to analysis of the local and global behaviors of nonlinear noisy systems but also has a wide range of applications.


Development of a stent capable of the controlled release of basic fibroblast growth factor and argatroban to treat cerebral aneurysms: In vitro experiment and evaluation in a rabbit aneurysm model.
An ideal stent to treat cerebral aneurysms should have an antithrombotic effect on the inner stent blood-facing side and a tissue organization effect on the outer aneurysmal side of the stent. The objective of this study is to evaluate the feasibility of a drug containing stent in the in vivo treatment of cerebral aneurysms. Argatroban, an antithrombotic drug, is encapsulated in biodegradable poly (d,l-lactide-co-glycolide) (PLGA) microspheres for the controlled release with an in vitro study conducted to evaluate the drug release and anticoagulation behavior of released drug. Basic fibroblast growth factor (bFGF), an organization drug, is released from gelatin hydrogels. The stents are coated with gelatin hydrogels incorporating bFGF and PLGA microspheres containing argatroban, and applied to the carotid artery aneurysm of an elastase-induced rabbit model. Most of the aneurysm cavity is occupied by loose connective tissues in the group treated with drug-coated stents, whereas extensive massive hematomas are observed in the group treated with drug-free stents. The occurrence rate of in-stent thrombus is small in the drug-coated stents. The stent incorporating bFGF and PLGA microspheres containing argatroban is an effective device for cerebral aneurysm treatment. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 2185-2194, 2019.


A HIV-1 Tat mutant protein disrupts HIV-1 Rev function by targeting the DEAD-box RNA helicase DDX1.
Previously we described a transdominant negative mutant of the HIV-1 Tat protein, termed Nullbasic, that downregulated the steady state levels of unspliced and singly spliced viral mRNA, an activity caused by inhibition of HIV-1 Rev activity. Nullbasic also altered the subcellular localizations of Rev and other cellular proteins, including CRM1, B23 and C23 in a Rev-dependent manner, suggesting that Nullbasic may disrupt Rev function and trafficking by intervening with an unidentified component of the Rev nucleocytoplasmic transport complex. To seek a possible mechanism that could explain how Nullbasic inhibits Rev activity, we used a proteomics approach to identify host cellular proteins that interact with Nullbasic. Forty-six Nullbasic-binding proteins were identified by mass spectrometry including the DEAD-box RNA helicase, DDX1. To determine the effect of DDX1 on Nullbasic-mediated Rev activity, we performed cell-based immunoprecipitation assays, Rev reporter assays and bio-layer interferometry (BLI) assays. Interaction between DDX1 and Nullbasic was observed by co-immunoprecipitation of Nullbasic with endogenous DDX1 from cell lysates. BLI assays showed a direct interaction between Nullbasic and DDX1. Nullbasic affected DDX1 subcellular distribution in a Rev-independent manner. Interestingly overexpression of DDX1 in cells not only restored Rev-dependent mRNA export and gene expression in a Rev reporter assay but also partly reversed Nullbasic-induced Rev subcellular mislocalization. Moreover, HIV-1 wild type Tat co-immunoprecipitated with DDX1 and overexpression of Tat could rescue the unspliced viral mRNA levels inhibited by Nullbasic in HIV-1 expressing cells. Nullbasic was used to further define the complex mechanisms involved in the Rev-dependent nuclear export of the 9 kb and 4 kb viral RNAs. All together, these data indicate that DDX1 can be sequestered by Nullbasic leading to destabilization of the Rev nucleocytoplasmic transport complex and decreased levels of Rev-dependent viral transcripts. The outcomes support a role for DDX1 in maintenance of a Rev nuclear complex that transports viral RRE-containing mRNA to the cytoplasm. To our knowledge Nullbasic is the first anti-HIV protein that specifically targets the cellular protein DDX1 to block Rev's activity. Furthermore, our research raises the possibility that wild type Tat may play a previously unrecognized but very important role in Rev function.


A small-scale, portable method for extracting microplastics from marine sediments.
Microplastics (plastic particles, 0.1 μm-5 mm in size) are widespread marine pollutants, accumulating in benthic sediments and shorelines the world over. To gain a clearer understanding of microplastic availability to marine life, and the risks they pose to the health of benthic communities, ecological processes and food security, it is important to obtain accurate measures of microplastic abundance in marine sediments. To date, methods for extracting microplastics from marine sediments have been disadvantaged by complexity, expense, low extraction efficiencies and incompatibility with very fine sediments. Here we present a new, portable method to separate microplastics from sediments of differing types, using the principle of density floatation. The Sediment-Microplastic Isolation (SMI) unit is a custom-built apparatus which consistently extracted microplastics from sediments in a single step, with a mean efficiency of 95.8% (±SE 1.6%; min 70%, max 100%). Zinc chloride, at a density of 1.5 g cm-3, was deemed an effective and relatively inexpensive floatation media, allowing fine sediment to settle whilst simultaneously enabling floatation of dense polymers. The method was validated by artificially spiking sediment with low and high density microplastics, and its environmental relevance was further tested by extracting plastics present in natural sediment samples from sites ranging in sediment type; fine silt/clay (mean size 10.25 ± SD 3.02 μm) to coarse sand (mean size 149.3 ± SD 49.9 μm). The method presented here is cheap, reproducible and is easily portable, lending itself for use in the laboratory and in the field, eg. on board research vessels. By employing this method, accurate estimates of microplastic type, distribution and abundance in natural sediments can be achieved, with the potential to further our understanding of the availability of microplastics to benthic organisms.


Anesthesia with Disuse Leads to Autophagy Up-regulation in the Skeletal Muscle.
It has been known that skeletal muscles show atrophic changes after prolonged sedation or general anesthesia. Whether these effects are due to anesthesia itself or disuse during anesthesia has not been fully clarified. Autophagy dysregulation has been implicated in muscle-wasting conditions. This study tested the hypothesis that the magnitude of skeletal muscle autophagy is affected by both anesthesia and immobility. The extent of autophagy was analyzed chronologically during general anesthesia. In vivo microscopy was performed using green fluorescent protein-tagged LC3 for the detection of autophagy using sternomastoid muscles of live mice during pentobarbital anesthesia (n = 6 and 7). Western blotting and histological analyses were also conducted on tibialis anterior muscles (n = 3 to 5). To distinguish the effect of anesthesia from that due to disuse, autophagy was compared between animals anesthetized with pentobarbital and those immobilized by short-term denervation without continuation of anesthesia. Conversely, tibialis anterior and sternomastoid muscles were electrically stimulated during anesthesia. Western blots and microscopy showed time-dependent autophagy up-regulation during pentobarbital anesthesia, peaking at 3 h (728.6 ± 93.5% of basal level, mean ± SE). Disuse by denervation without sustaining anesthesia did not lead to equivalent autophagy, suggesting that anesthesia is essential to cause autophagy. In contrast, contractile stimulation of the tibialis anterior and sternomastoid muscles significantly reduced the autophagy up-regulation during anesthesia (85% at 300 min). Ketamine, ketamine plus xylazine, isoflurane, and propofol also up-regulated autophagy. Short-term disuse without anesthesia does not lead to autophagy, but anesthesia with disuse leads to marked up-regulation of autophagy.


Genetic dissection of EphA receptor signaling dynamics during retinotopic mapping.
Retinal ganglion cells (RGCs) project axons from their cell bodies in the eye to targets in the superior colliculus of the midbrain. The wiring of these axons to their synaptic targets creates an ordered representation, or "map," of retinal space within the brain. Many lines of experiments have demonstrated that the development of this map requires complementary gradients of EphA receptor tyrosine kinases and their ephrin-A ligands, yet basic features of EphA signaling during mapping remain to be resolved. These include the individual roles played by the multiple EphA receptors that make up the retinal EphA gradient. We have developed a set of ratiometric "relative signaling" (RS) rules that quantitatively predict how the composite low-nasal-to-high-temporal EphA gradient is translated into topographic order among RGCs. A key feature of these rules is that the component receptors of the gradient--in the mouse, EphA4, EphA5, and EphA6--must be functionally equivalent and interchangeable. To test this aspect of the model, we generated compound mutant mice in which the periodicity, slope, and receptor composition of the gradient are systematically altered with respect to the levels of EphA4, EphA5, and a closely related receptor, EphA3, that we ectopically express. Analysis of the retinotopic maps of these new mouse mutants establishes the general utility of the RS rules for predicting retinocollicular topography, and demonstrates that individual EphA gene products are approximately equivalent with respect to axon guidance and target selection.


[The place of palliative operations in treatment of complaints caused by scaphoid pseudoarthrosis (author's transl)].
The application of palliative operations intending the termination or the reduction of complaints caused by scaphoid pseudarthrosis have been reviewed in details on the basis of literature and according to own experiences. The indications of styloidectomy and the indications of the removal of the proximal end, as well as the extent of styloidectomy have been exactly defined. Styloidectomy as supplemental surgical intervention is not more applied. The results obtained by styloidectomy have been reviewed (57) cases. They did not do denervation, the Bentzon's-operation is regarded to be out of date.


Nifedipine antagonizes alpha-adrenoceptor mediated splanchnic and systemic vasoconstriction in man.
Aim of the study was to investigate whether nifedipine interacts with alpha1-mediated splanchnic and systemic vasoconstriction in man. The effects of nifedipine on basal and phenylephrine (PE)-induced hemodynamic changes were studied in 6 normotensive men, using the hepatic venous catheter technique (indocyanine-green) and the thermodilution method. After a baseline period, nifedipine was given by constant infusion (0.5 microgram/kg/min) and, after equilibration, PE was infused at a constant rate in a dose sequence of 1, 2, 3, and 4 micrograms/kg/min, until the systolic blood pressure was raised by 30 mmHg. Control trials without nifedipine (saline) were also performed in each subject. At basal conditions nifedipine decreased systemic blood pressure and total systemic vascular resistance (TSVR) as well as total pulmonary vascular resistance (TPVR), and increased cardiac output (CO). PE provoked a dose-dependent increase in systemic blood pressure, TSVR and TPVR, and decreased CO. These PE-effects were clearly attenuated by nifedipine. In the splanchnic vascular bed nifedipine increased estimated splanchnic blood flow (ESBF) and decreased splanchnic vascular resistance (SVR) at basal conditions. The PE-induced decrease in ESBF and increase in SVR were inhibited or attenuated (depending on PE-dosage) by nifedipine. We conclude that nifedipine counteracts alpha1-adrenoceptor mediated systemic and splanchnic vasoconstriction and therefore, might also be useful in the treatment of intestinal vasospasm.


When You Watch Your Team Fall Apart - Coaches' and Sport Psychologists' Perceptions on Causes of Collective Sport Team Collapse.
Collective team collapse occurs when multiple players of a sport team experience a sudden and extreme underperformance within a game and are unable to return to their initial performance level. The occurrence of such a team collapse event commonly leads to the loss of the game or championship. A recent study investigated athletes' perceptions of the phenomenon and proposed a process model of causes of collective sport team collapse. The main goal of this study was to apply this process model to the data collected from coaches and sport psychologists. A further goal was to explore differences in perceptions of causes of team collapse among athletes, coaches, and sport psychologists of various professional German sport teams. Semi-structured interviews were conducted to investigate seven coaches' and four sport psychologists' perceptions. Following an abductive approach, a deductive content analysis was used to explore if the data supported the process model of collective sport team collapse. Perceived antecedents and critical events causing team collapse were similar among the three participant groups. Coaches and sport psychologists differed from athletes in their perception of emotional, cognitive, and behavioral outcomes of team collapse. Coaches tended to report behavioral factors, such as immobility or the blaming of other players, as critical factors maintaining team collapse. Sport psychologists reported cognitive factors, such as individualization or a lack of accountability between the players, to be relevant for team collapse maintenance. Overall, the data of this study supported the general structure of the process model of collective sport team collapse; however, minor amendments to the temporal cascade of causes of team collapse are introduced. Future research is encouraged to examine this model, to provide guidance to teams, coaches, and sport psychologists in dealing with collective sport team collapse.


Two methods of assessing the mortality factors affecting the larvae and pupae of Cameraria ohridella in the leaves of Aesculus hippocastanum in Switzerland and Bulgaria.
The horse-chestnut leaf miner, Cameraria ohridella, is an invasive alien species defoliating horse-chestnut, a popular ornamental tree in Europe. This paper presents quantitative data on mortality factors affecting larvae and pupae of the leaf miner in Switzerland and Bulgaria, both in urban and forest environments. Two sampling methods were used and compared: a cohort method, consisting of the surveying of pre-selected mines throughout their development, and a grab sampling method, consisting of single sets of leaves collected and dissected at regular intervals. The total mortality per generation varied between 14 and 99%. Mortality was caused by a variety of factors, including parasitism, host feeding, predation by birds and arthropods, plant defence reaction, leaf senescence, intra-specific competition and inter-specific competition with a fungal disease. Significant interactions were found between mortality factors and sampling methods, countries, environments and generation. No mortality factor was dominant throughout the sites, generations and methods tested. Plant defence reactions constituted the main mortality factor for the first two larval stages, whereas predation by birds and arthropods and parasitism were more important in older larvae and pupae. Mortality caused by leaf senescence was often the dominant mortality factor in the last annual generation. The cohort method detected higher mortality rates than the grab sampling method. In particular, mortality by plant defence reaction and leaf senescence were better assessed using the cohort method, which is, therefore, recommended for life table studies on leaf miners.


Body mass index trajectories of Indigenous Australian children and relation to screen time, diet, and demographic factors.
Limited cross-sectional data indicate elevated overweight/obesity prevalence among Indigenous versus non-Indigenous Australian children. This study aims to quantify body mass index (BMI) trajectories among Indigenous Australian children aged 3-6 and 6-9 years and to identify factors associated with the development of overweight/obesity. Three-year BMI change was examined in up to 1,157 children in the national Longitudinal Study of Indigenous Children. BMI trajectories among children with normal baseline BMI (n = 907/1,157) were quantified using growth curve models. Baseline prevalences of overweight/obesity were 12.1% and 25.4% among children of mean age 3 and 6 years, respectively. Of children with normal baseline BMI, 31.9% had overweight/obesity 3 years later; BMI increased more rapidly for younger versus older (difference: 0.59 kg/m2 /year; 95% CI: 0.50-0.69), female versus male (difference: 0.15 kg/m2 /year; 95% CI: 0.07-0.23), and Torres Strait Islander versus Aboriginal (difference: 0.36 kg/m2 /year; 95% CI: 0.17-0.55) children. Results were consistent with less rapid rates of BMI increase for children with lower sugar-sweetened beverage (including fruit juice) and high-fat food consumption. Children's BMI was lower in more disadvantaged areas. Overweight/obesity is common, and increases rapidly, in early childhood. Interventions are required to reduce the overweight/obesity prevalence among Indigenous Australian children in the first 3 years of life and to slow the rapid overweight/obesity onset from age 3 to 9 years.


Barriers and facilitators to improving health care for adults with intellectual and developmental disabilities: what do staff tell us?
Adults with intellectual and developmental disabilities (IDD) have high rates of morbidity and are less likely to receive preventive care. Emergency departments and primary care clinics are important entry points into the health care system. Improving care in these settings can lead to increased prevention activities, early disease identification, and ongoing management. We studied barriers and facilitators to improving the care of patients with IDD in three primary and three emergency care sites in Ontario. Data sources included structured implementation logs at each site, focus groups (n = 5) and interviews (n = 8). Barriers and facilitators were coded deductively based on the Consolidated Framework for Implementation Research (CFIR). Synthesis to higher level themes was achieved through review and discussion by the research team. Focus was given to differences between higher and lower implementing sites. All sites were challenged to prioritize care improvement for a small, complex population and varied levels of implementation were achieved. Having national guidelines, using local data to demonstrate need and sharing evidence on value were important engagement strategies. Factors present at higher implementing sites included strong champions, alignment with site mandate, and use of electronic prompts/reminders. Lower implementing sites showed more passive endorsement of the innovation and had lower capacity to implement. Providing effective care for small, complex groups, such as adults with IDD, is critical to improving long-term health outcomes but is challenging to achieve. At a systemic level, funding incentives, access to expertise and improved electronic record systems may enhance capacity.


Engineering in vitro models of hepatofibrogenesis.
Chronic liver disease is a major cause of morbidity and mortality worldwide marked by chronic inflammation and fibrosis/scarring, resulting in end-stage liver disease and its complications. Hepatic stellate cells (HSCs) are a dominant contributor to liver fibrosis by producing excessive extracellular matrix (ECM), irrespective of the underlying disease aetiologies, and for many decades research has focused on the development of a number of anti-fibrotic strategies targeting this cell. Despite major improvements in two-dimensional systems (2D) by using a variety of cell culture models of different complexity, an efficient anti-fibrogenic therapy has yet to be developed. The development of well-defined three-dimensional (3D) in vitro models, which mimic ECM structures as found in vivo, have demonstrated the importance of cell-matrix bio-mechanics, the complex interactions between HSCs and hepatocytes and other non-parenchymal cells, and this to improve and promote liver cell-specific functions. Henceforth, refinement of these 3D in vitro models, which reproduce the liver microenvironment, will lead to new objectives and to a possible new era in the search for antifibrogenic compounds.


Comparison of In Silico Tools for Splice-Altering Variant Prediction Using Established Spliceogenic Variants: An End-User's Point of View.
Assessing the impact of variants of unknown significance on splicing has become a critical issue and a bottleneck, especially with the widespread implementation of whole-genome or exome sequencing. Although multiple in silico tools are available, the interpretation and application of these tools are difficult and practical guidelines are still lacking. A streamlined decision-making process can facilitate the downstream RNA analysis in a more efficient manner. Therefore, we evaluated the performance of 8 in silico tools (Splice Site Finder, MaxEntScan, Splice-site prediction by neural network, GeneSplicer, Human Splicing Finder, SpliceAI, Splicing Predictions in Consensus Elements, and SpliceRover) using 114 NF1 spliceogenic variants, experimentally validated at the mRNA level. The change in the predicted score incurred by the variant of the nearest wild-type splice site was analyzed, and for type II, III, and IV splice variants, the change in the prediction score of de novo or cryptic splice site was also analyzed. SpliceAI and SpliceRover, tools based on deep learning, outperformed all other tools, with AUCs of 0.972 and 0.924, respectively. For de novo and cryptic splice sites, SpliceAI outperformed all other tools and showed a sensitivity of 95.7% at an optimal cut-off of 0.02 score change. Our results show that deep learning algorithms, especially those of SpliceAI, are validated at a significantly higher rate than other in silico tools for clinically relevant NF1 variants. This suggests that deep learning algorithms outperform traditional probabilistic approaches and classical machine learning tools in predicting the de novo and cryptic splice sites.


How much medical care do the uninsured use, and who pays for it?
With the number of uninsured people exceeding forty-one million in 2001, insuring the uninsured is again a major policy issue. This analysis establishes benchmarks for the inevitable debate over the cost of expanding coverage: How much is being spent on care for the uninsured, and where does the money come from? This information is essential for assessing how much new money will be required for expanded coverage, how much can be reallocated from existing sources, and how a new financing system would redistribute the burden of subsidizing care for the uninsured from private to public sources.


Visuospatial alpha and gamma oscillations scale with the severity of cognitive dysfunction in patients on the Alzheimer's disease spectrum.
Entrainment of neural oscillations in occipital cortices by external rhythmic visual stimuli has been proposed as a novel therapy for patients with Alzheimer's disease (AD). Despite this increased interest in visual neural oscillations in AD, little is known regarding their role in AD-related cognitive impairment and in particular during visuospatial processing. We used source-imaged magnetoencephalography (MEG) and an established visuospatial processing task to elicit multi-spectral neuronal responses in 35 biomarker-confirmed patients on the AD spectrum and 20 biomarker-negative older adults. Neuronal oscillatory responses were imaged to the level of the cortex, and group classifications and neurocognitive relationships were modeled using logistic and linear regression, respectively. Visuospatial neuronal oscillations in the theta, alpha, and gamma ranges significantly predicted the classification of patients on the AD spectrum. Importantly, the direction of these effects differed by response frequency, such that patients on the AD spectrum exhibited weaker alpha-frequency responses in lateral occipital regions, and stronger gamma-frequency responses in the primary visual cortex, as compared to biomarker-negative older adults. In addition, alpha and gamma, but not theta, oscillations robustly predicted cognitive status (i.e., MoCA and MMSE scores), such that patients with neural responses that deviated more from those of healthy older adults exhibited poorer cognitive performance. We find that the multi-spectral neural dynamics supporting visuospatial processing differentiate patients on the AD spectrum from cognitively normal, biomarker-negative older adults. Oscillations in the alpha and gamma bands also relate to cognitive status in ways that are informative for emerging clinical interventions.


Endurance treadmill running training benefits the biomaterial quality of bone in growing male Wistar rats.
This study investigated the effects of endurance running training on the bones of growing rats. Thirty-two male Wistar rats (7 weeks old) were assigned to a sedentary control group (CON, n = 10), a continuous endurance running group (CEN, n = 10), or an intermittent endurance running group (IEN, n = 12). After an 8-week training period, both exercise groups had significantly less body weight (BW) gain but higher aerobic capacity, shown by increased muscle citrate synthase (CS) activity. Bone area (BA), areal bone mineral density (aBMD), and bone mineral content (BMC) were measured by dual-energy Xray absorptiometry (DXA) in the total femur and sections of femora. Except for showing a significantly higher aBMD in total femora, the CON group was only slightly and nonsignificantly higher in other DXA measurements. In tissue weight measurements, the CON group showed a nonsignificantly higher tissue dry weight (P = 0.146), but a significantly lower tissue water content ratio (WCR, %) as compared to the exercise group. Despite having nonsignificantly lower long bone cross-sectional parameters, both exercise groups showed significantly better biomaterial properties, as measured by a three-point bending test. In extrinsic analysis, femora of the two exercise groups showed no difference in bending load and stiffness, but were significantly higher in post-yield bending energy and total ultimate bending energy (P < 0.05). Similar phenomena were revealed in tissue-level measurements; the CEN and IEN groups were significantly higher in ultimate toughness and post-yield toughness (P < 0.05). Higher post-yield energy shown by two exercise groups implied a change in bone matrix organization. In conclusion, this study demonstrated that two endurance treadmill training modes benefit bone, with subjects showing better tissue biomaterial properties without significantly increasing aBMD, BMC, or bone dimension. Further study would be valuable to investigate the effects of endurance running on other components of bone, such as organization of bone matrix and its relationship with bone biomaterial properties.