Endobronchial ultrasound to assess airway wall thickening: validation in vitro and in vivo.
Endobronchial ultrasound (EBUS) allows identification of airway wall structures and could potentially be utilised for in vivo studies of airway thickening in asthma. The present study investigated whether inflation of the fluid-filled balloon sheath over the transducer (necessary to provide sonic coupling with the airway wall) influenced in vitro measurements. In vivo comparability of EBUS with high resolution computed tomography scanning (HRCT), an established method for measuring wall thickness, was determined in control subjects. The airway diameter and wall thickness were studied using EBUS in 24 cartilaginous airways obtained from four sheep, before and after balloon sheath inflation during immersion in saline. To assess EBUS versus HRCT comparability of airway measures in vivo, 12 control subjects underwent imaging of the posterior basal bronchus of the right lower lobe by both techniques. Intra- and interobserver agreement were also assessed. Results with and without the balloon sheath gave comparable measures of airway internal diameter and wall thickness in vitro. Statistical analysis showed agreement between EBUS and HRCT, and intra- and interobserver variability in vivo. The current study concludes that endobronchial ultrasound, which does not present a radiation risk, could be utilised in the in vivo study of cartilaginous airway wall remodelling in respiratory diseases, such as asthma.


[Suitability of SSCP-PCR analysis for molecular detection of quinolone resistance in Campylobacter jejuni].
Foodborne infections with Campylobacter spp. are increasing, especially antibiotic resistant strains are emerging. Quinolone resistant isolates can cause failure of therapy in severe clinical infections. Molecular characterisation is needed for the detection of resistant variants of C. jejuni. Therefore 23 isolates from poultry and human medicine as well as three control strains were tested for their minimal inhibitory concentration, their Single-Strand-Conformation-Polymorphism (SSCP)-PCR pattern (a method for the detection of resistance determining point mutations), and their sequence of the quinolone resistance determining region (QRDR). Six different SSCP types could be identified: two types for quinolone resistant isolates and other types containing so called silent mutations without influence on the resistance. A genotypic monitoring of the quinolone resistance in C. jejuni can be useful for the early detection of new resistance variants. As a screening method for detection of point mutations in the QRDR the SSCP-PCR can be applied. Compared to other genotypic methods the SSCP-PCR is less time and cost consuming and needs only standard technical equipment.


Lambda-Carrageenan Enhances the Effects of Radiation Therapy in Cancer Treatment by Suppressing Cancer Cell Invasion and Metastasis through Racgap1 Inhibition.
Radiotherapy is used extensively in cancer treatment, but radioresistance and the metastatic potential of cancer cells that survive radiation remain critical issues. There is a need for novel treatments to improve radiotherapy. Here, we evaluated the therapeutic benefit of λ-carrageenan (CGN) to enhance the efficacy of radiation treatment and investigated the underlying molecular mechanism. CGN treatment decreased viability in irradiated cancer cells and enhanced reactive oxygen species accumulation, apoptosis, and polyploid formation. Additionally, CGN suppressed radiation-induced chemoinvasion and invasive growth in 3D lrECM culture. We also screened target molecules using a gene expression microarray analysis and focused on Rac GTPase-activating protein 1 (RacGAP1). Protein expression of RacGAP1 was upregulated in several cancer cell lines after radiation, which was significantly suppressed by CGN treatment. Knockdown of RacGAP1 decreased cell viability and invasiveness after radiation. Overexpression of RacGAP1 partially rescued CGN cytotoxicity. In a mouse xenograft model, local irradiation followed by CGN treatment significantly decreased tumor growth and lung metastasis compared to either treatment alone. Taken together, these results suggest that CGN may enhance the effectiveness of radiation in cancer therapy by decreasing cancer cell viability and suppressing both radiation-induced invasive activity and distal metastasis through downregulating RacGAP1 expression.


An alternative reference space for H&E color normalization.
Digital imaging of H&E stained slides has enabled the application of image processing to support pathology workflows. Potential applications include computer-aided diagnostics, advanced quantification tools, and innovative visualization platforms. However, the intrinsic variability of biological tissue and the vast differences in tissue preparation protocols often lead to significant image variability that can hamper the effectiveness of these computational tools. We developed an alternative representation for H&E images that operates within a space that is more amenable to many of these image processing tools. The algorithm to derive this representation operates by exploiting the correlation between color and the spatial properties of the biological structures present in most H&E images. In this way, images are transformed into a structure-centric space in which images are segregated into tissue structure channels. We demonstrate that this framework can be extended to achieve color normalization, effectively reducing inter-slide variability.


Before-School Running/Walking Club and Student Physical Activity Levels: An Efficacy Study.
Before-school programs, one of the least studied student-related comprehensive school physical activity program (CSPAP) components, may be a promising strategy to help youth meet the physical activity (PA) guidelines. This study's purpose was to examine: (a) how much PA children accrued during a before-school running/walking club and during the school day, (b) whether children compensated for the PA accumulated in the before-school program by decreasing their school-day PA, and (c) potential sex and body mass index (BMI) differences. An alternating treatments design with a baseline phase was first conducted at a private school (School A) and was subsequently replicated at a public school (School B). Participants (N = 88) were 3rd- and 4th-grade children. The before-school program involved a running/walking club that met twice per week (School A: 20 min; School B: 15 min). PA was measured using the NL-1000 pedometer. Data analysis included multilevel modeling and visual analysis. Children accumulated substantial amounts of PA in the before-school programs (School A: 1,731 steps, 10:02 moderate-to-vigorous PA minutes or 50% of program duration; School B: 1,502 steps, 8:30 moderate-to-vigorous PA minutes or 57% of program duration). Additionally, children did not compensate by decreasing their school-day PA on days they attended the before-school program. Sex differences were found in before-school program PA only for School B and in school-day PA for both schools. No BMI differences were found. Before-school programs, as part of CSPAPs, can help children increase their PA without resulting in decreased school-day PA and without taking time away from academics.


Correlation of parasites with growth of yellow perch.
The possible influence of parasites on the short-term and long-term growth and condition of yellow perch Perca flavescens was examined by investigating correlations between parasite abundance and specific growth variables. The following parasites were enumerated in age-1 yellow perch collected from Lake St. Pierre in June 2008: Apophallus brevis, Diplostomum spp., Ichthyocotylurus spp., Tylodelphys scheuringi, Phyllodistomum superbum, and Raphidascaris acus. Short-term growth was estimated using RNA/DNA ratios and long-term growth via the total length and condition as measured by the Fulton index. No correlation was found between parasite abundance and short-term growth, but a negative influence of combined infections of T. scheuringi and P. superbum on long-term growth was detected. In addition, the abundance of Ichthyocotylurus spp. was positively correlated with the condition of the yellow perch. Together these results suggest that limited or subtle pathogenic effects in juvenile fish are not discernable in recent growth but only in long-term growth indices. Furthermore, in future studies examination of parasite effects on fish growth should account for multiple infections.


Hepatic manifestation is associated with ALK1 in hereditary hemorrhagic telangiectasia: identification of five novel ALK1 and one novel ENG mutations.
Hereditary hemorrhagic telangiectasia (HHT), or Osler-Rendu-Weber syndrome, is a heterogeneous inherited disorder characterized by multi-systemic vascular dysplasia and wide variation in its phenotypic expression. Hepatic manifestation is seen in about 8 to 30 % of the patients. The molecular basis for liver involvement is unknown. We screened the two known HHT disease loci, the ALK1 (ACVRL1) and ENG genes, for mutations in a clinically well-characterized group of HHT patients with or without liver involvement. Mutations in the ALK1 gene were detected in eight out of 10 HHT patients with hepatic manifestation. Among nine HHT patients without liver involvement, four had mutations in the ALK1, and three in the ENG genes, respectively. In one patient with hepatic manifestation a mutation was detected in both the ALK1 and ENG genes. No mutation could be detected in two patients with liver involvement and, likewise, in two patients without hepatic manifestation. In this study, we have identified five novel ALK1 and one ENG disease-causing mutations. We conclude that hepatic manifestation in HHT patients is associated with mutations in the ALK1 gene, but rarely with ENG mutations.


[Immunohistological study of the normal human gastric mucosa and that of chronic gastritis].
Normal gastric mucosa and that in atrophic gastritis was studied by indirect immunoperoxidase method. Intestinal antigens CEA and beta 1MA were found in the foetal stomach and in the foci of intestinal metaplasia with and without dysplastic epithelial changes. Gastric antigens, pepsinogens of the foetal and 2-nd type, were found in foetal and adult stomach, as well as in the foci of intestinal metaplasia with dysplastic changes. The discovery of concomitant presence of gastric and colonic antigens in the dysplastic epithelium may indicate the existence of pluripotent stem cells capable of differentiation in the direction of gastric glandular epithelium, and in the direction of enterocytes. The possibility is suggested of origination of gastric carcinoma of different histologic structure from intestinal metaplasia with dysplastic changes.


Computer-assisted fluoroscopic navigation of pedicle screw insertion: an in vivo feasibility study.
Accurate placement of pedicle screws is difficult. We evaluated the feasibility and accuracy of pedicle screw insertion assisted by a real-time, 2-dimensional (2D) image-guided navigation system in 12 patients who underwent thoraco-lumbar and/or lumbar stabilization. 66 pedicle screws were inserted either by senior spine surgeons or residents. The accuracy of positioning of the screws was evaluated using postoperative plain radiographs and thin-cut CT. 61 of the 66 screws were inserted successfully. 5 screw insertions showed structural violations: 4 on the medial and 1 on the lateral pedicle wall. The accuracy was higher in the sagittal plane than in the axial plain. There was no difference between the surgical error rates caused by the senior surgeons and the residents. Using computer-assisted 2D fluoroscopic image navigation, it is possible to achieve reliable and accurate pedicle screw insertion during low thoracic and lumbar spinal surgery.


Immune defense and host life history.
Recent interest has focused on immune response in an evolutionary context, with particular attention to disease resistance as a life-history trait, subject to trade-offs against other traits such as reproductive effort. Immune defense has several characteristics that complicate this approach, however; for example, because of the risk of autoimmunity, optimal immune defense is not necessarily maximum immune defense. Two important types of cost associated with immunity in the context of life history are resource costs, those related to the allocation of essential but limited resources, such as energy or nutrients, and option costs, those paid not in the currency of resources but in functional or structural components of the organism. Resource and option costs are likely to apply to different aspects of resistance. Recent investigations into possible trade-offs between reproductive effort, particularly sexual displays, and immunity have suggested interesting functional links between the two. Although all organisms balance the costs of immune defense against the requirements of reproduction, this balance works out differently for males than it does for females, creating sex differences in immune response that in turn are related to ecological factors such as the mating system. We conclude that immune response is indeed costly and that future work would do well to include invertebrates, which have sometimes been neglected in studies of the ecology of immune defense.


Contraceptive Provision to Women With Intellectual and Developmental Disabilities Enrolled in Medicaid.
To compare contraceptive provision to women with and without intellectual and developmental disabilities enrolled in North Carolina Medicaid. Our retrospective cohort study used 2019 North Carolina Medicaid claims to identify women aged 15-44 years with and without intellectual and developmental disabilities at risk for pregnancy who were continuously enrolled during 2019 or had Family Planning Medicaid with at least one claim. We calculated the proportion in each cohort who received 1) most or moderately effective contraception, 2) long-acting reversible contraception, 3) short-acting contraception, and 4) individual methods. We classified contraceptive receipt by procedure type and disaggregated across sociodemographic characteristics. Adjusting for age, race, ethnicity, and urban or rural setting, we constructed logistic regression models to estimate most or moderately effective contraceptive provision odds by intellectual and developmental disability status and by level or type of intellectual and developmental disability. We performed subanalyses to estimate co-occurrence of provision and menstrual disorders. Among 9,508 women with intellectual and developmental disabilities and 299,978 without, a significantly smaller proportion with intellectual and developmental disabilities received most or moderately effective contraception (30.1% vs 36.3%, P <.001). With the exception of injectable contraception, this trend was consistent across all measures and remained statistically significant after controlling for race, ethnicity, age, and urban or rural status (adjusted odds ratio 0.75, 95% CI 0.72-0.79; P <.001). Among those who received most or moderately effective contraception, a significantly greater proportion of women with intellectual and developmental disabilities had co-occurring menstrual disorders (31.3% vs 24.3%, P <.001). These findings suggest disparities in contraceptive provision and potential differences in clinical indication by intellectual and developmental disability status. Future studies should investigate reasons for and barriers to contraceptive use among women with intellectual and developmental disabilities.


Safety of anti-tumor necrosis factor therapy during pregnancy in patients with inflammatory bowel disease.
Treatment of inflammatory bowel disease has significantly improved since the introduction of biological agents, such as infliximab, adalimumab, certolizumab pegol, and golimumab. The Food and Drug Administration has classified these factors in category B, which means that they do not demonstrate a fetal risk. However, during pregnancy fetuses are exposed to high anti-tumor necrosis factor (TNF) levels that are measurable in their plasma after birth. Since antibodies can transfer through the placenta at the end of the second and during the third trimesters, it is important to know the safety profile of these drugs, particularly for the fetus, and whether maintaining relapse of the disease compensates for the potential risks of fetal exposure. The limited data available for the anti-TNF drugs to date have not demonstrated any significant adverse outcomes in the pregnant women who continued their therapy from conception to the first trimester of gestation. However, data suggest that anti-TNFs should be discontinued during the third trimester, as they may affect the immunological system of the newborn baby. Each decision should be individualized, based on the distinct characteristics of the patient and her disease. Considering all the above, there is a need for more clinical studies regarding the effect of anti-TNF therapeutic agents on pregnancy outcomes.


The role of 18F-FDG PET/CT in the detection of osteosarcoma recurrence.
The aim of this study was to investigate the diagnostic accuracy of 18F-FDG-PET/CT in osteosarcoma patients suspicious for disease recurrence after adequate surgical therapy. Inclusion criteria were: a) adequate surgical treatment for proven osteosarcoma and documented complete remission after therapy; b) 18F-FDG-PET/CT performed during follow-up for clinical/diagnostic suspicion of relapse; c) new surgical treatment with excision of the suspected lesions; d) histological validation of 18F-FDG-PET/CT findings. Thirty-seven patients matching all inclusion criteria were retrospectively enrolled (20 men and 17 female). Primary surgical treatment consists of resection (31 cases) or amputation (six cases). 18F-FDG-PET/CT performance was assessed with a per-patient and per-site evaluation of sensitivity, specificity, accuracy, positive predicting value (PPV), and negative predicting value (NPV). The sites of relapse were classified as local, lung, lymphnodes (LNs), and distant (other skeletal segments and/or distant soft tissue). The disease-free survival (DFS) and the overall survival (OS) after 18F-FDG PET/CT were evaluated. 18F-FDG-PET/CT was positive in 89.2% (33/37) of patients. Local uptake only was observed in 35.1% patients (13/37); lung uptake only in 18.9% (7/37); distant uptake only in 2.7% (1/37) case; multiple sites of uptake in 32.4% (12/37). Histology resulted positive in 92% (34/37) of patients. A total of 51 pathologic lesions were evaluated (22 local relapse, 11 lung metastasis, 10 metastatic LNs, eight distant metastatic lesions). On a per-patient analysis 18F-FDG-PET/CT showed a sensitivity, specificity, accuracy, PPV, and NPV of 91%, 75%, 89%, 97%, 50%. On a per-site analysis the performance for local relapse was 96%, 100%, 97%, 100%, 93%, while for lung relapse detection was 80%, 100%, 92%, 100%, 88%. The mean follow-up after 18F-FDG-PET/CT was 21.5 months. At the last follow-up, 19% (7/37) of patients were death with disease, 38% (14/37) were alive with disease, and 43% (16/37) had no evidence of disease. Overall survival was 90% and 75% at 24 and 60 months, respectively. 18F-FDG-PET/CT showed valuable results for detecting recurrence(s) in osteosarcoma patients with suspicious of relapse after treatment, particularly in the detection of local relapse and lung metastasis.


Differential up-regulation of MAP kinase phosphatases MKP3/DUSP6 and DUSP5 by Ets2 and c-Jun converge in the control of the growth arrest versus proliferation response of MCF-7 breast cancer cells to phorbol ester.
Different levels of regulation account for the inactivation of MAP kinases by MAPK phosphatases (MKPs), in a cell type- and stimuli-dependent manner. MCF-7 human breast carcinoma cells treated with the phorbol 12-myristate 13-acetate (PMA) suffer growth arrest and show morphological alterations, which depend on the activation of the ERK1/2 MAP kinases. MKP3/DUSP6 and DUSP5 MAP kinase phosphatases, two negative regulators of ERK1/2, were specifically up-regulated in MCF-7 and SKBR3 cells in response to PMA. MKP3 and DUSP5 up-regulation required the prolonged activation of the ERK1/2 pathway, and correlated with the shutdown of this route. MKP3 induction relied on the activation of the Ets2 transcription factor, whereas DUSP5 induction depended on the activation of c-Jun. Diminishing the expression of MKP3 and DUSP5 raised the activation of ERK1/2, and accelerated growth arrest of PMA-treated MCF-7 cells. Conversely, MCF-7 cell lines expressing high levels of MKP3 or DUSP5 did not undergo PMA-triggered growth arrest, displayed a migratory phenotype, and formed colonies in soft agar. We propose that the differential up-regulation of MKP3 by Ets2 and of DUSP5 by c-Jun may converge in similar functional roles for these MAP kinase phosphatases in the growth arrest versus proliferation decisions of breast cancer cells.


Does phenylethylamine act as an endogenous amphetamine in some patients?
In brain capillary endothelium and catecholaminergic terminals a single decarboxylation step effected by aromatic amino-acid decarboxylase converts phenylalanine to phenylethylamine, at a rate comparable to that of the central synthesis of dopamine. Phenylethylamine, however, is not stored in intra-neuronal vesicles and is rapidly degraded by monoamine oxidase-B. Despite its short half-life, phenylethylamine attracts attention as an endogenous amphetamine since it can potentiate catecholaminergic neurotransmission and induce striatal hyperreactivity. Subnormal phenylethylamine levels have been linked to disorders such as attention deficit and depression; the use of selegiline (Deprenyl) in Parkinson's disease may conceivably favour recovery from deficient dopaminergic neurotransmission by a monoamine oxidase-B inhibitory action that increases central phenylethylamine. Excess phenylethylamine has been invoked particularly in paranoid schizophrenia, in which it is thought to act as an endogenous amphetamine and, therefore, would be antagonized by neuroleptics. The importance of phenylethylamine in mental disorders is far from fully elucidated but the evolution of phenylethylamine concentrations in relation to symptoms remains a worthwhile investigation for individual psychotic patients.


A novel Huntington's disease mouse model to assess the role of neuroinflammation on disease progression and to develop human cell therapies.
Huntington's disease (HD) is a fatal autosomal-dominant neurodegenerative disease caused by a trinucleotide CAG repeat expansion of the huntingtin gene (HTT) that affects 1 in every 10 000 individuals in the United States. Our lab developed a novel immune deficient HD mouse strain, the YACNSG, from a commonly used line, the YAC128 mouse, to enable transplantation studies using engineered human cells in addition to studying the impact of the immune system on disease progression. The primary goal of this project was to characterize this novel immune deQficient HD mouse model, using behavioral assays and histology to compare this new model to the immune competent YAC128 and immune deficient mice that had engraftment of a human immune system. Flow cytometry was used to confirm that the YACNSG strain lacked immune cells, and in vivo imaging was used to assess human mesenchymal stem/stromal cell (MSC) retention compared with a commonly used immune deficient line, the NSG mouse. We found that YACNSG were able to retain human MSCs longer than the immune competent YAC128 mice. We performed behavioral assessments starting at 4 months of age and continued testing monthly until 12 months on the accelerod and in the open field. At 12 months, brains were isolated and evaluated using immunohistochemistry for striatal volume. Results from these studies suggest that the novel immune deficient YACNSG strain of mice could provide a good model for human stem-cell based therapies and that the immune system appears to play an important role in the pathology of HD.


Separation of bile acid isomer plays a pivotal role in bioequivalence evaluation of ursodeoxycholic acid.
Based on our experiences in bile acid profiling, this work developed and validated a liquid chromatography electrospray ionization tandem mass spectrometry method to separate endogenous bile acid isomers and quantitatively determine ursodeoxycholic acid (UDCA), glycoursodeoxycholic acid (GUDCA) and tauroursodeoxycholic acid (TUDCA) in human plasma. The separation was performed on a CORTECS C18 column with the mobile phase consisting of 1.0 mM ammonium acetate and acetonitrile-methanol (80:20, v/v). UDCA, GUDCA and TUDCA were detected in the negative mode on a triple-quadrupole mass spectrometer at the ion transitions of m/z 391 > 391, m/z 448 > 74, m/z 498 > 80, respectively. Phosphate buffer was employed as the surrogate matrix to establish the isotope internal standard corrected calibration curves of analytes. The background-method with a linearity range of 10-200 ng/mL was partially validated to determine the endogenous levels of analytes in blank human plasma, which was incorporated into the validation of bioequivalence-method with a linearity range of 50-10000 ng/mL. The bioequivalence (BE)-method was fully validated with special focus on matrix effects, which have been critically evaluated using the precision and accuracy of quality control samples prepared from the blank human plasma of 12 individuals. It is disclosed for the first time that the BE results of UDCA formulation may yield false results when the method is insufficient to separate UDCA from isoursodeoxycholic acid, a microbial metabolite of both endogenous and exogenous UDCA. The present method has established a milestone for the evaluation of UDCA formulations and is expected to provide a valuable reference for the bioanalytical development of endogenous medicinal products.


Pregnancy outcome of Mexican-American women: the effect of generational residence in the United States.
To determine whether duration of generational residence in the United States is associated with the pregnancy outcome of Mexican Americans. This is a population-based study. Stratified analyses were performed on a data set of 1989-1991 Illinois computerized vital records of Mexican-American infants. First generation (N=2,203) and second or higher (N=4,192) US-born Mexican-American women had infant low birth-weight rates of 7.5% and 6.1%, respectively, compared to 5.1% for Mexican-born women (N=39,050); relative risk=1.4 (1.2-1.7) and 1.2 (1.1-1.4), respectively. Among women with one or more high-risk sociodemographic characteristics (age less than 20 years, educational attainment less than 12 years, unmarried, high parity, or inadequate prenatal care), first generation (N=1,624) and second or higher generation (N=2,874) US-born Mexican-American women had infant low birth-weight rates of 8.3% and 6.5%, respectively, vs 5.2% for Mexican-born women (N=33,625); relative risk = 1.6 (95% confidence interval [CI], 1.3-1.9) and 1.2 (95% CI, 1.0-1.4), respectively. Among women with the lowest sociodemographic risk profile, infant low birthweight rates did not vary between the subgroups. For second or higher generation US-born Mexican-American women, the rate of infant low birth weight does not exceed that of first generation US-born women; it actually approximates that of Mexican-born women across a broad range of sociodemographic characteristics.


Inducible nitric oxide synthase inhibits oxygen consumption in collateral-dependent myocardium.
Following coronary artery occlusion growth of collateral vessels can provide an effective blood supply to the dependent myocardium. The ischemia, which results in growth of collateral vessels, recruits an inflammatory response with expression of cytokines and growth factors, upregulation of endothelial nitric oxide (NO) synthase (eNOS) in vascular endothelial cells, and expression of inducible nitric oxide synthase (iNOS) in both vessels and cardiac myocytes. Because NO is a potent collateral vessel dilator, this study examined whether NO derived from iNOS or constitutive NOS regulates myocardial blood flow (MBF) in the collateral region. Nonselective NOS inhibition with N(G)-nitro-l-arginine (LNA) caused vasoconstriction with a significant decrease in MBF to the collateral region during exercise. In contrast, the highly selective iNOS inhibitor 1400W caused a 21 ± 5% increase of MBF in the collateral region. This increase in MBF following selective iNOS blockade was proportionate to an increase in myocardial O2 consumption (MVo2). The results suggest that NO produced by iNOS inhibits MVo2 in the collateralized region, so that the increase in MBF following iNOS blockade was the result of metabolic vasodilation secondary to an increase in MVo2. Thus the coordinated expression of iNOS to restrain MVo2 and eNOS to maintain collateral vasodilation act to optimize the O2 supply-demand relationship and protect the collateralized myocardium from ischemia.


Concentration-dependent alterations in the human plasma proteome following controlled exposure to diesel exhaust.
Traffic-related air pollution (TRAP) exposure is associated with systemic health effects, which can be studied using blood-based markers. Although we have previously shown that high TRAP concentrations alter the plasma proteome, the concentration-response relationship between blood proteins and TRAP is unexplored in controlled human exposure studies. We aimed to identify concentration-dependent plasma markers of diesel exhaust (DE), a model of TRAP. Fifteen healthy non-smokers were enrolled into a double-blinded, crossover study where they were exposed to filtered air (FA) and DE at 20, 50 and 150 μg/m3 PM2.5 for 4h, separated by ≥ 4-week washouts. We collected blood at 24h post-exposure and used label-free mass spectrometry to quantify proteins in plasma. Proteins exhibiting a concentration-response, as determined by linear mixed effects models (LMEMs), were assessed for pathway enrichment using WebGestalt. Top candidates, identified by sparse partial least squares discriminant analysis and LMEMs, were confirmed using enzyme-linked immunoassays. Thereafter, we assessed correlations between proteins that showed a DE concentration-response and acute inflammatory endpoints, forced expiratory volume in 1 s (FEV1) and methacholine provocation concentration causing a 20% drop in FEV1 (PC20). DE exposure was associated with concentration-dependent alterations in 45 proteins, which were enriched in complement pathways. Of the 9 proteins selected for confirmatory immunoassays, based on complementary bioinformatic approaches to narrow targets and availability of high-quality assays, complement factor I (CFI) exhibited a significant concentration-dependent decrease (-0.02 μg/mL per μg/m3 of PM2.5, p = 0.04). Comparing to FA at discrete concentrations, CFI trended downward at 50 (-2.14 ± 1.18, p = 0.08) and significantly decreased at 150 μg/m3 PM2.5 (-2.93 ± 1.18, p = 0.02). CFI levels were correlated with FEV1, PC20 and nasal interleukin (IL)-6 and IL-1β. This study details concentration-dependent alterations in the plasma proteome following DE exposure at concentrations relevant to occupational and community settings. CFI shows a robust concentration-response and association with established measures of airway function and inflammation.


Characteristics and Management of Facial Nerve Schwannomas and Hemangiomas.
To characterize facial nerve (FN) schwannomas (FNSs) and FN hemangiomas (FNHs) and their clinical features and management strategies, and to describe the results of cable nerve grafting after FN sectioning during tumor removal. This retrospective study included 84 FNS cases and 42 FNH cases managed between July 1989 and July 2020 at a quaternary referral center for skull base pathology. Clinical details, locations, management, and results of cable nerve grafting at 1 year and during an average period of 3.12 years were evaluated. Sural nerve interpositioning was performed for patients who experienced FN paralysis for less than 1 year and underwent nerve sectioning during tumor removal. FNSs more often involved multiple segments compared with FNHs. The cerebellopontine angle and the mastoid segments were involved in 16 (19.1%) and 34 (40.5%) FNS cases, respectively; however, the cerebellopontine angle and the mastoid segments were involved in 0 and 7 (16.7%) FNH cases, respectively. Sectioned nerves of 99 patients (78.6%) were restored using interposition cable grafting. At the last follow-up evaluation, 56.3% of FNSs and 60.7% of FNHs attained House-Brackmann (HB) grade III. Lower preoperative HB grades were associated with poorer postoperative outcomes. For FNSs, the mean HB grades were 4.13 at 1 year postoperatively and 3.75 at the last follow-up evaluation ( p = 0.001); however, for FNHs, the mean HB grades were 4.04 postoperatively and 3.75 at the last follow-up evaluation. Therefore, extradural coaptation yielded better outcomes. FNSs can occur along any part of the FN along its course, and FNHs are concentrated around the area of geniculate ganglion. The results of cable inter positioning grafts are better in patients with preoperative FN-HB-III or less when compared with higher grades. The outcome of the interpositioning continues to improve even after 1 year in extradural coaptation.


The impact of early reflections on binaural cues.
Animals live in cluttered auditory environments, where sounds arrive at the two ears through several paths. Reflections make sound localization difficult, and it is thought that the auditory system deals with this issue by isolating the first wavefront and suppressing later signals. However, in many situations, reflections arrive too early to be suppressed, for example, reflections from the ground in small animals. This paper examines the implications of these early reflections on binaural cues to sound localization, using realistic models of reflecting surfaces and a spherical model of diffraction by the head. The fusion of direct and reflected signals at each ear results in interference patterns in binaural cues as a function of frequency. These cues are maximally modified at frequencies related to the delay between direct and reflected signals, and therefore to the spatial location of the sound source. Thus, natural binaural cues differ from anechoic cues. In particular, the range of interaural time differences is substantially larger than in anechoic environments. Reflections may potentially contribute binaural cues to distance and polar angle when the properties of the reflecting surface are known and stable, for example, for reflections on the ground.


Live cell imaging reveals continuous STAT6 nuclear trafficking.
The STAT6 transcription factor is essential for the development of protective immunity; however, the consequences of its activity can also contribute to the pathogenesis of autoimmune disease. Tyrosine phosphorylation is known to activate STAT6 in response to cytokine stimulation, but there is a gap in our understanding of the mechanisms by which it enters the nucleus. In this study, live cell imaging was used in conjunction with photobleaching techniques to demonstrate the continual nuclear import of STAT6, independent of tyrosine phosphorylation. The protein domain required for nuclear entry includes the coiled coil region of STAT6 and functions similarly before or after cytokine stimulation. The dynamic nuclear shuttling of STAT6 seems to be mediated by the classical importin-alpha-importin-beta1 system. Although STAT6 is imported to the nucleus continually, it accumulates in the nucleus following tyrosine phosphorylation as a result of its ability to bind DNA. These findings will impact diagnostic approaches and strategies to block the deleterious effects of STAT6 in autoimmunity.


Drugless nanoparticles tune-up an array of intertwined pathways contributing to immune checkpoint signaling and metabolic reprogramming in triple-negative breast cancer.
Metabolic reprogramming 'Warburg effect' and immune checkpoint signaling are immunosuppressive hallmarks of triple-negative breast cancer (TNBC) contributing to the limited clinical applicability of immunotherapy. Biomaterials arise as novel tools for immunomodulation of the tumor microenvironment that can be used alongside conventional immunotherapeutics. Chitosan and lecithin are examples of versatile biomaterials with interesting immunomodulatory properties. In this study, we aimed at investigation of the role of carefully designed hybrid nanoparticles (NPs) on common mediators of both programmed death ligand 1 (PD-L1) expression and glycolytic metabolism. Hybrid lecithin-chitosan NPs were prepared and characterized. Their intracellular concentration, localization and effect on the viability of MDA-MB-231 cells were assessed. Glycolytic metabolism was quantified by measuring glucose consumption, adenosine triphosphate (ATP) generation, lactate production and extracellular acidification. Nitric oxide production was quantified using Greiss reagent. Gene expression of inducible nitric oxide synthase (iNOS), phosphatidylinositol-3-kinase (PI3K), protein kinase B (PKB or Akt), mammalian target of rapamycin (mTOR), hypoxia-inducible factor 1α(HIF-1α) and PD-L1 was quantified by quantitative reverse transcription polymerase chain reaction (q-RT-PCR). Chitosan, lecithin and the NPs-formulated forms have been shown to influence the 'Warburg effect' and immune checkpoint signaling of TNBC cells differently. The composition of the hybrid systems dictated their subcellular localization and hence the positive or negative impact on the immunosuppressive characteristics of TNBC cells. Carefully engineered hybrid lecithin-chitosan NPs could convert the immune-suppressive microenvironment of TNBC to an immune-active microenvironment via reduction of PD-L1 expression and reversal of the Warburg effect.


Reconcilable differences: a cross-sectional study of the relationship between socioeconomic status and the magnitude of short-acting beta-agonist use in asthma.
To assess the association between socioeconomic status (SES) and short-acting (SA) beta-agonist use, controlling for asthma severity. Cross-sectional study. Vancouver, BC, Canada. Two hundred two asthmatics between 19 years and 50 years of age and residing in the greater Vancouver regional district. The quantity of SA beta-agonist used in the previous year was collected by self-report; pulmonary function and beta-receptor genotype were measured on each participant. SES was measured at both the individual and population levels. Five methods of adjustment for asthma severity were used, as follows: the Canadian Asthma Consensus Guidelines, three previously developed asthma-severity scores, and forward stepwise multiple regression modeling. Polychotomous logistic regression was used to assess all relationships. Independent of the method used to measure SES or adjust for asthma severity, lower SES was consistently and significantly associated with the use of greater amounts of SA beta-agonist. Adjusting for severity using the multivariate model explained the most variance of SA beta-agonist use (R(2) adjusted, 0.35 to 0.37). In this model, social assistance recipients were more likely to use greater amounts of SA beta-agonist (odds ratio [OR], 3.4; 95% confidence interval [CI], 1.7 to 6.5). An inverse relationship between SA beta-agonist use and both annual household income (> $50,000; OR, 0.28; 95% CI, 0.13 to 0.60; and $20,000 to $50,000; OR, 0.44; 95% CI, 0.21 to 0.96; relative to <$20,000) and education (completing a bachelor's degree vs no formal education; OR, 0.25; 95% CI, 0.14 to 0.71). Participants living in a neighborhood with higher median household income (OR, 0.91; 95% CI, 0.84 to 0.98 per $1,000 increase) or a higher prevalence of having attained a bachelor's degree (OR, 0.96; 95% CI, 0.84 to 0.98 per 1% increase) were also less likely use greater amounts of SA beta-agonist. Results were consistent for neighborhood unemployment rate. The social gradient in asthma-related outcomes may be at least partially attributable to poorer asthma control in lower-SES asthmatics.


The solution structure of oxidized rat microsomal cytochrome b5.
The solution structure of oxidized rat microsomal cytochrome b5 has been obtained from 1H NMR spectra measured at 800 MHz. The available assignment has been extended to 78% of the total protons and 95% of the residues. From 1372 meaningful NOEs, a family of 40 structures has been obtained through the program DYANA; 235 pseudocontact shifts have been then added as further constraints, obtaining an essentially similar family of structures. This latter family has been further refined through restrained energy minimization. The final RMSD values with respect to the average structure are 0.58 +/- 0.10 A and 1.05 +/- 0.11 A for backbone and heavy atoms, respectively. The high quality of the structure allows meaningful comparisons with the solution structure of the reduced protein, with the X-ray and solution structures of the oxidized bovine isoenzyme, and with the solution structure of the apoprotein. Upon loss of one electron, the heme plane undergoes a change in its orientation, possibly due to the change of the total charge. Propionate 7 appears to have a conformation which is dependent on the oxidation state of the iron. Helices alpha2 and alpha4 also experience changes in their average positions in the two oxidation states. Finally, the backbone NHs experience different exchange properties in the two oxidation states. While those present in the beta sheets forming the basis of the heme pocket are nonexchanging in both oxidation states, the NHs in the helices forming the heme-binding pocket are exchanging with the bulk solvent in the oxidized form, indicating larger local mobility in this state. This observation could suggest that, to optimize the electron transfer process, the local mobility should be properly tuned.


Pincushion point-spread function for computer-generated holography.
Point-spread functions (PSFs) are non-stationary signals whose spatial frequency increases with the radius. These signals are only meaningful over a small spatial region when being propagated over short distances and sampled with regular sampling pitch. Otherwise, aliasing at steep incidence angles leads to the computation of spurious frequencies. This is generally addressed by evaluating the PSF in a bounded disk-shaped region, which has the added benefit that it reduces the required number of coefficient updates. This significantly accelerates numerical diffraction calculations in, e.g., wavefront recording planes for high-resolution holograms. However, the use of a disk-shaped PSF is too conservative since it only utilizes about 78.5% of the total bandwidth of the hologram. We therefore derive a novel, to the best of our knowledge, optimally shaped PSF fully utilizing the bandwidth formed by two bounding hyperbola. A number of numerical experiments with the newly proposed pincushion PSF were performed, reporting over three-fold reductions of the signal error and significant improvements to the visual quality of computer-generated holograms at high viewing angles.


Etiology of hearing loss affects auditory skill development and vocabulary development in pediatric cochlear implantation cases.
Cochlear implantation (CI) is an effective treatment for severe-to-profound hearing loss patients and is currently used as the standard therapeutic option worldwide. However, the outcomes of CI vary among patients. This study aimed to clarify the clinical features for each etiological group as well as the effects of etiology on CI outcomes. We collected clinical information for 308 pediatric cochlear implant cases, including the etiology, hearing thresholds, age at CI, early auditory skill development, total development, monosyllable perception, speech intelligibility and vocabulary development in school age, and compared them for each etiology group. Among the 308 CI children registered for this survey, the most common etiology of hearing loss was genetic causes. The genetic etiology group showed the most favorable development after CI followed by the unknown etiology group, syndromic hearing loss group, congenital CMV infection group, inner ear malformation group, and cochlear nerve deficiency group. Our results clearly indicated that the etiology of HL affects not only early auditory skill development, but also vocabulary development in school age. The results of the present study will aid in more appropriate CI outcome assessment and in more appropriate intervention or habilitation programs.


A novel interaction of PAK4 with PPARγ to regulate Nox1 and radiation-induced epithelial-to-mesenchymal transition in glioma.
Tumor recurrence in glioblastoma (GBM) is, in part, attributed to increased epithelial-to-mesenchymal transition (EMT) and enhanced tumor cell dissemination in adjacent brain parenchyma after ionizing radiation (IR). EMT is associated with aggressive behavior, increased stem-like characteristics and treatment resistance in malignancies; however, the underlying signaling mechanisms that regulate EMT are poorly understood. We identified grade-dependent p21-activated kinases 4 (PAK4) upregulation in gliomas and further determined its role in mesenchymal transition and radioresistance. IR treatment significantly elevated expression and nuclear localization of PAK4 in correlation with induction of reactive oxygen species (ROS) and mesenchymal transition in GBM cells. Stable PAK4 overexpression promoted mesenchymal transition by elevating EMT marker expression in these cells. Of note, transcription factor-DNA-binding arrays and chromatin immunoprecipitation experiments identified the formation of a novel nuclear PAK4/PPARγ complex which was recruited to the promoter of Nox1, a peroxisome proliferator-activated receptor gamma (PPARγ) target gene. In addition, IR further elevated PAK4/PPARγ complex co-recruitment to Nox1 promoter, and increased Nox1 expression and ROS levels associated with mesenchymal transition in these cells. Conversely, specific PAK4 downregulation decreased PPARγ-mediated Nox1 expression and suppressed EMT in IR-treated cells. In vivo orthotopic tumor experiments showed inhibition of growth and suppression of IR-induced PPARγ and Nox1 expression by PAK4 downregulation in tumors. Our results provide the first evidence of a novel role for PAK4 in IR-induced EMT and suggest potential therapeutic efficacy of targeting PAK4 to overcome radioresistance in gliomas.


Understanding the Role of Alternatives in Data Analysis Practices.
Data workers are people who perform data analysis activities as a part of their daily work but do not formally identify as data scientists. They come from various domains and often need to explore diverse sets of hypotheses and theories, a variety of data sources, algorithms, methods, tools, and visual designs. Taken together, we call these alternatives. To better understand and characterize the role of alternatives in their analyses, we conducted semi-structured interviews with 12 data workers with different types of expertise. We conducted four types of analyses to understand 1) why data workers explore alternatives; 2) the different notions of alternatives and how they fit into the sensemaking process; 3) the high-level processes around alternatives; and 4) their strategies to generate, explore, and manage those alternatives. We find that participants' diverse levels of domain and computational expertise, experience with different tools, and collaboration within their broader context play an important role in how they explore these alternatives. These findings call out the need for more attention towards a deeper understanding of alternatives and the need for better tools to facilitate the exploration, interpretation, and management of alternatives. Drawing upon these analyses and findings, we present a framework based on participants' 1) degree of attention, 2) abstraction level, and 3) analytic processes. We show how this framework can help understand how data workers consider such alternatives in their analyses and how tool designers might create tools to better support them.


[Diagnostic value of determining spermidine in the urine of patients with melanoblastoma of the skin].
To estimate the diagnostic value of determination of one of polyamines (spermidine) in the urine the authors examined 58 patients with skin melanoblastomas of different localization and 10 healthy persons. It was found that in 16 of 25 patients having only primary tumor, in all 9 patients having primary tumor with metastases in regional lymph nodes, and also in 14 of 20 patients, who after previous therapy developed recurrence or metastases in regional lymph nodes, spermidine excretion exceeded its normal level. In three patients, subjected previously to radical treatment and considered as being clinically recovered, normal spermidine level was excreted. The data obtained enabled the authors to use this test as an adjuvant criterion in examination and treatment of such patients.


The copious capabilities of non-coding RNAs in cancer regulation, diagnosis and treatment.
Globally, cancer is one of the leading causes of mortality, accounting for 10 million deaths per year. Non-coding RNAs (ncRNAs) play integral and diverse roles in cancer, possessing the ability to both promote oncogenesis and impede tumor formation. This review discusses the various roles of microRNAs, transfer RNA-derived small RNAs, long non-coding RNAs and lncRNA-derived microproteins in cancer progression and prevention. We highlight the diagnostic and therapeutic potential of these ncRNAs, with a particular focus on detection in liquid biopsies and targeting of ncRNAs with small inhibitory molecules. Ultimately, the biological functions of cancer-associated ncRNAs, as well as the development of ncRNA-based technologies, are compelling areas for further research, holding the possibility of revolutionizing cancer treatment and diagnosis.


Changes in lipid pattern of HeLa cells exposed to immunoglobulin G and complement.
1. Immunoglobulin G was isolated from sera of non-immunized rabbits or rabbits immunized with whole HeLa cell homogenate. The anti-HeLa immunoglobulin G and its Fab fragment precipitated the particulate 400000g-min. fraction of HeLa cell homogenate. 2. Immunoglobulin G from immunized or non-immunized rabbits and fresh or inactivated complement were added to HeLa cell cultures. Changes in the cell count and cellular contents of DNA, RNA, protein, total and individual phospholipids, cholesterol (and esters) and ganglioside were followed. 3. Addition of immunoglobulin G from non-immunized rabbits and guinea-pig serum (complement) caused a transient increase in DNA followed by a permanent increase in RNA, protein, dry weight and number of cells per culture. 4. Addition of anti-HeLa immunoglobulin G and active complement caused an increase in the cellular content of cholesterol, total phospholipids, lysophosphatidylcholine and lysophosphatidylethanolamine greater than the increase of the controls and a decrease in the molar percentages of phosphatidylcholine and phosphatidylethanolamine as compared with the controls. 5. The cholesterol/phospholipid ratio remained constant. 6. The appearance of lysophosphoglycerides was transient, reaching a maximum 3hr. after addition of anti-HeLa immunoglobulin G. 7. The content of lysophosphoglycerides in HeLa cultures exposed to immunoglobulin G from non-immunized rabbits ranged from 50% to 30% of the values obtained from cultures exposed to the anti-HeLa immunoglobulin G and complement. 8. The changes in the lipid pattern of the HeLa cells were associated with the appearance of juxta-nuclear vacuoles in cells, but were apparently not specifically related to the presence of active complement.


In vitro proteolysis of nematode FMRFamide-like peptides (FLPs) by preparations from a free-living nematode (Panagrellus redivivus) and two plant-parasitic nematodes (Heterodera glycines and Meloidogyne incognita).
Proteolytic activities in extracts from three nematodes, the plant parasites Heterodera glycines and Meloidogyne incognita, and the free-living Panagrellus redivivus, were surveyed for substrate preferences using a battery of seven FRET-modified peptide substrates, all derived from members of the large FMRF-amide like peptide (FLP) family in nematodes. Overall protease activity in P. redivivus was four- to fivefold greater than in either of the parasites, a result that might reflect developmental differences. Digestion of the M. incognita FLP KHEFVRFa (substrate Abz-KHEFVRF-Y(3-NO2)a) by M. incognita extract was sevenfold greater than with H. glycines extract and twofold greater than P. redivivus, suggesting species-specific preferences. Additional species differences were revealed upon screening 12 different protease inhibitors. Two substrates were used in the screen, Abz-KHEFVRF-Y(3-NO2)a and Abz-KPSFVRF-Y(3-NO2)a), which was digested equally by all three species. The effects of various inhibitor, substrate and extract source combinations on substrate digestion suggest that M. incognita differs significantly from P. redivivus and H. glycines in its complement of cysteine proteases, particularly cathepsin L-type protease.


Innervation of root dentine in human premolars.
Based on autoradiographic studies it is generally held that the mammalian root dentine is only sparsely innervated. Previous electron microscopic studies on human teeth did not reveal nerve fibres beyond radicular predentine. It is the purpose of this communication to provide ultrastructural evidence for the presence of nerve fibres in apical root dentine of human premolars. Two healthy mandibular second premolars, removed due to orthodontic reasons, which formed part of a previous study, were utilized for this investigation. Root discs of about 0.6 mm thickness were removed at about 2 mm cervical to the root apex and processed for light and electron microscopy. Transmission electron microscopic examination revealed numerous nerve fibres along the pulp-predentine border and in patches of predentine. Distinct nerve fibres were observed in the inner mineralized portion of the radicular dentine. The axons existed in close association to the odontoblastic processes, but no synaptic contacts or junctional complexes could be observed.


Overexpression of copper-zinc superoxide dismutase attenuates acute activation of activator protein-1 after transient focal cerebral ischemia in mice.
Reactive oxygen species (ROS) have been implicated in reperfusion injury after focal cerebral ischemia (FCI). ROS are known to regulate the activity of transcription factors such as activator protein-1 (AP-1), which is a dimer consisting of members of the Jun and Fos families. We investigated the role of ROS in AP-1 activity after FCI using transgenic mice that overexpressed copper-zinc superoxide dismutase (SOD1) and that had reduced infarction volume after FCI. The SOD1 transgenic mice and their wild-type littermates were subjected to middle cerebral artery occlusion and reperfusion by intraluminal suture blockade. After 60 minutes of middle cerebral artery occlusion, mice were allowed to recover for 1, 2, and 4 hours before euthanasia. Protein expression of c-Jun and c-Fos was examined by immunohistochemistry and Western blotting. AP-1 DNA-protein binding activity was assessed by electrophoretic mobility shift assays. In wild-type mice, immunohistochemistry demonstrated acute c-Jun and c-Fos activation in ischemic cortex and its outer boundary. Expression of both was reduced in SOD1 transgenic mice. Western blotting confirmed that SOD1 overexpression was associated with reduced c-Jun and c-Fos protein levels in ischemic brain. Electrophoretic mobility shift assays revealed that the ischemia-enhanced DNA binding activity observed in wild-type mice was reduced in SOD1 transgenic mice. Supershift assays indicated that c-Jun participated in the bound AP-1 complex. SOD1 overexpression prevents early activation of AP-1 after transient FCI in mice. This may block the expression of downstream target genes that are injurious, thereby reducing the infarction volume after transient FCI in mice.


Occurrence and associative value of non-identifiable fingermarks.
Fingermarks that have insufficient characteristics for identification often have discernible characteristics that could form the basis for lesser degrees of correspondence or probability of occurrence within a population. Currently, those latent prints that experts judge to be insufficient for identification are not used as associative evidence. How often do such prints occur and what is their potential value for association? The answers are important. We could be routinely setting aside a very important source of associative evidence, with high potential impact, in many cases; or such prints might be of very low utility, adding very little, or only very rarely contributing to cases in a meaningful way. The first step is to better understand the occurrence and range of associative value of these fingermarks. The project goal was to explore and test a theory that in large numbers of cases fingermarks of no value for identification purposes occur and are readily available, though not used, and yet have associative value that could provide useful information. Latent fingermarks were collected from nine state and local jurisdictions. Fingermarks included were those (1) collected in the course of investigations using existing jurisdictional procedures, (2) originally assessed by the laboratory as of no value for identification (NVID), (3) re-assessed by expert review as NVID, but with least three clear and reliable minutiae in relationship to one another, and (4) determined to show at least three auto-encoded minutiae. An expected associative value (ESLR) for each mark was measured, without reference to a putative source, based on modeling within-variability and between-variability of AFIS scores. This method incorporated (1) latest generation feature extraction, (2) a (minutiae-only) matcher, (3) a validated distortion model, and (4) NIST SD27 database calibration. Observed associative value distributions were determined for violent crimes, property crimes, and for existing objective measurements of latent print quality. 750 Non Identifiable Fingermarks (NIFMs) showed values of Log10 ESLR ranging from 1.05-10.88, with a mean value of 5.56 (s.d. 2.29), corresponding to an ESLR of approximately 380,000. It is clear that there are large numbers of cases where NIFMs occur that have high potential associative value as indicated by the ESLR. These NIFMs are readily available, but not used, yet have associative value that could provide useful information. These findings lead to the follow-on questions, "How useful would NIFM evidence be in actual practice?" and, "What developments or improvements are needed to maximize this contribution?"


Transcriptional regulation of tissue organization and cell morphogenesis: the fly retina as a case study.
Understanding how a functional organ can be produced from a small group of cells remains an outstanding question in cell and developmental biology. The developing compound eye of Drosophila has long been a model of choice for addressing this question by dissecting the cellular, genetic and molecular pathways that govern cell specification, differentiation, and multicellular patterning during organogenesis. In this review, the author focussed on cell and tissue morphogenesis during fly retinal development, including the regulated changes in cell shape and cell packing that ultimately determine the shape and architecture of the compound eye. In particular, the author reviewed recent studies that highlight the prominent roles of transcriptional and hormonal controls that orchestrate the cell shape changes, cell-cell junction remodeling and polarized membrane growth that underlie photoreceptor morphogenesis and retinal patterning.


Research to practice: emotional development and maternal/infant attachment.
A mother's responsiveness to her infant's signals is important for developing their personal relationship and the child's social and cognitive competence. While interacting, both mother and infant emit signals to capture each other's attention and to indicate whether to join, sustain, or terminate their interaction. Maternal sensitivity to these signals is a central feature in the development of optimal or secure attachment. However, a mother's perceptions and expectations of her infant's behavior affects her sensitivity to infant signals. Because of the effect of these parental perceptions, modifying the parent's cognitive sets and coping strategies to help them better deal with the challenge of responding to infant distress can be beneficial.


Birth anthropometry predicts neonatal and infant mortality in rural Bangladesh: a focus on circumferential measurements.
Low birth weight predicts risk of infant death. However, several birth measurements may be equally predictive, for which cutoffs and associated risks are less explored. We assessed and optimized population cutoffs of birth length, weight, and midupper arm circumference (MUAC), head circumference (HC), and chest circumference (CC) for predicting neonatal (≤28 d) and infant (≤365 d) mortality in northwest Bangladesh. Among 28,026 singletons born in an antenatal micronutrient supplement trial, 21,174 received anthropometry ≤72 h after birth, among whom 583 died in infancy. Optimization for predicting mortality for each measurement was guided by the Youden Index (sensitivity + specificity - 1). Relative risk ratios (RRRs) and positive predictive values (PPVs) were calculated across cutoff ranges for individual and any pair of measurements. Optimal cutoffs, harmonized to 100-g or 0.5-cm readings, for neonatal and infant mortality were 44.5 cm for length, 2200 g for weight, 9.0 cm for MUAC, 31.0 cm for HC, and 28.5 cm for CC, below which all predicted mortality. However, a CC <28.5 cm, alone and combined with HC <31.0 cm, yielded the highest RRR [9.68 (95% CI: 7.84, 11.94) and 15.74 (95% CI: 12.54, 19.75), respectively] and PPV (11.3% and 10.7%) for neonatal mortality and highest RRR [6.02 (95% CI: 5.15, 7.02) and 9.19 (95% CI: 7.72, 10.95)] and PPV (16.3% and 14.5%) for infant mortality. Pairs of measurements revealed a higher RRR for neonatal and infant mortality than individual measurements of any one pair, although the ranges of PPV remained comparable. In Bangladesh, multiple birth measurements alone or in combination, particularly chest circumference, predict neonatal and infant mortality.


Adsorption of cellulase on cellulose: Effect of physicochemical properties of cellulose on adsorption and rate of hydrolysis.
In the cellulase-cellulose reaction system, the adsorption of cellulase on the solid cellulose substrate was found to be one of the important parameters that govern the enzymatic hydrolysis rate of cellulose. The adsorption of cellulase usually parallels the rate of hydrolysis of cellulose. The affinity for cellulase varies depending on the structural properties of cellulose. Adsorption parameters such as the half-saturation constant, the maximum adsorption constant, and the distribution coefficient for both the cellulase and cellulsoe have been experimentally determined for several substrates. These adsorption parameters vary with the source of cellulose and the pretreatment methods and are correlated with the crystallinity and the specific surface area of cellulose substrates. The changing pattern of adsorption profile of cellulase during the hydrolysis reaction has also been elucidated. For practical utilization of cellulosic materials, the cellulose structural properties and their effects on cellulase adsorption, and the rate of hydrolysis must be taken into consideration.


[Endoprosthesis of mammary glands using hydrogel prosthesis PAAG "Interfall"].
The results of the mammarial glands endoprosthesis in 60 women patients, of them in 57--with prostheses PAAG "Interfall", applied for the first time, were analyzed. The occurrence frequency for postoperative complications was 19%, including sensitivity disorders of papillo-areolar complex were noted in 14% of observations and seroma--in 5%. Preoperative, intraoperative, postoperative tactic of management of women patients, operated for the first time and with purulent-septic complications occurring after mammoplasty using application of gel and prostheses PAAG "Interfall" was elaborated.


Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E.
The coordinated action of cell cycle progression and cell growth (an increase in cell size and cell mass) is critical for sustained cellular proliferation, yet the biochemical signals that control cell growth are poorly defined, particularly in mammalian systems. We find that cell growth and cell cycle progression are separable processes in mammalian cells and that growth to appropriate cell size requires mTOR- and PI3K-dependent signals. Expression of a rapamycin-resistant mutant of mTOR rescues the reduced cell size phenotype induced by rapamycin in a kinase-dependent manner, showing the evolutionarily conserved role of mTOR in control of cell growth. Expression of S6K1 mutants that possess partial rapamycin-resistant activity or overexpression of eIF4E individually and additively partially rescues the rapamycin-induced decrease in cell size. In the absence of rapamycin, overexpression of S6K1 or eIF4E increases cell size, and, when coexpressed, they cooperate to increase cell size further. Expression of a phosphorylation site-defective mutant of 4EBP1 that constitutively binds the eIF4E-Cap complex to inhibit translation initiation reduces cell size and blocks eIF4E effects on cell size. These data show that mTOR signals downstream to at least two independent targets, S6K1 and 4EBP1/eIF4E, that function in translational control to regulate mammalian cell size.


Intelligent Evaluation Algorithm of English Writing Based on Semantic Analysis.
In order to solve the intelligent evaluation of English writing, this paper proposes a method based on the English semantic neural network algorithm. This paper first briefly analyzes the research background of the English semantic analysis system, then expounds on the relevant technologies of the English distance similarity algorithm, semantic analysis intelligent algorithm structure, word analysis algorithm, sentence part of speech analysis algorithm, sentence semantic analysis algorithm, and neural network algorithm, and finally expounds the database and method implementation of the English semantic analysis system, so as to provide guarantee for the design of the English semantic analysis system. The experimental results show that the recognition accuracy of the BRF network for English characters can reach 96.35%, which is 7.79% higher than that of the BP network; the AUC of the BRF network reaches 0.89, which is closer to 1 compared with 0.72 of the BP network. The test results are in good agreement with the antinoise curve test results of the figure. It is proved that the English semantic neural network algorithm can effectively improve the accuracy of English translation and further improve the efficiency of the system.


Epidemiology and clinicopathologic characteristics of childhood nephrotic syndrome in Benin-City, Nigeria.
Medical records of 58 children, 38 (65.5%) males and 20 (34.5%) females with nephrotic syndrome (NS) admitted to the paediatric wards of the University of Benin Teaching Hospital (UBTH) Benin-City, Nigeria, between January, 1991 and December, 1995 were reviewed. The aim of the study was to document the epidemiologic as well as certain clinico-pathologic characteristics of the disease in Benin-City. More males than females (ratio of 1.9:1) and older children (mean +/- (SEM) 8.2 +/- 0.5 years; range 2-15 years) were affected. About 62% of the patients were aged 7 years and above. There was a high incidence of hypertension (41.4%) and microscopic haematuria (60%) in the patients. Hypercholesterolaemia and hypoalbuminaemia were seen in only 21.6% and 30.2% of evaluated patients respectively. Hypercholesterolaemia and hypoalbuminaemia as diagnostic criteria for NS in our locale may not be very useful. About 51.7% of patients responded to the initial course of prednisolone, out of whom 43.3% relapsed (26.7%) frequently and 16.7% infrequently. Mortality rate was 6.9%. Urinary tract infection (UTI) occurred in 44.8% of the patients and was caused largely by Staphylococcus aureus and untyped coliform organisms.


Columnar cell lesions, mammographic density and breast cancer risk.
Mammographic density is the third largest risk factor for ductal carcinoma in-situ (DCIS) and invasive breast cancer. However, the question of whether risk-mediating precursor histological changes, such as columnar cell lesions (CCLs), can be found in dense but non-malignant breast tissues has not been systematically addressed. We hypothesized that CCLs may be related to breast composition, in particular breast density, in non-tumour containing breast tissue. We examined randomly selected tissue samples obtained by bilateral subcutaneous mastectomy from a forensic autopsy series, where tissue composition was assessed, and in which there had been no selection of subjects or histological specimens for breast disease. We reviewed H&E slides for the presence of atypical and non-atypical CCLs and correlated with histological features measured using quantitative microscopy. CCLs were seen in 40 out of 236 cases (17%). The presence of CCLs was found to be associated with several measures of breast tissue composition, including radiographic density: high Faxitron Wolfe Density (P = 0.037), high density estimated by percentage non-adipose tissue area (P = 0.037), high percentage collagen (P = 9.2E-05) and high percentage glandular area (P = 2E-05). DCIS was identified in two atypical CCL cases. The extent of CCL was not associated with any of the examined variables. Our study is the first to report a possible association between CCLs and breast tissue composition, including mammographic density. Our data suggest that prospective elucidation of the strength and nature of the clinicopathological correlation may lead to an enhanced understanding of mammographic density and evidence based management strategies.


Severe SARS-CoV-2 placenta infection can impact neonatal outcome in the absence of vertical transmission.
The effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the pathophysiology of the placenta and its impact on pregnancy outcome has not yet been fully elucidated. Here, we present a comprehensive clinical, morphological, and molecular analysis of placental tissues from pregnant women with and without SARS-CoV-2 infection. SARS-CoV-2 could be detected in half of placental tissues from SARS-CoV-2-positive women. The presence of the virus was not associated with any distinctive pathological, maternal, or neonatal outcome features. SARS-CoV-2 tissue load was low in all but one patient who exhibited severe placental damage leading to neonatal neurological manifestations. The placental transcriptional response induced by high viral load of SARS-CoV-2 showed an immunopathology phenotype similar to autopsy lung tissues from patients with severe coronavirus disease 2019. This finding contrasted with the lack of inflammatory response in placental tissues from SARS-CoV-2-positive women with low viral tissue load and from SARS-CoV-2-negative women. Importantly, no evidence of vertical transmission of SARS-CoV-2 was found in any newborns, suggesting that the placenta may be an effective maternal-neonatal barrier against the virus even in the presence of severe infection. Our observations suggest that severe placental damage induced by the virus may be detrimental for the neonate independently of vertical transmission.


Extracellular signal-regulated kinase 8-mediated c-Jun phosphorylation increases tumorigenesis of human colon cancer.
Extracellular signal-regulated kinase 8 (ERK8), a recently discovered member of the mitogen-activated protein kinase protein family, has been less studied than other family members, leaving its physiologic functions mostly unknown. The biological consequences of overexpression of ERK8 in JB6 Cl41 epidermal skin cells or knockdown of ERK8 in HCT15 colorectal cancer cells was studied. Kinase assays and transient transfection experiments were performed to study the signaling pathway between ERK8 and c-Jun. We found that ERK8 is relatively highly expressed in HCT15 human colorectal cancer cells and plays an important role in the promotion and progression of colorectal cancer. ERK8 promoted neoplastic transformation, and knockdown of ERK8 in HCT15 colorectal cancer cells reduced the tumorigenic properties of these cell lines. Furthermore, a direct interaction between ERK8 and c-Jun was shown. With epidermal growth factor treatment, overexpression of ERK8 in JB6 Cl41 cells caused an increased phosphorylation of c-Jun at Ser(63) and Ser(73), resulting in increased activator protein-1 transactivation. In contrast, knockdown of ERK8 in HCT15 colorectal cancer cells blocked c-Jun phosphorylation. The interaction between ERK8 and c-Jun seems to increase the tumorigenic properties of HCT15 colorectal cancer cells. Thus, ERK8-regulated signaling might serve as a potential therapeutic target in colorectal cancer.


Sirtuin 1 alleviates diabetic neuropathic pain by regulating synaptic plasticity of spinal dorsal horn neurons.
Accumulating evidence has demonstrated that the enhanced synaptic plasticity of nociceptive interneurons in the spinal dorsal horn is the basis of central sensitization in neuropathic pain. Our previous results demonstrated that sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, alleviates neuropathic pain in type 2 diabetes mellitus rats. SIRT1 has also been reported to regulate synaptic plasticity in different brain neurons. However, the role of SIRT1 in synaptic plasticity of spinal dorsal horn neurons remains unknown. In this study, we found that in the spinal dorsal horn of diabetic neuropathic pain (DNP) rats and db/db mice, decreased SIRT1 expression was accompanied by enhanced structural synaptic plasticity. The levels of postsynaptic density protein 95 (PSD-95), growth-associated protein 43 (GAP43), and synaptophysin increased in the spinal dorsal horn of DNP rats and db/db mice and in high glucose-cultured primary spinal neurons. Upregulation of spinal SIRT1 by SIRT1 activator SRT1720 relieved pain behavior, inhibited the enhanced structural synaptic plasticity in rats and db/db mice with DNP, and decreased the levels of synapse-associated proteins in DNP rats, db/db mice, and high glucose-cultured spinal neurons. SIRT1-shRNA induced pain behavior and enhanced structural synaptic plasticity in normal rats and increased synapse-associated proteins levels in normal rats and spinal neurons. Intrathecal injection of AAV-Cre-EGFP into SIRT1 mice also induced pain behavior and enhanced synaptic plasticity of the spinal dorsal horn neurons. These results suggest that SIRT1 plays an important role in the progression of DNP by regulating synaptic plasticity of spinal dorsal horn neurons.


[Nutrition and behavioral eating disorders: anorexia and bulimia nervosa].
Behavioral eating disorders (BED's) have shown an intense growth in the last years. They are considered to be caused by multiple factors, showing a bio-psycho-socio-cultural etiology. Although there are clinical signs that could alert the physician and allow an early diagnosis, their final diagnosis must meet certain criteria set in the DSM-IV (1994). Despite the fact that anorexia nervosa and bulimia nervosa in their typical forms, are the most known, there are atypical or incomplete forms of both that should be kept in mind when making the diagnosis. Anorexia nervosa is accompanied by somatic-nutritional problems that may condition the patient's life, requiring specific nutritional care. Bulimia nervosa is often accompanied by medical complications that require an exhaustive assessment. As for the nutritional support in anorexia nervosa, this must be proportional to the nutritional status of the patient and there should be no hesitation to resort to artificial nutrition using enteral nutrition through a tube in the case of severe malnutrition. In these cases there must be careful monitoring for the appearance of the re-nutrition syndrome, and this can be avoided by the slow and progressive administration of energetic nutrients, with special precautions in the supply of carbohydrates, and administering an adequate supplement of vitamins and electrolytes. Patients with a BED require a multi-disciplinary care with the simultaneous and coordinated action of a team of professionals. This type of care coupled with the experience of the team with regard to BED's and their treatment, and together with other actions and situations, may favor the final prognosis of a patient with a BED.


Prostaglandin E2 increases transforming growth factor-beta type III receptor expression through CCAAT enhancer-binding protein delta in osteoblasts.
Variations in individual TGF-beta receptors (TbetaRs) may modify TGF-beta activity and significantly alter its effects on connective tissue growth or repair. Differences in the amount of TbetaR type III (TbetaRIII) relative to signal transducing TbetaRI occur on bone cells during differentiation or in response to other growth regulators. Here we investigated prostaglandin (PG) E2, a potent effector during trauma, inflammation, or mechanical load, on TbetaR expression in primary osteoblast-enriched cultures. PGE2 rapidly increased TbetaRIII mRNA and protein expression and enhanced TbetaRIII gene promoter activity through a discrete region within 0.4 kb of the transcription start site. PGE2 alters osteoblast function through multiple signal-inducing pathways. In this regard, protein kinase A (PKA) activators, PGE1 and forskolin, also enhanced gene expression through the TbetaRIII gene promoter, whereas protein kinase C activators, PGF2alpha and phorbol myristate acetate, did not. The stimulatory effect of PGE2 on TbetaRIII promoter activity was suppressed by a dominant negative PKA-regulatory subunit, but not by dominant negative protein kinase C. PGE2 specifically increased nuclear factor CCAAT enhancer-binding protein delta (C/EBPdelta) binding to a half-binding site upstream of the basal TbetaRIII promoter region, and promoter activity was sensitive to C/EBPdelta overexpression and to dominant-negative C/EBPdelta competition. In parallel with their effect on TbetaRIII expression, activators of PKA decreased TGF-beta-induced activity. In summary, high levels of PGE2 that occur with inflammation or trauma may, through PKA-activated C/EBPdelta, preferentially increase TbetaRIII expression and in this way delay TGF-beta-dependent activation of osteoblasts during the early stabilization phase of bone repair.


Recognizing and Effectively Managing Hypermobility-Related Conditions.
Hypermobility spectrum disorder (HSD) and hypermobile Ehlers-Danlos syndrome (hEDS) can cause widespread or chronic pain, fatigue, and proprioceptive and coordination deficits resulting in functional restrictions. These conditions are common and often unrecognized, and patients are likely to present in physical therapy for musculoskeletal injuries, pain, or coordination deficits. Although physical therapy is considered central to managing these conditions, many patients report pain and iatrogenic injuries due to inappropriate interventions. The diagnostic classification for these conditions was revised in 2017 to supersede previous diagnostic categories of Joint Hypermobility Syndrome and Ehlers-Danlos Syndrome-hypermobility type/type III. It is now known that these conditions affect multiple body systems and not just joints and that patients require a holistic approach. This Perspective article will describe the 2017 diagnostic classification system, clinical presentation, examination, evaluation, and management of patients with HSD/hEDS. Both adult and pediatric cases are presented to illustrate the patient management concepts discussed. This knowledge can lead to more effective management of this patient population.


Necropsy diagnosis of myocarditis: a retrospective study using CD45RO immunohistochemistry.
To use CD45RO immunohistochemistry to investigate the numbers of T lymphocytes found in sections of myocardium from a routine necropsy series, and to determine the incidence of myocarditis in this series. Myocardial sections from 163 routine hospital necropsies were stained with CD45RO and the numbers of positive lymphocytes/mm2 were counted. The results were correlated with the H/E opinion and the clinical context of the necropsy. Most (143) cases showed low numbers (0-3) of CD45RO positive lymphocytes/mm2. Fifteen cases showed 7-13 positive lymphocytes/mm2, comprising a wide variety of clinical conditions, generally with no specific cardiac pathology. Five cases showed 14 or more positive lymphocytes/mm2, comprising one case of active myocarditis, three cases of cardiac transplant rejection, and one post-transplant lymphoproliferative disorder, all conditions in which large numbers of lymphocytes would be expected. The incidence of myocarditis in our series was 0.6%. In most cases the normal myocardium has a low T lymphocyte count (0-3/mm2). In some cases immunohistochemistry shows more positive cells than would have been expected on light microscopy. Immunohistochemistry is a useful and reliable means of confirming a diagnosis of myocarditis. The results support the conclusion of the 1997 ISFC task force that 14 or more lymphocytes or macrophages/mm2 of myocardium in the appropriate clinical context is a reliable threshold for the diagnosis of chronic myocarditis.


Quality and stability of reduction of operated acromioclavicular dislocation using dual acromioclavicular and coracoclavicular stabilization.
Dual stabilization is advocated in acute acromioclavicular dislocation (ACD), but has been little assessed. This preliminary study performed clinical and radiological assessment of dual acromioclavicular (AC) and coracoclavicular (CC) stabilization in acute ACD. The study hypothesis was that dual stabilization allows satisfactory reduction that remains stable over time. A button was used under endoscopy for CC stabilization. For AC stabilization, a short approach was used; the joint was cleansed then stabilized by an anchored tape between the acromion and the clavicle to promote ligament healing. Clinical assessment was based on a visual analog pain scale (VAS), joint range of motion and QuickDASH and Constant scores. Radiological reduction was assessed on the ratio of CC distance between the operated and healthy sides on two views. MRI was used in follow-up to screen for ligament healing: thickening and continuity. Thirty-five patients with stage 3-5 acute dislocation were included. At a minimum 24 months' follow-up, mean clinical scores were very satisfactory, with recovery of motion and pain relief. Radiography showed 94% stable reduction in both vertical and horizontal planes. MRI confirmed CC and AC ligament healing. Postoperative complications mainly comprised 4 cases of reduction loss (11%). One clavicle fracture occurred, at 6 months. Dual AC-CC stabilization provided very good radiographic reduction in both horizontal and vertical planes. Functional results were very satisfactory, and complications were few, with some cases of reduction loss. These good results encourage us to continue with dual stabilization in acute ACD. II; prospective cohort.


Treatment of bleeding complications when using oral anticoagulants for prevention of strokes.
Major bleeding in patients taking oral anticoagulants for stroke prevention can progress to catastrophic bleeding if it is not controlled. This is especially of concern if the bleeding is related to the use of a novel oral anticoagulant (NOAC) such as dabigatran or rivaroxaban, given the dearth of literature addressing the reversal of their anticoagulant effects. The goal of treatment is to prevent progression to catastrophic hemorrhage or exsanguination, and decrease bleeding-related morbidity and mortality. Clinical decisions in such instances should be made in a timely fashion to address the necessity for intervention. Animal models have shown potential for the use of 'fresh frozen plasma (FFP) or prothrombin complex concentrate (PCC) in reversing bleeding related to novel oral anticoagulants. However, there is paucity of clinical trials assessing the efficacy of these agents in humans in such clinical scenarios. Hence, there are no guidelines or ideal agents to use in such a scenario. We do not recommend the use of FFP for bleeding related to NOACs. In the setting of early overdose of dabigatran (within 3-4 hours), activated charcoal may be given, and hemodialysis may be used if there is evidence of critical organ bleeding. In our opinion, 4-factor PCC or 3-factor PCC at a dose of about 50 U/kg may be given in an emergency setting to manage bleeding related to factor Xa inhibitors such as rivaroxaban or apixaban, but not direct thrombin inhibitors such as dabigatran. We are also of the opinion that aPCC (FEIBA®) would not be helpful for management of direct thrombin inhibitor (dabigatran)-related bleeding, based on current available efficacy data in humans. We reserve the use of Novoseven® as a last resort, given the lack of pre-clinical or clinical data supporting its ability to reverse the anticoagulant effects of NOACs, except in one case report where it was used in combination with hemodialysis.


The problem of "just for fun": patterns of use situations among active club drug users.
Existing research has demonstrated the significance of situational antecedents to substance use. The current study used a cluster analytic approach to identify groups of club drug users who report using substances in similar situations (assessed by the Inventory of Drug Taking Situations) with longitudinal data from 400 active drug users. A three-cluster solution emerged in baseline data and was replicated in 12-month follow-up data. Groups were identified as Situationally Restricted, Pleasure Driven, and Situationally Broad users. Group differences were observed on measures of mental health, attitudes towards substance use, amount of substance use, and rates of substance dependence. Cluster membership predicted substance dependence after controlling for past dependence, current use, and current depression/anxiety.


[Antithrombotic recombinant antibodies].
Coronary syndromes, stroke and other ischaemic arterial diseases are the leading cause of death in the world and will probably remain it at least until 2020. Cardiovascular diseases kill 17 million people each year with an expected increase to 20 million in 2020 and 24 million in 2030. The global impact of recurrence and death during the 6 months following an acute coronary syndrome remains at 8-15% in the present state of medical practice. Acute ischaemic syndromes have a common aetiology that is the formation of a platelet-rich clot at the site of severe coronary stenosis and of eroded atherosclerotic plaques. Therapy consists of medical treatments associating thrombolysis, antiplatelet drugs, and the re-opening of the coronary artery by angioplasty. But these treatments do not prevent morbidity and mortality reaching 15% at 6 months. Finally the treatment of stroke is very limited. There is thus a real clinical need to improve existing treatments and to discover new molecules. Platelet activation is a critical step in ischaemic cardiovascular diseases. This is the reason why antiplatelet drugs are most often prescribed in these cases. Currently, only one recombinant antithrombotic antibody is used in therapy. This is a chimeric Fab, c7E3 or abciximab, which inhibits the final phase of platelet aggregation. Abciximab is prescribed in acute coronary syndromes treated by angioplasty. However, treatment by abciximab can induce severe complications, principally, hemorrages and thrombopenia. Other platelet receptors involved in the earlier steps of platelet activation, such as the phases of contact with and of activation by the subendothelium matrix, have been identified as potential targets for the development of antithrombotic antibodies and are described in this revue.


Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis. Myasthenia Gravis Clinical Study Group.
We have conducted a trial to randomly assess the efficacy and tolerance of intravenous immunoglobulin (i.v.Ig) or plasma exchange (PE) in myasthenia gravis (MG) exacerbation and to compare two doses of i.v.Ig. Eighty-seven patients with MG exacerbation were randomized to receive either three PE (n = 41), or i.v.Ig (n = 46) 0.4 gm/kg daily further allocated to 3 (n = 23) or 5 days (n = 23). The main end point was the variation of a myasthenic muscular score (MSS) between randomization and day 15. The MSS variation was similar in both groups (median value, +18 in the PE group and +15.5 in the i.v.Ig group, p = 0.65). Similar efficacy, although slightly reduced in the 5-day group was observed with both i.v.Ig schedules. The tolerance of i.v.Ig was better than that of PE with a total of 14 side effects observed in 9 patients, 8 in the PE group and 1 in the i.v.Ig group (p = 0.01). Although our trial failed to show a pronounced difference in the efficacy of both treatments, it exhibited a very limited risk for i.v.Ig. i.v.Ig is an alternative for the treatment of myasthenic crisis. The small sample sizes in our trial, however, could explain why a difference in efficacy was not observed. Further studies are needed to compare PE with i.v.Ig and to determine the optimal dosage of i.v.Ig.


"Default" generation of neonatal regulatory T cells.
CD4(+)Foxp3(+) regulatory T (Treg) cells were shown to control all aspects of immune responses. How these Treg cells develop is not fully defined, especially in neonates during development of the immune system. We studied the induction of Treg cells from neonatal T cells with various TCR stimulatory conditions, because TCR stimulation is required for Treg cell generation. Independent of the types of TCR stimulus and without the addition of exogenous TGF-beta, up to 70% of neonatal CD4(+)Foxp3(-) T cells became CD4(+)Foxp3(+) Treg cells, whereas generally <10% of adult CD4(+)Foxp3(-) T cells became CD4(+)Foxp3(+) Treg cells under the same conditions. These neonatal Treg cells exert suppressive function and display relatively stable Foxp3 expression. Importantly, this ability of Treg cell generation gradually diminishes within 2 wk of birth. Consistent with in vitro findings, the in vivo i.p. injection of anti-CD3 mAb to stimulate T cells also resulted in a >3-fold increase in Treg cells in neonates but not in adults. Furthermore, neonatal or adult Foxp3(-) T cells were adoptively transferred into Rag1(-/-) mice. Twelve days later, the frequency of CD4(+)Foxp3(+) T cells converted from neonatal cells was 6-fold higher than that converted from adult cells. Taken together, neonatal CD4(+) T cells have an intrinsic "default" mechanism to become Treg cells in response to TCR stimulations. This finding provides intriguing implications about neonatal immunity, Treg cell generation, and tolerance establishment early in life.


Interdependence in women with breast cancer and their partners: an interindividual model of distress.
The aim of this investigation was to test whether interdependence in dyads living with breast cancer could account for person-partner crossover effects in distress outcomes. The sample consisted of 95 dyads with early-stage breast cancer. By using reciprocal dyadic data from women with breast cancer and their partners, we fit a structural equation model of the actor-partner interdependence model to examine the interaction of participants' depression and stress in predicting their partner's health outcomes. Results revealed a pattern of influence whereby the interaction of high levels of depression coupled with high levels of stress in women with breast cancer was associated with lowered physical health and well-being in their partners. Although depression seemed to be the key mechanism in predicting distressing outcomes, when depression was combined with any additional stress, the level of physical distress was significantly greater. Results provided preliminary empirical support for crossover effects in the physical well-being of close relational partners in a cancer-related context. Further, results showed that distressing outcomes need not be limited to emotional distress but can also include physical distress. The findings from this study illustrate why it is not sufficient to concentrate care solely on the patient with cancer. Monitoring the social well-being of patients as they go through the cancer process could be as important as assessing their psychological state or other peripheral biomarkers. This line of inquiry would be advanced by including methods other than self-report in assessments of psychological and physical health.


A systematic comparison of the actual, potential, and theoretical health effects of cobalt and chromium exposures from industry and surgical implants.
Humans are exposed to cobalt (Co) and chromium (Cr) from industry and surgical devices, most notably orthopedic joint replacements. This review compares the potential health effects of exposure to Co and Cr contaminants from these two different sources, both in the locally exposed tissues and at sites distant to the primary exposure. Surgical implantation results largely in exposures to ions, corrosion products, and particles of Co and Cr. Industrial exposures are predominantly to metal compounds and particles. Although there are large literatures on industrial and surgical exposures to these metals, there has yet to be a systematic comparison of the two to test whether more general lessons might be learned about the human toxicology of Co and Cr. Both industrial and surgical exposures cause inflammatory and other immune reactions in the directly exposed tissues. In the lung there is a well-established risk of cancer following long-term exposures to hexavalent Cr; however, the development of sarcoma in the connective tissues adjacent to implants in response to metal particles is rare. Both types of exposure are associated with changes in the peripheral blood, including evidence of oxidative stress, and altered numbers of circulating immune cells. There is dissemination of Co and Cr to sites distant to the orthopedic implant, but less is known about systemic dissemination of these metals away from the lung. The effects of industrial exposures in the reproductive, renal, and cardiac systems have been investigated, but this has yet to be explored after surgical exposures. The form of the metal (and associated elements) in both instances is key to the toxicological effects arising in the body and further characterization of debris released from devices is certainly recommended, as is the impact of nanotoxicology on the health and safety of workers and patients. Biomonitoring schemes currently used in industry could be translated, if required, into suitable programs for orthopedic out-patients. Cross-communication between experts in industrial and occupational medicine and regulatory agencies may be useful.


Prognostic value of metabolic parameters and clinical impact of ¹⁸F-fluorocholine PET/CT in biochemical recurrent prostate cancer.
To evaluate the therapeutic impact of (18)F-fluorocholine (FCH) PET/CT in biochemical recurrent prostate cancer (PC) and to investigate the value of quantitative FCH PET/CT parameters in predicting progression-free survival (PFS). This retrospective study included 172 consecutive patients with PC who underwent FCH PET/CT for biochemical recurrence. Mean rising PSA was 10.7 ± 35.0 ng/ml. Patients with positive FCH PET were classified into three groups: those with uptake only in the prostatic bed, those with locoregional disease, and those with distant metastases. Referring physicians were asked to indicate the hypothetical therapeutic strategy with and without the FCH PET/CT results. Clinical variables and PET parameters including SUVmax, SUVpeak, SUVmean, total lesion choline kinase activity (TLCKA) and standardized added metabolic activity (SAM) were recorded and a multivariate analysis was performed to determine the factors independently predicting PFS. In 137 of the 172 patients, the FCH PET/CT scan was positive, and of these, 29.9 % (41/137) had prostatic recurrence, 42.3 % (58/137) had pelvic lymph node recurrence with or without prostatic recurrence, and 27.7 % (38/137) had distant metastases. The FCH PET/CT result led to a change in treatment plan in 43.6 % (75/172) of the 172 patients. Treatment was changed in 49.6 % (68/137) of those with a positive FCH PET/CT scan and in 20 % (7/35) of those with a negative FCH PET/CT scan. After a median follow-up of 29.3 months (95 % CI 18.9 - 45.9 months), according to multivariate analysis age <70 years, SAM ≥23 and SUVmean ≥3 were parameters independently predicting PFS. A nomogram constructed using the three parameters showed 49 months of PFS in patients with the best scores (0 or 1) and only 11 months in patients with a poor score (score 3). This study indicates that a positive FCH PET result in PC patients with biochemical recurrence predicts a shorter PFS and confirms the major impact of the FCH PET result on the management of biochemical recurrent PC.


Processing of global and selective stop signals: application of Donders' subtraction method to stop-signal task performance.
This paper applied Donders' subtraction method to examine the processing of global and selective stop signals in the stop-signal paradigm. Participants performed on three different versions of the stop task: a global task and two selective tasks. A global task required participants to inhibit their response to a go signal whenever a stop signal was presented (Stop-a task). A selective stop task required participants to inhibit to one stop signal but not to the other (Stop-c task). Another selective stop task required them to inhibit when the response indicated by go and stop signals was the same but not when they were different (Stop-b task). Stop-signal reaction time (SSRT) was shortest for Stop-a and longest for Stop-b, with intermediate values for the Stop-c task. Additional control experiments that manipulated stop probability confirmed the robustness of global and selective stopping latencies even when the stop-signal probability varied. The current findings contribute to the conclusion that Donders' subtraction method provides a useful tool for estimating the durations of subprocesses that together comprise SSRT.