Traction release of subretinal fluid.
The purpose of this investigation was to establish whether the hazards of drainage of subretinal fluid could be reduced. The technique employed utilizes a three-pronged circular grid with a central aperture, 1 mm in diameter. This rigid grid engages the sclera perpendicularly and can be satisfactorily controlled with one hand. Traction with this device elevates the scleral wall to a variable degree depending upon the rigidity of the sclera and the intraocular tension. This scleral elevation allows the point of penetration of the subretinal space to be further removed from the plane of the detached retina than normally would be achieved by conventional techniques. The data presented illustrates the advantages of this approach in terms of reducing the risk of retinal penetration, inadvertent vitreous release, and failure to penetrate the subretinal space in the drainage maneuver. It is suggested that this technique adds an additional safety feature to this problem area of retinal detachment surgery.


Hydrophobic Polyampholytes and Nonfreezing Cold Temperature Stimulate Internalization of Au Nanoparticles to Zwitterionic Liposomes.
Nanomedicine relies on the effective internalization of nanoparticles combined with polymeric nanocarriers into living cells. Thus, exploration of internalization is essential for improving the efficacy of nanoparticle-based strategies in clinical practice. Here, we investigated the physicochemical internalization of gold nanoparticles (AuNPs) conjugated with hydrophobic polyampholytes into cell-sized liposomes at a low but nonfrozen temperature. The hydrophobic polyampholytes localized in the disordered phase of the membrane, and internalization of AuNPs was enhanced in the presence of hydrophobic polyampholytes together with incubation at -3 °C as compared to 25 °C. These results contribute toward a mechanistic understanding for developing a model nanomaterials-driven delivery system based on hydrophobic polyampholytes and low temperature.


Bioavailability and population pharmacokinetics of voriconazole in lung transplant recipients.
This study was undertaken to characterize the pharmacokinetics and bioavailability of voriconazole in adult lung transplant patients during the early postoperative period, identify factors significantly associated with various pharmacokinetic parameters, and make recommendations for adequate dosing regimens. Thirteen lung transplant patients received two intravenous infusions (6 mg/kg, twice daily [b.i.d.]) immediately posttransplant followed by oral doses (200 mg, b.i.d.) for prophylaxis. Blood samples (9/interval) were collected during one intravenous and one oral dosing interval from each patient. Voriconazole plasma concentrations were measured by high-pressure liquid chromatography (HPLC). NONMEM was used to develop pharmacokinetic models, evaluate covariate relationships, and perform Monte Carlo simulations. There was a good correlation (R(2) = 0.98) between the area under the concentration-time curve specific for the dose evaluated (AUC(0-∞)) and trough concentrations. A two-compartment model adequately described the data. Population estimates of bioavailability, clearance, V(c), and V(p) were 45.9%, 3.45 liters/h, 54.7 liters, and 143 liters. Patients with cystic fibrosis (CF) exhibited a significantly lower bioavailability (23.7%, n = 3) than non-CF patients (63.3%, n = 10). Bioavailability increased with postoperative time and reached steady levels in about 1 week. V(p) increased with body weight. Bioavailability of voriconazole is substantially lower in lung transplant patients than non-transplant subjects but significantly increases with postoperative time. CF patients exhibit significantly lower bioavailability and exposure of voriconazole and therefore need higher doses. Intravenous administration of voriconazole during the first postoperative day followed by oral doses of 200 mg or 400 mg appeared to be the optimal dosing regimen. However, voriconazole levels should be monitored, and the dose should be individualized based on trough concentrations as a good measure of drug exposure.


The effects of montelukast on tissue inflammatory and bone marrow responses in murine experimental allergic rhinitis: interaction with interleukin-5 deficiency.
The cysteinyl leukotrienes (cysLTs) are potent lipid mediators in allergic disease, acting through the receptors, cysLT1R and cysLTR2, and are produced by eosinophils derived from eosinophil/basophil (Eo/B) bone marrow (BM) progenitors. We have demonstrated the suppressive effects of either interleukin-5 (IL-5) deficiency or montelukast on eosinophil recruitment in murine allergic rhinitis, but neither of them fully abrogated the symptoms caused by residual inflammation and cytokine redundancy in eliciting BM Eo/B responses. We hypothesized that IL-5 deficiency and montelukast act synergistically to suppress tissue inflammatory and BM responses. Our objective was to investigate the effects of the cysLT1R antagonist, montelukast, on in vivo tissue inflammatory and BM responses in murine experimental allergic rhinitis with or without IL-5 deficiency. Three groups of age-matched BALB/c mice with or without IL-5 deficiency were tested: controls (ovalbumin sensitization and challenge, placebo treatment) and two montelukast-treated groups (2.5 mg/kg or 5 mg/kg). Nasal symptoms, BM and nasal mucosal eosinophils, basophils, and BM Eo/B colony-forming units (CFU) were evaluated. Montelukast decreased nasal symptoms in a dose-dependent manner, and significantly decreased the number of eosinophils in both BM and nasal tissue in IL-5-replete mice compared to controls. In IL-5-deficient mice, in which eosinophilia was absent, montelukast significantly decreased both nasal symptoms and basophils in BM and nasal mucosal tissue, and lowered IL-5-responsive Eo/B-CFU ex vivo, compared to controls. The addition of cysLT1R blockade to IL-5 deficiency more fully attenuates symptoms and upper airway inflammation than either factor alone, providing evidence of systemic, BM mechanisms in allergic rhinitis.


Reassortment patterns of avian influenza virus internal segments among different subtypes.
The segmented RNA genome of avian Influenza viruses (AIV) allows genetic reassortment between co-infecting viruses, providing an evolutionary pathway to generate genetic innovation. The genetic diversity (16 haemagglutinin and 9 neuraminidase subtypes) of AIV indicates an extensive reservoir of influenza viruses exists in bird populations, but how frequently subtypes reassort with each other is still unknown. Here we quantify the reassortment patterns among subtypes in the Eurasian avian viral pool by reconstructing the ancestral states of the subtypes as discrete states on time-scaled phylogenies with respect to the internal protein coding segments. We further analyzed how host species, the inferred evolutionary rates and the dN/dS ratio varied among segments and between discrete subtypes, and whether these factors may be associated with inter-subtype reassortment rate. The general patterns of reassortment are similar among five internal segments with the exception of segment 8, encoding the Non-Structural genes, which has a more divergent phylogeny. However, significant variation in rates between subtypes was observed. In particular, hemagglutinin-encoding segments of subtypes H5 to H9 reassort at a lower rate compared to those of H1 to H4, and Neuraminidase-encoding segments of subtypes N1 and N2 reassort less frequently than N3 to N9. Both host species and dN/dS ratio were significantly associated with reassortment rate, while evolutionary rate was not associated. The dN/dS ratio was negatively correlated with reassortment rate, as was the number of negatively selected sites for all segments. These results indicate that overall selective constraint and host species are both associated with reassortment rate. These results together identify the wild bird population as the major source of new reassortants, rather than domestic poultry. The lower reassortment rates observed for H5N1 and H9N2 may be explained by the large proportion of strains derived from domestic poultry populations. In contrast, the higher rates observed in the H1N1, H3N8 and H4N6 subtypes could be due to their primary origin as infections of wild birds with multiple low pathogenicity strains in the large avian reservoir.


[Inter-arterial anastomosis in dextral position of the aortic arch in patients with tetralogy of Fallot].
The article discusses the results of formation of inter-arterial anastomoses in 58 (12.7%) patients with a severe form of Fallot's tetralogy in dextra-position of the arch of the aorta. The specific features of the course and diagnosis of dextra-position of the aortic arch in Fallot's tetralogy are analysed, and the significance of radiologic and echocardiographic examination in the choice of the position and type of interarterial anastomoses is determined. It is proved that Blalock-Taussig's anastomoses must be formed on the side opposite to the aortic arch, while shunting operations must be carried out on the side on which the arch of the aorta is located.


Brachioplasty with superficial fascial system suspension.
Although significant innovations in brachioplasty occurred in the 1970s, it remains an unpopular procedure. Current brachioplasty techniques are somewhat unpredictable and are commonly associated with significant untoward results. Recent anatomic studies demonstrate that in youth the posteromedial arm soft tissues are firmly suspended to a tough yet dynamic fascial system sling that ultimately gains its strength from the clavicular periosteum by means of the clavipectoral and axillary fasciae. Loosening of the connections of the arm superficial fascial system to the axillary fascia, as well as relaxation of the axillary fascia itself, with age, weight fluctuations, and gravitational pull yields a "loose hammock" effect, resulting in significant ptosis of the posteromedial arm. On the basis of this anatomic concept, the brachioplasty procedure was modified to provide secure anchoring of the arm flap to the axillary fascia along with strong superficial fascial system repair of incisions, reducing the risk of widening or migration of scars and unnatural contours. Five patients having brachioplasty with or without liposuction were followed for 6 to 12 months. The primary indication for surgery is moderate to severe skin laxity of the arms with or without associated arm fat deposits. Results were consistent, and complications were limited.


The Association Between Familial Homelessness, Aggression, and Victimization Among Children.
The purpose of this study was to evaluate the relationship between the number of periods children were exposed to familial homelessness and childhood aggression and victimization. Survey data were obtained from 4,297 fifth-grade children and their caregivers in three U.S. cities. Children and primary caregivers were surveyed longitudinally in 7th and 10th grades. Family homelessness, measured at each wave as unstable housing, was self-reported by the caregiver. Children were categorized into four mutually exclusive groups: victim only, aggressor only, victim-aggressor, and neither victim nor aggressor at each time point using validated measures. Multinomial, multilevel mixed models were used to evaluate the relationship among periods of homelessness and longitudinal victimization, aggression, and victim aggression compared to children who were nonvictims and nonaggressors. Results suggest that children who experienced family homelessness were more likely than domiciled children to report aggression and victim aggression but not victimization only. Multivariate analyses suggested that even brief periods of homelessness were positively associated with aggression and victim aggression (relative to neither) compared to children who were never homeless. Furthermore, childhood victimization and victim aggression significantly decreased from 5th grade to 10th grade while aggression significantly increased in 10th grade. Children who experienced family homelessness for brief periods of time were significantly more likely to be a victim-aggressor or aggressor compared to those who were never homeless. Prevention efforts should target housing security and other important factors that may reduce children's likelihood of aggression and associated victimization.


Ethnoveterinary contemporary knowledge of farmers in pre-alpine and alpine regions of the Swiss cantons of Bern and Lucerne compared to ancient and recent literature - Is there a tradition?
The term "traditional" is well established in European (human) medicine and even appears in recent European regulations on herbal medicinal products connected to a simplified registration. In contrast, a scientific discussion of a Traditional European Veterinary Herbal Medicine is still lacking in spite of a rising interest, in herbal medicine for animals in particular of veterinarians. There is only limited systematic ethnoveterinary research in Europe, with exception of the Mediterranean region, Switzerland and Austria. We conducted a survey on the ethnoveterinary knowledge of farmers in the pre-alpine and alpine regions of the Swiss cantons of Bern and Lucerne. We compared the findings with earlier studies conducted in Switzerland and with recent and past human and veterinary medicinal literature. We wanted to know to what extent (dependent to different definition of the term "traditional") the ethnoveterinary knowledge of Swiss farmers could be considered as "traditional" in a European veterinary medicinal context. Semistructured interviews with 44 dialog partners, mainly smallholder cattle farmers, were conducted in 2014. Detailed information about homemade herbal remedies (plant species, plant part, manufacturing process) and the corresponding use reports (target animal species, category of use, route of administration, dosage, source of knowledge, frequency of use, last time of use and farmers satisfaction) were collected. To compare our data with literature, one German book of veterinary pharmacology published in 1900, one typescript of Swiss lectures in veterinary pharmacology from 1944, four books of veterinary herbal medicine published between 1984 and 2016, and one recent publication comparing current Swiss (human) ethnomedicinal plant knowledge with modern and past literature were analyzed. Information on a total of 315 homemade remedies containing one single plant species (homemade single species herbal remedy reports, HSHR) was collected from participating farmers. These HSHR were prepared from 83 plant species belonging to 46 botanical families. Plants of the families Asteraceae, Lamiaceae and Rosaceae were most frequently used. Matricaria recutita L., Calendula officinalis L., Quercus robur L., Thymus vulgaris L. and Symphytum officinale L. were the most frequently documented species. A total of 404 use reports (UR) were gathered for the 315 HSHR. The largest number of UR was for treatments of gastrointestinal disorders and metabolic dysfunctions, followed by skin alterations and sores. For more than half of the UR the source of knowledge was family, ancestors and friends, and for approximately one quarter the information was from courses and other educational events. For nearly 90% of the UR farmers mentioned at least one use during the last 10 years, and in more than 50% of the UR the last use was within the past year. Compared with recent and past literature and depending on different definitions of the term "traditional" as used for human medicine, between 43% and 84% of all 83 and between 57% and 100% of the most often mentioned 21 plant species show a "traditional" European veterinary use. For the treatment of their animals farmers in the pre-alpine and alpine regions of the Swiss cantons of Bern and Lucerne mostly used plants which have a track record as medicinal herbs in Europe over several centuries. Almost half of the plant species had specific veterinary uses for about 120 years and even more for at least 30 years. The majority of the plant species thus fulfill the criteria of "traditional" according to several definitions and even more up to a certain degree the criteria of "traditional use" as defined in European regulations for human medicinal products. Ethnoveterinary research combined with data from historical sources may serve as a sound foundation for the development and definition of a Traditional European Veterinary Herbal Medicine maybe even with regard to the recent discussion about a simplified registration for Traditional Herbal Veterinary Medicinal Products.


AAV-2-mediated expression of IGF-1 in skeletal myoblasts stimulates angiogenesis and cell survival.
The transplantation of skeletal myoblasts is being tested in various organ systems to facilitate tissue repair and regeneration. Previous studies have indicated that transplanted cells for varied reasons were not surviving in sufficient numbers following transplantation, thus negatively affecting overall therapeutic efficacy of the approach. We hypothesize that the genetic modification of myoblasts to express insulin-like growth factor 1 (IGF-1) locally may enhance the survival of transplanted cells by stimulating neo-vascularization, decreasing apoptosis, and promoting cell proliferation. Using an adeno-associated virus (adeno-associated virus type 2) vector system, the IGF-1 gene was introduced into canine skeletal myoblasts. As a negative control, myoblasts transduced with the green fluorescence protein (GFP) was used. Relative angiogenic response induced by IGF-1 myoblast was compared to VEGF165-induced neo-vascularization using Matrigel plugs under similar conditions. In vitro evaluation and characterization revealed that the secreted IGF-1 protein was biologically and functionally active in promoting endothelial cell proliferation, migration and assembly into vessel-like structures. Matrigel plugs containing the three test groups were implanted subcutaneously in nude mice (n = 5). After 3 weeks, analysis of explanted samples revealed an enhanced neo-vascularization with an average microvessel density per field for IGF-1 at 55.9 versus 33.4 for vascular endothelial growth factor and 24 for GFP. Additionally, apoptosis was significantly reduced (p <or= 0.02) and proliferative capacity of implanted cells significantly increased (p <or= 0.01) with the IGF-1-transduced myoblasts. We conclude that the genetic modification of skeletal myoblasts with the IGF-1 gene offers a potential means for enhanced cell survival following transplantation.


Riboflavin, self-report, and serum norethindrone. Comparison of their use as indicators of adolescent compliance with oral contraceptives.
The purpose of this study was to test the reliability of using the tablet marker, riboflavin, as an indicator of adolescent compliance with oral contraceptives, as compared with self-reports and more costly quantitative determinations of serum norethindrone levels. In a pilot study, a total of 31 urine samples were obtained from 11 subjects, aged 14 to 18 years. A follow-up study was conducted on 26 girls, aged 14 to 19 years, who were randomly selected from an ongoing study of oral contraceptive compliance. Subjects were given an oral contraceptive (Ortho-Novum 1/35), combined with 28 mg of riboflavin. In both studies, urinary fluorescence tests for riboflavin and self-reports were found to be significantly associated. In the follow-up study, both self-reports and urinary fluorescence tests were significantly associated with serum norethindrone levels. When the urinary fluorescence test agreed with self-report, compliance or noncompliance was confirmed by serum norethindrone levels in 90% of the cases. The findings suggest that riboflavin, combined with self-report, can be used as an accurate and cost-effective indicator of adolescent compliance with oral contraceptives.


SMAD3 silencing enhances DNA damage in radiation therapy by interacting with MRE11-RAD50-NBS1 complex in glioma.
Radiotherapy is the major treatment modality for malignant glioma. However, the treatment response of radiotherapy is suboptimal due to resistance. Here we aimed to explore the effect and mechanism of Mothers against decapentaplegic homologue (SMAD3) silencing in sensitizing malignant glioma to radiotherapy. Clonogenic assay was used to evaluate the sensitivity of glioma cells to increasing doses of radiation. Glioma cells were transfected with small-interfering RNAs (siRNAs) specific to SMAD3. Overexpression of SMAD3 was achieved by transfecting expression plasmid encoding SMAD3 cDNA. Changes in MRE11-RAD50-NBS1 mRNA and protein levels were assessed through qPCR analysis and western blot analysis, respectively. Chromatin immunoprecipitation (ChIP) was used to confirm the interaction between SMAD3 and MRE11-RAD50-NBS1 (MRN) complex. Silencing of SMAD3 increased sensitivity of glioma cells to radiotherapy. MRE11, RAD50 and NBS1 were overexpressed in response to radiotherapy, which was attenuated by SMAD3 silencing while boosted by SMAD3 overexpression. ChIP analysis confirmed the interaction of SMAD3 with MRE11, RAD50 and NBS1 under radiotherapy, which was inhibited by SMAD3 silencing. SMAD3 silencing is an effective strategy for sensitizing glioma to radiotherapy, which is mediated by the interaction of SMAD3 with the MRN complex.


Photophysics and photochemistry of photodynamic therapy: fundamental aspects.
Photodynamic therapy (PDT) is a treatment modality for cancer and various other diseases. The clinical protocol covers the illumination of target cells (or tissue), which have been loaded with a photoactive drug (photosensitizer). In this review we describe the photophysical and primary photochemical processes that occur during PDT. Interaction of light with tissue results in attenuation of the incident light energy due to reflectance, absorption, scattering, and refraction. Refraction and reflection are reduced by perpendicular light application, whereas absorption can be minimized by the choice of a photosensitizer that absorbs in the far red region of the electromagnetic spectrum. Interaction of light and the photosensitizer can result in degradation, modification or relocalization of the drug, which differently affect the effectiveness of PDT. Photodynamic therapy itself, however, employs the light-induced chemical reactions of the activated photosensitizer (triplet state), resulting in the production of various reactive oxygen species, amongst them singlet oxygen as the primary photochemical product. Based on these considerations, the properties of an ideal photosensitizer for PDT are discussed. According to the clinical experience with PDT, it is proposed that the innovative concept of PDT is most successfully implemented into the mainstream of anticancer therapies by following an application-, i.e. tumor-centered approach with a focus on the actual clinical requirements of the respective tumor type.


Effects of vitamin C, vitamin E, and molecular hydrogen on the placental function in trophoblast cells.
This study aimed to investigate the effects of three different antioxidants, namely vitamin C, vitamin E, and molecular hydrogen, on cytotrophoblasts in vitro. Two trophoblast cell lines, JAR and JEG-3, were exposed to different concentrations of vitamin C (0, 25, 50, 100, 500, 1,000, 5,000 μmol/L), vitamin E (0, 25, 50, 100, 500, 1,000, 5,000 μmol/L), and molecular hydrogen (0, 25, 50, 100, 500 μmol/L) for 48 h. The cell viability was detected using the MTS assay. The secretion of human chorionic gonadotropin (hCG) and the tumor necrosis factor-α (TNF-α) were assessed and the expression of TNF-α mRNA was observed by real-time RT-PCR. Cell viability was significantly suppressed by 500 μmol/L vitamins C and E (P < 0.05), but not by 500 μmol/L molecular hydrogen (P > 0.05). The expression of TNF-α was increased by 100 μmol/L vitamin C and 50 μmol/L vitamins E, separately or combined (P < 0.05), but not by molecular hydrogen (0-500 μmol/L), as validated by real-time RT-PCR. But the secretion of hCG was both inhibited by 50-500 μmol/L molecular hydrogen and high levels of vitamin C and E, separately or combined. High levels of antioxidant vitamins C and E may have significant detrimental effects on placental function, as reflected by decreased cell viability and secretion of hCG; and placental immunity, as reflected by increased production of TNF-a. Meanwhile hydrogen showed no such effects on cell proliferation and TNF-α expression, but it could affect the level of hCG, indicating hydrogen as a potential candidate of antioxidant in the management of preeclampsia (PE) should be further studied.


Associations of Unhealthy Lifestyle and Nonalcoholic Fatty Liver Disease With Cardiovascular Healthy Outcomes.
The role of nonalcoholic fatty liver disease (NAFLD) as a mediator in the association between various unhealthy lifestyles and major adverse cardiovascular events and all-cause death remains unclear. This study used data from the UK Biobank, with follow-up until the end of 2021. It involved the calculation of unweighted and weighted lifestyle scores using the Cox model to classify participants on the basis of these scores. Additionally, the research assessed the mediation effect proportion of NAFLD using the difference method and examined the interaction and joint effects of lifestyle and NAFLD on health outcomes. Among the 134 616 enrolled participants, 4024 had records of major adverse cardiovascular events, while among the 130 144 participants included in the analysis of all-cause death, 6697 deaths occurred. The proportions of the association between overall lifestyle and major adverse cardiovascular events mediated by NAFLD were 19.4% and 21.7% (95% CI, 16.2-22.6 and 17.8-25.7) for scores 1 and 2, respectively, and those for all-cause death were 14.1% and 10.1% (95% CI, 11.3-17.1 and 7.9-12.2). After fully adjusting for traditional cardiovascular risk factors, the mediating effects declined across both outcomes. The associations between overall lifestyle and outcomes were stronger among those of the non-NAFLD group, and significant interactions were observed between overall lifestyle and NAFLD status. The joint analysis revealed that patients with NAFLD with unhealthy lifestyle had the highest risk of major adverse cardiovascular events and all-cause death. Improving lifestyle and addressing metabolic risk factors are essential for cardiovascular risk management in patients with NAFLD.


Eight polymorphic microsatellite loci for the Australian plague locust, Chortoicetes terminifera.
Few population genetics studies have been carried out on major locust species. In particular, an understanding of the population genetic structure of the Australian plague locust, Chortoicetes terminifera, is lacking. We isolated and characterized eight polymorphic microsatellite loci in C. terminifera, and described experimental conditions for polymerase chain reaction multiplexing and genotyping these loci. The number of alleles per locus ranged from 11 to 29 and the expected heterozygosity ranged from 0.797 to 0.977. One locus was found to be X-linked. Results of cross-taxon amplification tests are reported in four species of the Oedipodinae subfamily.


BeWo trophoblast cell susceptibility to Toxoplasma gondii is increased by interferon-gamma, interleukin-10 and transforming growth factor-beta1.
The present study aimed to investigate BeWo trophoblast cell susceptibility to Toxoplasma gondii infection under stimulation with anti-inflammatory cytokines in comparison with HeLa cells. Both cell types were submitted to different treatments with recombinant cytokines [interleukin (IL)-10 and transforming growth factor (TGF)-beta1] or the respective antibodies (anti-IL-10 and anti-TGF-beta) before and after T. gondii infection. The effect of interferon (IFN)-gamma was also assessed alone or in combination with anti-inflammatory cytokines or the respective antibodies after the parasite infection. Cells were fixed, stained and parasites quantified under light microscopy to evaluate intracellular replication (mean number of parasites per cell in 100 infected cells) and infection index (percentage of infected cells per 100 examined cells). In contrast with HeLa cells, treatments with IL-10 or TGF-beta1 induced a considerable augmentation in both T. gondii intracellular replication and invasion into BeWo cells. In addition, treatment with IFN-gamma alone or associated with IL-10 or TGF-beta1 increased the same parameters in BeWo cells, whereas the opposite effect was observed in HeLa cells. When endogenous IL-10 or TGF-beta was blocked, both BeWo and HeLa cells were able to control the parasite infection only in the presence of IFN-gamma. Together, these results indicate that the higher susceptibility of BeWo cells to T. gondii may be due to immunomodulation mechanisms, suggesting that the role of trophoblast cells in maintaining a placental microenvironment favourable to pregnancy may facilitate the infection into the placental tissues.


Persuasion, Influence, and Value: Perspectives from Communication and Social Neuroscience.
Opportunities to persuade and be persuaded are ubiquitous. What determines whether influence spreads and takes hold? This review provides an overview of evidence for the central role of subjective valuation in persuasion and social influence for both propagators and receivers of influence. We first review evidence that decisions to communicate information are determined by the subjective value a communicator expects to gain from sharing. We next review evidence that the effects of social influence and persuasion on receivers, in turn, arise from changes in the receiver's subjective valuation of objects, ideas, and behaviors. We then review evidence that self-related and social considerations are two key inputs to the value calculation in both communicators and receivers. Finally, we highlight biological coupling between communicators and receivers as a mechanism through which perceptions of value can be transmitted.


A sparse orthogonal collimator for small animal intensity-modulated radiation therapy part I: Planning system development and commissioning.
To achieve more translatable preclinical research results, small animal irradiation needs to more closely simulate human radiotherapy. Although the clinical gold standard is intensity-modulated radiation therapy (IMRT), the direct translation of this method for small animals is impractical. In this study we describe the treatment planning system for a novel dose modulation device to address this challenge. Using delineated target and avoidance structures, a rectangular aperture optimization (RAO) problem was formulated to penalize deviations from a desired dose distribution and limit the number of selected rectangular apertures. RAO was used to create IMRT plans with highly concave targets in the mouse brain, and the plan quality was compared to that using a hypothetical miniaturized multileaf collimator (MLC). RAO plans were also created for a realistic application of mouse whole liver irradiation and for a highly complex two-dimensional (2D) dose distribution as a proof-of-principle. Beam commissioning data, including output and off-axis factors and percent depth dose (PDD) curves, were acquired for our small animal irradiation system and incorporated into the treatment planning system. A plan post-processing step was implemented for aperture size-specific dose recalculation and aperture weighting reoptimization. The first RAO test case achieved highly conformal doses to concave targets in the brain, with substantially better dose gradient, conformity, and target dose homogeneity than the hypothetical miniaturized MLC plans. In the second test case, a highly conformal dose to the liver was achieved with significant sparing of the kidneys. RAO also successfully replicated a complex 2D dose distribution with three prescription dose levels. Energy spectra for field sizes 1 to 20 mm were calculated to match the measured PDD curves, with maximum and mean dose deviations of 4.47 ± 0.30% and 1.71 ± 0.18%. The final reoptimization of aperture weightings for the complex RAO test plan was able to reduce the maximum and mean dose deviations between the optimized and recalculated dose distributions from 10.3% to 6.6% and 4.0% to 2.8%, respectively. Using the advanced optimization techniques, complex IMRT plans were achieved using a simple dose modulation device. Beam commissioning data were incorporated into the treatment planning process to more accurately predict the resulting dose distribution. This platform substantially reduces the gap in treatment plan quality between clinical and preclinical radiotherapy, potentially increasing the value and flexibility of small animal studies.


Validity and Reliability of Form C of the Multidimensional Health Locus of Control Scale in Pregnant Women.
The health locus of control (HLC) can indirectly determine the health status. The current study aimed to assess the validity and reliability of Form C of the Multidimensional Health Locus of Control (MHLC-C) scale in pregnant women. 554 pregnant women participated in this cross-sectional study conducted in 2017; they referred to community health centers affiliated with Mashhad and Gonabad Medical Sciences Universities. Multi-stage random sampling was done. In this study, first, the questionnaire was translated into Farsi; then, face validity and construct validity were done through exploratory factor analysis, and concurrent criterion validity was also examined. Moreover, the reliability was assessed through internal consistency and stability methods. The results of the exploratory factor analysis showed that the MHLC-C scale consisted of four subscales, i.e. Chance, Internal, Other People, and Doctors, which accounted for 51.18% of variance. The results of the reliability analysis showed an acceptable internal consistency for the scale (Cronbach's alpha coefficient for subscales from 0.62 to 0.90). Also, the test-retest results showed good stability for all subscales other than Doctors (P<0.05). The concurrent validity of Forms B and C of MHLC scale showed a positive and significant correlation between subscales. The results of this study showed that the MHLC-C scale had acceptable validity and reliability in pregnant women and is suggested as an applicable criterion for assessing individuals control beliefs with any medical or health-related condition in Iran.


Brazilian cohort and genes encoding for drug-metabolizing enzymes and drug transporters.
Background & aim: Genetic variability in drug absorption, distribution, metabolism and excretion (ADME) genes contributes to the high heterogeneity of drug responses. The present study investigated polymorphisms of ADME genes frequencies and compared the findings with populations from other continents, available in the 1000 Genome Project (1 KGP) and the Exome Aggregation Consortium (ExAC) databases. Methodology & results: We conducted a study of 100 patients in Brazil and a total of 2003 SNPs were evaluated by targeted next-generation sequencing in 148 genes, including Phase I enzymes (n = 50), Phase II enzymes (n = 38) and drug transporters (n = 60). Overall, the distribution of minor allele frequency (MAF) suggests that the distribution of 2003 SNPs is similar between Brazilian cohort, 1 KGP and ExAC; however, we found moderate SNP allele-frequency divergence between Brazilian cohort and both 1000 KGP and ExAC. These differences were observed in several relevant genes including CYP3A4, NAT2 and SLCO1B1. Conclusion: We concluded that the Brazilian population needs clinical assessment of drug treatment based on individual genotype rather than ethnicity.


[Comparative evaluation of effects of various bronchodilators in sarcoidosis].
The investigation was undertaken to compare three bronchodilators on patients with respiratory sarcoidosis. Ninety patients (66 females and 24 males) with intrathoracic sarcoidosis were examined. X-ray stages I, II, III, and IV were seen in 48.9, 46.7, 3.3, and 1.1%, respectively. A flow-volume curve was recorded on a Masterscreen Pnevmo apparatus (Erich Jaeger) before and after inhalations of salbutamol (200 micrograms, a flask), ipratropium bromide (40 micrograms, a flask), and 1 ml of berodual solution through a Boreal nebulizer. The mean baseline values of forced expiration were normal, except for MOS75 (51.0 +/- 1.3% of the normal values). After salbutamol, the increment of MOS75 was higher than that after ipratropium (20.7 +/- 3.1% and 12.3 +/- 2.3%, respectively, p < 0.05); however, after berodual nebulization, the increase in MOS50 was greater than that after inhalation of ipratropium (17.2 +/- 1.9% versus 10.7 +/- 1.6%, p < 0.05) or salbutamol (10.1 +/- 6%, p < 0.01). The changes in these parameters in smokers and nonsmokers were similar. The one-month or more inhalation of budesonide (benacort) potentiated the bronchodilating action of salbutamol on all the parameters of forced expiration, but failed to affect the effect of ipratropium and berodual. Prednisolone did not affect the effects of bronchodilators. A combination of beta 2 agonist and inhaled steroid may be effective in intrathoracic sarcoidosis with the bronchial obstruction syndrome. The mechanism of varying action of the drugs having different mechanisms of action requires further investigations.


Antihypertensive principles from the leaves of Melastoma candidum.
Three active principles were isolated from the leaf of Melastoma candidum using the screening of hypotensive effects on spontaneously hypertensive rats (SHR). Intravenous injection of castalagin, procyanidin B-2, or helichrysoside into SHR lowered the mean blood pressure in a dose-dependent manner, with helichrysoside being the most potent compound. Plasma noradrenaline (NA) levels, both basal in SHR and elevated in normal rats through cold-stress stimulation, were attenuated by these compounds in a way which was not influenced by adrenalectomy. Decrease of NA release from sympathetic nerves was assumed to be responsible. Moreover, the hypertensive effect of various vasoconstrictors in anesthetized rats was reduced by helichrysoside. The same results were also observed in castalagin or procyanidin B-2 treated animals. The results indicate that the three principles possess the ability to lower blood pressure through a decrease of sympathetic tone as well as due to direct vasodilatation in SHRs.


Spatial and temporal relationship between native mammals and free-roaming dogs in a protected area surrounded by a metropolis.
With rapid urbanization worldwide, anthropogenic impacts such as human settlements and invasive carnivores (dogs Canis familiaris, cats Felis catus) are altering spatial distributions and temporal activity patterns of native species. In this study, we focused on spatiotemporal responses of native mammals to anthropogenic impacts in a protected area surrounded by a large metropolis (i.e. Yangmingshan National Park inside Taipei-Keelung metropolis in northern Taiwan). We collected site use data of 11 mammal species (i.e. dogs, cats, nine native species) between 2012 and 2017 with a camera system comprising 121 camera sites. We quantified anthropogenic disturbances as distance to human settlements and activity levels of free-roaming dogs and cats. Species richness and occurrences of the native mammals increased with increasing distances to human settlements and decreasing activity level of dogs, with the latter having a stronger effect than the former. Diel activity overlap between native mammals and dogs was lower during April-July season, coinciding with the breeding season for several native mammals. In contrast, activity level of cats showed no relationships with species richness, occurrences or diel activities of the native mammals. This study demonstrated negative impacts of human settlements and free-roaming dogs on native mammal communities for protected areas in urban environments, and highlights dog activity as a major anthropogenic threat to wildlife.


Repurposing of Antibiotic Sulfisoxazole Inhibits Lipolysis in Pre-Clinical Model of Cancer-Associated Cachexia.
Clinical management of cancer-associated cachexia, a multi-organ wasting syndrome, has been challenging without effective treatment strategies. An effective treatment that directly targets cancer-induced wasting is desperately needed to improve the quality of life and the survival of cancer patients. Recently, an antibiotic SFX was shown to have anti-tumour and anti-metastatic effects in mouse models of breast cancer. Hence, in this study, we examined the efficacy of SFX in the treatment of cancer-induced cachexia. C26 cachexic mice models were administered with SFX, and the tumour volume and body weight were regularly measured. Blood glucose, skeletal muscles, and adipose tissue were examined at the endpoint. Contrary to a previous study, SFX did not reduce the tumour volume in mice bearing C26 cells. Administration of SFX neither revealed any survival benefit nor rescued C26 cachectic mice from muscle wasting. Interestingly, SFX administration partially rescued (~10%) tumour-induced weight loss by preserving both the subcutaneous and intestinal fat mass. Together, these results suggest that the administration of SFX could partially rescue cancer-induced weight loss by inhibiting lipolysis. As anti-cachexia therapies are scarce, the results could facilitate the design of combinatorial therapies involving SFX, standard-of-care chemotherapeutics, and drugs that inhibit muscle atrophy for the treatment of cancer cachexia.


Is Astigmatism Correction Necessary for Patients With Cataract Who Have Corneal Astigmatism of Less Than 0.75 D?
To investigate the proportion of patients with predicted refractive astigmatism (PRA) of 0.75 diopters (D) or greater and associated risk factors among cataract surgery candidates with low corneal astigmatism. A retrospective cross-sectional study was conducted in Zhongshan Ophthalmic Center, Guangzhou, China. Patients with cataract who had preoperative simulated keratometric astigmatism of less than 0.75 D were recruited. The PRA was calculated by Barrett toric calculator using posterior corneal astigmatism (PCA) measured by the IOLMaster 700 (Carl Zeiss Meditec AG) and corneal surgically induced astigmatism (SIA). Two corneal incision locations (temporal [0°/180°], 135° incision) and varying magnitudes (0.10 to 0.60 D) were considered for SIA. Multiple logistic regression analysis was used to explore risk factors associated with PRA of 0.75 D or greater and build predictive model. Sensitivity analysis was performed using PRA threshold of 0.50 D. A total of 1,750 eyes from 1,750 patients were included (mean age: 60.14 ± 13.24 years, 42.91% male, 1,010 right eyes and 740 left eyes). The 135° incision (odds ratio [OR]: 17.86) and against-the-rule (ATR) astigmatism (OR: 37.55) are the major risk factors for PRA of 0.75 D or greater. Higher simulated keratometric astigmatism (OR: 2.03), larger PCA (OR: 1.64), and surgically induced astigmatism (OR: 1.29) also significantly increased the risk of PRA of 0.75 D or greater. Nomogram model were constructed with an area under curve of 0.90. For patients with corneal astigmatism of less than 0.75 D, temporal incision and measured PCA is preferred. Those patients with ATR astigmatism should be considered for astigmatism correction when using a 135° incision. [J Refract Surg. 2023;39(12):850-855.].


Dovitinib induces apoptosis and overcomes sorafenib resistance in hepatocellular carcinoma through SHP-1-mediated inhibition of STAT3.
The multiple kinase inhibitor dovitinib is currently under clinical investigation for hepatocellular carcinoma (HCC). Here, we investigated the mechanistic basis for the effects of dovitinib in HCCs. Dovitinib showed significant antitumor activity in HCC cell lines PLC5, Hep3B, Sk-Hep1, and Huh-7. Dovitinib downregulated phospho-STAT3 (p-STAT3) at tyrosine 705 and subsequently reduced the levels of expression of STAT3-related proteins Mcl-1, survivin, and cyclin D1 in a time-dependent manner. Ectopic expression of STAT3 abolished the apoptotic effect of dovitinib, indicating that STAT3 is indispensable in mediating the effect of dovitinib in HCC. SHP-1 inhibitor reversed downregulation of p-STAT3 and apoptosis induced by dovitinib, and silencing of SHP-1 by RNA interference abolished the effects of dovitinib on p-STAT3, indicating that SHP-1, a protein tyrosine phosphatase, mediates the effects of dovitinib. Notably, dovitinib increased SHP-1 activity in HCC cells. Incubation of dovitinib with pure SHP-1 protein enhanced its phosphatase activity, indicating that dovitinib upregulates the activity of SHP-1 via direct interactions. In addition, dovitinib induced apoptosis in two sorafenib-resistant cell lines through inhibition of STAT3, and sorafenib-resistant cells showed significant activation of STAT3, suggesting that targeting STAT3 may be a useful approach to overcome drug resistance in HCC. Finally, in vivo, dovitinib significantly suppressed growth of both Huh-7 and PLC5 xenograft tumors and downregulated p-STAT3 by increasing SHP-1 activity. In conclusion, dovitinib induces significant apoptosis in HCC cells and sorafenib-resistant cells via SHP-1-mediated inhibition of STAT3.


Valuation of EQ-5D-5L Health States in Poland: the First EQ-VT-Based Study in Central and Eastern Europe.
Cost-utility analyses are becoming increasingly important in Central and Eastern Europe. We aimed to develop a Polish utility tariff for EQ-5D-5L health states. Face-to-face, computer-assisted interviews were collected in a representative sample. Each respondent followed a standardised protocol to collect ten composite time trade-off and seven discrete choice experiment observations. In the Bayesian approach, several model specifications were compared based on model fit, the usability of the final value set and how they reflect the elicitation procedure (e.g. censoring). A hybrid approach (using composite time trade-off and discrete choice experiment data) was employed in the final set, which was compared with the existing ones: EQ-5D-3L and EQ-5D-5L cross-walk. Data from 1252 respondents (11,480 composite time trade-off valuations and 8764 discrete choice experiment pairs) were collected over the period June to October 2016. The final model accounted for random parameters, error scaling with fat tails, censoring at - 1, unwillingness to trade in time trade-off by the religious people and Cauchy distribution in discrete choice experiments. Pain/discomfort impacts the utility most: the disutility equals 0.575 when at level 5. In the value set, 4.4% of EQ-5D-5L states are worse than dead. The new value set has a comparable range (minimum of - 0.590 compared to - 0.523) and the same ordering of the first three dimensions (pain/discomfort, mobility, self-care) as the EQ-5D-3L value set and the EQ-5D-5L cross-walk value set. Moreover, it is more sensitive to a moderate decline in health. The new value set supports consistency with past decisions in cost-utility studies, while offering a better assessment of even moderate improvements in health. It could represent an option for Central and Eastern Europe countries lacking their own value sets.


Numerical Simulation on Seismic Response of the Filled Joint under High Amplitude Stress Waves Using Finite-Discrete Element Method (FDEM).
This paper numerically investigates the seismic response of the filled joint under high amplitude stress waves using the combined finite-discrete element method (FDEM). A thin layer of independent polygonal particles are used to simulate the joint fillings. Each particle is meshed using the Delaunay triangulation scheme and can be crushed when the load exceeds its strength. The propagation of the 1D longitude wave through a single filled joint is studied, considering the influences of the joint thickness and the characteristics of the incident wave, such as the amplitude and frequency. The results show that the filled particles under high amplitude stress waves mainly experience three deformation stages: (i) initial compaction stage; (ii) crushing stage; and (iii) crushing and compaction stage. In the initial compaction stage and crushing and compaction stage, compaction dominates the mechanical behavior of the joint, and the particle area distribution curve varies little. In these stages, the transmission coefficient increases with the increase of the amplitude, i.e., peak particle velocity (PPV), of the incident wave. On the other hand, in the crushing stage, particle crushing plays the dominant role. The particle size distribution curve changes abruptly with the PPV due to the fragments created by the crushing process. This process consumes part of wave energy and reduces the stiffness of the filled joint. The transmission coefficient decreases with increasing PPV in this stage because of the increased amount of energy consumed by crushing. Moreover, with the increase of the frequency of the incident wave, the transmission coefficient decreases and fewer particles can be crushed. Under the same incident wave, the transmission coefficient decreases when the filled thickness increases and the filled particles become more difficult to be crushed.


Cutaneous manifestations of liver diseases.
The cutaneous manifestations of liver disorders are protean. In addition to the well-recognized stigmata of liver cirrhosis, various infectious, metabolic, autoimmune, hereditary, developmental, and neoplastic liver disorders can result in various cutaneous and mucosal changes as well as in pruritus and abnormal hair and nail growth. Although many of these changes are nonspecific, some are associated with distinct liver diseases and correlate with the severity of hepatic pathology. Familiarization with the spectrum of these manifestations is important for early detection and treatment of hepatic diseases. We review the medical literature and discuss the spectrum of dermatologic manifestations of liver cirrhosis and of important liver diseases, their etiopathogenesis, significance, and treatment.


NMR structural analysis of Sleeping Beauty transposase binding to DNA.
The Sleeping Beauty (SB) transposon is the most widely used DNA transposon in genetic applications and is the only DNA transposon thus far in clinical trials for human gene therapy. In the absence of atomic level structural information, the development of SB transposon relied primarily on the biochemical and genetic homology data. While these studies were successful and have yielded hyperactive transposases, structural information is needed to gain a mechanistic understanding of transposase activity and guides to further improvement. We have initiated a structural study of SB transposase using Nuclear Magnetic Resonance (NMR) and Circular Dichroism (CD) spectroscopy to investigate the properties of the DNA-binding domain of SB transposase in solution. We show that at physiologic salt concentrations, the SB DNA-binding domain remains mostly unstructured but its N-terminal PAI subdomain forms a compact, three-helical structure with a helix-turn-helix motif at higher concentrations of NaCl. Furthermore, we show that the full-length SB DNA-binding domain associates differently with inner and outer binding sites of the transposon DNA. We also show that the PAI subdomain of SB DNA-binding domain has a dominant role in transposase's attachment to the inverted terminal repeats of the transposon DNA. Overall, our data validate several earlier predictions and provide new insights on how SB transposase recognizes transposon DNA.


Neuronal amyloid-β accumulation within cholinergic basal forebrain in ageing and Alzheimer's disease.
The mechanisms that contribute to selective vulnerability of the magnocellular basal forebrain cholinergic neurons in neurodegenerative diseases, such as Alzheimer's disease, are not fully understood. Because age is the primary risk factor for Alzheimer's disease, mechanisms of interest must include age-related alterations in protein expression, cell type-specific markers and pathology. The present study explored the extent and characteristics of intraneuronal amyloid-β accumulation, particularly of the fibrillogenic 42-amino acid isoform, within basal forebrain cholinergic neurons in normal young, normal aged and Alzheimer's disease brains as a potential contributor to the selective vulnerability of these neurons using immunohistochemistry and western blot analysis. Amyloid-β1-42 immunoreactivity was observed in the entire cholinergic neuronal population regardless of age or Alzheimer's disease diagnosis. The magnitude of this accumulation as revealed by optical density measures was significantly greater than that in cortical pyramidal neurons, and magnocellular neurons in the globus pallidus did not demonstrate a similar extent of amyloid immunoreactivity. Immunoblot analysis with a panel of amyloid-β antibodies confirmed accumulation of high concentration of amyloid-β in basal forebrain early in adult life. There was no age- or Alzheimer-related alteration in total amyloid-β content within this region. In contrast, an increase in the large molecular weight soluble oligomer species was observed with a highly oligomer-specific antibody in aged and Alzheimer brains when compared with the young. Similarly, intermediate molecular weight oligomeric species displayed an increase in aged and Alzheimer brains when compared with the young using two amyloid-β42 antibodies. Compared to cortical homogenates, small molecular weight oligomeric species were lower and intermediate species were enriched in basal forebrain in ageing and Alzheimer's disease. Regional and age-related differences in accumulation were not the result of alterations in expression of the amyloid precursor protein, as confirmed by both immunostaining and western blot. Our results demonstrate that intraneuronal amyloid-β accumulation is a relatively selective trait of basal forebrain cholinergic neurons early in adult life, and increases in the prevalence of intermediate and large oligomeric assembly states are associated with both ageing and Alzheimer's disease. Selective intraneuronal amyloid-β accumulation in adult life and oligomerization during the ageing process are potential contributors to the degeneration of basal forebrain cholinergic neurons in Alzheimer's disease.


Therapeutic trials of biologics in primary biliary cholangitis: An open label study of abatacept and review of the literature.
Primary biliary cholangitis (PBC) is a classic autoimmune disease in which humoral, cytotoxic, and innate immune responses have been implicated with the specific targeting of a mitochondrial antigen. The mainstay of treatment remains the bile acid ursodeoxycholic acid (UDCA). Corticosteroids may have some benefits, but to date, clinical trials of biologics targeting B cells and IL-12/23 have not shown any efficacy. Because activated T cells target the intrahepatic bile ducts in PBC and pre-clinical models suggested that blocking CD80/CD86 with CTLA-4 Ig might have therapeutic benefit in PBC, we performed an open-label trial to determine if CTLA-4 Ig (abatacept) is safe and potentially efficacious in PBC patients with an incomplete response to UDCA. PBC patients with an alkaline phosphatase (ALP) > 1.67 × the upper limit of normal after 6 months on UDCA treatment or who were intolerant of UDCA received abatacept 125 mg s.q. weekly for 24 weeks. The co-primary endpoint was ALP normalization or a >40% reduction from baseline. Among 16 subjects enrolled and who received at least 1 dose of abatacept, 1 (6.3%) met the co-primary endpoint. Absolute and percent changes in ALP [median (95% CI)] were +2.8 U/L (-90.9-96.6) and -0.28% (-21.1-15.5), respectively. No significant changes were observed in ALP, ALT, total bilirubin, albumin, immunoglobulins, or liver stiffness. Abatacept treatment decreased several non-terminally differentiated CD4+ but not CD8+ T cell populations, including decreases in CD4+ CCR5+ (p = 0.02) and CD4+ PD1+ (p = 0.03) lymphocytes. In contrast there were increases in CD4+ CCR7+ lymphocytes (p = 0.034). Treatment emergent adverse events occurred in 4 subjects. Abatacept was well tolerated in this population of PBC patients but like other biologics in PBC was ineffective in achieving biochemical responses associated with improved clinical outcomes.


[Prevalence of atopy in chronic fatigue syndrome].
Several hypotheses have been postulated to explain the etiopathogenesis of chronic fatigue syndrome (CFS). Among these, immunologic dysfunction has been proposed. Up to 30 % of these patients have a history of allergic disease. The aim of this study was to investigate whether allergic sensitization is higher in patients with CFS than in the general population. Twenty-five patients with CFS and 20 controls were evaluated. A clinical history for allergy was taken and immediate hypersensitivity tests were performed. Twelve patients (48 %) and eight controls (40 %) had a family history of atopy. Personal histories of atopy were as follows: rhinoconjunctivitis: 12 patients (48 %), seven controls (35 %); asthma: five patients (20 %), two controls (10 %); food allergy: three patients (12 %); atopic dermatitis: two patients; contact dermatitis: two patients. No statistically significant differences were found between the groups in any of the variables (p > 0.05). In the CSF group, 3.4 % (15/441) of the inhalant prick tests were positive, and in the control group 3.8 % (16/420) were positive. None of the tests for hypersensitivity to food or latex were positive. In our study atopy was not more prevalent in patients with CFS than in healthy controls, although the CSF group tended to report more respiratory symptoms and drug allergies.


Accuracy of minimally invasive percutaneous thoracolumbar pedicle screws using 2D fluoroscopy: a retrospective review through 3D CT analysis.
In the literature, there is a large variation in the reported misplacement rates of pedicle screws. The use of minimally invasive surgical techniques is increasing and as such there has only been a small amount of data to look at the misplacement rate of percutaneously inserted thoracic and lumbar pedicle screws. A retrospective analysis of post-operative computed tomography (CT) scans were performed on 108 patients who underwent minimally invasive percutaneously inserted thoracic and lumbar pedicle screws by a single surgeon. Analysis of the screw trajectory using strict guidelines was performed using multiplanar reconstruction CT scan data to determine the accuracy of the pedicle screws. A total of 614 screws were inserted in vertebral levels T2 to S1. Twenty-five (4.07%) screws were considered misplaced having breached the pedicular cortex. Thoracic pedicle screws had a statistically higher misplacement rate than lumbar pedicle screws (14.67% vs. 2.60% respectively, P<0.001). A single screw required replacement (0.16%) and there were no permanent neurological deficits. The misplacement rates were lower than those reported for open screw placement and equivalent to 3D CT navigated misplacement rates. Percutaneously inserted pedicle screws using 2D fluoroscopy offers a safe and accurate option for spinal stabilisation with an extremely low misplacement rate and morbidity. Overall, the low misplacement rates were equivalent and in most cases lower compared to open and computer assisted navigation techniques. However, we would recommend that given a misplacement rate of 14.67% for thoracic pedicle screws that computer assisted navigation may be able to offer further improvements in accuracy.


Functional maturation of CD4+CD25+CTLA4+CD45RA+ T regulatory cells in human neonatal T cell responses to environmental antigens/allergens.
A number of laboratories have reported cord blood T cell responses to ubiquitous environmental Ags, including allergens, by proliferation and cytokine secretion. Moreover, the magnitude of these responses has been linked with risk for subsequent expression of allergy. These findings have been widely interpreted as evidence for transplacental priming and the development of fetal T memory cells against Ags present in the maternal environment. However, we present findings below that suggest that neonatal T cell responses to allergens (and other Ags) differ markedly from those occurring in later life. Notably, in contrast to allergen-responsive adult CD4(+) T cell cultures, responding neonatal T cell cultures display high levels of apoptosis. Comparable responses were observed against a range of microbial Ags and against a parasite Ag absent from the local environment, but not against autoantigen. A notable finding was the appearance in these cultures of CD4(+)CD25(+)CTLA4(+) T cells that de novo develop MLR-suppressive activity. These cells moreover expressed CD45RA and CD38, hallmarks of recent thymic emigrants. CFSE-labeling studies indicate that the CD4(+)CD25(+) cells observed at the end of the culture period were present in the day 0 starting populations, but they were not suppressive in MLR responses. Collectively, these findings suggest that a significant component of the reactivity of human neonatal CD4(+) T cells toward nominal Ag (allergen) represents a default response by recent thymic emigrants, providing an initial burst of short-lived cellular immunity in the absence of conventional T cell memory, which is limited in intensity and duration via the parallel activation of regulatory T cells.


Urea transporters UT-A1 and UT-A3 accumulate in the plasma membrane in response to increased hypertonicity.
The UT-A1 and UT-A3 urea transporters are expressed in the terminal inner medullary collecting duct (IMCD) and play an important role in the production of concentrated urine. We showed that both hyperosmolarity and vasopressin increase urea permeability in perfused rat terminal IMCDs and that UT-A1 and UT-A3 accumulate in the plasma membrane in response to vasopressin. In this study, we investigated whether hyperosmolarity causes UT-A1 and/or UT-A3 to accumulate in the plasma membrane or represents a complimentary stimulatory pathway. Rat IMCD suspensions were incubated in 450 vs. 900 mosM solutions. We biotinylated the IMCD surface proteins, collected, and analyzed them. Membrane accumulation was assessed by Western blotting of the biotinylated protein pool probed with anti-UT-A1 or anti-UT-A3. We studied the effect of NaCl, urea, and sucrose as osmotic agents. Membrane-associated UT-A1 and UT-A3 increased relative to control levels when either NaCl (UT-A1 increased 37 +/- 6%; UT-A3 increased 46 +/- 13%) or sucrose (UT-A1 increased 81 +/- 13%; UT-A3 increased 60 +/- 8%) was used to increase osmolarity. There was no increase in membrane UT-A1 or UT-A3 when urea was added. Analogously, UT-A1 phosphorylation was increased in NaCl- and sucrose- but not in urea-based hyperosmolar solutions. Hypertonicity also increased UT-A3 phosphorylation. We conclude that the increase in the urea permeability in response to hyperosmolarity reflects both UT-A1 and UT-A3 movement to the plasma membrane and may be a direct response to tonicity. Furthermore, this movement is accompanied by, and may require, increased phosphorylation in response to hypertonicity.


[The degree of the severity of the course of acute lung diseases in newborn infants in the early neonatal period].
In a prospective clinical investigation, a comparative evaluation was done of degrees of severity of most commonly encountered acute lung disorders in 95 newborn infants who had been treated in the Lviv Regional Neonatal Centre. It has been ascertained that particular features of the course of acute lung diseases in early neonatal period are determined by gravity of the affection of the lung that can be assessed with the aid of the calculable index. The newborn babies aged 11 to 23 h presenting with respiratory distress syndrome displayed significant differences in values for the lung affection severity index, the same being true of those children having been dying at a later age or surviving with subsequent bronchopulmonary dysplasia being formed. The above index can be used in the differential diagnosis of lung diseases, it has also prognostic significance for assessment of risk of death in a child or that of subsequent development of bronchopulmonary dysplasia.


Passive permeability of human red blood cells to calcium.
Ca2+ influx was measured into human erythrocytes in which efflux was blocked by either introduction of an intracellular Ca2+ chelator, introduction of the Ca2+ chelator followed by ATP depletion, or depletion of the Ca2+ pump cofactors ATP and Mg2+. The Ca2+ influx under all three conditions was 14-20 mumol . 1 cells-1 . h-1, which is an order of magnitude higher than the influx previously reported for cells depleted of either ATP or Mg2+ separately. The difference between the two values was explained by the finding of substantial Ca2+ efflux from the Ca2+-loaded ATP-depleted cells, whereas this efflux was insignificant from cells loaded with quin 2 and then ATP depleted. Under these latter conditions Ca2+ influx estimates the unidirectional permeability to this cation. Studies using this technique showed that Ca2+ influx was the same in media of isotonic sodium, potassium, lithium, choline, or magnesium chlorides. Moreover the dependence of Ca2+ influx on external Ca2+ concentration was well described by the sum of saturable and nonsaturable (linear) components.


Influence of different soccer-specific maximal actions on physiological, perceptual and accelerometer measurement loads.
The aim of this study was to compare the effect of different soccer-specific maximal actions (Continuous run, Sprint, Sprint with change of direction [Sprint COD], Jump and Shot) upon physiological (oxygen uptake and heart rate) and perceptual (rating of perceived exertion [RPE]) responses and accelerometer load. Ten moderately to well-trained male soccer players volunteered to serve as subjects in this study. A repeated within-subject design was used in which each subject was tested on five occasions on different days, one test each day, during a period of 2 weeks. Each of the five tests had a distance of 900 m and lasted 5 minutes, thus the mean speed for all five tests was 3 m/s. During the test, oxygen uptake, heart rate and accelerometer load were measured. Immediately after each test, RPE was recorded, and after the test, oxygen uptake was measured for 5 minutes while the subject sat in an upright position on a chair. In the comparison of different soccer-specific maximal actions upon physiological and perceptual responses and accelerometer load, this study found that the total accelerometer load was lowest in Sprint and Sprint COD conditions, although the physiological (oxygen uptake and heart rate) and perceptual (RPE) responses were highest in the respective conditions. The Jump condition experienced lower RPE than Sprint and Sprint COD but achieved the highest accelerometer load. Accelerometer load is not a valid measurement for energy costs or RPE but may function as a complementary tool to investigate the player loads during matches and training.


Iron(III)-Oxo Cluster Chemistry with Dimethylarsinate Ligands: Structures, Magnetic Properties, and Computational Studies.
A program has been initiated to develop FeIII/oxo cluster chemistry with the "pseudocarboxylate" ligand dimethylarsinate (Me2AsO2-) for comparison with the well investigated FeIII/oxo/carboxylate cluster area. The synthesis and characterization of three polynuclear FeIII complexes are reported, [Fe12O4(O2CtBu)8(O2AsMe2)17(H2O)3]Cl3 (1), Na2[Fe12Na2O4(O2AsMe2)20(NO3)6(Me2AsO2H)2(H2O)4](NO3)6 (2), and [Fe3(O2AsMe2)6(Me2AsO2H)2(hqn)2](NO3) (3), where hqnH is 8-hydroxyquinoline. The Fe12 core of 1 is a type never previously encountered in FeIII carboxylate chemistry, consisting of two Fe6 units each of which comprises two {Fe3(μ3-O2-)} units bridged by three Me2AsO2- groups and linked into an Fe12 loop structure by two anti-anti η1:η1:μ Me2AsO2- groups, a bridging mode extremely rare with carboxylates. 2 also consists of two Fe6 units, differing in their ligation from those in 1, and this time linked together into a linear structure by a central {Na2(NO3)2} bridging unit. 3 is a linear Fe3 complex with no monatomic bridges between FeIII ions, a very rare situation in FeIII chemistry with any ligands and unprecedented in Fe carboxylate chemistry. The distinct differences observed in arsinate vs carboxylate ligation modes are rationalized largely based on the greater basicity of the former vs the latter. Variable-temperature dc and ac magnetic susceptibility data reveal all Fe2 pairwise interactions to be antiferromagnetic. For 1 and 2, the different Jij couplings were estimated by use of a magnetostructural correlation for high nuclearity FeIII-oxo clusters and by density functional theory calculations using broken symmetry methods, allowing identification of their relative spin vector alignments and thus rationalization of their S = 0 ground states. The Jij values were then used as input values to give excellent fits of the experimental χMT vs T data. For 3, the fits of the experimental χMT vs T data to the Van Vleck equation or with PHI gave a very weak J12 = -0.8(1) cm-1 (H = -2JŜi·Ŝj convention) between adjacent FeIII ions and an S = 5/2 ground state. These initial FeIII arsinate complexes also provide structural parameters that help validate literature assignments of arsinate binding modes to iron oxide/hydroxide minerals as part of environmental concerns of using arsenic-containing herbicides in agriculture.


Quantitative Construction of Boronic-Ester Linkages in Covalent Organic Frameworks for the Carbon Dioxide Reduction.
Covalent organic frameworks (COFs) have been utilized for catalyzing the reduction of carbon dioxide (CO2RR) due to their atomic metal centers and controllable pore channels, which are facilitated by different covalent bonds. However, the exploration of boron-based linkages in these catalytic COFs has been limited owing to potential instability. Herein, we present the construction of boronic ester-linked COFs through nucleophilic substitution reactions in order to catalyze the CO2RR. The inclusion of abundant fluorine atoms within the frameworks enhances their hydrophobicity and subsequently improves water tolerance and chemical stability of COFs. The content of boron atoms in the COF linkages was carefully controlled, with COFs featuring a higher density of boron atoms exhibiting increased electronic conductivity, enhanced reductive ability, and stronger binding affinity towards CO2. Consequently, these COFs demonstrate improved activity and selectivity. The optimized COFs achieve the highest activity, achieving a turnover frequency of 1695.3 h-1 and a CO selectivity of 95.0% at -0.9 V. Operando synchrotron radiation measurements confirm the stability of Co (II) atoms as catalytically active sites. By successfully constructing boronic ester-linked COFs, we not only address potential instability concerns but also achieve exceptional catalytic performance for CO2RR.


Comparative genomics of human stem cell factor (SCF).
Stem cell factor (SCF) is a critical protein with key roles in the cell such as hematopoiesis, gametogenesis and melanogenesis. In the present study a comparative analysis on nucleotide sequences of SCF was performed in Humanoids using bioinformatics tools including NCBI-BLAST, MEGA6, and JBrowse. Our analysis of nucleotide sequences to find closely evolved organisms with high similarity by NCBI-BLAST tools and MEGA6 showed that human and Chimpanzee (Pan troglodytes) were placed into the same cluster. By using JBrowse, we found that SCF in Neanderthal had a single copy number similar to modern human and partly conserved nucleotide sequences. Together, the results approved the gene flow and genetics similarity of SCF among human and P. troglodytes. This may suggest that during evolution, SCF gene transferred partly intact either on the basis of sequence or function from the same ancestors to P. troglodytes, the ancient human like Neanderthal, and then to the modern human.


Depression, anxiety and obsessive-compulsive symptoms and quality of life in children with attention-deficit hyperactivity disorder (ADHD) during three-month methylphenidate treatment.
The current study was designed to investigate the changes that occur in depression, anxiety, obsessive-compulsive symptoms and health-related quality of life during methylphenidate (MPH) treatment in children with attention-deficit hyperactivity disorder (ADHD). Forty-five treatment naive children with ADHD, aged 8-14, were assessed based on self, parent and teacher reports at the baseline and at the end of the first and third month of MPH treatment regarding changes in inattention, hyperactivity, impulsivity, depression, anxiety and obsessive-compulsive symptoms. Changes in the quality of life were also noted. Repeated measures of analysis of variance (ANOVA) tests with Bonferroni corrections were conducted in order to evaluate the data. Symptoms of inattention, hyperactivity and impulsivity were significantly reduced (p < 0.017) following a three-month MPH treatment. There were significant decreases in depression (p = 0.004), trait anxiety (p = 0.000) and checking compulsion symptom scores (p = 0.001). Moreover, parents reported significant improvements in psychosocial (p = 0.001) and total scores (p = 0.009) of quality of life, despite no change in physical health scores (p > 0.05). Children's ratings of quality of life measures showed no significant changes in physical health and psychosocial scores (p > 0.05), while total scores significantly improved (p = 0.001) after the treatment. Over a three-month MPH treatment, depression, trait anxiety and checking compulsion symptoms decreased and quality of life seemed to improve along with those of inattention, hyperactivity and impulsivity.


p38 mitogen-activated protein kinase (MAPK) first regulates filamentous actin at the 8-16-cell stage during preimplantation development.
The MAPK (mitogen-activated protein kinase) superfamily of proteins consists of four separate signalling cascades: the c-Jun N-terminal kinase or stress-activated protein kinases (JNK/SAPK); the ERKs (extracellular-signal-regulated kinases); the ERK5 or big MAPK1; and the p38 MAPK group of protein kinases, all of which are highly conserved. To date, our studies have focused on defining the role of the p38 MAPK pathway during preimplantation development. p38 MAPK regulates actin filament formation through the downstream kinases MAPKAPK2/3 (MAPK-activated protein kinase 2/3) or MAPKAPK5 [PRAK (p38 regulated/activated kinase)] and subsequently through HSP25/27 (heat-shock protein 25/27). We recently reported that 2-cell-stage murine embryos treated with cytokine-suppressive anti-inflammatory drugs (CSAIDtrade mark; SB203580 and SB220025) display a reversible blockade of development at the 8-16-cell stage, indicating that p38 (MAPK) activity is required to complete murine preimplantation development. In the present study, we have investigated the stage-specific action and role of p38 MAPK in regulating filamentous actin during murine preimplantation development. Treatment of 8-cell-stage embryos with SB203580 and SB220025 (CSAIDtrade mark) resulted in a blockade of preimplantation development, loss of rhodamine phalloidin fluorescence, MK-p (phosphorylated MAPKAPK2/3), HSP-p (phosphorylated HSP25/27) and a redistribution of alpha-catenin immunofluorescence by 12 h of treatment. In contrast, treatment of 2- and 4-cell-stage embryos with CSAIDtrade mark drugs resulted in a loss of MK-p and HSP-p, but did not result in a loss of rhodamine phalloidin fluorescence. All these effects of p38 MAPK inhibition were reversed upon removal of the inhibitor, and development resumed in a delayed but normal manner to the blastocyst stage. Treatment of 8-cell embryos with PD098059 (ERK pathway inhibitor) did not affect development or fluorescence of MK-p, HSP-p or rhodamine phalloidin. Murine preimplantation development becomes dependent on p38 MAPK at the 8-16-cell stage, which corresponds to the stage when p38 MAPK first regulates filamentous actin during early development.


Evolution of global and local grey matter atrophy on serial MRI scans during the progression from MCI to AD.
Mild cognitive impairment (MCI) often represents a prodromal form of dementia, conferring a significantly higher risk of converting to probable Alzheimer's disease (AD). The aim of this study is to characterise the differences of grey matter (GM) distribution and dynamics between progressive and stable MCI subjects during a 2 year period preceding the conversion to AD. We included 48 stable MCI and 12 progressive MCI cases based on the availability of 3 serial scans acquired with approximately 1 year scan interval. For the progressive MCI group, the third scan was acquired at the time of the clinical diagnosis of AD, while the first two scans were acquired approximately 2 and 1 years earlier. For the stable MCI group, the three scans were acquired at approximately 1 year intervals during a period free from significant cognitive decline. We used longitudinal voxel-based morphometry (VBM) for mapping the progression of GM loss over time. For the progressive MCI group, the cross-sectional analysis revealed areas of lower GM volumes in the parahippocampal gyrus, precuneus and posterior cingulate 12 months before the AD diagnosis. For the longitudinal VBM analysis the progressive MCI group revealed increased GM loss in cortical regions belonging to the temporal neocortex, parahippocampal cortex, and cingulate gyrus. The frontal lobe, insula and the cerebellum were also affected. This accelerated atrophy may offer new insights into the understanding of neurodegenerative pathology and the clinical relevance of these changes remains to be verified by subsequent studies.


Heated tobacco product use and its relationship to quitting combustible cigarettes in Korean adults.
We assessed the prevalence of, and factors associated with, heated tobacco product (HTP) use and analysed the association between HTP use and quitting combustible cigarettes (CCs) in Korean adults. We conducted an online survey with 7,000 adults (males, 2,300; females, 4,700; ages 20-69) out of 70,000 age-, sex- and provincial-distribution-matched individuals based on 2018 national population statistics. Females were oversampled because the prevalence of tobacco product use is very low among women in Korea. Chi-square tests were used for bivariate analyses, and odds ratios were assessed after adjusting for sociodemographic variables. The prevalence of current CC, electronic cigarette (EC), and HTP use was 24.8% (males, 40.4%; females, 9.3%), 6.8% (males, 10.1%; females, 3.4%), and 10.2% (males, 16.2%; females, 4.3%), respectively. Among the 574 current HTP users, 77 (13.4%) were HTP-only users and >80% were either dual users of HTP and CC/EC, or triple users of HTP, EC, and CC. Among the current CC users, the odds of having attempted to quit CCs in the past year were greater among EC-only users (aOR 2.92; 95% CI 1.81-4.69) and dual users of HTPs and ECs (aOR 8.42; 95% CI 4.85-14.62) than among non-HTP and non-EC users. Among 2,121 ever CC smokers, the likelihood of being a former CC smoker was 0.19 (95% CI 0.15-0.24) for HTP users, 0.29 (95% CI 0.20-0.42) for EC users, and 0.03 (95% CI 0.01-0.06) for users of both HTPs and ECs compared with non-HTP and non-EC users. EC-only use and dual use of HTPs and ECs were associated with increased attempts to quit CCs; however, HTP and EC use was associated with lower odds of CC smoking abstinence.


Mannose-binding lectin (MBL) codon 54 gene polymorphism protects against development of pre-eclampsia, HELLP syndrome and pre-eclampsia-associated intrauterine growth restriction.
Insufficient invasion of the spiral arteries by trophoblast cells is associated with the etiology of pre-eclampsia, the syndrome of hemolysis, elevated liver enzymes and low platelet counts (HELLP) and pre-eclampsia-associated intrauterine growth restriction (IUGR). Mannose-binding lectin (MBL) is a component of the innate immune system. MBL-mediated activation of the complement cascade is an important event in the destruction of invading trophoblasts. The gene coding for MBL is polymorphic, and variant alleles result in greatly reduced circulating MBL levels. The aim of this study was to test the association between an MBL polymorphism and pre-eclampsia, HELLP syndrome and IUGR. DNA was extracted from buccal swabs of 51 women with pre-eclampsia, 81 women with HELLP syndrome and 184 healthy pregnant controls. Aliquots were tested for a single nucleotide MBL gene polymorphism at codon 54 by PCR and endonuclease digestion. Homozygosity for the wild-type allele was more frequent in patients with pre-eclampsia (P = 0.04) and HELLP syndrome (P = 0.02) when compared with controls. The presence of the variant allele was more prevalent among controls than in women with pre-eclampsia (P = 0.02) or HELLP syndrome (P = 0.028). Twenty-two (55%) patients with pre-eclampsia and 43 (53%) women with HELLP syndrome delivered an IUGR neonate. MBL-54 heterozygosity was more frequent in controls (27.2%) than in pre-eclamptic women (4.5%, P = 0.025) and those with HELLP syndrome (11.7%, P = 0.05) who delivered an IUGR neonate. Genotype frequencies of neonates born to mothers in all study groups were similar. Carriage of the MBL codon 54 polymorphism protects against pre-eclampsia, HELLP syndrome and IUGR and implies that an MBL-mediated event might be involved in the pathogenesis of these disorders.


Comprehensive Characterization of Tumor Purity and Its Clinical Implications in Gastric Cancer.
Solid tumour tissues are composed of tumour and non-tumour cells, such as stromal cells and immune cells. These non-tumour cells constitute an essential part of the tumour microenvironment (TME), which decrease the tumour purity and play an important role in carcinogenesis, malignancy progression, treatment resistance and prognostic assessment. However, the implications of various purity levels in gastric cancer (GC) remain largely unknown. In the present study, we used an in-silico approach to infer the tumour purity of 2,259 GC samples obtained from our hospital and 12 public datasets based on the transcriptomic data. We systematically evaluated the association of tumour purity with clinical outcomes, biological features, TME characteristics and treatment response in GC. We found that tumour purity might be a patient-specific intrinsic characteristic of GC. Low tumour purity was independently correlated with shorter survival time and faster recurrence and significantly associated with mesenchymal, invasive and metastatic phenotypes. Integrating GC purity into a clinical prognostic nomogram significantly improved predictive validity and reliability. In addition, low tumour purity was strongly associated with immune and stromal cell functions. Fibroblasts, endothelial cells and monocytes were markedly enriched in low-purity tumours, serving as robust indicators of a poor prognosis. Moreover, patients with low GC purity may not benefit more from adjuvant chemotherapy. Our findings highlight that tumour purity confers important clinical, biological, microenvironmental and treatment implications for patients with GC. Therefore, a comprehensive evaluation of tumour purity in individual tumours can provide more insights into the molecular mechanisms of GC, facilitate precise classification and clinical prediction and help to develop more effective individualised treatment strategies.


Intravesical nanocrystalline silver decreases experimental bladder inflammation.
Interstitial cystitis is a sterile bladder inflammatory disease characterized by pelvic pain, urinary urgency and frequency. Nanocrystalline silver has anti-inflammatory properties, prompting us to investigate its effect in experimental bladder inflammation. Nanocrystalline silver (0.01%, 0.05%, 0.1%, 0.5% or 1%) or phosphate buffered saline (Invitrogen) (0.5 ml) was introduced intravesically in Sprague-Dawley female rat (Charles River Laboratories, Wilmington, Massachusetts) bladders for 20 minutes, followed by vehicle or protamine sulfate (10 mg/ml for 30 minutes) and lipopolysaccharide (Sigma) (2 mg/ml for 45 minutes). Urine was collected throughout for histamine assay. The catheter was removed, the rat was returned to its cage and 4 hours later it was sacrificed. The bladder was harvested, minced and cultured overnight. The medium was collected for tumor necrosis factor-alpha assay. Mean +/- SD total urine histamine increased from 270 +/- 190 ng in 4 controls to 842 +/- 239 ng after protamine sulfate/lipopolysaccharide and it decreased to 505 +/- 187 ng in 6 animals after pretreatment with 1% nanocrystalline silver (p = 0.036). Tumor necrosis factor-alpha release in explant medium increased from 0.02 +/- 0.03 pg/mg in 6 controls to 0.28 +/- 0.15 pg/mg in 14 animals after treatment with protamine sulfate/lipopolysaccharide and it decreased to 0.12 +/- 0.11 pg/mg in 10 animals pretreated with nanocrystalline silver (p = 0.009). Nanocrystalline silver was not effective at less than 1% and at 1% alone it released 0.05 +/- 0.07 pg/mg tumor necrosis factor-alpha in 7 rats (vs phosphate buffered saline in 6, p = 0.387). Nanocrystalline silver (1%) significantly decreased bladder inflammation and mast cell activation. These effects were apparent even 4 days later. Intravesical administration of nanocrystalline silver (1%) decreased urine histamine, bladder tumor necrosis factor-alpha and mast cell activation without any toxic effect. This action may be useful for interstitial cystitis.


Attraction Versus Action in Pedophilic Desire: The Role of Personality Traits and Childhood Experience.
Comparison of pedophilic individuals who do and do not refrain from sexually engaging with children may offer critically important information regarding the differential contributors to pedophilic attraction versus behavior. This study compared 5 traits that are potentially contributory to pedophilic attraction or behavior in both minor-attracted persons (MAPs) who refrain from sexually engaging with minors (nonacting MAPs) and those who have acted on pedophilic attractions and subsequently entered the criminal justice system (forensic MAPs). Subjects included 195 nonacting MAPs, 50 forensic MAPs, and 60 healthy controls. Data on nonacting MAPs were drawn from an online survey, and data on the other 2 groups were based on prior in-person evaluations. Measures included the Millon Clinical Multiaxial Inventory-II (MCMI-II), Barratt Impulsiveness Scale (BIS-11), the MAP Questionnaire, and the Sexual History Questionnaire (SHQ). Both MAP groups scored higher than healthy controls on the domains of socially inhibited personality traits, propensity toward cognitive distortions, and subjects' own childhood sexual abuse (CSA). Forensic MAPs scored higher than nonacting MAPs on the CSA domain, but the 2 MAP groups differed little on the other 2 domains. Forensic MAPs also scored higher than the other 2 groups on the antisocial domain, whereas nonacting MAPs did not differ from controls on this measure. Nonacting MAPs scored higher than controls on impulsivity. Antisocial personality traits may be a primary driver of pedophilic behavior that is unrelated to pedophilic attraction. Socially inhibited personality traits and propensity toward cognitive distortions are associated with pedophilic attraction, although the direction of causation is not clear. CSA seems to increase the risk of both attraction and behavior.


Perspective: Evolution and detection of genetic robustness.
Robustness is the invariance of phenotypes in the face of perturbation. The robustness of phenotypes appears at various levels of biological organization, including gene expression, protein folding, metabolic flux, physiological homeostasis, development, and even organismal fitness. The mechanisms underlying robustness are diverse, ranging from thermodynamic stability at the RNA and protein level to behavior at the organismal level. Phenotypes can be robust either against heritable perturbations (e.g., mutations) or nonheritable perturbations (e.g., the weather). Here we primarily focus on the first kind of robustness--genetic robustness--and survey three growing avenues of research: (1) measuring genetic robustness in nature and in the laboratory; (2) understanding the evolution of genetic robustness: and (3) exploring the implications of genetic robustness for future evolution.


[Individual choice of ribonuclease and fluorofur doses in the treatment of patients with acute pancreatitis].
A method is suggested for individual calculation of optimal doses of ribonuclease and fluorofur on the basis of a standardized index--the degree of severity. A CM 1404 computer was used in solving the problem. From analysis of 500 case records by means of programs of discriminant and multidimensional linear regressive analysis a mathematical dependence was found between some parameters indirectly reflecting the severity of the patient's condition, the ribonuclease dose, and the efficacy of the treatment. A similar dependence for fluorofur was also studied. The discovered statistical regularity was realized as a nomogram for calculating the degree of severity and individual optimal doses of ribonuclease and fluorofur. The method was used in 114 patients. All the compared indices were found to be better than those in the group of patients for whom the dose of the agents (ribonuclease) was calculated on the basis of a constant dose per kg weight.


Imaging epidermal growth factor receptor expression in vivo: pharmacokinetic and biodistribution characterization of a bioconjugated quantum dot nanoprobe.
To develop and validate an optical imaging nanoprobe for the discrimination of epidermal growth factor (EGF) receptor (EGFR)-overexpressing tumors from surrounding normal tissues that also expresses EGFR. Near-infrared (NIR) quantum dots (QD) were coupled to EGF using thiol-maleimide conjugation to create EGF-QD nanoprobes. In vitro binding affinity of these nanoprobes and unconjugated QDs was evaluated in a panel of cell lines, with and without anti-EGFR antibody pretreatment. Serial optical imaging of HCT116 xenograft tumors was done after systemic injection of QD and EGF-QD. EGF-QD showed EGFR-specific binding in vitro. In vivo imaging showed three distinct phases, tumor influx ( approximately 3 min), clearance ( approximately 60 min), and accumulation (1-6 h), of EGF-QD nanoprobes. Both QD and EGF-QD showed comparable nonspecific rapid tumor influx and clearance followed by attainment of an apparent dynamic equilibrium at approximately 60 min. Subsequently (1-6 h), whereas QD concentration gradually decreased in tumors, EGF-QDs progressively accumulated in tumors. On delayed imaging at 24 h, tumor fluorescence decreased to near-baseline levels for both QD and EGF-QD. Ex vivo whole-organ fluorescence, tissue homogenate fluorescence, and confocal microscopic analyses confirmed tumor-specific accumulation of EGF-QD at 4 h. Immunofluorescence images showed diffuse colocalization of EGF-QD fluorescence within EGFR-expressing tumor parenchyma compared with patchy perivascular sequestration of QD. These results represent the first pharmacokinetic characterization of a robust EGFR imaging nanoprobe. The measurable contrast enhancement of tumors 4 h after systemic administration of EGF-QD and its subsequent normalization at 24 h imply that this nanoprobe may permit quantifiable and repetitive imaging of EGFR expression.


Two mechanisms for optic flow and scale change processing of looming.
The detection of looming, the motion of objects in depth, underlies many behavioral tasks, including the perception of self-motion and time-to-collision. A number of studies have demonstrated that one of the most important cues for looming detection is optic flow, the pattern of motion across the retina. Schrater et al. have suggested that changes in spatial frequency over time, or scale changes, may also support looming detection in the absence of optic flow (P. R. Schrater, D. C. Knill, & E. P. Simoncelli, 2001). Here we used an adaptation paradigm to determine whether the perception of looming from optic flow and scale changes is mediated by single or separate mechanisms. We show first that when the adaptation and test stimuli were the same (both optic flow or both scale change), observer performance was significantly impaired compared to a dynamic (non-motion, non-scale change) null adaptation control. Second, we found no evidence of cross-cue adaptation, either from optic flow to scale change, or vice versa. Taken together, our data suggest that optic flow and scale changes are processed by separate mechanisms, providing multiple pathways for the detection of looming.


Molecular determinants of Listeria monocytogenes virulence.
Listeria monocytogenes is the etiological agent of listeriosis, a severe human foodborne infection characterized by gastroenteritis, meningitis, encephalitis, abortions, and perinatal infections. This gram-positive bacterium is a facultative intracellular pathogen that induces its own uptake into nonphagocytic cells and spreads from cell to cell using an actin-based motility process. This review covers both well-established and recent advances in the characterization of L. monocytogenes virulence determinants and their role in the pathophysiology of listeriosis.


Semiparametric Regression Analysis of Multiple Right- and Interval-Censored Events.
Health sciences research often involves both right- and interval-censored events because the occurrence of a symptomatic disease can only be observed up to the end of follow-up, while the occurrence of an asymptomatic disease can only be detected through periodic examinations. We formulate the effects of potentially time-dependent covariates on the joint distribution of multiple right- and interval-censored events through semiparametric proportional hazards models with random effects that capture the dependence both within and between the two types of events. We consider nonparametric maximum likelihood estimation and develop a simple and stable EM algorithm for computation. We show that the resulting estimators are consistent and the parametric components are asymptotically normal and efficient with a covariance matrix that can be consistently estimated by profile likelihood or nonparametric bootstrap. In addition, we leverage the joint modelling to provide dynamic prediction of disease incidence based on the evolving event history. Furthermore, we assess the performance of the proposed methods through extensive simulation studies. Finally, we provide an application to a major epidemiological cohort study. Supplementary materials for this article are available online.


Mechanical thrombectomy in acute stroke: prospective pilot trial of the solitaire FR device while under conscious sedation.
The best approach between general anesthesia and conscious sedation to perform mechanical thrombectomy remains unknown. The goal of our study was to evaluate the feasibility, safety, and efficacy of mechanical thrombectomy under conscious sedation in patients with acute ischemic stroke, using the Solitaire FR device, in a prospective, single-center, single-arm study. The study included consecutive patients with acute ischemic stroke due to a large artery occlusion within 6 hours of symptom onset for the anterior circulation, and within 24 hours for the posterior circulation. After intravenous thrombolysis (when no contraindications), thrombectomy was performed with the Solitaire device in patients under conscious sedation. Primary efficacy and safety end points were good functional outcome (mRS ≤2) at 3 months and mortality at 3 months. Secondary end points were recanalization (TICI ≥2) and failure rate. From May 2010 to July 2011, 36 patients were treated. Median baseline NIHSS score was 17.5. The occlusion site was MCA in 21 patients (58.4%), ICA-MCA tandem occlusion in 9 patients (25.0%), terminal ICA in 2 patients (5.5%), and basilar artery in 4 patients (11.1%). Twenty-three patients (63.9%) received intravenous thrombolysis. Superselective catheterization of the occluded vessel was not feasible in 5/36 cases (13.9%). Successful revascularization was achieved in 28/36 patients (77.8%). After 3 months, 22 patients (61.1%) showed good functional outcome (mRS ≤2) and the median NIHSS score was 8.5. Overall mortality rate at 3 months was 22.2% (8/36). In acute ischemic stroke, mechanical thrombectomy while under conscious sedation is feasible in a large percentage of cases (86.1%) and is associated with a short procedure delay and a high percentage of good functional outcomes at 3 months (61.1%).


Family-focused autism spectrum disorder research: a review of the utility of family systems approaches.
A family member with an autism spectrum disorder presents pervasive and bidirectional influences on the entire family system, suggesting a need for family-focused autism spectrum disorder research. While there has been increasing interest in this research area, family-focused autism spectrum disorder research can still be considered relatively recent, and there are limitations to the existing literature. The purpose of this article is to provide theoretical and methodological directions for future family-focused autism spectrum disorder research. In particular, this article proposes Family Systems approaches as a common theoretical framework for future family-focused autism spectrum disorder research by considering theoretical concepts such as Boundaries, Ambiguous Loss, Resilience and Traumatic Growth. We discuss reasons why these concepts are important to researching families living with autism spectrum disorder and provide recommendations for future research. The potential for research grounded in Family Systems approaches to influence clinical support services is also discussed.