Characterization and regulation of prostaglandin E2 receptors on normal and malignant murine B lymphocytes.
Prostaglandin E2 (PGE2) is a pleiotropic lipid molecule synthesized by macrophages, follicular dendritic cells, and fibroblasts, inhabitants of the B cell microenvironment. It is a potent regulator of B lymphocyte functions including activation and immunoglobulin class switching. To understand the effects of PGE2 on B lymphocyte function, the features of the putative PGE2 receptor on cells of the B lineage must be delineated. This receptor has not yet been characterized on B lymphocytes. Murine B cell lymphomas were used as a model to evaluate B lineage PGE2 receptors since they elevate intracellular cAMP in response to PGE2. Scatchard analysis indicates that the PGE2 receptor on both CH31 and CH12 exists in a single high-affinity state, with the CH12 B lymphoma possessing three times more receptors per cell compared to CH31. Interestingly, the PGE2 receptor is subject to regulation as a 20-hr LPS treatment increased PGE2 receptor number by two- to threefold on CH12 and CH31 B cell lymphomas, while dissociation constants remained similar. Finally, Scatchard analysis of normal murine splenic B lymphocytes demonstrates that they also possess high-affinity receptors for PGE2. Treatment of normal B cells with IL-4 increased PGE2 receptor levels fourfold from approximately 50 to 200 sites/cell while the affinity of the receptor slightly decreased. These results are the first to describe the number and affinity of PGE2 receptors on cells of the B lineage. These findings also suggest that B lymphocyte-activating molecules such as LPS and IL-4 may enhance sensitivity to PGE2 by upregulating the number of PGE2 receptors on B cells. Moreover, these observations may be of importance in developing strategies to specifically control the spread of PGE2-sensitive B lymphomas.


Hybrid density functional theoretical study of NASICON-type NaxTi2(PO4)3 (x = 1-4).
Sodium Super Ionic Conductor (NASICON) structured phosphate framework compounds represent a very attractive class of materials for their use as Na-ion battery electrodes. A series of NASICON-structured NaxTi2(PO4)3 compounds corresponding to varying degrees of sodiation (x = 1-4) have been investigated using high-level hybrid density functional theory calculations using the Linear Combination of Atomic Orbitals and Gaussian-type basis set formalism together with hybrid B1WC and HSE06 exchange-correlation functionals. Using primitive cells of NaxTi2(PO4)3 compounds with different stoichiometry, sodium sublattice structure and titanium oxidation states are constructed and analyzed using group theoretical symmetry considerations. The existence of mixed titanium oxidation states for x = 4 (Ti2+/Ti3+) and x = 2 (Ti3+/Ti4+) and a single oxidation state for x = 1 (Ti4+) and x = 3 (Ti3+) has been demonstrated. The results show a necessary set of symmetry reductions taking place due to the highest possible sodium/vacancy and titanium charge ordering with changing x. For each composition, an electroneutrality condition for the oxidation states of all atoms was applied which led to the discovery of several energy minima corresponding to different electronic configurations as identified by different Ti magnetic moments. An interesting relation between the bulk electronic properties of NaxTi2(PO4)3 compounds and the variation of sodium content was also found. In addition to sodium and titanium oxidation state charge ordering, the existence of large differences between the origin and the size of the band gap is shown. The band gap changes from the 4.05 eV 2p-3d gap in Na1Ti2(PO4)3 to the 0.59 eV 3d-3d gap in Na4Ti(PO4)3 with extra states due to mixed titanium valence. These results serve as an important electronic structure benchmark for further studies of such polyanion materials and help to explain some important properties of these systems relevant to battery applications.


Associations of home confinement during COVID-19 lockdown with subsequent health and well-being among UK adults.
During the COVID-19 pandemic, the United Kingdom (UK) government introduced public health safety measures to mitigate the spikes in infection rates. This included stay-at-home orders that prevented people from leaving their homes for work or study, except for urgent medical care or buying essential items. This practice could have both short and long-term implications for health and wellbeing of people in the UK. Using longitudinal data of 10,630 UK adults, this study prospectively examined the association between home confinement status during the stringent lockdown in the UK (March 23-May 13, 2020) and 20 indicators of subjective well-being, social well-being, pro-social/altruistic behaviors, psychological distress, and health behaviors assessed approximately one month after the stringent lockdown ended. All analyses adjusted for socio-demographic characteristics and social isolation status in the beginning of the pandemic. Home confinement during the lockdown was associated with greater subsequent compliance with COVID-19 rules, more perceived major stressors, and a lower prevalence of physical activity. There was modest evidence of associations with lower life satisfaction, greater loneliness, greater depressive symptoms, greater anxiety symptoms, and more perceived minor stressors post-lockdown. However, there was little evidence that home confinement was associated with other indices of subsequent health and well-being. While our study shows that home confinement impacts some indices of subsequent health and wellbeing outcomes even after lockdown, the degree of the psychological adaptation to the difficult confinement behavior remains unclear and should be further studied. The online version contains supplementary material available at 10.1007/s12144-022-03001-5.


Assessment of pollution of river Ganges by tannery effluents using genotoxicity biomarkers in murrel fish, Channa punctatus (Bloch).
River pollution due to rapid industrialization and anthropogenic activities adversely affects the aquatic organisms, especially fish. Here, we assessed the genotoxicity, mutagenicity and bioaccumulative aspects of tannery effluents in freshwater murrel, Channa punctatus, an inhabitant of river Ganges. Test specimens were collected from three different polluted sites of the river within and nearby Kanpur area during different seasons and blood samples of these specimens were processed for comet assay and micronucleus test as genotoxicity biomarkers. A significantly (P < 0.05) higher micronuclei induction, nuclear abnormalities and % tail DNA was observed in the specimens collected from the polluted sites. Bioaccumulation studies in the muscle (1.202 μg/g) and gill tissues (< 0.300 μg/g) of the specimens revealed the concentration of chromium (core component of tanning industry) above the maximum permissible limits as prescribed by World Health Organization (WHO). The findings of the present analysis indicated contamination of river Ganges with tannery effluents which induce genotoxicity in fish with seasonal variation.


Surface tension of Nanofluid-type fuels containing suspended nanomaterials.
The surface tension of ethanol and n-decane based nanofluid fuels containing suspended aluminum (Al), aluminum oxide (Al2O3), and boron (B) nanoparticles as well as dispersible multi-wall carbon nanotubes (MWCNTs) were measured using the pendant drop method by solving the Young-Laplace equation. The effects of nanoparticle concentration, size and the presence of a dispersing agent (surfactant) on surface tension were determined. The results show that surface tension increases both with particle concentration (above a critical concentration) and particle size for all cases. This is because the Van der Waals force between particles at the liquid/gas interface increases surface free energy and thus increases surface tension. At low particle concentrations, however, addition of particles has little influence on surface tension because of the large distance between particles. An exception is when a surfactant was used or when (MWCNTs) was involved. For such cases, the surface tension decreases compared to the pure base fluid. The hypothesis is the polymer groups attached to (MWCNTs) and the surfactant layer between a particle and the surround fluid increases the electrostatic force between particles and thus reduce surface energy and surface tension.


General fibrosis syndrome.
Fibrosis of the extraocular muscles can involve multiple muscles, including the levator, and become part of the general fibrosis syndrome, which is characterized by the replacement of normal muscle tissue by fibrous tissue of varying degrees. The characteristics of this syndrome are well described although they are often confused with other similar entities. Fourteen patients are presented who display the typical characteristics of the syndrome with three members of one family being highlighted in our study. It is not currently known or described that visual acuities are problems in these children, but refractive error may not only be significant but it may vary with time and failure to pay particular attention to this fact may lead to amblyopia. The surgical correction of the strabismus is difficult but should be attempted because of the benefit it can offer, particularly from the cosmetic standpoint.


Presence of Ascogregarina culicis and Ascogregarina sp. in natural sympatric populations of Aedes aegypti and Ae. albopictus (Diptera: Culicidae) in Argentina.
Aedes aegypti is the main vector of the four arboviruses in America which have the greatest impact on human health. The introduction of Aedes albopictus in South America and Argentina acquires importance given the possibility that this species may be a new vector of arboviruses in this region. For this reason, the studies of the biology of their parasites, such as Ascogregarina spp., should be important for the knowledge of the invasive behavior of these vectors. We reported the finding of Ascogregarina culicis in Aedes aegypti and Ascogregarina sp. in Ae. albopictus populations in subtropical Argentina. The prevalence of parasitism by A. culicis in Ae. aegypti and Ascogregrarina sp. in Ae. albopictus was 34.81% (n = 464) and 37.23% (n = 70), respectively, differing between the seasons and habitats. The infection intensity caused by A. culicis and Ascogregarina sp. varied between 1 to 250 and 1 to 327 trophozoites respectively. Ascogregarina culicis was found throughout the all sampling period of Ae. aegypti (June 2016-April 2018). However the presence of Ascogregarina sp. in the midgut of Ae. albopictus was not recorded throughout the whole sampling period despite the presence of the host.


Factor XI and recurrent venous thrombosis: an observational cohort study.
Essentials Factor XI is a potential target for anticoagulation. The association between factor XI and venous thrombosis recurrence was tested in a cohort study. Low factor XI was associated with reduced risk of recurrent venous thrombosis. A sex-and age-adjusted linear association between D-Dimer and factor XI was found. SUMMARY: Background and objectives Low factor XI activity (FXIa) reduces the risk of venous thromboembolism (VTE), and FXI is regarded as a potential target for anticoagulation. Patients/methods We studied the relationship between FXIa and VTE in 851 patients with unprovoked VTE in whom anticoagulation had been stopped. Results Recurrent VTE was recorded in 265 patients. The sex-adjusted and age-adjusted hazard ratio (HR) of recurrence was 0.94 (95% confidence interval [CI] 0.89-0.99) for each decrease of 10 IU dL-1 in FXIa. The HRs of recurrence were 0.73 (95% CI 0.54-0.99) for patients with FXIa below the 34th percentile, and 1.05 (95% CI 0.79-1.39) for patients with FXIa between the 34th and 67th percentiles, as compared with patients with higher FXIa. The probability of recurrence was lower among patients with FXIa below the 34th percentile than in patients with higher FXIa (P = 0.029). At 10 years, the probabilities of recurrence were 31%, 43% and 41% among patients with FXIa below the 34th percentile, with FXIa between the 34th and 67th percentiles, or with higher FXIa, respectively. We found a significant sex-adjusted and age-adjusted linear association between D-dimer levels, measured 3 weeks after anticoagulation, and FXIa. When patients' age and sex are taken into account, a patient with 10 IU dL-1 lower FXIa is expected to have a 2.79% (95% CI 0.95-4.59%) lower D-dimer value (P = 0.003). Conclusions Our findings of a lower thrombosis risk and less pronounced hemostatic system activation among patients with low FXIa is in line with the concept that FXI is a promising target for anticoagulation.


Optimizing scalable, technology-supported behavioral interventions to prevent opioid misuse among adolescents and young adults in the emergency department: A randomized controlled trial protocol.
Preventing opioid misuse and opioid use disorder is critical among at-risk adolescents and young adults (AYAs). An Emergency Department (ED) visit provides an opportunity for delivering interventions during a rapidly changing opioid landscape. This paper describes pilot data and the protocol for a 2 × 2 factorial randomized controlled trial testing efficacy of early interventions to reduce escalation of opioid (prescription or illicit) misuse among at-risk AYAs. Interventions are delivered using technology by health coaches. AYAs ages 16-30 in the ED screening positive for prescription opioid use (+ ≥ 1 risk factor) or opioid misuse will be stratified by risk severity, sex, and age group. Participants will be randomly assigned to a condition at intake, either a live video health coach-delivered single session or a control condition of an enhanced usual care (EUC) community resource brochure. They are also randomly assigned to one of two post-intake conditions: health coach-delivered portal-like messaging via web portal over 30 days or EUC delivered at 30 days post-intake. Thus, the trial has four groups: health coach-delivered session+portal, health coach-delivered session+EUC, EUC + portal, and EUC + EUC. Outcomes will be measured at 3-, 6-, and 12-months. The primary outcome is opioid misuse based on a modified Alcohol Smoking and Substance Involvement Screening Test. Secondary outcomes include other opioid outcomes (e.g., days of opioid misuse, overdose risk behaviors), other substance misuse and consequences, and impaired driving. This study is innovative by testing the efficacy of feasible and scalable technology-enabled interventions to reduce and prevent opioid misuse and opioid use disorder. Trial Registration:ClinicalTrials.gov University of Michigan HUM00177625 NCT Registration: NCT04550715.


Association of Medicare Mandatory Bundled Payment System for Hip and Knee Joint Replacement With Racial/Ethnic Difference in Joint Replacement Care.
There are marked racial/ethnic differences in hip and knee joint replacement care as well as concerns that value-based payments may exacerbate existing racial/ethnic disparities in care. To examine changes in joint replacement care associated with Medicare's Comprehensive Care for Joint Replacement (CJR) model among White, Black, and Hispanic patients. Retrospective cohort study of Medicare claims from 2013 through 2017 among White, Black, and Hispanic patients undergoing joint replacement in 67 treatment (selected for CJR participation) and 103 control metropolitan statistical areas. The CJR model holds hospitals accountable for spending and quality of joint replacement care during care episodes (index hospitalization through 90 days after discharge). The primary outcomes were spending, discharge to institutional postacute care, and readmission during care episodes. Among 688 346 patients, 442 163 (64.2%) were women, and 87 286 (12.7%) were 85 years or older. Under CJR, spending decreased by $439 for White patients (95% CI, -$718 to -$161; from pre-CJR spending in treatment metropolitan statistical areas of $25 264) but did not change for Black patients and Hispanic patients. Discharges to institutional postacute care decreased for all groups (-2.5 percentage points; 95% CI, -4.7 to -0.4, from pre-CJR risk of 46.2% for White patients; -6.0 percentage points; 95% CI, -9.8 to -2.2, from pre-CJR risk of 59.5% for Black patients; and -4.3 percentage points; 95% CI, -7.6 to -1.0, from pre-CJR risk of 54.3% for Hispanic patients). Readmission risk decreased for Black patients by 3.1 percentage points (95% CI, -5.9 to -0.4, from pre-CJR risk of 21.8%) and did not change for White patients and Hispanic patients. Under CJR, Black-White differences in discharges to institutional postacute care decreased by 3.4 percentage points (95% CI, -6.4 to -0.5, from the pre-CJR Black-White difference of 13.3 percentage points). No evidence was found demonstrating that Black-White differences changed for other outcomes or that Hispanic-White differences changed for any outcomes under CJR. In this cohort study of patients receiving joint replacements, CJR was associated with decreased readmissions for Black patients. Furthermore, Black patients experienced a greater decrease in discharges to institutional postacute care relative to White patients, representing relative improvements despite concerns that value-based payment models may exacerbate existing disparities. Nonetheless, differences between White and Black patients in joint replacement care still persisted even after these changes.


Ipsilateral Facial Tactile Hypesthesia in a Patient with Lateral Medullary Syndrome.
Various sensory impairments have been reported in patients with lateral medullary syndrome, also known as Wallenberg syndrome. The typical sensory impairments experienced by patients with this condition are ipsilateral facial and contralateral trunk and limb thermal hypesthesia and hypoalgesia. Tactile (light touch) sensation is not generally diminished. Here we report the case of a 35-year-old man with lateral medullary infarction who had atypical sensory impairment. We examined the results from the neurological examination of the patient as well as findings from computed tomography of the head and magnetic resonance imaging. Magnetic resonance imaging showed left lateral medullary infarction caused by left posterior inferior cerebellar artery dissection. Neurological examination revealed both tactile and thermal/pain hypesthesia on the left side of the patient's face, and thermal/pain hypesthesia on his right upper and lower limbs. There are two types of tactile sensation: epicritic and protopathic. Facial tactile sensation is usually thought to be associated with epicritic tactile sensation, which travels through principal sensory nuclei of the trigeminal nerve. The protopathic pathway travels down through the spinal tract via the trigeminal nerve and is not considered a primary pathway. However, in this case the protopathic tactile sensation pathway might be involved, and it caused facial tactile hypesthesia. Because most of previous case reports and literature reviews focused only on thermal/pain hypesthesia, we believe that this case provides critical information on the brainstem neuroanatomy, especially for the protopathic tactile sensation pathway in patients with stroke.


The contribution of medical measures to the decline of mortality from respiratory tuberculosis: an age-period-cohort model.
The decline of mortality in the more developed nations has been related to two major influences, economic development and the introduction of medical measures. The contribution of medical measures has been a source of continuing controversy. Most previous studies employ either a birth cohort or calendar year arrangement of mortality data to address this controversy. The present study applies an age-period-cohort model to mortality from respiratory tuberculosis in England and Wales, Italy, and New Zealand in an attempt to separate economic influences from that of medical measures. The results of the analysis indicate that while the overall contribution of medical measures is small when examined by calendar year, specific birth cohorts both in Italy and in England and Wales benefited substantially from these measures. The environmental conditions in New Zealand, however, were such that the introduction of medical measures barely affected declining mortality levels from respiratory tuberculosis.


An update on MSA: premotor and non-motor features open a window of opportunities for early diagnosis and intervention.
In this review, we describe the wide clinical spectrum of features that can be seen in multiple system atrophy (MSA) with a focus on the premotor phase and the non-motor symptoms providing an up-to-date overview of the current understanding in this fast-growing field. First, we highlight the non-motor features at disease onset when MSA can be indistinguishable from pure autonomic failure or other chronic neurodegenerative conditions. We describe the progression of clinical features to aid the diagnosis of MSA early in the disease course. We go on to describe the levels of diagnostic certainty and we discuss MSA subtypes that do not fit into the current diagnostic criteria, highlighting the complexity of the disease as well as the need for revised diagnostic tools. Second, we describe the pathology, clinical description, and investigations of cardiovascular autonomic failure, urogenital and sexual dysfunction, orthostatic hypotension, and respiratory and REM-sleep behavior disorders, which may precede the motor presentation by months or years. Their presence at presentation, even in the absence of ataxia and parkinsonism, should be regarded as highly suggestive of the premotor phase of MSA. Finally, we discuss how the recognition of the broader spectrum of clinical features of MSA and especially the non-motor features at disease onset represent a window of opportunity for disease-modifying interventions.


Direction-specific adaptation of motion-onset auditory evoked potentials.
Auditory evoked potentials (AEPs) to motion onset in humans are dominated by a fronto-central complex, with a change-negative deflection 1 (cN1) and a change-positive deflection 2 (cP2) component. Here the contribution of veridical motion detectors to motion-onset AEPs was investigated with the hypothesis that direction-specific adaptation effects would indicate the contribution of such motion detectors. AEPs were recorded from 33 electroencephalographic channels to the test stimulus, i.e. motion onset of horizontal virtual auditory motion (60° per s) from straight ahead to the left. AEPs were compared in two experiments for three conditions, which differed in their history prior to the motion-onset test stimulus: (i) without motion history (Baseline), (ii) with motion history in the same direction as the test stimulus (Adaptation Same), and (iii) a reference condition with auditory history. For Experiment 1, condition (iii) comprised motion in the opposite direction (Adaptation Opposite). For Experiment 2, a noise in the absence of coherent motion (Matched Noise) was used as the reference condition. In Experiment 1, the amplitude difference cP2 - cN1 obtained for Adaptation Same was significantly smaller than for Baseline and Adaptation Opposite. In Experiment 2, it was significantly smaller than for Matched Noise. Adaptation effects were absent for cN1 and cP2 latencies. These findings demonstrate direction-specific adaptation of the motion-onset AEP. This suggests that veridical auditory motion detectors contribute to the motion-onset AEP.


Overall Survival Benefit from Trastuzumab-Based Treatment in HER2-Positive Metastatic Breast Cancer: A Retrospective Analysis.
The purposes of our study were to compare the clinical outcomes of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) patients with or without trastuzumab treatment and HER2-negative patients, and to explore factors that might predict the survival benefit associated with trastuzumab treatment in HER2-positive breast cancer. A total of 421 patients with mBC were analyzed in this retrospective study. All patients had first-line chemotherapy with or without trastuzumab. They were classified into 3 groups according to their HER2 status and trastuzumab treatment: HER2-positive mBC patients with or without trastuzumab treatment and HER2-negative patents. Trastuzumab administration in HER2-positive mBC patients significantly prolonged overall survival (33 vs. 26 months; P = 0.003) and led to a 49.8% reduction in death risk. In the subgroup analysis, HER2-positive patients with hormone receptor (HR)-negative status (29 vs. 17 months; P = 0.000) or visceral metastasis (30 vs. 21 months; P = 0.000) had more survival benefit when treated with trastuzumab. Trastuzumab administration significantly improved the overall survival in HER2-positive mBC patients, who gained a prognosis comparable to that of patients with HER2-negative disease. HR status and metastasis site might be important surrogate makers that predict survival benefit from trastuzumab-based treatment.


Building surrogate temporal network data from observed backbones.
Many systems of socioeconomic interests find a convenient representation in the form of temporal networks, i.e., sets of nodes and interactions occurring at specified times. In the corresponding data sets, however, crucial elements coexist with nonessential ones and noise. Several methods have thus been proposed to extract a "network backbone," i.e., the set of most important links in a network data set. The outcome of such methods can be seen as compressed versions of the original data. However, the question of how to practically use such reduced views of the data has not been tackled: for instance, using them directly in numerical simulations of processes on networks might lead to important biases. Overall, such reduced views of the data might not be actionable without an adequate decompression method. Here, we address this issue by putting forward and exploring several systematic procedures to build surrogate data from various kinds of temporal network backbones. In particular, we explore how much information about the original data needs to be retained alongside the backbone so that the surrogate data can be used in data-driven numerical simulations of spreading processes on a wide range of spreading parameters. We illustrate our results using empirical temporal networks with a broad variety of structures and properties. Our results give hints on how to best summarize complex data sets so that they remain actionable. Moreover, they show how ensembles of surrogate data with similar properties can be obtained from an original single data set, without any modeling assumptions.


Military Medical Students' Coping With Stress to Maintain Well-being.
Previous studies have shown that medical students experience a great level of burnout and poor well-being during their clinical training periods. In this study, we sought to understand how military medical students cope with stress to prevent burnout and support their well-being. We also investigated if these coping strategies are associated with military medical students' self-reported well-being, burnout, and depression levels. The findings could help inform programming, resources, and educational strategies to better support students to thrive in their careers long term. Using a cross-sectional research design, we surveyed military medical students and conducted content analysis on participant responses to the open-ended item by trained coders. Coding was based on the existing coping theory frameworks as well as categories that emerged inductively to represent the data. The primary four strategies military medical students utilized included social connection (59.9%), exercise (58.3%), personal relaxation (36%), and work-life balance (15.7%). The use of work-life balance strategy was significantly associated with more positive well-being and lower depression compared to those who did not use this strategy. Three main coping typologies were further extracted, including personal care, connection, and cognitive strategies. Based on the typologies, 62% of students were recognized as multi-type copers (who combined more than two coping typologies), who reported significantly more positive well-being compared to students who relied on a single typology. The findings demonstrate that certain coping strategies are more positively associated with a good state of well-being and less burnout, and that utilization of multiple types of coping strategies is more supportive. This study amplifies the voice of military medical students concerning the importance of prioritizing self-care and available resources given the unique pressures and demands of their dual military medical curriculum.


Durable complete responses in metastatic melanoma treated with interleukin-2 in combination with interferon alpha and chemotherapy.
Biochemotherapy, which uses recombinant interferon alpha (rIFN-alpha) and recombinant interleukin-2 (rIL-2) in combination with chemotherapy is a promising therapy for metastatic malignant melanoma. Various biochemotherapy regimens have produced overall objective response rates of > 50% and durable complete remission (CR) in approximately 10%-of treated patients. One such biochemotherapy regimen, consisting of sequential administration of cisplatin, vinblastine, and dacarbazine (CVD regimen) followed by rIFN-alpha and rIL-2, has produced a response rate of 60% and a CR rate of 20% in the most recent cohort of 62 patients treated at The University of Texas M.D. Anderson Cancer Center. The duration of partial responses with this and similar regimens typically averages 6 to 9 months; however, more than half of the CRs achieved with this regimen have been durable for 3+ to 5+ years. This has raised the possibility of long-term survival in approximately 10% of patients with metastatic melanoma. If confirmed, this will represent a significant advance in the treatment of metastatic melanoma.


Carcinoma cells that have undergone an epithelial-mesenchymal transition differentiate into endothelial cells and contribute to tumor growth.
Hypoxia stimulates neoangiogenesis, promoting tumor outgrowth, and triggers the epithelial-mesenchymal transition (EMT), which bestows cells with mesenchymal traits and multi-lineage differentiation potential. Here, we investigated whether EMT can confer endothelial attributes upon carcinoma cells, augmenting tumor growth and vascularization. Following orthotopic implantation of MCF-7 human epithelial breast cancer cells into mice, tumors of different sizes were immunostained for markers of hypoxia and EMT. Larger tumors were well-vascularized with CD31-positive cells of human origin. Hypoxic regions, demarcated by HIF-1α staining, exhibited focal areas of E-cadherin loss and elevated levels of vimentin and the EMT-mediator FOXC2. Implantation of MCF-7 cells, co-mixed with human mammary epithelial (HMLE) cells overexpressing the EMT-inducer Snail, markedly potentiated tumor growth and vascularization, compared with MCF-7 cells injected alone or co-mixed with HMLE-vector cells. Intra-tumoral vessels contained CD31-positive cells derived from either donor cell type. FOXC2 knockdown abrogated the potentiating effects of HMLE-Snail cells on MCF-7 tumor growth and vascularization, and compromised endothelial transdifferentiation of mesenchymal cells cultured in endothelial growth medium. Hence, cells that have undergone EMT can promote tumor growth and neovascularization either indirectly, by promoting endothelial transdifferentiation of carcinoma cells, or directly, by acquiring an endothelial phenotype, with FOXC2 playing key roles in these processes.


[Hematodermic CD4+ CD56+ neoplasm in childhood].
Hematodermic CD4+ CD56+ neoplasm with plasmacytoid dendritic cell phenotype is a rare and aggressive neoplasm recently recognized by the WHO-EORTC classification. It generally appears in elderly adults, exceptionally in childhood. We present a 12-year-old girl with severe mental retardation, genetic clinical features and multiple nodular cutaneous lesions on legs and arms. Histologically the nodules showed diffuse dermal infiltrate of medium and small cells and expression of CD4, CD56, CD43, S100 and plasmacytoid dendritic markers: CD123, BDCA-2 under flow cytometry study. Peripheral blood and bone marrow were not involved. Clinical remission of cutaneous lesions was observed after two weeks of acute lymphoblastic leukemia therapy.


Malat1 as an evolutionarily conserved lncRNA, plays a positive role in regulating proliferation and maintaining undifferentiated status of early-stage hematopoietic cells.
The metastasis-associated lung adenocarcinoma transcription 1 (Malat1) is a highly conserved long non-coding RNA (lncRNA) gene. Previous studies showed that Malat1 is abundantly expressed in many tissues and involves in promoting tumor growth and metastasis by modulating gene expression and target protein activities. However, little is known about the biological function and regulation mechanism of Malat1 in normal cell proliferation. In this study we conformed that Malat1 is highly conserved across vast evolutionary distances amongst 20 species of mammals in terms of sequence, and found that mouse Malat1 expresses in tissues of liver, kidney, lung, heart, testis, spleen and brain, but not in skeletal muscle. After treating erythroid myeloid lymphoid (EML) cells with All-trans Retinoic Acid (ATRA), we investigated the expression and regulation of Malat1 during hematopoietic differentiation, the results showed that ATRA significantly down regulates Malat1 expression during the differentiation of EML cells. Mouse LRH (Lin-Rhodamine(low) Hoechst(low)) cells that represent the early-stage progenitor cells show a high level of Malat1 expression, while LRB (Lin - Hoechst(Low) Rhodamine(Bright)) cells that represent the late-stage progenitor cells had no detectable expression of Malat1. Knockdown experiment showed that depletion of Malat1 inhibits the EML cell proliferation. Along with the down regulation of Malat1, the tumor suppressor gene p53 was up regulated during the differentiation. Interestingly, we found two p53 binding motifs with help of bioinformatic tools, and the following chromatin immunoprecipitation (ChIP) test conformed that p53 acts as a transcription repressor that binds to Malat1's promoter. Furthermore, we testified that p53 over expression in EML cells causes down regulation of Malat1. In summary, this study indicates Malat1 plays a critical role in maintaining the proliferation potential of early-stage hematopoietic cells. In addition to its biological function, the study also uncovers the regulation pattern of Malat1 expression mediated by p53 in hematopoietic differentiation. Our research shed a light on exploring the Malat1 biological role including therapeutic significance to inhibit the proliferation potential of malignant cells.


Aging of human hematopoietic stem cells is linked to changes in Cdc42 activity.
In this study, we characterize age-related phenotypes of human hematopoietic stem cells (HSC). We report increased frequencies of HSC, hematopoietic progenitor cells and lineage negative cells in the elderly but a decreased frequency of multi-lymphoid progenitors. Aged human HSC further exhibited a delay in initiating division ex vivo though without changes in their division kinetics. The activity of the small RhoGTPase Cdc42 was elevated in aged human hematopoietic cells and we identified a positive correlation between Cdc42 activity and the frequency of HSC upon aging. The frequency of human HSC polar for polarity proteins was, similar to the mouse, decreased upon aging, while inhibition of Cdc42 activity via the specific pharmacological inhibitor of Cdc42 activity, CASIN, resulted in re-polarization of aged human HSC with respect to Cdc42. Elevated activity of Cdc42 in aged HSC thus contributed to age-related changes in HSC. Xenotransplant, using NBSGW mice as recipients, showed elevated chimerism in recipients of aged compared to young HSC. Aged HSC treated with CASIN ex vivo displayed an engraftment profile similar to recipients of young HSC. Taken together, our work reveals strong evidence for a role of elevated Cdc42 activity in driving aging of human HSC, and similar to mice, this presents a likely possibility for attenuation of aging in human HSC.


[Amebiasis and amebic liver abscess in Mexico: a present-day public health problem].
Amebiasis still remains as a major public health problem in the world. It is one of the most common reasons for medical consult. There are more than half a million cases of amebiasis just at the Mexican Institute of the Social Security. There is still a lack of epidemiologic information on amebiasis in Mexico. To describe the secular trend fro amebiasis and for amebic liver abscess in the Mexican population, as well as in those covered by IMSS Solidaridad. An ecologic trend study was carried on. Incidence rate of amebiasis in all of its forms of presentation, and of amebic liver abscess, were plotted against each year for the 1986-1994 period. Amebiasis incidence in all of its forms of presentation showed a stable trend in this period, as it was seen with amebic liver abscess. Amebiasis is more common in the first years of life. On the contrary, amebic liver abscess showed an inverted 'J' pattern; its occurrence is higher in the extreme years of life. Fatality rates have shown a descendent trend. Amebiasis reflects socioeconomic conditions in Mexico and the fact that Mexican is still an endless culture. There is a need to promote health education, better diagnostic procedures and detection of asymptomatic carriers. Health policies for mothers that are asymptomatic carriers should be reviewed, due to the high rates of amebiasis and amebic liver abscess in children under one year of age.


Predictors of Diffusing Capacity in Children With Sickle Cell Disease: A Longitudinal Study.
Background: Gas exchange abnormalities in Sickle Cell Disease (SCD) may represent cardiopulmonary deterioration. Identifying predictors of these abnormalities in children with SCD (C-SCD) may help us understand disease progression and develop informed management decisions. Objectives: To identify pulmonary function tests (PFT) estimates and biomarkers of disease severity that are associated with and predict abnormal diffusing capacity (DLCO) in C-SCD. Methods: We obtained PFT data from 51 C-SCD (median age:12.4 years, male: female = 29:22) (115 observations) and 22 controls (median age:11.1 years, male: female = 8:14), formulated a rank list of DLCO predictors based on machine learning algorithms (XGBoost) or linear mixed-effect models, and compared estimated DLCO to the measured values. Finally, we evaluated the association between measured or estimated DLCO and clinical outcomes, including SCD crises, pulmonary hypertension, and nocturnal desaturation. Results: Hemoglobin-adjusted DLCO (%) and several PFT indices were diminished in C-SCD compared to controls. Both statistical approaches ranked FVC (%), neutrophils (%), and FEF25-75 (%) as the top three predictors of DLCO. XGBoost had superior performance compared to the linear model. Both measured and estimated DLCO demonstrated a significant association with SCD severity: higher DLCO, estimated by XGBoost, was associated with fewer SCD crises [beta = -0.084 (95%CI: -0.13, -0.033)] and lower TRJV [beta = -0.009 (-0.017, -0.001)], but not with nocturnal desaturation (p = 0.12). Conclusions: In this cohort of C-CSD, DLCO was associated with PFT estimates representing restrictive lung disease (FVC, TLC), airflow obstruction (FEF25-75, FEV1/FVC, R5), and inflammation (neutrophilia). We used these indices to estimate DLCO, and show association with disease outcomes, underscoring the prediction models' clinical relevance.


Corrigendum: A 3-year controlled randomized clinical study on the performance of two glass-ionomer cements in Class II cavities of permanent teeth.
To compare the clinical performance of two glass-ionomer cements in combination with two light-cured coatings in Class II cavities. In total, 43 Equia Fil/Equia Coat and 42 Fuji IX GP Fast/Fuji Coat LC restorations were placed, in 34 patients. Only Class II cavities with two- or three-surface restorations were included. The clinical performance was evaluated at baseline, after 1, 2, and 3 years using the FDI criteria. For the statistical analysis, Fisher exact test, Wilcoxon signed-rank test and Mann-Whitney U test were applied. The success and survival of the restorations were calculated with the Kaplan-Meier method and a log-rank test was used to detect significant differences between the tested materials. At the 3-year recall, no significant differences could be detected between the two glass-ionomer cements for any of the evaluated criteria (Mann-Whitney U test, P > .05). When comparing the baseline with the recall data at 3 years for each material separately, significant changes could be observed in both materials for the criteria "surface luster," "fracture of material and retention," and "approximal anatomical form" (Wilcoxon signed-rank test, P < .05). Additionally, the Equia Fil restorations showed a notable change for the criteria "marginal adaptation" (Wilcoxon signed-rank test, P = .039). At the 3-year follow up, the Equia Fil and the Fuji IX GP Fast restorations exhibited an overall survival rate of 89.3% and 88.0%, respectively. Three fillings in each group failed. The two glass-ionomer cements tested performed similarly in Class II cavities in adult patients, with a moderate failure rate after 3 years. (Original article published in Quintessence Int 2019;50:592-602; doi: 10.3290/j.qi.a42692).


Undeveloped green space and free-time physical activity in 11 to 13-year-old children.
Research on the association between the physical environment and physical activity in children has focused on built and developed features or total green space. The impact of natural, undeveloped green spaces is unknown. The objective of this study was to determine whether the presence of undeveloped green spaces in the home neighborhood are associated with physical activity in 11 to 13-year-olds. This was a cross-sectional study of grade 6 to 8 urban residing Canadian students who participated in the 2009/10 Health Behaviour in School-Aged Children survey. Children self-reported the frequency they participated in physical activity in their free-time outside of school hours. Geographic Information Systems (GIS) were used to assess the proportion of land area within 1 km of participants' homes that was devoted to publicly accessible meadows (i.e., field vegetated primarily by grass and other non-woody plants) and treed areas (i.e., field vegetated primarily by trees and shrubs). Ordinal logistic regression models were used to examine the relationships between the undeveloped green space areas and free-time physical activity. Several intrapersonal, family, and neighborhood environment factors were controlled for in these regression models. The proportion of neighborhood land covered by meadows was not associated with the physical activity outcome (p > 0.6). However, the proportion of neighborhood land covered by treed areas was independently associated with the physical activity outcome (p = 0.02). For each additional 5% increase in the proportion of neighborhood land covered by treed areas there was a corresponding 5% increase (95% confidence interval: 1-10% increase) in the relative odds of increasing free-time physical activity outside of school hours. The physical activity levels of 11 to 13-year-old children was associated with the amount of space in their home neighborhood devoted to treed areas.


Characterization of Euphorbia characias latex amine oxidase.
A copper-containing amine oxidase from the latex of Euphorbia characias was purified to homogeneity and the copper-free enzyme obtained by a ligand-exchange procedure. The interactions of highly purified apo- and holoenzyme with several substrates, carbonyl reagents, and copper ligands were investigated by optical spectroscopy under both aerobic and anaerobic conditions. The extinction coefficients at 278 and 490 nm were determined as 3.78 x 10(5) M-1 cm-1 and 6000 M-1 cm-1, respectively. Active-site titration of highly purified enzyme with substrates and carbonyl reagents showed the presence of one cofactor at each enzyme subunit. In anaerobiosis the native enzyme oxidized one equivalent substrate and released one equivalent aldehyde per enzyme subunit. The apoenzyme gave exactly the same 1:1:1 stoichiometry in anaerobiosis and in aerobiosis. These findings demonstrate unequivocally that copper-free amine oxidase can oxidize substrates with a single half-catalytic cycle. The DNA-derived protein sequence shows a characteristic hexapeptide present in most 6-hydroxydopa quinone-containing amine oxidases. This hexapeptide contains the tyrosinyl residue that can be modified into the cofactor 6-hydroxydopa quinone.


Negative mood and mind wandering increase long-range temporal correlations in attention fluctuations.
There is growing evidence that the intermittent nature of mind wandering episodes and mood have a pronounced influence on trial-to-trial variability in performance. Nevertheless, the temporal dynamics and significance of such lapses in attention remains inadequately understood. Here, we hypothesize that the dynamics of fluctuations in sustained attention between external and internal sources of information obey so-called critical-state dynamics, characterized by trial-to-trial dependencies with long-range temporal correlations. To test this, we performed behavioral investigations measuring reaction times in a visual sustained attention task and cued introspection in probe-caught reports of mind wandering. We show that trial-to-trial variability in reaction times exhibit long-range temporal correlations in agreement with the criticality hypothesis. Interestingly, we observed the fastest responses in subjects with the weakest long-range temporal correlations and show the vital effect of mind wandering and bad mood on this response variability. The implications of these results stress the importance of future research to increase focus on behavioral variability.


Use of single-mode waveguides to correct the optical defects of a nulling interferometer.
In the area of long-baseline nulling interferometry, high rejection ratios are needed to cancel out the light of a bright central source and look for nearby faint structures or companions. These rejection requirements directly translate into drastic optical constraints. We discuss the possibility of using single-mode waveguides for such applications. Conversely to simple pinholes, single-mode waveguides efficiently correct wave-front defects of both high- and low-order spatial frequencies, ensure a perfect matching of the amplitude profiles coming from the various beams, and can be used with almost optimum coupling efficiency over a broad optical bandpass (typically an octave). They then appear to greatly enhance the feasibility of high-dynamic interferometric coronagraphs.


Understanding the role of individual units in a deep neural network.
Deep neural networks excel at finding hierarchical representations that solve complex tasks over large datasets. How can we humans understand these learned representations? In this work, we present network dissection, an analytic framework to systematically identify the semantics of individual hidden units within image classification and image generation networks. First, we analyze a convolutional neural network (CNN) trained on scene classification and discover units that match a diverse set of object concepts. We find evidence that the network has learned many object classes that play crucial roles in classifying scene classes. Second, we use a similar analytic method to analyze a generative adversarial network (GAN) model trained to generate scenes. By analyzing changes made when small sets of units are activated or deactivated, we find that objects can be added and removed from the output scenes while adapting to the context. Finally, we apply our analytic framework to understanding adversarial attacks and to semantic image editing.


Utility of Ultrasound Guidance for Central Venous Access in Children.
Placement of a central venous catheter (CVC) in a pediatric patient is an important skill for pediatric emergency medicine physicians but can be challenging and time consuming. Ultrasound (US) guidance has been shown to improve success of central line placement in adult patients. This article aims to review the literature and evaluate the benefit of US guidance in the placement of CVCs, specifically in pediatric emergency department patients, and to review the procedure. Four meta-analyses of US-guided CVC placement in adult patients concluded that US guidance reduces placement failure, decreases complications, and decreases the need for multiple attempts. Two studies in the emergency department setting support these conclusions. Pediatric-specific data related to US-guided CVC placement include data suggesting a benefit with US guidance, as well as data indicating no difference in outcome measures when US guidance is used compared with the landmark technique. The evidence surrounding US-guided CVC insertion supports its use in adult patients. Pediatric-specific literature is sparse and includes mixed results. As more pediatric emergency physicians adopt the use of point-of-care US, we expect an increase in data supporting its use for CVC placement in pediatric emergency department patients.


The scaffolding protein NHERF1 sensitizes EGFR-dependent tumor growth, motility and invadopodia function to gefitinib treatment in breast cancer cells.
Triple negative breast cancer (TNBC) patients cannot be treated with endocrine therapy or targeted therapies due to lack of related receptors. These patients overexpress the epidermal growth factor receptor (EGFR), but are resistant to tyrosine kinase inhibitors (TKIs) and anti-EGFR therapies. Mechanisms suggested for resistance to TKIs include EGFR independence, mutations and alterations in EGFR and in its downstream signalling pathways. Ligand-induced endocytosis and degradation of EGFR play important roles in the downregulation of the EGFR signal suggesting that its activity could be regulated by targeting its trafficking. Evidence in normal cells showing that the scaffolding protein Na+/H+ exchanger regulatory factor 1 (NHERF1) can associate with EGFR to regulate its trafficking, led us to hypothesize that NHERF1 expression levels could regulate EGFR trafficking and functional expression in TNBC cells and, in this way, modulate its role in progression and response to treatment. We investigated the subcellular localization of NHERF1 and its interaction with EGFR in a metastatic basal like TNBC cell model, MDA-MB‑231, and the role of forced NHERF1 overexpression and/or stimulation with EGF on the sensitivity to EGFR specific TKI treatment with gefitinib. Stimulation with EGF induces an interaction of NHERF1 with EGFR to regulate its localization, degradation and function. NHERF1 overexpression is sufficient to drive its interaction with EGFR in non-stimulated conditions, inhibits EGFR degradation and increases its retention time in the plasma membrane. Importantly, NHERF1 overexpression strongly sensitized the cell to the pharmacological inhibition by gefitinib of EGFR-driven growth, motility and invadopodia-dependent ECM proteolysis. The further determination of how the NHERF1‑EGFR interaction is regulated may improve our understanding of TNBC resistance to the action of existing anticancer drugs.


Rapid screening of aminopeptidase N inhibitors by capillary electrophoresis with electrophoretically mediated microanalysis.
In this work, an electrophoretically mediated microanalysis (EMMA) method with a partial-filling technique was setup to evaluate the inhibitory potency of novel compounds toward aminopeptidase N (APN). It was necessary to optimize the electrophoretic conditions with respect to the kinetic constraints and for attaining high sensitivity. In our setup, a part of the capillary was filled with the incubation buffer for the enzyme reaction, whereas the rest was filled with a suitable BGE for the separation of substrates and products. To monitor the performance of the newly developed method, the kinetic constants (Km and Vmax) for the catalyzed dissociation of L-Leucine-p-nitroanilide in the presence of APN as well as the inhibition constant (IC50 ) of a known competitive inhibitor, that is bestatin, were determined and these results were compared with those obtained by a classical spectrophotometric assay. The developed EMMA method was subsequently applied to the screening of 30 APN inhibitors. Whereas the inhibition potency of these inhibitors (expressed in IC50 values) were significantly underestimated by the EMMA method, the order of the inhibitory potential of these various compounds was found in agreement with the literature.


Major royal jelly proteins prevents NAFLD by improving mitochondrial function and lipid accumulation through activating the AMPK / SIRT3 pathway in vitro.
Nonalcoholic fatty liver disease (NAFLD) is a metabolic syndrome, whose main characteristics are excessive lipid accumulation and oxidative stress. Major royal jelly proteins (MRJPs) is a kind of water-soluble protein, which is abundant in royal jelly (RJ). The aim of this study was to evaluate the effect of MRJPs on lipid accumulation and oxidative stress of liver cells. Here, we first optimized the conditions for extracting MRJPs from RJ and identified the extraction effect and product by SDS-PAGE. Then, we used oleic acid (OA) of 1.0 mM to induce hepatocytes for 24 hr to establish a stable cell models of lipid accumulation, and we found that pre-administration (24 hr) of MRJPs (0.2, 0.5, and 1.0 g/L) could significantly reduce the lipid drop content and triglyceride level in the model cells, and simultaneously reduce the alanine aminotransferase and aspertate aminotransferase levels in the cell culture supernatant. In addition, pre-incubation (24 hr) with MRJPs (0.2, 0.5, and 1.0 g/L) could restore superoxide dismutase (SOD) level and mitochondrial membrane potential as compared with OA group. Furthermore, MRJPs administration significantly upregulated the expression of Silent Information Regulator 2 Associated Protein 3, mitochondrial superoxide dismutase (SOD2), and cytochrome c oxidase subunit IV in OA-treated HepG2 cells. The study for the first time provides evidences on the lipid-lowering effect of MRJPs at the cellular level, which can further provide support for the development and application of polypeptide drugs in the future, and can also provide a choice for the prevention and treatment of liver metabolic diseases represented by NAFLD. PRACTICAL APPLICATION: Our study proved that MRJPs had substantial preventing effect on OA-induced lipid accumulation and mitochondrial dysfunction in HepG2 cells. This research can further provide theoretical support for the development and application of peptide drugs in the future. Besides, it can not only further broaden our understanding of NAFLD and other diseases, but also provide ideas for research on oxidative stress and lipid accumulation in the body.


Swagger, sway, and sexuality: Judging sexual orientation from body motion and morphology.
People can accurately judge the sexual orientation of others, but the cues they use have remained elusive. In 3 studies, the authors examined how body shape and motion affect perceived sexual orientation. In 2 studies, participants judged the sexual orientation of computer-generated animations in which body shape and motion were manipulated. Gender-typical combinations (e.g., tubular body moving with shoulder swagger or hourglass body moving with hip sway) were perceived generally to be heterosexual; gender-atypical combinations were perceived generally to be homosexual. These effects were stronger for male targets. Body shape affected perceived sexual orientation of women, but motion affected perceived sexual orientation of both men and women. Study 3 replicated and extended these findings. Participants judged dynamic outlines of real people (men and women, both gay and straight) in which body shape and motion were measured. Again, gender-atypical body motion affected perceived sexual orientation and, importantly, affected accuracy as well.


The effect of administration of fenbendazole on the microbial hindgut population of the horse.
Anthelmintics are used as anti-worming agents. Although known to affect their target organisms, nothing has been published regarding their effect on other digestive tract organisms or on metabolites produced by them. The current work investigated effects of fenbendazole, a benzimidazole anthelmintic, on bacteria and ciliates in the equine digestive tract and on and their major metabolites. Animals receiving anthelmintic treatment had high faecal egg counts relative to controls. Analysis was performed over two weeks, with temporal differences detected in bacterial populations but with no other significant differences detected. This suggests fenbendazole has no detectable effect on organisms other than its targets. Moreover it does not appear to make a contribution to changing the resulting metabolome.


Learning outcomes for health professions: the concept of the swiss competencies framework.
Modern conceptions of education are based on normative goals concerning learning outcomes in terms of competencies to acquire. The objective of the Swiss competencies framework was to define general and profession-specific learning outcomes for Bachelor's and Master's degree programmes in nursing, physiotherapy, occupational therapy (ergotherapy), midwifery, nutrition counselling, and technicians in medical radiology. In addition, national authorities needed an instrument that allowed the integration of the old professional trainings into a nationally-harmonised education system and that showed the specificities of the levels (higher vocational education; bachelor and master degree at university level). While the general learning outcomes were derived from legal bases, the profession-specific learning outcomes are elaborated according to the competency-based CanMEDS framework. In the CanMEDS framework, knowledge, skills, and attitudes are condensed into meta-competencies which in turn are divided into seven roles, including the medical expert (central role). Taxonomic characteristics and indicators were elaborated in an iterative process that involved regulators, the universities of applied sciences and professional organisations. For the degree programmes mentioned above, the framework developed focuses not only on professional expertise, but also on collaboration with other health professions. Moreover, the interface-management in care taking processes is a critical success factor. Based on this conception, three levels of objectives were identified: general competencies, profession-specific learning outcomes and learning objectives to be implemented in the universities of applied sciences. The general competencies are composed of four dimensions and apply to all health professionals. The profession-specific learning outcomes for the Bachelor's and Master's degree programmes are outlined with 3 to 5 indicators each in all seven professions concerned. The definition and identification of these learning outcomes allows locating the different study programmes on the correct level of tertiary education. The resulting competency framework can be applied to all health professions. The general and job-specific learning outcomes are a coherent, coordinated set of standards, which represent the objectives of Bachelor's and Master's degree programmes in a differentiated way and promote inter-professional collaboration.


Calcium ions and cell fusion. Effects of chemical fusogens on the permeability of erythrocytes to calcium and other ions.
1. Fusogenic and non-fusogenic chemicals were tesetd for their ability to allow 45Ca2+ and 3H2O to enter hen and human erythrocytes. 2. The ratio of 45Ca2+/3H2O in treated cells to that in untreated cells is referred to as the entry ratio. 3. Within 1 min at 37 degrees C both water-soluble and lipid-soluble fusogens increased the value of the entry ratio, which reached maximum values in 5--10 min. 4. Values of the entry ratio in the range of 4--12 were found under conditions that led to cell fusion. 5. Closely related but non-fusogenic chemicals did not significantly alter the entry ratio. 6. The entry ratios for 86Rb+, 22Na+ and 35SO42- were also significantly increased by both lipid-soluble and water-soluble fusogens, though the increases were not as large as those for 45Ca2+. 7. It is suggested that fusogenic compounds increase the permeability of biological membranes to ions, and that an increase in the concentration of intracellular Ca2+ initiates or facilitates events that lead to the chemically induced fusion of erythrocytes.


Antibody-mediated rejection with detection of de novo donor-specific anti-human leukocyte antigen Class II antibodies after lung transplantation: Problems in diagnosis, treatment and monitoring on a case report basis.
Lung transplantation, like other transplants, carries a risk of graft rejection due to genetic differences between the donor and the recipient. In this paper, we focus on antibody-mediated rejection, which can cause acute and more importantly chronic graft dysfunction and subsequently shortened allograft survival. We present the case of a 46-year-old patient who, two months after lung transplantation (LTx), developed AMR manifested by the deterioration of graft function and de novo production of donor-specific antibodies (DSA): DQ3 (DQ7, DQ8, DQ9). As the patient was after left single LTx and heavily oxygen dependent a transbronchial biopsy was deemed to be high risk and it was decided to determine the clinical significance of the detected antibodies by their ability to bind complement. The test confirmed that the detected DSAs have the ability cause cytotoxicity of the transplanted organ. After treatment with methotrexate, intravenous immunoglobulin G (IVIg) and alemtuzumab, the patient's condition improved and a complete decrease in DSA was obtained. However, after a year, the production of antibodies increased sharply. Treatment with IVIg, cyclophosphamide and plasmapheresis slightly improved the patient's condition, reducing the MFI DSA values by half, but leaving them at high levels. Based on this clinical case, we discuss problems with making a diagnosis, choosing the right AMR treatment and monitoring the patient's condition during treatment. We also indicate a poor prognosis in the case of the production of DSA antibodies at the DQ locus.


[Chronic myeloid leukemia].
Chronic myeloid leukemia is still the most characteristic entity of the chronic myeloproliferative diseases. The tumor promoter role of able-dependent tyrosine kinase activation, which is enhanced by bcr/abl rearrangement (due the classical translocation of Philadelphia chromosomal abnormality) has been quite well clarified. The better understanding of the role of altered cell signalling pathways in the pathogenesis of chronic myeloid leukaemia opened new areas for extensive and fruitful pharmacological research. The first, non-myelosuppressive agent, which was able to reduce the number of Philadelphia positive clonal cells was the interferon group, which drug could substantially prolong the chronic phase and mortality of chronic myeloid leukaemia. Imatinib mesylate, a tyrosine-kinase inhibitor seems to be able to produce clinical and major cytogenetic response in more than 80% of patients. Imatinib is also a powerful agent in the accelerated or blastic phased of chronic myeloid leukaemia. With the advent of these new drugs the therapeutic algorithm of chronic myeloid leukaemia and allogenous bone marrow transplantation seems to be reconsidered, too.


In situ observation of plasmon tuning in a single gold nanoparticle during controlled melting.
In this Letter we study the relations among shape, symmetry, and plasmon resonance shift in a single gold nanoparticle during laser melting. A beam of an argon ion laser is focused on a selected particle, while its optical and shape properties can be observed with the help of a combined dark-field/photoluminescence microscope and an atomic force microscope, respectively. Starting from a spherical shape, radiation pressure forms the melting gold particle into an upright standing rod on a glass substrate, showing a characteristic dipole scattering pattern. A red-shift of the photoluminescence signal and the scattering spectrum is observed. The melting process can be controlled allowing the formation of different particle heights and plasmon resonance shifts. In situ tuning of the plasmon resonance of individual particles is possible with this reversible melting process.


Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking.
The basolateral amygdala (BLA) has a crucial role in emotional learning irrespective of valence. The BLA projection to the nucleus accumbens (NAc) is thought to modulate cue-triggered motivated behaviours, but our understanding of the interaction between these two brain regions has been limited by the inability to manipulate neural-circuit elements of this pathway selectively during behaviour. To circumvent this limitation, we used in vivo optogenetic stimulation or inhibition of glutamatergic fibres from the BLA to the NAc, coupled with intracranial pharmacology and ex vivo electrophysiology. Here we show that optical stimulation of the pathway from the BLA to the NAc in mice reinforces behavioural responding to earn additional optical stimulation of these synaptic inputs. Optical stimulation of these glutamatergic fibres required intra-NAc dopamine D1-type receptor signalling, but not D2-type receptor signalling. Brief optical inhibition of fibres from the BLA to the NAc reduced cue-evoked intake of sucrose, demonstrating an important role of this specific pathway in controlling naturally occurring reward-related behaviour. Moreover, although optical stimulation of glutamatergic fibres from the medial prefrontal cortex to the NAc also elicited reliable excitatory synaptic responses, optical self-stimulation behaviour was not observed by activation of this pathway. These data indicate that whereas the BLA is important for processing both positive and negative affect, the glutamatergic pathway from the BLA to the NAc, in conjunction with dopamine signalling in the NAc, promotes motivated behavioural responding. Thus, optogenetic manipulation of anatomically distinct synaptic inputs to the NAc reveals functionally distinct properties of these inputs in controlling reward-seeking behaviours.


Atheroprotective potentials of curcuminoids against ginger extract in hypercholesterolaemic rabbits.
The anti-atherogenic potentials of total ginger (Zingiber officinale) extract (TGE) or curcuminoids extracted from turmeric (Curcuma longa), members of family Zingiberaceae, were compared in hypercholesterolaemia. Rabbits were fed either normal or atherogenic diet. The rabbits on atherogenic diet received treatments with TGE or curcumenoids and placebo concurrently for 6 weeks (n = 6). The anti-atherogenic effects of curcuminoids and ginger are mediated via multiple mechanisms. This effect was correlated with their ability to lower cholesteryl ester transfer protein activity. Ginger extract exerted preferential effects on plasma lipids, reverse cholesterol transport, cholesterol synthesis and inflammatory status. Curcuminoids, however, showed superior antioxidant activity.


Multiplex Immunofluorescence in Formalin-Fixed Paraffin-Embedded Tumor Tissue to Identify Single-Cell-Level PI3K Pathway Activation.
Identifying cancers with high PI3K pathway activity is critical for treatment selection and eligibility into clinical trials of PI3K inhibitors. Assessments of tumor signaling pathway activity need to consider intratumoral heterogeneity and multiple regulatory nodes. We established a novel, mechanistically informed approach to assessing tumor signaling pathways by quantifying single-cell-level multiplex immunofluorescence using custom algorithms. In a proof-of-concept study, we stained archival formalin-fixed, paraffin-embedded (FFPE) tissue from patients with primary prostate cancer in two prospective cohort studies, the Health Professionals Follow-up Study and the Physicians' Health Study. PTEN, stathmin, and phospho-S6 were quantified on 14 tissue microarrays as indicators of PI3K activation to derive cell-level PI3K scores. In 1,001 men, 988,254 tumor cells were assessed (median, 743 per tumor; interquartile range, 290-1,377). PI3K scores were higher in tumors with PTEN loss scored by a pathologist, higher Gleason grade, and a new, validated bulk PI3K transcriptional signature. Unsupervised machine-learning approaches resulted in similar clustering. Within-tumor heterogeneity in cell-level PI3K scores was high. During long-term follow-up (median, 15.3 years), rates of progression to metastases and death from prostate cancer were twice as high in the highest quartile of PI3K activation compared with the lowest quartile (hazard ratio, 2.04; 95% confidence interval, 1.13-3.68). Our novel pathway-focused approach to quantifying single-cell-level immunofluorescence in FFPE tissue identifies prostate tumors with PI3K pathway activation that are more aggressive and may respond to pathway inhibitors.


Phase I and II study of fludarabine phosphate in leukemia: therapeutic efficacy with delayed central nervous system toxicity.
Fludarabine phosphate (9-beta-D-arabinofuranosyl-2-fluoroadenine), a novel purine nucleoside, has demonstrated excellent preclinical antitumor activity and little toxicity in phase I clinical trials. We evaluated the clinical use of fludarabine given as a continuous intravenous (IV) infusion for remission induction in patients with relapsed or refractory leukemia. Thirty infusions were administered to 25 patients. At doses less than or equal to 125 mg/m2/d for five days, only three of 17 patients cleared their bone marrow of leukemic cells, and none achieved complete remission (CR). Nine patients received doses of 150 mg/m2/d for five days or 125 mg/m2/d for seven days. Four of these patients achieved CR (three patients with acute nonlymphoblastic leukemia (ANLL), one patient with acute lymphoblastic leukemia (ALL]. However, severe CNS toxicity was encountered in five patients at the two highest dose levels. Initial symptoms of neurotoxicity were delayed from 21 to 43 days after starting treatment and consisted of optic neuritis, cortical blindness, altered mental status, and generalized seizure. Only one patient regained visual and neurologic function; four other patients experienced progressive neurologic deterioration and died. Clinicopathologic evaluation suggested widespread, severe demyelination as the etiology of these reactions. We conclude that fludarabine is an effective drug for remission induction in acute leukemia. However, doses required to achieve CR are associated with unacceptable CNS toxicity. In view of its potent antileukemic activity, further evaluation of fludarabine at lower doses (less than or equal to 75 mg/m2/d for five days) may be warranted in combination with other chemotherapeutic agents for the treatment of patients with acute leukemia.


Electrocyclic ring opening of cis-bicyclo[m.n.0]alkenes: the anti-Woodward-Hoffmann quest.
The dubbed anti-Woodward-Hoffmann ring-opening reaction of cis-bicyclo[4.2.0]oct-7-ene to yield cis,cis-cycloocta-1,3-diene has been intensively studied with robust, high-level computational methods. This reaction has been found to proceed through a conrotatory allowed pathway to afford cis,trans-cycloocta-1,3-diene followed by E to Z isomerization, instead of a disrotatory forbidden pathway, as suggested. Computational calculations of kinetic isotope effects are consistent with this interpretation and the experimental values. The study of lower bicyclic homologues with [3.2.0], [2.2.0] and [2.1.0] skeletons indicates the feasibility of a mechanistic change towards the anti-Woodward-Hoffmann disrotatory path. This is clearly favored for the ring opening of the highly strained cis-bicyclo[2.1.0]pent-2-ene and is highly competitive with the conrotatory path for cis-bicyclo[2.2.0]hex-2-ene. Therefore, the rearrangement of the smallest bicyclic cyclobutene is predicted computationally to be an anti-Woodward-Hoffmann disrotatory electrocyclic ring-opening reaction.


Corrosion products from dental alloys and effects of mercuric and cupric ions on a neuroeffector system.
The release of corrosion products during long-term immersion in vitro of dental alloys, with particular reference to dissimilar alloys in contact has been studied. The effects of Hg2+ and Cu2+ in low concentrations on the guinea-pig ileum have also been studied. The following conclusions were drawn: In an aggressive solution the release of elements from amalgams could be continuous and subsurface corrosion could cause a considerable increase in the corrosion products released. The change in microstructure observed in cross-sections of the corroded specimens was related to the amounts of corrosion products released into the saline solution. In an aggressive solution the corrosion products could increase when amalgams, Co-Cr, and Ni-Cr alloys are in contact with gold alloys, a high-Cu amalgam is in contact with a conventional amalgam, a type III gold alloy is in contact with gold alloys for metallo-ceramic purposes. The high-Cu amalgams released more corrosion products into the saline solution than a conventional one. Greater quantities of corrosion products were released from amalgams at pH 4 than at pH 6. Hg2+ and Cu2+ both had diverse and dose-dependent effects on the guinea-pig ileum. In low concentrations, 10nM, both ions exerted effects, probably on the muscle cell membrane.


Biosynthesis of Indoleacetic Acid from Tryptophan-C in Cell-free Extracts of Pea Shoot Tips.
A 2-step, 1-dimensional thin-layer chromatographic procedure for isolating indoleacetic acid (IAA) was developed and utilized in investigations of the biosynthesis of IAA from tryptophan-(14)C in cell-free extracts of pea (Pisum sativum L.) shoot tips. Identification of a (14)C-product as IAA was by (a) co-chromatography of authentic IAA and (14)C-product on thin-layer chromatography, and (b) gas-liquid and thin-layer chromatography of authentic and presumptive IAA methyl esters. Dialysis of enzyme extracts and addition of alpha-ketoglutaric acid and pyridoxal phosphate to reaction mixtures resulted in approximately 2- to 3-fold increases in net yields of IAA over yields in non-dialyzed reaction mixtures which did not contain additives essential to a transaminase reaction of tryptophan. Addition of thiamine pyrophosphate to reaction mixtures further enhanced net biosynthesis of IAA. It is concluded that the formation of indolepyruvic acid and its subsequent decarboxylation probably are sequential reactions in the major pathway of IAA biosynthesis from tryptophan in cell-free extracts of Pisum shoot tips. Comparison of maximum net IAA biosynthesis in extracts of shoot tips of etiolated and light-grown dwarf and tall pea seedlings revealed an order, on a unit protein N basis, of: light-grown tall > light-grown dwarf > etiolated tall congruent with etiolated dwarf. It is concluded that the different rates of stem elongation among etiolated and light-grown dwarf and tall pea seedlings are correlated, in general, with differences in net IAA biosynthesis and sensitivity of the tissues to IAA.


Prevention of allergic rhinitis by ginger and the molecular basis of immunosuppression by 6-gingerol through T cell inactivation.
The incidence of allergies has recently been increasing worldwide. Immunoglobulin E (IgE)-mediated hypersensitivity is central to the pathogenesis of asthma, hay fever and other allergic diseases. Ginger (Zingiber officinale Roscoe) and its extracts have been valued for their medical properties including antinausea, antiinflammation, antipyresis and analgesia properties. In this study, we investigated the antiallergic effects of ginger and 6-gingerol, a major compound of ginger, using a mouse allergy model and primary/cell line culture system. In mice with ovalbumin (OVA)-induced allergic rhinitis, oral administration of 2% ginger diet reduced the severity of sneezing and nasal rubbing by nasal sensitization of OVA and suppressed infiltration of mast cells in nasal mucosa and secretion of OVA-specific IgE in serum. 6-Gingerol inhibited the expression of not only Th2 cytokines but also Th1 cytokines in OVA-sensitized spleen cells. Accordingly, 6-gingerol suppressed in vitro differentiation of both Th1 cells and Th2 cells from naïve T cells. In addition, 6-gingerol suppressed both superantigen staphylococcal enterotoxin B (SEB)- and anti-CD3-induced T cell proliferation. 6-Gingerol also abrogated PMA plus ionomycin- and SEB-induced IL-2 production in T cells, suggesting that 6-gingerol affected T cell receptor-mediated signal transduction rather than the antigen-presentation process. Indeed, 6-gingerol inhibited the phosphorylation of MAP kinases, calcium release and nuclear localization of c-fos and NF-κB by PMA and ionomycin stimulation. Thus, our results demonstrate that 6-gingerol suppresses cytokine production for T cell activation and proliferation, thereby not causing B cell and mast cell activation and resulting in prevention or alleviation of allergic rhinitis symptoms.


Kir5.1 channels: potential role in epilepsy and seizure disorders.
Inwardly rectifying potassium (Kir) channels are broadly expressed in many mammalian organ systems, where they contribute to critical physiological functions. However, the importance and function of the Kir5.1 channel (encoded by the KCNJ16 gene) have not been fully recognized. This review focuses on the recent advances in understanding the expression patterns and functional roles of Kir5.1 channels in fundamental physiological systems vital to potassium homeostasis and neurological disorders. Recent studies have described the role of Kir5.1-forming Kir channels in mouse and rat lines with mutations in the Kcnj16 gene. The animal research reveals distinct renal and neurological phenotypes, including pH and electrolyte imbalances, blunted ventilatory responses to hypercapnia/hypoxia, and seizure disorders. Furthermore, it was confirmed that these phenotypes are reminiscent of those in patient cohorts in which mutations in the KCNJ16 gene have also been identified, further suggesting a critical role for Kir5.1 channels in homeostatic/neural systems health and disease. Future studies that focus on the many functional roles of these channels, expanded genetic screening in human patients, and the development of selective small-molecule inhibitors for Kir5.1 channels, will continue to increase our understanding of this unique Kir channel family member.


Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function.
Multiple independent mutations in neuroligin genes were identified in patients with familial autism, including the R451C substitution in neuroligin-3 (NL3). Previous studies showed that NL3(R451C) knock-in mice exhibited modestly impaired social behaviors, enhanced water maze learning abilities, and increased synaptic inhibition in the somatosensory cortex, and they suggested that the behavioral changes in these mice may be caused by a general shift of synaptic transmission to inhibition. Here, we confirm that NL3(R451C) mutant mice behaviorally exhibit social interaction deficits and electrophysiologically display increased synaptic inhibition in the somatosensory cortex. Unexpectedly, however, we find that the NL3(R451C) mutation produced a strikingly different phenotype in the hippocampus. Specifically, in the hippocampal CA1 region, the NL3(R451C) mutation caused an ∼1.5-fold increase in AMPA receptor-mediated excitatory synaptic transmission, dramatically altered the kinetics of NMDA receptor-mediated synaptic responses, induced an approximately twofold up-regulation of NMDA receptors containing NR2B subunits, and enhanced long-term potentiation almost twofold. NL3 KO mice did not exhibit any of these changes. Quantitative light microscopy and EM revealed that the NL3(R451C) mutation increased dendritic branching and altered the structure of synapses in the stratum radiatum of the hippocampus. Thus, in NL3(R451C) mutant mice, a single point mutation in a synaptic cell adhesion molecule causes context-dependent changes in synaptic transmission; these changes are consistent with the broad impact of this mutation on murine and human behaviors, suggesting that NL3 controls excitatory and inhibitory synapse properties in a region- and circuit-specific manner.


Impairment of Moloney murine leukemia virus integration in a cell line underexpressing DNA topoisomerase II.
The possible intervention of nuclear proteins as cofactors of integrase-catalyzed integration of retroviral DNA into the host cell genome is not fully understood. Among various nuclear proteins, DNA topoisomerase II appears to be a plausible candidate. This hypothesis is supported by a series of evidence, including the fact that integration is markedly affected by the topology of the target DNA and mainly occurs in transcribed regions in which topoisomerase II is preferentially located. In an attempt to confirm the validity of this hypothesis, we have comparatively investigated the early stages of a recombinant Moloney murine leukemia virus (psi neo) in two related Chinese hamster cell lines (DC3F and R/DC3F) expressing different levels of both isoforms of topoisomerase II. R/DC3F is derived from the parental cell line DC3F and displays a resistant phenotype towards the usual anticancer topoisomerase II inhibitors (actinomycin D, doxorubicin, and taxol). Results show that the early stages of the retroviral cycle are markedly impaired in cells underexpressing topoisomerase II (R/DC3F). This alteration mimics Fv-1 restriction and is characterized by about a 6-fold decrease in viral DNA synthesis and total inhibition of viral genome integration. The specific impairment of integration in R/DC3F cells compared to DC3F cells is assessed by the absence of G418-resistant colonies upon viral infection and a lack of the viral genome in cellular nuclear DNA as detected by the PCR procedure. These features are observed in relevant infecting conditions leading, in both cell lines, to the same amount of linear viral DNA and to the occurrence of two long terminal repeats containing circular DNA in the nuclear fractions.


Complete nucleotide sequence of a severe isolate of cucumber vein yellowing virus from Jordan.
The complete genome of a severe isolate of Cucumber vein yellowing virus (CVYV) from Jordan was sequenced. Comparison with the genome of a Spanish CVYV isolate inducing very mild symptoms in cucumber cultivars revealed a nucleotide identity of 94% for the complete genome and an amino acid identity of 96% for the coding region. Comparison of synonymous and non-synonymous substitutions suggested a negative selection at amino acid and nucleotide levels with different degrees depending on the different coding regions. Finally, specific amino acid changes in the zinc finger domain of P1b and in the P1-P3 proteolytic site were found which could be involved in the virulence of CVYV.


Trends in self-reported spontaneous abortions: 1970-2000.
Little is known about how the miscarriage rate has changed over the past few decades in the United States. Data from Cycles IV to VI of the National Survey of Family Growth (NSFG) were used to examine trends from 1970 to 2000. After accounting for abortion availability and the characteristics of pregnant women, the rate of reported miscarriages increased by about 1.0% per year. This upward trend is strongest in the first seven weeks and absent after 12 weeks of pregnancy. African American and Hispanic women report lower rates of early miscarriage than do whites. The probability of reporting a miscarriage rises by about 5% per year of completed schooling. The upward trend, especially in early miscarriages, suggests awareness of pregnancy rather than prenatal care to be a key factor in explaining the evolution of self-reported miscarriages. Any beneficial effects of prenatal care on early miscarriage are obscured by this factor. Differences in adoption of early-awareness technology, such as home pregnancy tests, should be taken into account when analyzing results from self-reports or clinical trials relying on awareness of pregnancy in its early weeks.


Use of high-sensitivity digital ELISA improves the diagnostic performance of circulating brain-specific proteins for detection of traumatic brain injury during triage.
Background: Historically, limited sensitivity associated with traditional immunoassay methods has prevented the use of brain-specific proteins as blood biomarkers of traumatic brain injury (TBI) during triage, as these proteins exhibit low circulating concentrations. Digital ELISA is a newly-developed technique that is up to 1000 times more sensitive than conventional ELISA methods. The purpose of this study was to determine whether the use of digital ELISA over conventional ELISA improves the performance of brain-specific proteins as blood biomarkers of TBI during triage.Methods: Blood was sampled from TBI patients (n = 13) at emergency department admission, as well as from neurologically normal controls (n = 72). Serum levels of two brain-specific proteins, neurofilament light chain (NfL) and Tau, were measured via digital ELISA. Estimated conventional ELISA measures were generated by adjusting values according to the lower limits of detection achievable with commercially available conventional ELISA assays, and receiver operating characteristic (ROC) analysis was used to compare the diagnostic performance of digital ELISA measures to estimated conventional ELISA measures in terms of their ability to discriminate between TBI patients and controls.Results: Used in combination, digital ELISA measures of NfL and Tau could discriminate between groups with 100% sensitivity and 91.7% specificity. Estimated conventional ELISA measures could only discriminate between groups with 7.7% sensitivity and 94.4% specificity. This difference in diagnostic performance was statistically significant when comparing areas under ROC curves.Conclusions: The use of digital ELISA over conventional ELISA methods improves the diagnostic performance of circulating brain-specific proteins for detection of TBI during triage.


Radiation dose reduction with application of non-linear adaptive filters for abdominal CT.
To evaluate the effect of non-linear adaptive filters (NLAF) on abdominal computed tomography (CT) images acquired at different radiation dose levels. Nineteen patients (mean age 61.6 ± 7.9 years, M:F = 8:11) gave informed consent for an Institutional Review Board approved prospective study involving acquisition of 4 additional image series (200, 150, 100, 50 mAs and 120 kVp) on a 64 slice multidetector row CT scanner over an identical 10 cm length in the abdomen. The CT images acquired at 150, 100 and 50 mAs were processed with the NLAF. Two radiologists reviewed unprocessed and processed images for image quality in a blinded randomized manner. CT dose index volume, dose length product, patient weight, transverse diameters, objective noise and CT numbers were recorded. Data were analyzed using Analysis of Variance and Wilcoxon signed rank test. Of the 31 lesions detected in abdominal CT images, 28 lesions were less than 1 cm in size. Subjective image noise was graded as unacceptable in unprocessed images at 50 and 100 mAs, and in NLAF processed images at 50 mAs only. In NLAF processed images, objective image noise was decreased by 21% (14.4 ± 4/18.2 ± 4.9) at 150 mAs, 28.3% (15.7 ± 5.6/21.9 ± 4) at 100 mAs and by 39.4% (18.8 ± 9/30.4 ± 9.2) at 50 mAs compared to unprocessed images acquired at respective radiation dose levels. At 100 mAs the visibility of smaller structures improved from suboptimal in unprocessed images to excellent in NLAF processed images, whereas diagnostic confidence was respectively improved from probably confident to fully confident. NLAF lowers image noise, improves the visibility of small structures and maintains lesion conspicuity at down to 100 mAs for abdominal CT.


[Recurrent respiratory papillomatosis: a cause of progressive respiratory distress].
A 5-year-old girl was brought to the emergency department because of respiratory distress of 3 months' evolution that had worsened over the previous 3 weeks. Cervical radiograph and cervical computerized axial tomography showed an endolaryngeal mass almost completely occluding the airway. Urgent laryngoscopy revealed an endolaryngeal fleshy mass, which was excised during the procedure. Histological diagnosis was laryngeal papilloma. Although infrequent in children, laryngeal papilloma is the most common laryngeal tumor in pediatrics. It is currently named juvenile onset recurrent respiratory papillomatosis. The human papilloma virus (HPV) causes the disease by vertical transmission from a mother with active or latent vulvar HPV infection.


Association between cytokine profiles and lung injury in COVID-19 pneumonia.
Coronavirus disease 2019 (COVID-19) is a new respiratory and systemic disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The purpose of the present study was to investigate the association between cytokine profiles and lung injury in COVID-19 pneumonia. This retrospective study was conducted in COVID-19 patients. Demographic characteristics, symptoms, signs, underlying diseases, and laboratory data were collected. The patients were divided into COVID-19 with pneumonia and without pneumonia. CT severity score and PaO2/FiO2 ratio were used to assess lung injury. 106 patients with 12 COVID-19 without pneumonia and 94 COVID-19 with pneumonia were included. Compared with COVID-19 without pneumonia, COVID-19 with pneumonia had significantly higher serum interleukin (IL)-2R, IL-6, and tumor necrosis factor (TNF)-α. Correlation analysis showed that CT severity score and PaO2/FiO2 were significantly correlated with age, presence of any coexisting disorder, lymphocyte count, procalcitonin, IL-2R, and IL-6. In multivariate analysis, log IL6 was the only independent explanatory variables for CT severity score (β = 0.397, p < 0.001) and PaO2/FiO2 (β = - 0.434, p = 0.003). Elevation of circulating cytokines was significantly associated with presence of pneumonia in COVID-19 and the severity of lung injury in COVID-19 pneumonia. Circulating IL-6 independently predicted the severity of lung injury in COVID-19 pneumonia.


Constitutive CD40 signaling in B cells selectively activates the noncanonical NF-kappaB pathway and promotes lymphomagenesis.
CD40, a member of the tumor necrosis factor (TNF) receptor family, plays an essential role in T cell-dependent immune responses. Because CD40 is widely expressed on the surface of tumor cells in various B cell malignancies, deregulated CD40 signaling has been suggested to contribute to lymphomagenesis. In this study, we show that B cell-specific expression of a constitutively active CD40 receptor, in the form of a latent membrane protein 1 (LMP1)/CD40 chimeric protein, promoted an increase in the number of follicular and marginal zone B cells in secondary lymphoid organs in transgenic mice. The B cells displayed an activated phenotype, prolonged survival and increased proliferation, but were significantly impaired in T cell-dependent immune responses. Constitutive CD40 signaling in B cells induced selective and constitutive activation of the noncanonical NF-kappaB pathway and the mitogen-activated protein kinases Jnk and extracellular signal-regulated kinase. LMP1/CD40-expressing mice older than 12 mo developed B cell lymphomas of mono- or oligoclonal origin at high incidence, thus showing that the interplay of the signaling pathways induced by constitutive CD40 signaling is sufficient to initiate a tumorigenic process, ultimately leading to the development of B cell lymphomas.


Multi-Atlas Segmentation with Joint Label Fusion.
Multi-atlas segmentation is an effective approach for automatically labeling objects of interest in biomedical images. In this approach, multiple expert-segmented example images, called atlases, are registered to a target image, and deformed atlas segmentations are combined using label fusion. Among the proposed label fusion strategies, weighted voting with spatially varying weight distributions derived from atlas-target intensity similarity have been particularly successful. However, one limitation of these strategies is that the weights are computed independently for each atlas, without taking into account the fact that different atlases may produce similar label errors. To address this limitation, we propose a new solution for the label fusion problem in which weighted voting is formulated in terms of minimizing the total expectation of labeling error and in which pairwise dependency between atlases is explicitly modeled as the joint probability of two atlases making a segmentation error at a voxel. This probability is approximated using intensity similarity between a pair of atlases and the target image in the neighborhood of each voxel. We validate our method in two medical image segmentation problems: hippocampus segmentation and hippocampus subfield segmentation in magnetic resonance (MR) images. For both problems, we show consistent and significant improvement over label fusion strategies that assign atlas weights independently.


Novel Triazolyl berberine derivatives prepared via CuAAC click chemistry: Synthesis, Anticancer Activity and Structure-Activity Relationships.
To search for novel anticancer agents, we designed and synthesized a series of new triazolyl berberine derivatives. The evaluation of all the synthesized compounds and their anticancer activities against a panel of four human cancer cell lines including MCF-7 (breast), MCF-7/ADR (breast), SW-1990 (pancreatic), SMMC-7721 (liver) and the non-cancer cell line HUVEC (human umbilical vein endothelial cell). The results showed that most of the compounds displayed better anticancer activities against MCF-7 and SMMC-7721 compared with berberine. Among these derivatives, compounds 5p and 5a exhibited the most potent inhibitory activities against the SMMC-7721 and SW-1990 cell lines with IC50 values of 14.861 ± 2.4 μM and 16.798 ± 3.4 μM. Furthermore, compounds 5p, 5a and 5n exhibited much better selectivity toward the normal cell line HUVEC than berberine.


[Nucleolar organizer regions in uterine cervical cancer and its precursor epithelial lesions].
The number of nucleolar organizer regions was assessed in 115 histological samples of uterine cervical carcinoma or precursor epithelial lesions. Normal endocervical or exocervical epithelial tissues were used as controls. Nucleolar organizer regions were stained with colloidal silver in formalin fixed histological samples and quantified in 100 cells, according to Crocker's method. The mean number of nucleolar organizer regions were 13.7 in infiltrative carcinoma, 9.15 in carcinoma in situ, 9.3 in severe dysplasia, 8.4 in moderate dysplasia, 7.5 in mild dysplasia, 6.4 in condylomas and 3.2 and 2.9 in normal exocervical and endocervical epithelia respectively. There were significant differences in the number of nucleolar organizer regions between normal and abnormal tissues and between the different lesions except between moderate and mild dysplasia and between carcinoma in situ and moderate and severe dysplasia. The highest number of nucleolar organizer lesions was always observed in the basal strata of both normal and abnormal tissues. It is concluded that nucleolar organizer regions are a good index of cellular proliferation in uterine epidermoid cervical carcinoma and its precursor lesions, and have a diagnostic value in infiltrative carcinoma.


Data Quality and Data Quantity: Complements or Contradictions?
Although data quality is well defined, the relationship to data quantity remains unclear. Especially the big data approach promises advantages of volume in comparison with small samples in good quality. Aim of this study was to review this issue. Based on the experiences with six registries within a German funding initiative, the definition of data quality provided by the International Organization for Standardization (ISO) was confronted with several aspects of data quantity. The results of a literature search combining both concepts were considered additionally. Data quantity was identified as an umbrella of some inherent characteristics of data like case and data completeness. The same time, quantity could be regarded as a non inherent characteristic of data beyond the ISO standard focusing on the breadth and depth of metadata, i.e. data elements along with their value sets. The FAIR Guiding Principles take into account the latter solely. Surprisingly, the literature agreed in demanding an increase in data quality with volume, turning the big data approach inside out. A usage of data without context - as it could be the case in data mining or machine learning - is neither covered by the concept of data quality nor of data quantity.


Incidence of sporting injury in New Zealand youths aged 6-15 years.
To document the incidence of injury in 6-15 year olds playing rugby union, rugby league, and netball, and to identify the common mechanisms, sites, severity, and time of injury. Cross sectional data were collected by trained observers who watched 258 games of rugby union, netball, and rugby league over a four week period. The condition of the injured participants was monitored until recovery. In total, 5174 players were observed and an injury rate of 18 per 1000 player hours was calculated. Of all observed injuries, 29% required some form of medical treatment. A significant difference (p<0.05) in the distribution of injury over the four quarters of the games was recorded, most occurring in the first three quarters. In total, 81% of the injuries were classified as contact injuries, and these mainly occurred through direct contact with the opposition. Of all observed injuries, 27% were recurrent. The incidence of injury in rugby union, netball, and rugby league is low for children aged between 6 and 15 years relative to adult rates.