Accumulation of malignant renal stem cells is associated with epigenetic changes in normal renal progenitor genes.
Recent studies indicate a dual epigenetic role of the Polycomb group (PcG) proteins in self-renewal of stem cells and oncogenesis. Their elevation in our previous human kidney microarray screen led us examine whether they participate in processes involving normal and malignant renal progenitors. We therefore analyzed the expression of the PcG genes (EZH2, BMI-1, EED, SUZ12) in relation to that of the nephric-progenitor genes (WT1, PAX2, SALL1, SIX2, CITED1) using real-time polymerase chain reaction and methylation assays during renal development, regeneration, and tumorigenesis. Although all of the nephric-progenitor genes were shown to be developmentally regulated, analysis of polycomb gene expression during murine nephrogenesis and in an in vitro induction model of the nephrogenic mesenchyme indicated dynamic regulation only for EZH2 in the normal renal progenitor population. In contrast, induction of adult kidney regeneration by ischemia/reperfusion injury resulted primarily in rapid elevation of BMI-1, whereas EZH2 was silenced. Analysis of renal tumorigenesis in stem cell-like tumor xenografts established by serial passage of Wilms' tumor (WT) in immunodeficient mice showed cooperative upregulation of all PcG genes. This was accompanied by upregulation of WT1, PAX2, and SALL1 but downregulation of SIX2. Accordingly, methylation-specific quantitative polymerase chain reaction demonstrated promoter hypomethylation of WT1, PAX2, and SIX2 in primary WT and fetal kidneys, whereas progressive WT xenografts showed hypermethylation of SIX2, possibly leading to loss of renal differentiation. PcG genes vary in expression during renal development, regeneration, and tumorigenesis. We suggest a link between polycomb activation and epigenetic alterations of the renal progenitor population in initiation and progression of renal cancer.


Some factors affecting the transverse strength of repaired denture acrylic resin.
The aim of this study was to determine the transverse strength of repaired autopolymerising poly(methyl methacrylate) (PMMA) resin. The edge profile (EP) of the repair surface and the powder-to-liquid (PL) ratio of the autopolymerising acrylic resin used for repairs were studied to determine their effects on the transverse strength of rectangular test specimens. Neither the EP nor the PL ratio affected the transverse strength of the test specimens (EP: P = 0.692, PL: P = 0.575). However, the EP significantly affected the type of failure (P < 0.001). The results suggest that autopolymerising PMMA of various PL ratios can be used to repair the fractured pieces of autopolymerising PMMA without affecting the strength of the repair.


[Skeletal muscle antigens bound with a polyurethane glue].
The reaction of anaphylaxia with desensibilization on guinea pigs and the method of double diffusion in agar gel were used to study the antigenic composition of the rat skeletal muscles 3, 7 and 30 days after their cross sections were connected with polyurethane glue and silk. It is shown that in the postoperative period, besides antigens similar to those of the normal muscles, other antigens which may belong to stage-specific ones appears in the fraction of soluble proteins. The antigenic composition of the skeletal muscles is the same with both methods of connection of the tissues defects.


CT observations pertinent to septic cavernous sinus thrombosis.
The use of high-resolution computed tomography (CT) is described in four patients with septic cavernous sinus thrombosis. In all patients CT findings included multiple irregular filling defects in the enhancing cavernous sinus. Unilateral or bilateral inflammatory changes in the orbital soft tissues were also present. Enlargement of the superior ophthalmic vein due to extension of thrombophlebitis was noted in three patients.


Beta(1-->3)-glucan exposure levels among workers in four British Columbia sawmills.
Beta(1-->3)-glucans were extracted from wood dust samples taken during the summer of 1997 at four British Columbia sawmills. Personal dust samples were collected using a GSP-sampler for inhalable dust and the sampling strategy targeted all production and maintenance jobs at least once at each mill. Potential exposure determinants data were documented concurrently, including weather conditions, log storage methods, wood conditions, species, production level, jobs and tasks. beta(1-->3)-glucans were measured by enzyme inhibition immunoassay (EIA). A total of 223 personal beta(1-->3)-glucan samples were analyzed. 45.7% were below the limit of detection (LOD). Geometric mean concentration ranged from 3.5 to 18.9 micro g/m(3) across the four mills. The highest levels were measured at the Interior mills, particularly in the log processing and sawmill areas. Multivariate regression models indicated that land-based log storage, clean-up jobs, high wood dust concentration, lumber yard department and the interaction between land-based log storage method and log processing department were associated with increased beta(1-->3)-glucan concentration.


Soil erosion assessment using geographical information system (GIS) and remote sensing (RS) study from Ankara-Guvenc Basin, Turkey.
The objective of this research was to assess vulnerable soil erosion risk with qualitative approach using GIS in Ankara-Guvenc Basin. The study area is located about 44 km north of Ankara and covers 17.5 km2. The selected theme layers of this model include topographic factor, soil factors (depth, texture, impermeable horizon) and land use. Slope layer and land use-land cover data were prepared by using DEM and Landsat-TM satellite image. According to land use classification, the most common land use type and land cover are rangeland (50.5%) then, rainfed (36.4%), week forest land (3.2%), irrigated land (0.7%) and other various lands (rock out crop and lake) (9.2%). Each land characteristic is also considered as a thematic layer in geographical information systems (GIS) process. After combination of the layers, soil erosion risk map was produced. The results showed that 44.4% of the study area is at high soil erosion risk, whereas 42% of the study area is insignificantly and slightly susceptible to erosion risk. In addition, it was found that only 12.6% of the total area is moderately susceptible to erosion risk. Furthermore, conservation land management measures were also suggested for moderate, high and very high erosion risk areas in Ankara-Guvenc Basin.


Evaluation of fine structure of tubular zeolite NaA membrane by FTIR-ATR and FIB-TEM.
A zeolite NaA (LTA) membrane supported by an alumina porous support tube for pervaporation (PV) dehydration of ethanol was characterized by transmission electron microscopy (TEM) using a focused ion beam (FIB) thin-layer specimen preparation technique and by Fourier transform infrared attenuated total reflectance method (FTIR-ATR) using a diamond prism as the waveguide. FIB-TEM clearly presented cross-section images up to about 15 microm depth from the membrane surface. FTIR-ATR monitored the Si-O asymmetric stretching vibration spectrum. The Si-O spectrum was compared with the TEM image and their relationships were discussed. By combining the two methods, we could study the thickness of surface LTA crystals, the grain boundary, the LTA/alumina interface structure and the crystallinity and density of materials inside of the alumina porous support. Consequently, fine structure changes of the LTA membrane corresponding to the hydrothermal synthesis condition could be sensitively detected.


Allogeneic stem cell transplantation in patients with atypical chronic myeloid leukaemia: a retrospective study from the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation.
Atypical chronic myeloid leukaemia (aCML) is an aggressive malignancy for which allogeneic haematopoietic stem cell transplantation (allo-HSCT) represents the only curative option. We describe transplant outcomes in 42 patients reported to the European Society for Blood and Marrow Transplantation (EBMT) registry who underwent allo-HSCT for aCML between 1997 and 2006. Median age was 46 years. Median time from diagnosis to transplant was 7 months. Disease status was first chronic phase in 69%. Donors were human leucocyte antigen (HLA)-identical siblings in 64% and matched unrelated (MUD) in 36%. A reduced intensity conditioning was employed in 24% of patients. T-cell depletion was applied in 87% and 26% of transplants from MUD and HLA-identical siblings, respectively. According to the EBMT risk-score, 45% of patients were 'low-risk', 31% 'intermediate-risk' and 24% 'high-risk'. Following allo-HSCT, 87% of patients achieved complete remission. At 5 years, relapse-free survival was 36% and non-relapse mortality (NRM) was 24%, while relapse occurred in 40%. Patient age and the EBMT score had an impact on overall survival. Relapse-free survival was higher in MUD than in HLA-identical sibling HSCT, with no difference in NRM. In conclusion, this study confirmed that allo-HSCT represents a valid strategy to achieve cure in a reasonable proportion of patients with aCML, with young patients with low EBMT risk score being the best candidates.


Variability of predictive markers (hormone receptors, Her2, Ki67) and intrinsic subtypes of breast cancer in four consecutive years 2015-2018.
Accurate monitoring of predictive markers is of utmost importance as oncological treatment decisions almost entirely depend on these factors. In this study, we conducted a quality control assessment on hormone receptors, Her2 status, Ki67 Labelling Index (LI) and histological grading in breast cancer over 4 years (2015-2018). Altogether 2214 consecutive breast cancer cases were included. Data on estrogen (ER) and progesterone receptors (PR), Her2 and Ki67, were available in all cases and were tested mostly on preoperative biopsies, in selected cases on postoperative surgical specimens. ER, PR, and Ki67 were assessed with immunohistochemistry (IHC), Her2 status with IHC and fluorescence in situ hybridization. ER/PR were positive in 74-79% cases, ER/PR/Her2 negative in 6.16-10.70% and Her2 positive in 11.49-13.88%/year. Ki67 had median values as 15-17.5% in ER/PR-positive cases, 55-60% in triple-negative cases and 30-32.50% in Her2-positive cases. Histological grading distribution for well (G1), moderately (G2) and poorly (G3) differentiated carcinomas was 15.8-19.1% for G1, 54.2-54.8% for G2 and 21.7-23.7% for G3 cases. Variation in yearly distributions was not significant in any of these markers. Predictive markers displayed a yearly similar distribution in breast cancer cases independently of grading or of intrinsic subtypes. These results point to a qualitative high performance of predictive marker assessment in breast cancer, corresponding to expected on average positivity rate per marker and per year. It is recommended to monitor positivity rate of ER, PR, Ki67 and Her2 yearly or periodically to comply with quality assurance requirements.


Imputation of missing covariate values in epigenome-wide analysis of DNA methylation data.
DNA methylation is a widely studied epigenetic mechanism and alterations in methylation patterns may be involved in the development of common diseases. Unlike inherited changes in genetic sequence, variation in site-specific methylation varies by tissue, developmental stage, and disease status, and may be impacted by aging and exposure to environmental factors, such as diet or smoking. These non-genetic factors are typically included in epigenome-wide association studies (EWAS) because they may be confounding factors to the association between methylation and disease. However, missing values in these variables can lead to reduced sample size and decrease the statistical power of EWAS. We propose a site selection and multiple imputation (MI) method to impute missing covariate values and to perform association tests in EWAS. Then, we compare this method to an alternative projection-based method. Through simulations, we show that the MI-based method is slightly conservative, but provides consistent estimates for effect size. We also illustrate these methods with data from the Atherosclerosis Risk in Communities (ARIC) study to carry out an EWAS between methylation levels and smoking status, in which missing cell type compositions and white blood cell counts are imputed.


Temperament and character as schizophrenia-related endophenotypes in non-psychotic siblings.
Quantitative endophenotypes are needed to better understand the pathogenesis of schizophrenia. The psychobiological model of temperament and character suggests that personality traits are heritable and regulated by brain systems influencing schizophrenia susceptibility. Thus, measures of temperament and character may serve as schizophrenia-related endophenotypes in individuals with schizophrenia and their non-psychotic siblings. Individuals with schizophrenia (n=35), their non-psychotic siblings (n=34), controls (n=63), and their siblings (n=56) participated in a study of the clinical, neurocognitive and neuromorphological characteristics of schizophrenia. A mixed-model approach assessed group differences on the Temperament and Character Inventory (TCI). Neurocognitive deficits and psychopathology were correlated with the TCI. Configurations of TCI domains were examined using a generalized linear model. Individuals with schizophrenia and their non-psychotic siblings had higher harm avoidance than controls and their siblings. Individuals with schizophrenia had lower self-directedness and cooperativeness, and higher self-transcendence than their non-psychotic siblings, controls, and the siblings of controls. Neurocognition was not related to temperament and character in individuals with schizophrenia or either control group. In non-psychotic siblings, self-directedness and cooperativeness were correlated with working memory and crystallized IQ. Evidence supports harm avoidance as a schizophrenia-related endophenotype. An increased risk of schizophrenia may be associated with asociality (configured as high harm avoidance and low reward dependence), schizotypy (configured as low self-directedness, low cooperativeness, and high self-transcendence), and neurocognitive deficits (poor executive functioning, working/episodic memory, attention, and low IQ). The non-psychotic siblings demonstrated features of a mature character profile including strong crystallized IQ, which may confer protection against psychopathology.


Correlates of depressive illness among the elderly in a mixed urban community in Lagos, Nigeria.
Little is known about the factors associated with depression among elderly Nigerians despite research evidence suggesting that some correlates of depression may be important in early detection, treatment and prognosis. This study aimed to determine the correlates of depression among a community based elderly population. The study population made up of 350 consenting participants was selected using multistage stratified random sampling technique. Face-to-face interviews were conducted among the participants using a research instrument consisting of two parts: a self-designed questionnaire to elicit their socio-demographic profile, level of social support as well as their health status and the 30-item Geriatric Depression Scale to diagnose depression using cut-off score ≥11. Both the English and Yoruba versions of the study instruments were used depending on the level of education of the participants. Depression was found to be associated with being younger old (χ(2) = 6.19, p = 0.045), prolonged stay in current residence (χ(2) = 6.62, p = 0.01), living in less developed area of the community and not having children (χ(2) = 0.03, p = 0.01), while higher social support (χ(2) = 4.19, p = 0.041) seems protective. However, only low social support (odds ratio [OR] = 0.573; 95% confidence interval [CI], 0.330-0.994; p = 0.048), living in less developed area (OR = 5.342; 95% CI = 1.027, 27.776; p = 0.046) and prolonged stay in current residence (OR = 0.407; 95% CI = 0.205, 0.806; p = 0.01) independently predicted depression in participants. To enhance early detection and treatment of depressive disorders in the elderly, physicians should be alert to the diagnosis of depression in late life, especially among the younger old, elderly not having children, those with low social support as well as prolonged stay in a residence and living in less developed parts of the community. Further research is needed to shed light on the intriguing link between depression and associated factors in geriatric population.


The effect of breast support on the kinematics of the breast during the running gait cycle.
Although breast pain has been related to vertical breast displacement and velocity, the influence of breast support on multi-planar breast kinematics and breast comfort has yet to be ascertained. The aims of this study were to investigate multi-planar breast displacement, velocity, and acceleration with and without breast support during running and to establish the correlation with breast comfort. Fifteen females ran at 2.8 m x s(-1) in no bra, an everyday bra, and a sports bra. Three-dimensional coordinates of breast and body markers were tracked during ten gait cycles and following each trial the participants rated their breast comfort. Relative breast displacement was calculated and derived for velocity and acceleration. Vertical breast displacement, velocity, and acceleration peaked at, before, and after mid-stance, respectively. The patterns of displacement and velocity trajectories were unaffected by increasing breast support, though the magnitudes were significantly reduced. The magnitude and trajectory of breast acceleration was unaffected by increasing breast support and showed no correlation with comfort. Breast velocity displayed the strongest relationship to comfort (r = 0.61). Considerable mediolateral and anteroposterior breast kinematics were identified, suggesting that future studies and bra design may benefit from three-dimensional analysis. In conclusion, improvements in breast support may be defined by reductions in breast velocity and displacement.


Salivary proteomics for oral cancer biomarker discovery.
This study aims to explore the presence of informative protein biomarkers in the human saliva proteome and to evaluate their potential for detection of oral squamous cell carcinoma (OSCC). Whole saliva samples were collected from patients (n = 64) with OSCC and matched healthy subjects (n = 64). The proteins in pooled whole saliva samples of patients with OSCC (n = 16) and matched healthy subjects (n = 16) were profiled using shotgun proteomics based on C4 reversed-phase liquid chromatography for prefractionation, capillary reversed-phase liquid chromatography with quadruple time-of-flight mass spectrometry, and Mascot sequence database searching. Immunoassays were used for validation of the candidate biomarkers on a new group of OSCC (n = 48) and matched healthy subjects (n = 48). Receiver operating characteristic analysis was exploited to evaluate the diagnostic value of discovered candidate biomarkers for OSCC. Subtractive proteomics revealed several salivary proteins at differential levels between the OSCC patients and matched control subjects. Five candidate biomarkers were successfully validated using immunoassays on an independent set of OSCC patients and matched healthy subjects. The combination of these candidate biomarkers yielded a receiver operating characteristic value of 93%, sensitivity of 90%, and specificity of 83% in detecting OSCC. Patient-based saliva proteomics is a promising approach to searching for OSCC biomarkers. The discovery of these new targets may lead to a simple clinical tool for the noninvasive diagnosis of oral cancer. Long-term longitudinal studies with large populations of individuals with oral cancer and those who are at high risk of developing oral cancer are needed to validate these potential biomarkers.


Analysis of Tub4p, a yeast gamma-tubulin-like protein: implications for microtubule-organizing center function.
gamma-Tubulin is a conserved component of microtubule-organizing centers and is thought to be involved in microtubule nucleation. A recently discovered Saccharomyces cerevisiae gene (TUB4) encodes a tubulin that is related to, but divergent from, gamma-tubulins. TUB4 is essential for cell viability, and epitope-tagged Tub4 protein (Tub4p) is localized to the spindle pole body (Sobel, S.G., and M. Snyder. 1995.J. Cell Biol. 131:1775-1788). We have characterized the expression of TUB4, the association of Tub4p with the spindle pole body, and its role in microtubule organization. Tub4p is a minor protein in the cell, and expression of TUB4 is regulated in a cell cycle-dependent manner. Wild-type Tub4p is localized to the spindle pole body, and a Tub4p-green fluorescent protein fusion is able to associate with a preexisting spindle pole body, suggesting that there is dynamic exchange between cytoplasmic and spindle pole body forms of Tub4p. Perturbation of Tub4p function, either by conditional mutation or by depletion of the protein, results in spindle as well as spindle pole body defects, but does not eliminate the ability of microtubules to regrow from, or remain attached to, the spindle pole body. The spindle pole bodies in tub4 mutant cells duplicate but do not separate, resulting in a monopolar spindle. EM revealed that one spindle pole body of the duplicated pair appears to be defective for the nucleation of microtubules. These results offer insight into the role of gamma-tubulin in microtubule-organizing center function.


Bone Mineral Density T-Scores Derived from CT Attenuation Numbers (Hounsfield Units): Clinical Utility and Correlation with Dual-energy X-ray Absorptiometry.
Clinical computed tomography (CT) studies performed for other indications can be used to opportunistically assess vertebral bone without additional radiation or cost. Reference values for young women are needed to evaluate diagnostic accuracy and track changes in CT bone mineral density values across the lifespan. The purpose of this study was to determine reference values for lumbar trabecular CT attenuation (Hounsfield units [HU]) and determine the diagnostic accuracy of HU T-scores (T-scoreHU) for identifying individuals with osteoporosis. We performed a retrospective single-center cohort study of patients undergoing CT of the lumbar spine. Reference values for lumbar spine Hounsfield units were determined from a reference sample of 190 young women aged 20-30 years undergoing CT scan of the lumbar spine. A separate sample of 252 older subjects undergoing CT and dual-energy X-ray absorptiometry (DXA) within a 6-month period that served as a validation cohort. Osteoporosis was defined by T-scoreDXA ≤ -2.5. Reference values were determined for lumbar HU from L1 to L4 from the reference cohort (24.0 ± 2.9 years). T-scoreHU was calculated in the validation cohort (58.9 ± 7.5 yrs). Receiver operating characteristic (ROC) curves were used to assess sensitivity and specificity of T-scoreHU for this task. Reference group HU ranged from 227 ± 42 at L3 to 236 ± 42 at L1 (P < 0.001). Validation group T-scoreDXA was -0.7 ± 1.5 and -0.9 ± 1.2 at lumbar and femoral sites respectively. Mean T-scoreHU was -2.3. T-scoreHU of -3.0, corresponding to 110 HU, was 48% sensitive and 91% specific for osteoporosis in the validation group. ROC area under the curve ranged from 0.825 to 0.853 depending on lumbar level assessed. Although lumbar trabecular HU T-scores are lower than DXA T-scores, thresholds can be selected to achieve high sensitivity and specificity when screening for osteoporosis. Patients with a lumbar T-scoreHU ≤ -3.0 should be referred for additional evaluation. Further research into HU T-scores and clinical correlates may also provide a tool to assess changes in vertebral bone and the relationship to fracture risk across the lifespan.


Curcumin and cancer stem cells: curcumin has asymmetrical effects on cancer and normal stem cells.
Curcumin has been shown to have numerous cytotoxic effects on cancer stem cells (CSCs). This is due to its suppression of the release of cytokines, particularly interleukin (IL)-6, IL-8 and IL-1, which stimulate CSCs, and also to its effects at multiple sites along CSC pathways, such as Wnt, Notch, Hedgehog and FAK. In spite of its multiple actions targeting CSCs, curcumin has little toxicity against normal stem cells (NSCs). This may be due to curcumin's different effects on CSCs and NSCs.


An Exploration of Service Providers' Experiences With Latinos Convicted of a Sex Offense.
Despite the growing Latino presence in the U.S. criminal justice system and among those who have committed sex offenses specifically, little is known about the barriers and challenges faced by this population when accessing treatment services. This study sought to gather more information about responsivity factors that may be specific to Latinos who have committed sexual offenses. Service providers who worked with Latinos convicted of sexual offenses completed an online survey and answered questions regarding perceived challenges and barriers they encountered when working with Latino clients and were asked to provide recommendations concerning services and treatment provision. Service providers frequently reported issues related to a lack of culturally sensitive services, bilingual professionals, and clients' limited knowledge about the U.S. legal system. Among service providers with experience working with undocumented Latino immigrants, some indicated specific challenges such as stressors related to their immigration status and a lack of resources. Professionals' recommendations were consistent with the challenges reported and findings are discussed as they pertain to responsivity issues in the provision of treatment services to Latino individuals who have committed sexual offenses.


Structures of cellular retinoic acid binding proteins I and II in complex with synthetic retinoids.
Retinoids play important roles in diverse cellular processes including growth, cell differentiation and vision. Many natural and synthetic retinoids are used as drugs in dermatology and oncology. A large amount of data has been accumulated on the cellular activity of different synthetic retinoids. They are stabilized and transported inside the cell cytoplasm by binding and transport proteins, such as cellular retinol-binding proteins and cellular retinoic acid binding proteins (CRABPs). The structures of human CRABP II in complex with two different synthetic retinoids, Ro13-6307 and Ro12--7310 (at 2.1 and 2.0 A resolution, respectively) and of bovine CRABP I in complex with a retinobenzoic acid, Am80 (at 2.8 A resolution) are described. The binding affinities of human CRABP I and II for the retinoids studied here have been determined. All these compounds have comparable binding affinities (nanomolar range) for both CRABPs. Apart from the particular interactions of the carboxylate group of the retinoids with specific protein groups, each structure reveals characteristic interactions. Studying the atomic details of the interaction of retinoids with retinoid-binding proteins facilitates the understanding of the kinetics of retinoid trafficking inside the cytoplasm.


Histoplasmosis-related Healthcare Use, Diagnosis, and Treatment in a Commercially Insured Population, United States.
Infections with Histoplasma can range from asymptomatic to life-threatening acute pulmonary or disseminated disease. Histoplasmosis can be challenging to diagnose and is widely underrecognized. We analyzed insurance claims data to better characterize histoplasmosis testing and treatment practices and its burden on patients. We used the IBM MarketScan Research Databases to identify patients with histoplasmosis (International Classification of Diseases, Ninth Revision, Clinical Modification codes 115.00-115.99) during 2012-2014. We analyzed claims in the 3 months before to the 1 year after diagnosis and examined differences between patients with probable (hospitalized or >1 outpatient visit) and suspected (1 outpatient visit) histoplasmosis. Among 1935 patients (943 probable, 992 suspected), 54% had codes for symptoms or findings consistent with histoplasmosis and 35% had ≥2 healthcare visits in the 3 months before diagnosis. Overall, 646 (33%) had any fungal-specific laboratory test: histoplasmosis antibody test (n = 349 [18%]), Histoplasma antigen test (n = 349 [18%]), fungal smear (n = 294 [15%]), or fungal culture (n = 223 [12%]); 464 (24%) had a biopsy. Forty-nine percent of probable patients and 10% of suspected patients were prescribed antifungal medication in the outpatient setting. In total, 19% were hospitalized. Patients' last histoplasmosis-associated healthcare visits occurred a median of 6 months after diagnosis. Some histoplasmosis patients experienced severe disease, apparent diagnostic delays, and prolonged illness, whereas other patients lacked symptoms and were likely diagnosed incidentally (eg, via biopsy). Low rates of histoplasmosis-specific testing also suggest incidental diagnoses and low provider suspicion, highlighting the need for improved awareness about this disease.


Spoken word recognition in toddlers who use cochlear implants.
The purpose of this study was to assess the time course of spoken word recognition in 2-year-old children who use cochlear implants (CIs) in quiet and in the presence of speech competitors. Children who use CIs and age-matched peers with normal acoustic hearing listened to familiar auditory labels, in quiet or in the presence of speech competitors, while their eye movements to target objects were digitally recorded. Word recognition performance was quantified by measuring each child's reaction time (i.e., the latency between the spoken auditory label and the first look at the target object) and accuracy (i.e., the amount of time that children looked at target objects within 367 ms to 2,000 ms after the label onset). Children with CIs were less accurate and took longer to fixate target objects than did age-matched children without hearing loss. Both groups of children showed reduced performance in the presence of the speech competitors, although many children continued to recognize labels at above-chance levels. The results suggest that the unique auditory experience of young CI users slows the time course of spoken word recognition abilities. In addition, real-world listening environments may slow language processing in young language learners, regardless of their hearing status.


Predictive Performance of Oximetry to Detect Sleep Apnea in Patients Taking Opioids.
Long-term use of opioids for treatment of chronic pain is associated with significant risks including worsening unrecognized or untreated sleep apnea that may increase morbidity and mortality. Overnight oximetry has been validated for predicting sleep apnea in surgical and sleep clinic patients. The objective of the study was to assess the predictive accuracy of oxygen desaturation index (ODI 4%) from home overnight oximetry when compared to apnea hypopnea index (AHI) from polysomnography for predicting sleep apnea in patients taking opioids for chronic pain. This was a planned post hoc analysis of a prospective cohort study conducted at 5 pain clinics. Patient characteristics and daily morphine milligram equivalent (MME) dose were recorded. All consented patients underwent home overnight oximetry (PULSOX-300i, Konica Minolta Sensing, Inc, Osaka, Japan) and in-laboratory polysomnography. The predictive performance of ODI 4% from oximetry was assessed against AHI from polysomnography. Among 332 consented patients, 181 with polysomnography and overnight oximetry data were analyzed. The mean age and body mass index of 181 patients were 52 ± 13 years and 29 ± 6 kg/m2, respectively, with 40% men. The area under the receiver operating curve for ODI to predict moderate-to-severe sleep apnea (AHI ≥15 events/h) and severe sleep apnea (AHI ≥30 events/h) was 0.82 (95% confidence interval [CI], 0.75-0.88) and 0.87 (95% CI, 0.80-0.94). ODI ≥5 events/h had a sensitivity of 85% (95% CI, 74-92) and specificity of 57% (95% CI, 52-61) to predict moderate-to-severe sleep apnea. ODI ≥15 events/h had a sensitivity of 71% (95% CI, 55-83) and specificity of 88% (95% CI, 84-91) to predict severe sleep apnea. Overnight home oximetry has a high predictive performance in predicting moderate-to-severe and severe sleep apnea in patients on opioids for chronic pain. It is a useful additional tool for health care providers for the screening of sleep apnea in this high-risk group.


Clinical and Molecular Characteristics and Burden of Kidney Cancer Among Hispanics and Native Americans: Steps Toward Precision Medicine.
Cancer disparities in Native Americans (NAs) and Hispanic Americans (HAs) vary significantly in terms of cancer incidence and mortality rates across geographic regions. This review reports that kidney and renal pelvis cancers are unevenly affecting HAs and NAs compared to European Americans of non-Hispanic origin, and that currently there is significant need for improved data and reporting to be able to advance toward genomic-based precision medicine for the assessment of such cancers in these medically underserved populations. More specifically, in states along the US-Mexico border, HAs and NAs have higher kidney cancer incidence rates as well as a higher prevalence of kidney cancer risk factors, including obesity and chronic kidney disease. They are also more likely to receive suboptimal care compared to European Americans. Furthermore, they are underrepresented in epidemiologic, clinical, and molecular genomic studies of kidney cancer. Therefore, we maintain that progress in precision medicine for kidney cancer care requires an understanding of various factors among HAs and NAs, including the real kidney cancer burden, variations in clinical care, issues related to access to care, and specific clinical and molecular characteristics.


Esophageal adenocarcinoma microenvironment: Peritumoral adipose tissue effects associated with chemoresistance.
Peritumoral microenvironment affects cancer development and chemoresistance, and visceral adipose tissue may play a critical role. We aimed to identify depot-specific adipose characteristics associated with carcinogenesis and resistance to neoadjuvant therapy in esophageal adenocarcinoma (EAC). We analyzed: (i) the peritumoral adipose tissue of rats following the induction of esophageal carcinogenesis; (ii) the peritumoral and distal (omental) adipose tissue of patients affected by EAC; (iii) adipose-derived stem cells (ADSC) isolated from healthy patients and treated with conditioned medium (CM), collected from tumoral and adipose tissue of patients with EAC. In peritumoral adipose tissue of rats, CD34, CD31 and vascular endothelial growth factor (VEGF) expression increased progressively during EAC development. In patients with EAC, expression of CD34, CD45, CD90 and nucleostemin (NSTM) was higher in peritumoral than in distal adipose tissue and decreased in the presence of neoadjuvant therapy. Moreover, expression of NSTM, octamer-binding transcription factor 4 (OCT-4) and VEGF was higher in peritumoral (but not in distal) adipose tissue of chemoresistant patients. In ADSC, treatment with peritumoral adipose tissue CM increased the adipogenic potential and the expression of CD34, CD90, NSTM and OCT-4. These effects were similar to those induced by cancer-derived CM, but were not observed in ADSC treated with distal adipose tissue CM and were partially reduced by a leptin antagonist. Last, ADSC treated with peritumoral CM of chemoresistant patients displayed increased expression of NSTM, OCT-4, leptin, leptin receptor, alpha-smooth muscle actin (α-SMA), CD34 and VEGF. These results suggest that peritumoral adipose tissue may promote, by paracrine signaling, the expression of depot-specific factors associated with therapeutic resistance.


Sodium-lithium countertransport activity is linked to chromosome 5 in baboons.
The genes involved in the regulation of cellular sodium transport characteristics, which are correlated with some forms of essential hypertension, have not yet been identified. We are studying the genes and environmental factors that affect red blood cell sodium-lithium countertransport (SLC) activity and intracellular sodium (ICNa) concentration in 634 baboons that comprise 11 pedigrees of 2 and 3 generations each. To detect and locate possible quantitative trait loci (QTLs) that affect SLC activity and ICNa concentration, we performed a genome screen by using a maximum likelihood-based variance-components linkage analysis program (SOLAR). SLC and ICNa phenotypes as well as genotypes on 281 microsatellite loci were available for all pedigreed animals. Both SLC and ICNa traits were highly heritable (residual heritability 0.593+/-0.083 [P<0.0001] and 0.739+/-0.082 [P<0.0001], respectively). We obtained evidence that a possible QTL for SLC activity is located on the baboon homologue of human chromosome 4 between D4S2456 and D4S2365 with a maximum multipoint lod score of 9.3 (P<10(-)(10)) near D4S1645. This QTL accounts for approximately two thirds of the total additive genetic variation in SLC activity in baboons. Although ICNa concentration was highly heritable, we found no evidence for linkage to a QTL with use of this methodology. Thus, we have evidence that a gene located on the baboon homologue of human chromosome 4 (baboon chromosome 5) affects cell sodium transport in baboons.


Three-dimensional non-parametric method for limbus detection.
To present a novel non-parametric algorithm for detecting the position of the human eye limbus in three dimensions and a new dynamic method for measuring the full 360° visible iris boundary known as white-to-white distance along the eye horizontal line. The study included 88 participants aged 23 to 65 years (37.7±9.7), 47 females and 41 males. Clinical characteristics, height data and the apex coordinates and 1024×1280 pixel digital images of the eyes were taken by an Eye Surface Profiler and processed by custom-built MATLAB codes. A dynamic light intensity frequency based white-to-white detection process and a novel three-dimensional method for limbus detection is presented. Evidence of significant differences (p<0.001) between nasal-temporal and superior-inferior white-to-white distances in both right and left eyes were found (nasal-temporal direction; 11.74±0.42 mm in right eyes and 11.82±0.47 mm in left eyes & superior-inferior direction; 11.52±0.45 mm in right eyes and 11.55±0.46 mm in left eyes). Average limbus nasal-temporal diameters were 13.64±0.55 mm for right eyes, and 13.74±0.40 mm for left eyes, however the superior-inferior diameters were 13.65±0.54 mm, 13.75±0.38 mm for right and left eyes, respectively. No significant difference in limbus contours has been observed either between the nasal-temporal direction (p = 0.91) and the superior-inferior direction (p = 0.83) or between the right (p = 0.18) and left eyes (p = 0.16). Evidence of tilt towards the nasal-temporal side in the three-dimensional shape of the limbus was found. The right eyes mean limbus contour tilt around the X-axis was -0.3±1.35° however, their mean limbus contour tilt around the Y-axis was 1.76±0.9°. Likewise, the left eyes mean limbus contour tilt around the X-axis was 0.77±1.25° and the mean limbus contour tilt around the Y-axis was -1.54±0.89°. The white-to-white distance in the human eye is significantly larger in the nasal-temporal direction than in the superior-inferior direction. The human limbus diameter was found not to vary significantly in these directions. The 3D measures show that the limbus contour does not lay in one plane and tends to be higher on the nasal-inferior side of the eye.


Enhancing students' engagement on using Blackboard as an online learning community tool in Clinical Biochemistry.
This article was migrated. The article was marked as recommended. Background and aim of the study: Proper online students'/teacher communication and awareness of the use of Blackboard as an online learning community could result in the improvement of student academic achievement. So, the aim of the current project was directed to encourage students and faculty for using Blackboard as an online learning community tool. Moreover, it aimed to measures their perceptions. Subjects and Methods: The study was directed to the second year Medical students during teaching of Clinical Biochemistry. We started by pre-implementation survey, followed by orientation workshop, engaging students for Blackboard implementation then ended in post-implementation survey to evaluate how come students are engaged and satisfied. Results: The first questionnaire group indicated the students' perceptions of Blackboard use and usefulness as an online learning community tool. The second questionnaire group was related to the Interest & Enjoyment of using Backboard. While Blackboard Tools are presented in the third questionnaire questions group. The comparison regarding the total perception of the three groups of the questionnaire between pre-implementation versus post-implementation survey results showed significant improvement of students' perception in the post-implementation phase. By correlating grades in Clinical Biochemistry and total GPA to the questionnaire groups, total perceptions showed a non-significant correlation between all studied parameters in the pre-implementation phase while significant positive correlations were detected in the post-implementation phase. Conclusion: Based on the presented second-year medical students' perception and satisfaction, we could confirm that the Blackboard online platform is a very successful online line learning community tool. Blackboard together with face to face classroom-based learning methods helps students for better learning achievement. Moreover, the online learning community is considered a complementary tool to that of classroom-based learning as it facilitates students/students and students'/faculty communication and minimizes the time required for physical contacts.


From Affective Experience to Motivated Action: Tracking Reward-Seeking and Punishment-Avoidant Behaviour in Real-Life.
Many of the decisions and actions in everyday life result from implicit learning processes. Important to psychopathology are, for example, implicit reward-seeking and punishment-avoidant learning processes. It is known that when specific actions get associated with a rewarding experience, such as positive emotions, that this will increase the likelihood that an organism will engage in similar actions in the future. Similarly, when actions get associated with punishing experiences, such as negative emotions, this may reduce the likelihood that the organism will engage in similar actions in the future. This study examines whether we can observe these implicit processes prospectively in the flow of daily life. If such processes take place then we expect that current behaviour can be predicted by how similar behaviour was experienced (in terms of positive and negative affect) at previous measurement moments. This was examined in a sample of 621 female individuals that had participated in an Experience Sampling data collection. Measures of affect and behaviour were collected at 10 semi-random moments of the day for 5 consecutive days. It was examined whether affective experience that was paired with certain behaviours (physical activity and social context) at previous measurements modified the likelihood to show similar behaviours at next measurement moments. Analyses were performed both at the level of observations (a time scale with units of ± 90 min) and at day level (a time scale with units of 24 h). As expected, we found that affect indeed moderated the extent to which previous behaviour predicted similar behaviour later in time, at both beep- and day-level. This study showed that it is feasible to track reward-seeking and punishment-avoidant behaviour prospectively in humans in the flow of daily life. This opens up a new toolbox to examine processes determining goal-oriented behaviour in relation to psychopathology in humans.


[Clinical characteristics and outcome of malignant hydronephrosis associated with colorectal carcinoma].
Objective: To explore the clinical characteristics and outcome of hydronephrosis associated with advanced or metastatic colorectal carcinoma. Methods: Clinical data of 311 patients with locally advanced or metastatic colorectal carcinoma between June 2017 and March 2020 in National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital were retrospectively collected. Thirty-nine patients with hydronephrosis diagnosed by CT scan were analyzed. Kaplan-Meier method was used for survival analysis, Log rank method was used for comparison of survival between the two groups with or without hydronephrosis, and univariate and multivariate analyses was performed by Cox proportional risk regression model. Results: The incidence rate of malignant hydronephrosis associated with metastatic colorectal carcinoma was 12.5% (39/311), 26 were male, and 13 were female. The median age was 43 years (23-74 years). Among the 39 patients, 29 had unilateral hydronephrosis and 10 had bilateral hydronephrosis. Eleven patients with hydronephrosis at the initiate diagnosis, 28 patients with hydronephrosis at relapse or advanced course, and the median time to hydronephrosis was 17 months (4-62 months). The disease control rate (DCR, 77.8% and 84.6%, respectively) and progression free survival (PFS were 6 and 7 months) were not significantly different between patients with hydronephrosis and without hydronephrosis received the first-line chemotherapy (P>0.05). The median overall survival (OS) after presence of hydronephrosis was 26 months (95%CI: 8.3, 43.7). Multivariate analyses showed that the blood vessel invasion (LVSI) was an independent risk factor for OS (P<0.05). Conclusions: Malignant hydronephrosis had no effect on the efficacy of the first-line chemotherapy and PFS of patients with colorectal carcinoma received the first-line chemotherapy. LVSI was the independent prognostic factor for OS of patients with malignant hydronephrosis.


Prophylactic and therapeutic properties of a sodium citrate preparation in the management of calcium oxalate urolithiasis: randomized, placebo-controlled trial.
The purpose of this study was to investigate the prophylactic and therapeutic effects of a hitherto untested preparation containing sodium citrate in the management of calcium oxalate urolithiasis. In this study, a host of calcium oxalate kidney stone risk factors was investigated using a randomised, placebo controlled, "within-patient" clinical trial. The trial involved four groups of subjects: healthy male controls, healthy female controls , calcium oxalate stone-forming males and calcium oxalate stone-forming females. There were 30 subjects in each group. Twenty subjects in each group ingested the preparation containing sodium citrate and ten subjects in each group ingested a placebo for 7 days. Collection of 24 h urines were carried out at baseline, at day 7 and day 10 (i.e. 3 days after suspension of drug/placebo ingestion). These were analysed for biochemical and physicochemical risk factors. They were also tested for their inhibitory properties in crystallization experiments. Data were statistically analyzed using analysis of variance (ANOVA). Key risk factors were significantly and beneficially altered across all groups after ingestion of the preparation. The pH and urinary citrate excretion increased while urinary oxalate and calcium excretions decreased, as did relative supersaturations of calcium oxalate and uric acid. In addition, inhibition of calcium oxalate crystallization increased. Beneficial carryover effects were observed for some risk factors. The results of this study have demonstrated, for the first time, that a sodium citrate-containing preparation favourably alters the risk factors for calcium oxalate urolithiasis.


Antimalarial dyes revisited: xanthenes, azines, oxazines, and thiazines.
In 1891 Guttmann and Ehrlich (P. Guttmann and P. Ehrlich, Berlin Klin. Wochenschr. 28:953-956, 1891) were the first to report the antimalarial properties of a synthetic, rather than a natural, material when they described the clinical cure of two patients after oral administration of a thiazine dye, methylene blue. Since that time, sporadic reports of the antimalarial properties of several xanthene and azine dyes related to methylene blue have been noted. We report here the results from a reexamination of the antimalarial properties of methylene blue. Janus green B, and three rhodamine dyes and disclose new antimalarial data for 16 commercially available structural analogs of these dyes. The 50% inhibitory concentrations for the chloroquine-susceptible D6 clone and SN isolate and the chloroquine-resistant W2 clone of Plasmodium falciparum were determined by the recently described parasite lactate dehydrogenase enzyme assay. No cross-resistance to chloroquine was observed for any of the dyes. For the 21 dyes tested, no correlation was observed between antimalarial activity and cytotoxicity against KB cells. No correlation between log P (where P is the octanol/water partition coefficient) or relative catalyst efficiency for glucose oxidation and antimalarial activity or cytotoxicity was observed for the dyes as a whole or for the thiazine dyes. The thiazine dyes were the most uniformly potent structural class tested, and among the dyes in this class, methylene blue was notable for both its high antimalarial potency and selectivity.


4,4'-Methylene diphenyl diisocyanate exposure induces expression of alternatively activated macrophage-associated markers and chemokines partially through Krüppel-like factor 4 mediated signaling in macrophages.
Occupational exposure to the most widely used monomeric diisocyanate (dNCO), 4,4'-methylene diphenyl diisocyanate (MDI), may lead to the development of occupational asthma (OA). Alveolar macrophages with alternatively activated (M2) phenotype have been implicated in allergic airway responses and the pathogenesis of asthma. Recent in vivo studies demonstrate that M2 macrophage-associated markers and chemokines are induced by MDI-exposure, however, the underlying molecular mechanism(s) by which this proceeds is unclear.Following MDI exposure (in vivo and in vitro) M2 macrophage-associated transcription factors (TFs), markers, and chemokines were determined by RT-qPCR, western blots, and ELISA.Expression of M2 macrophage-associated TFs and markers including Klf4/KLF4, Cd206/CD206, Tgm2/TGM2, Ccl17/CCL17, Ccl22/CCL22, and CCL24 were induced by MDI/MDI-GSH exposure in bronchoalveolar lavage cells (BALCs)/THP-1 macrophages. The expression of CD206, TGM2, CCL17, CCL22, and CCL24 are upregulated by 3.83-, 7.69-, 6.22-, 6.08-, and 1.90-fold in KLF4-overexpressed macrophages, respectively. Endogenous CD206 and TGM2 were downregulated by 1.65-5.17-fold, and 1.15-1.78-fold, whereas CCL17, CCL22, and CCL24 remain unchanged in KLF4-knockdown macrophages. Finally, MDI-glutathione (GSH) conjugate-treated macrophages show increased chemotactic ability to T-cells and eosinophils, which may be attenuated by KLF4 knockdown.Our data suggest that MDI exposure may induce M2 macrophage-associated markers partially through induction of KLF4.


Does Mantoux Test Result Predicts BCG Immunotherapy Efficiency and Severe Toxicity in Non-Muscle Invasive Bladder Cancer.
To evaluate on a large group of patients whether Mantoux tuberculin skin test (TST) result is associated with BCG immunotherapy effectiveness and whether it can predict occurrence of moderate to severe toxicity. We analysed group of 823 patients with intermediate and high risk NMIBCs who were treated with BCG. The study included 412 patients with the history TST and 411 without TST. A standard dose of Statens Serum Institute tuberculin RT23 was used. The reaction was read 48-72 hours later by evaluating the diameter of palpable induration. The size of the induration was considered positive when the measurement was greater than or equal to 6 mm and excessively positive when bigger than 26 mm. Whole BCG immunotherapy schedule consisted of 27 instillations. The patients were followed for median 61 months. The 5-year recurrence and progression free survival (RFS, PFS) did not differ between the groups in both total study population and in tumour subgroup analysis. TST result in both total study population and in subgroups was not statistically associated with RFS, PFS and cancer specific survival.The moderate-to-severe toxicity was observed in 181(44%) TST patients, and in 196(47%) patients without TST. Incidence of toxicity was not statistically different and also not statistically associated with TST result in any of the tumour subgroups of TST group. This study shows, that TST does not have value in prediction of bladder cancer recurrence, progres-sion nor cancer specific survival. Also it doesn't have a value in predicting therapy toxicity.


Regulated expression of the Mac-1, LFA-1, p150,95 glycoprotein family during leukocyte differentiation.
The regulation of Mac-1, LFA-1, and p150,95 expression during leukocyte differentiation was examined. LFA-1 was present on almost all cell types studied. Both Mac-1 and p150,95 were present on the more mature cells of the myelomonocytic series, but only p150,95 was detected on some B cell lines and cloned cytotoxic T lymphocytes. Phorbol myristate acetate (PMA) stimulation of B chronic lymphocytic leukemia cells dramatically increased p150,95 expression. The resultant Mac-1, LFA-1, p150,95 phenotype resembled hairy cell leukemia, a B cell plasmacytoid leukemia. The promonocytic cell line U937 and the promyeloblastic cell line HL-60 expressed only LFA-1. Monocytic differentiation of U937 cells was stimulated by PMA, and induced the concomitant expression of Mac-1 and p150,95, with more p150,95 induced than Mac-1. Granulocyte/macrophage colony-stimulating factor (GM-CSF) stimulation of U937 cells gave similar results. PMA-stimulated monocytic differentiation of the HL-60 cell line also induced expression of both Mac-1 and p150,95. The number of p150,95 molecules on PMA-stimulated U937 and HL-60 cells were 5 X 10(5) and 3 X 10(5), respectively. Retinoic acid stimulated myeloid differentiation of HL-60 cells and induced expression of both Mac-1 and p150,95. These cells acquired a Mac-1, LFA-1, p150,95 profile that resembled that of granulocytes, with more Mac-1 than p150,95 induced. GM-CSF stimulation of HL-60 cells induced a similar Mac-1 and p150,95 phenotype. The contributions of Mac-1, LFA-1, and p150,95 to aggregation of PMA-differentiated U937 cells were assessed. Monoclonal antibodies to the beta subunit and the LFA-1 alpha subunit, but not those to p150,95 or Mac-1 alpha subunit, inhibited this homotypic adherence.


Biostable electrospun microfibrous scaffolds mitigate hypertrophic scar contraction in an immune-competent murine model.
Burn injuries in the United States account for over one million hospital admissions per year, with treatment estimated at four billion dollars. Of severe burn patients, 30-90% will develop hypertrophic scars (HSc). In this study, we evaluate the impact of an elastomeric, randomly-oriented biostable polyurethane (PU) scaffold on HSc-related outcomes. In vitro, fibroblast-seeded PU scaffolds contracted significantly less and demonstrated fewer αSMA(+) myofibroblasts compared to fibroblast-seeded collagen lattices. In a murine HSc model, collagen coated PU (ccPU) scaffolds significantly reduced HSc contraction as compared to untreated control wounds and wounds treated with the clinical standard of care. Our data suggest that electrospun ccPU scaffolds meet the requirements to reduce HSc contraction including reduction of in vitro HSc related outcomes, diminished scar stiffness, and reduced scar contraction. While clinical dogma suggests treating severe burn patients with rapidly biodegrading skin equivalents, our data suggest that a more long-term scaffold may possess merit in reducing HSc. In severe burns treated with skin grafting, between 30% and 90% of patients develop hypertrophic scars (HSc). There are no therapies to prevent HSc, and treatments are marginally effective. This work is the first example we are aware of which studies the impact of a permanent electrospun elastomer on HSc contraction in a murine model that mimics the human condition. Collagen coated polyurethane scaffolds decrease αSMA+ myofibroblast formation in vitro, prevent stiffening of scar tissue, and mitigate HSc contraction. Unlike current standards of care, electrospun, polyurethane scaffolds do not lose architecture over time. We propose that the future bioengineering strategy of mitigating HSc contraction should consider a long-term elastomeric matrix which persists within the wound bed throughout the remodeling phase of repair.


SARS-CoV-2 vaccination response in pediatric oncology patients.
There remains limited knowledge about the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in pediatric oncology patients, which is essential to provide counseling and risk adaptation in this vulnerable population. The goal of this study was to understand immunogenicity after vaccination in pediatric oncology patients, and determine if certain clinical factors impacted response. Patients 0-25 years of age with a diagnosis of cancer and actively receiving therapy were enrolled on study. We excluded patients who were completely vaccinated prior to their cancer diagnosis. Blood samples were collected pre-vaccination, as well as 2, 4-6, and 8-12 weeks after vaccination. Healthy children who were fully vaccinated enrolled as controls. Clinical data and complete blood counts around time of vaccination were collected. To study B- and T-cell immunity, we measured neutralizing antibodies by enzyme-linked immunoassay and interferon gamma secretion by enzyme-linked immunospot, respectively. Twenty-six patients enrolled on study, for which 11 were evaluable oncology patients and seven were healthy controls. Adequate B-cell response was seen in 36.4% of patients, and adequate T-cell response in 77.8% of patients. Numbers were too small to detect differences based on malignancy type. There was no differences in immunity based on absolute lymphocyte count (ALC) or intensity of therapy. Pediatric oncology patients have a suboptimal immune response to SARS-CoV-2 vaccination. Booster doses will be imperative to provide optimal protection against COVID-19; however, blood counts may not be a useful guide to optimize the time of administration.


Growth vs. DNA strand breaks in Hodgkin's disease: impaired proliferative ability of Hodgkin and Reed-Sternberg cells.
We re-appraised the cell renewal pattern in Hodgkin's disease (HD), considering that most, though not all, Hodgkin/Reed-Sternberg (H-RS) cells exhibit abortive mitoses and that a substantial fraction of these exhibits DNA damage suggestive of imminent or actual cell death. Using combined immunohistochemistry and in situ end-labeling to detect strand breaks, the percentage per case of CD30+ (mainly H-RS) cells with DNA fragmentation (DNA fragmentation index [DFI]) was estimated. For each case, we registered the mitotic index (MI) of CD30+ cells and the percentage of Ki-67+ atypical large cells. To quantify the sum of our parameters for mitosis, whether successful or not, and DNA damage, we introduced the kinetic event index (KEI = MI + DFI). Only DFI and KEI distinguished significantly between mixed cellularity and nodular sclerosis HD. The values for MI and DFI, and therefore for KEI, CD30+ and CD30- small lymphoid cells were proportional. The percentages of Ki-67+ large atypical cells (median 50%) did not correlate significantly with either MIs or DFIs of CD30+ cells. Cluster analysis revealed the existence, independent of histological subtype, of 2 large groups of HD with different KEIs. Our findings suggest that cell deletion plays an important role in HD. Further, it appears that proliferation-associated antigens in H-RS cells do not reflect successful cell production in this disorder.


Delta9-tetrahydrocannabinol increase plasma testosterone concentrations in mice.
Oral administration of delta 9-tetrahydrocannabinol had a biphasic effect on plasma testosterone concentrations in male mice, causing rapid sustained increases at low doses and subsequent decreases at higher doses. In hypophysectomized and intact mice receiving gonadotropins (human chorionic gonadotropin), treatment with delta 9-tetrahydrocannabinol maintained higher plasma testosterone concentrations. Thus, this cannabinoid may interact with gonadotropin and directly influence testicular steroidogenesis in vivo.


First discovery of a primitive coelacanth fin fills a major gap in the evolution of lobed fins and limbs.
The fossil record provides unique clues about the primitive pattern of lobed fins, the precursors of digit-bearing limbs. Such information is vital for understanding the evolutionary transition from fish fins to tetrapod limbs, and it guides the choice of model systems for investigating the developmental changes underpinning this event. However, the evolutionary preconditions for tetrapod limbs remain unclear. This uncertainty arises from an outstanding gap in our knowledge of early lobed fins: there are no fossil data that record primitive pectoral fin conditions in coelacanths, one of the three major groups of sarcopterygian (lobe-finned) fishes. A new fossil from the Middle-Late Devonian of Wyoming preserves the first and only example of a primitive coelacanth pectoral fin endoskeleton. The strongly asymmetrical skeleton of this fin corroborates the hypothesis that this is the primitive sarcopterygian pattern, and that this pattern persisted in the closest fish-like relatives of land vertebrates. The new material reveals the specializations of paired fins in the modern coelacanth, as well as in living lungfishes. Consequently, the context in which these might be used to investigate evolutionary and developmental relationships between vertebrate fins and limbs is changed. Our data suggest that primitive actinopterygians, rather than living sarcopterygian fishes and their derived appendages, are the most informative comparators for developmental studies seeking to understand the origin of tetrapod limbs.


Salt loading augments vascular responses to indomethacin in stroke-prone SHR.
We examined whether endogenous prostaglandins (PGs) participated in control of hindquarters vascular resistance during salt loading in stroke-prone spontaneously hypertensive rates (SHR-SP). SHR-SP and Wistar-Kyoto rats (WKY) were fed either a normal (0.3% NaCl) or high (8% NaCl) salt diet for 5 wk. High salt increased blood pressure and hindquarter vascular resistance (VR) in SHR-SP (P less than 0.01) but not in WKY. Indomethacin given intravenously increased hindquarter VR in SHR-SP during high salt as well as during normal salt (P less than 0.01) but not in either group of WKY. In SHR-SP the increase in hindquarter VR by PG synthesis inhibitors were two times greater during high salt than during normal salt (P less than 0.01). In addition, hindquarter vasodilatation by bradykinin was greater (P less than 0.05) in SHR-SP during high salt than that during normal salt, but vasodilatation by prostaglandin E1 or nitroglycerin was not different between the two groups. These results suggest that vascular synthesis of endogenous PGs was greater in SHR-SP during high salt than that during normal salt. Increased endogenous PGs may play an important role in the regulation of hindquarter VR during high salt intake in SHR-SP.


A Prediction Model for Severe Maternal Morbidity in Laboring Patients at Term.
To determine the factors associated with severe maternal morbidity in a modern cohort of women laboring at term and to create a prediction model. This is a retrospective cohort study of all term, laboring patients with live births at a single tertiary care center from 2004 to 2014. The primary outcome was composite maternal morbidity including organ failure, amniotic fluid embolism, anesthesia complications, sepsis, shock, thrombotic events, transfusion, or hysterectomy. Multivariable logistic regression was used to identify independent risk factors. Antepartum, intrapartum, and combined risk scores were created and test characteristics were analyzed. Among 19,249 women delivering during the study period, 323 (1.68%) patients experienced severe morbidity, with blood transfusion the most common complication (286, 1.49%). Factors in the antepartum model included advanced maternal age, race, hypertension, nulliparity, history of cesarean delivery, smoking, and unfavorable Bishop score. Intrapartum factors included mode of delivery, use of cervical ripening agents or oxytocin, prolonged second stage, and macrosomia. The combined model had an area under the curve of 0.76 (95% confidence interval [CI], 0.73, 0.79). This three-part risk scoring system can help clinicians counsel patients and guide clinical decision making for anticipating severe maternal morbidity and necessary resources.


The utility of the environmental scan for public health practice: lessons from an urban program to increase cancer screening.
The environmental scan is a tool that can be utilized to collect data to design health programs uniquely tailored to the needs of communities. However, it remains relatively undefined, unevaluated and underutilized in the field of public health. While individual studies indicate the utility of the environmental scan for public health, it is difficult to find a theoretical framework or guidelines on how to design, implement or evaluate the process within public health practice. The purpose of this study was to elicit lessons learned to maximize the utility of the environmental scan as a tool for public health. This process occurred through the development and implementation of an environmental scan as part of the needs-assessment phase of a project to increase cancer screening among African Americans in Baltimore, MD. Data collection methods for the environmental scan included a review of community stakeholders, cancer incidence and community assets and liabilities in target communities, focus-group sessions and key informant interviews with service providers. The environmental scan was conducted in 2003 and allowed for rapid acquisition and use of information about events, trends and relationships in the neighborhoods targeted for our project and enabled researchers to move forward with implementing the cancer-screening project. The researchers conclude that the environmental scan has considerable potential to be a creative, responsive, cost-effective and mobilizing tool for public health practice. However, further application and critical review are necessary to make it a more effective public health tool and an established research methodology.


The importance of being flexible: the case of basic region leucine zipper transcriptional regulators.
Large volumes of protein sequence and structure data acquired by proteomic studies led to the development of computational bioinformatic techniques that made possible the functional annotation and structural characterization of proteins based on their primary structure. It has become evident from genome-wide analyses that many proteins in eukaryotic cells are either completely disordered or contain long unstructured regions that are crucial for their biological functions. The content of disorder increases with evolution indicating a possibly important role of disorder in the regulation of cellular systems. Transcription factors are no exception and several proteins of this class have recently been characterized as premolten/molten globules. Yet, mammalian cells rely on these proteins to control expression of their 30,000 or so genes. Basic region:leucine zipper (bZIP) DNA-binding proteins constitute a major class of eukaryotic transcriptional regulators. This review discusses how conformational flexibility "built" into the amino acid sequence allows bZIP proteins to interact with a large number of diverse molecular partners and to accomplish their manifold cellular tasks in a strictly regulated and coordinated manner.


Identification and DNA sequence of the mobilization region of the 5-nitroimidazole resistance plasmid pIP421 from Bacteroides fragilis.
The nucleotide sequence of the DNA mobilization region of the 5-nitroimidazole resistance plasmid pIP421, from strain BF-F239 of Bacteroides fragilis, was determined. It contains a putative origin of transfer (oriT) including three sets of inverted repeats and two sequences reminiscent of specific integration host factor binding sites. The product of the mobilization gene mob421 (42.2 kDa) is a member of the Bacteroides mobilization protein family, which includes the MobA of pBI143, NBUs, and Tn4555. Sequence similarity suggests that it has both oriT binding and nicking activities. The transfer frequency of pIP421 in a B. fragilis donor strain possessing a Tc(r) or Tc(r) Em(r)-like conjugative transposon was significantly enhanced by tetracycline. Moreover, the mobilization region of pIP421 confers the ability to be mobilized from Escherichia coli by an IncP plasmid.


Changes in vascular and extravascular volumes of eel muscle in response to catecholamines: the function of the caudal lymphatic heart.
1. Vascular volume changes in an isolated saline-perfused eel tail preparation in response to catecholamines were small (less than 2%) and are explicable in terms of changes in volume of pre-capillary resistance vessels. 2. Extravascular-extracellular (interstitial) volume increased less than 3% during infusion of adrenaline (AD) at concentrations of 1 x 10(-6) to 1 x 10(-3) M. Injection of doses of AD and noradrenaline (NA) between 1 nmol and 100 nmol caused maximum interstitial volume changes of less than 11%. 3. Isoprenaline caused only very small changes in vascular and interstitial volume. 4. Caudal lymph heart frequency increases when high concentrations (greater than 1 x 10(-6) M) and doses (greater than 1 nmol) of AD and NA were administered. 5. Caudal lymph heart frequency increases were significantly correlated with changes in outflow after vascular volume adjustments. One function of the caudal lymph heart is to return interstitial fluid to the vascular system.


ENIGMA brain injury: Framework, challenges, and opportunities.
Traumatic brain injury (TBI) is a major cause of disability worldwide, but the heterogeneous nature of TBI with respect to injury severity and health comorbidities make patient outcome difficult to predict. Injury severity accounts for only some of this variance, and a wide range of preinjury, injury-related, and postinjury factors may influence outcome, such as sex, socioeconomic status, injury mechanism, and social support. Neuroimaging research in this area has generally been limited by insufficient sample sizes. Additionally, development of reliable biomarkers of mild TBI or repeated subconcussive impacts has been slow, likely due, in part, to subtle effects of injury and the aforementioned variability. The ENIGMA Consortium has established a framework for global collaboration that has resulted in the largest-ever neuroimaging studies of multiple psychiatric and neurological disorders. Here we describe the organization, recent progress, and future goals of the Brain Injury working group.


Identification of vibration modes in single-molecule junctions by strong inelastic signals in noise.
Conductance measurements in single-molecule junctions (SMJs) are on many occasions accompanied by inelastic spectroscopy and shot-noise measurements in order to obtain information about different vibration modes (or vibrons) and channels involved in the transport respectively. We have extended the single-molecule shot-noise measurements, which were previously performed at low bias, to high bias and we have studied the effects of these vibrons on the noise for a Deuterium (D2) molecule between Pt leads. We report here two important findings from these measurements. First, we find in our noise measurements that at the vibron energies of the molecule, a two-level fluctuation (TLF) is excited in the junction. Second, we show that in the presence of this TLF, a form of enhanced noise spectroscopy can be performed to detect inelastic electron-vibron interactions, by studying the third derivative of the noise (d3SI/dV3). This is possible because TLFs are insensitive to elastic scattering of electrons from defects, which nevertheless leave their signature in the usual inelastic electron tunnelling spectroscopy (IETS) measurements.


In vivo Evaluation of Anti-Hyperglycemic, Anti-hyperlipidemic and Anti-Oxidant Status of Liver and Kidney of Thymol in STZ-Induced Diabetic Rats.
The evaluation of the positive and protective effects thymol as a natural compound on the STZ -induced diabetic rats. In this study, seven groups of the streptozotocin induced diabetic and normal rats (overall 42 males) were tested through various biochemical and histopathological factors such as: serum glucose, insulin, creatinine, lipids, lipoproteins, liver function-related enzymes, and antioxidant status in liver and kidney. The obtained results in this work indicated that thymol had a significant anti-hypoglycemic, anti-hypolipidemic activities on the STZ-induced diabetic rats. Further, the assessment different biochemical parameters revealed that the levels of creatinine, low-density lipoprotein cholesterol, very low density lipoprotein cholesterol, and liver function-related enzymes such as aspartate aminotransferase and alanine aminotransferase were decreased in the treated diabetes rats under 20 and 40 mg/kg thymol compared to the control diabetes group. Considerably, the anti-oxidant enzymes status that were achieved from the liver and kidney organs were modulated after treatment with thymol in the diabetic rats. The results of this research has brough a new aspect concerning the proteevtive and positive effects of thymol on the diabetic complications in the animal model.


Streptococcus pneumoniae in biofilms are unable to cause invasive disease due to altered virulence determinant production.
It is unclear whether Streptococcus pneumoniae in biofilms are virulent and contribute to development of invasive pneumococcal disease (IPD). Using electron microscopy we confirmed the development of mature pneumococcal biofilms in a continuous-flow-through line model and determined that biofilm formation occurred in discrete stages with mature biofilms composed primarily of dead pneumococci. Challenge of mice with equal colony forming units of biofilm and planktonic pneumococci determined that biofilm bacteria were highly attenuated for invasive disease but not nasopharyngeal colonization. Biofilm pneumococci of numerous serotypes were hyper-adhesive and bound to A549 type II pneumocytes and Detroit 562 pharyngeal epithelial cells at levels 2 to 11-fold greater than planktonic counterparts. Using genomic microarrays we examined the pneumococcal transcriptome and determined that during biofilm formation S. pneumoniae down-regulated genes involved in protein synthesis, energy production, metabolism, capsular polysaccharide (CPS) production, and virulence. We confirmed these changes by measuring CPS by ELISA and immunoblotting for the toxin pneumolysin and the bacterial adhesins phosphorylcholine (ChoP), choline-binding protein A (CbpA), and Pneumococcal serine-rich repeat protein (PsrP). We conclude that biofilm pneumococci were avirulent due to reduced CPS and pneumolysin production along with increased ChoP, which is known to bind C-reactive protein and is opsonizing. Likewise, biofilm pneumococci were hyper-adhesive due to selection for the transparent phase variant, reduced CPS, and enhanced production of PsrP, CbpA, and ChoP. These studies suggest that biofilms do not directly contribute to development of IPD and may instead confer a quiescent mode of growth during colonization.


Two-scale dispersal estimation for biological invasions via synthetic likelihood.
Biological invasions reshape environments and affect the ecological and economic welfare of states and communities. Such invasions advance on multiple spatial scales, complicating their control. When modeling stochastic dispersal processes, intractable likelihoods and autocorrelated data complicate parameter estimation. As with other approaches, the recent synthetic likelihood framework for stochastic models uses summary statistics to reduce this complexity; however, it additionally provides usable likelihoods, facilitating the use of existing likelihood-based machinery. Here, we extend this framework to parameterize multi-scale spatio-temporal dispersal models and compare existing and newly developed spatial summary statistics to characterize dispersal patterns. We provide general methods to evaluate potential summary statistics and present a fitting procedure that accurately estimates dispersal parameters on simulated data. Finally, we apply our methods to quantify the short and long range dispersal of Chagas disease vectors in urban Arequipa, Peru, and assess the feasibility of a purely reactive strategy to contain the invasion.


Extended unified SEM approach for modeling event-related fMRI data.
There has been increasing emphasis in fMRI research on the examination of how regions covary in a distributed neural network. Event-related data designs present a unique challenge to modeling how couplings among regions change in the presence of experimental manipulations. The present paper presents the extended unified SEM (euSEM), a novel approach for acquiring effective connectivity maps with event-related data. The euSEM adds to the unified SEM, which models both lagged and contemporaneous effects, by estimating the direct effects that experimental manipulations have on blood-oxygen-level dependent activity as well as the modulating effects the manipulations have on couplings among regions. Monte Carlos simulations included in this paper offer support for the model's ability to recover covariance patterns used to estimate data. Next, we apply the model to empirical data to demonstrate feasibility. Finally, the results of the empirical data are compared to those found using dynamic causal modeling. The euSEM provides a flexible approach for modeling event-related data as it may be employed in an exploratory, partially exploratory, or entirely confirmatory manner.


Patients with severe sepsis vary markedly in their ability to generate activated protein C.
Activated protein C (APC) supplementation significantly reduces mortality in patients with severe sepsis, presumably by down-regulating coagulation, inflammation, and apoptosis. In vivo, endogenous APC is generated from protein C (PC) "on demand" in response to elevated thrombin levels. Thrombomodulin and endothelial cell protein C receptor are endothelial receptors required to generate APC endogenously. Since these receptors may be down-regulated in sepsis, we measured plasma markers of APC generation in 32 patients with severe sepsis to determine whether APC generation is impaired and whether markers of APC generation correlate with 28-day mortality. Relative to normals, all patients had elevated F1 + 2 and thrombin-antithrombin complex (TAT) levels (markers of thrombin generation and inhibition, respectively), and 28 of 32 patients had reduced PC levels. In 20 patients, APC levels paralleled elevated F1 + 2 levels, whereas 12 patients had low APC levels despite elevated F1 + 2 levels, suggesting that APC generation is impaired in the latter. No significant differences exist between survivors and nonsurvivors with respect to baseline PC levels, F1 + 2 levels, and APACHE II (acute physiology and chronic health evaluation) scores. Baseline APC levels were higher in survivors (P = .024), and baseline F1 + 2/APC ratios were lower in survivors (P = .047). Larger studies are warranted to establish whether APC generation profiles aid in managing sepsis.


Intravitreal Anti-Vascular Endothelial Growth Factor Agents for the Treatment of Diabetic Retinopathy: A Review of the Literature.
Background: Diabetic retinopathy (DR) is the leading cause of blindness in the working-age population. The purpose of this review is to gather the existing literature regarding the use of the approved anti-vascular endothelial growth (anti-VEGF) agents in the treatment of DR. Methods: A comprehensive literature review in PubMed engine search was performed for articles written in English language up to 1 July 2021, using the keywords "diabetic retinopathy", "ranibizumab", "aflibercept", and "anti-VEGF". Emphasis was given on pivotal trials and recent robust studies. Results: Intravitreal anti-VEGF agents have been found to significantly improve visual acuity and reduce retinal thickness in patients with diabetic macular edema (DME) in a long-term follow-up ranging from 1 to 5 years and are considered the standard-of-care in such patients. Regarding DR, intravitreal anti-VEGF agents provided ≥2-step improvement in DR severity on color fundus photography in about 30-35% of patients with NPDR at baseline, in the majority of clinical trials originally designed to evaluate the efficacy of intravitreal anti-VEGF agents in patients with DME. Protocol S and CLARITY study have firstly reported that intravitreal anti-VEGF agents are non-inferior to panretinal photocoagulation (PRP) in patients with proliferative DR (PDR). However, the use of new imaging modalities, such as optical coherence tomography-angiography and wide-field fluorescein angiography, reveals conflicting results about the impact of anti-VEGF agents on the regression of retinal non-perfusion in patients with DR. Furthermore, one should consider the high "loss to follow-up" rate and its devastating consequences especially in patients with PDR, when deciding to treat the latter with intravitreal anti-VEGF agents alone compared to PRP. In patients with PDR, combination of treatment of intravitreal anti-VEGF agents and PRP has been also supported. Moreover, in the specific case of vitreous hemorrhage or tractional retinal detachment as complications of PDR, intravitreal anti-VEGF agents have been found to be beneficial as an adjunct to pars plana vitrectomy (PPV), most commonly given 3-7 days before PPV, offering reduction in the recurrence of vitreous hemorrhage. Conclusions: There is no general consensus regarding the use of intravitreal anti-VEGF agents in patients with DR. Although anti-VEGF agents are the gold standard in the treatment of DME and seem to improve DR severity, challenges in their use exist and should be taken into account in the decision of treatment, based on an individualized approach.


Secretion of a foreign protein from budding yeasts is enhanced by cotranslational translocation and by suppression of vacuolar targeting.
Budding yeasts are often used to secrete foreign proteins, but the efficiency is variable. To identify roadblocks in the yeast secretory pathway, we used a monomeric superfolder GFP (msGFP) as a visual tracer in Saccharomyces cerevisiae and Pichia pastoris. One roadblock for msGFP secretion is translocation into the ER. Foreign proteins are typically fused to the bipartite α-factor secretion signal, which consists of the signal sequence followed by the pro region. The α-factor signal sequence directs posttranslational translocation. For msGFP, posttranslational translocation is inefficient with the α-factor signal sequence alone but is stimulated by the pro region. This requirement for the pro region can be bypassed by using the Ost1 signal sequence, which has been shown to direct cotranslational translocation. A hybrid secretion signal consisting of the Ost1 signal sequence followed by the α-factor pro region drives efficient translocation followed by rapid ER export. A second roadblock for msGFP secretion in S. cerevisiae occurs during exit from the Golgi, when some of the msGFP molecules are diverted to the vacuole. Deletion of the sorting receptor Vps10 prevents vacuolar targeting of msGFP at the expense of missorting vacuolar hydrolases such as carboxypeptidase Y (CPY) to the culture medium. However, a truncation of Vps10 blocks vacuolar targeting of msGFP while permitting CPY to be sorted normally. With budding yeasts, if the secretion or processing of a foreign protein is poor, we recommend two options. First, use the Ost1 signal sequence to achieve efficient entry into the secretory pathway while avoiding the processing issues associated with the α-factor pro region. Second, truncate Vps10 to suppress diversion to the vacuole. These insights obtained with msGFP highlight the value of applying cell biological methods to study yeast secretion.


Computational fitness landscape for all gene-order permutations of an RNA virus.
How does the growth of a virus depend on the linear arrangement of genes in its genome? Answering this question may enhance our basic understanding of virus evolution and advance applications of viruses as live attenuated vaccines, gene-therapy vectors, or anti-tumor therapeutics. We used a mathematical model for vesicular stomatitis virus (VSV), a prototype RNA virus that encodes five genes (N-P-M-G-L), to simulate the intracellular growth of all 120 possible gene-order variants. Simulated yields of virus infection varied by 6,000-fold and were found to be most sensitive to gene-order permutations that increased levels of the L gene transcript or reduced levels of the N gene transcript, the lowest and highest expressed genes of the wild-type virus, respectively. Effects of gene order on virus growth also depended upon the host-cell environment, reflecting different resources for protein synthesis and different cell susceptibilities to infection. Moreover, by computationally deleting intergenic attenuations, which define a key mechanism of transcriptional regulation in VSV, the variation in growth associated with the 120 gene-order variants was drastically narrowed from 6,000- to 20-fold, and many variants produced higher progeny yields than wild-type. These results suggest that regulation by intergenic attenuation preceded or co-evolved with the fixation of the wild type gene order in the evolution of VSV. In summary, our models have begun to reveal how gene functions, gene regulation, and genomic organization of viruses interact with their host environments to define processes of viral growth and evolution.


Traditions in spider monkeys are biased towards the social domain.
Cross-site comparison studies of behavioral variation can provide evidence for traditions in wild species once ecological and genetic factors are excluded as causes for cross-site differences. These studies ensure behavior variants are considered within the context of a species' ecology and evolutionary adaptations. We examined wide-scale geographic variation in the behavior of spider monkeys (Ateles geoffroyi) across five long-term field sites in Central America using a well established ethnographic cross-site survey method. Spider monkeys possess a relatively rare social system with a high degree of fission-fusion dynamics, also typical of chimpanzees (Pan troglodytes) and humans (Homo sapiens). From the initial 62 behaviors surveyed 65% failed to meet the necessary criteria for traditions. The remaining 22 behaviors showed cross-site variation in occurrence ranging from absent through to customary, representing to our knowledge, the first documented cases of traditions in this taxon and only the second case of multiple traditions in a New World monkey species. Of the 22 behavioral variants recorded across all sites, on average 57% occurred in the social domain, 19% in food-related domains and 24% in other domains. This social bias contrasts with the food-related bias reported in great ape cross-site comparison studies and has implications for the evolution of human culture. No pattern of geographical radiation was found in relation to distance across sites. Our findings promote A. geoffroyi as a model species to investigate traditions with field and captive based experiments and emphasize the importance of the social domain for the study of animal traditions.


Folic acid inhibits endothelial cell proliferation through activating the cSrc/ERK 2/NF-κB/p53 pathway mediated by folic acid receptor.
Folate is important for normal cell division. Folate deficiency has been implicated in various diseases, including atherosclerosis, neural tube defects, and cancer. However, the effect of folate on angiogenesis was unclear. The aim of this study was to investigate the anti-angiogenic action of folic acid (FA). FA (0-10 μmol/L) concentration-dependently decreased DNA synthesis and proliferation in cultured human umbilical venous endothelial cells (HUVEC). Western blot analyses demonstrated that the levels of p21, p27 and p53 protein in HUVEC were increased by FA. The FA-inhibited [3H]thymidine incorporation was completely blocked when the expressions of p21 and p27 were knocked-down together. Knock-down of p53 prevented the FA-induced increases in p21 and p27 protein level. The levels of phosphorylated Src (p-Src) and p-Src-FA receptor (FR) complex in HUVEC were increased by FA. Knock-down of FR reduced the FA-induced increases of p-Src and p53. The FA-induced increases of p21, p27 and p53 protein levels were abolished when cSrc was knocked-down. FA also increased NF-κB nuclear translocation and binding onto the p53 promoter. The FA-induced up-regulation of the p53 promoter activity was prevented by knocked-down of ERK. Matrigel angiogenesis assay in mice demonstrate the anti-angiogenic effect of FA in vivo. In conclusion, our data indicate that FA bound to FR in HUVEC, subsequently activated the cSrc/ERK 2/NF-κB/p53 signaling pathway, which in turn up-regulated the expression of p21 and p27, and finally resulted in cell cycle arrest at the G0/G1 phase. In the present study, we uncover a completely novel role of FA for anti-angiogenesis.


Severity of pneumonia due to new H1N1 influenza virus in ferrets is intermediate between that due to seasonal H1N1 virus and highly pathogenic avian influenza H5N1 virus.
The newly emerged influenza A(H1N1) virus (new H1N1 virus) is causing the first influenza pandemic of this century. Three influenza pandemics of the previous century caused variable mortality, which largely depended on the development of severe pneumonia. However, the ability of the new H1N1 virus to cause pneumonia is poorly understood. The new H1N1 virus was inoculated intratracheally into ferrets. Its ability to cause pneumonia was compared with that of seasonal influenza H1N1 virus and highly pathogenic avian influenza (HPAI) H5N1 virus by using clinical, virological, and pathological analyses. Our results showed that the new H1N1 virus causes pneumonia in ferrets intermediate in severity between that caused by seasonal H1N1 virus and by HPAI H5N1 virus. The new H1N1 virus replicated well throughout the lower respiratory tract and more extensively than did both seasonal H1N1 virus (which replicated mainly in the bronchi) and HPAI H5N1 virus (which replicated mainly in the alveoli). High loads of new H1N1 virus in lung tissue were associated with diffuse alveolar damage and mortality. The new H1N1 virus may be intrinsically more pathogenic for humans than is seasonal H1N1 virus.


Roles of periventricular neurons in retinotectal transmission in the optic tectum.
The midbrain roof is a retinorecipient region referred to as the optic tectum in lower vertebrates, and the superior colliculus in mammals. The retinal fibers projecting to the tectum transmit visual information to tectal retinorecipient neurons. Periventricular neurons are a subtype of these neurons that have their somata in the deepest layer of the teleostean tectum and apical dendrites ramifying at more superficial layers consisting of retinal fibers. The retinotectal synapses between the retinal fibers and periventricular neurons are glutamatergic, and ionotropic glutamate receptors mediate the transmission in these synapses. This transmission involves long-term potentiation, and is modulated by hormone action. Visual information processed in the periventricular neurons is transmitted to adjacent tectal cells and target nuclei of periventricular neuron axonal branches, some of which relay the visual information to other brain areas controlling behavior. We demonstrated that periventricular neurons play a principal role in visual information processing in the teleostean optic tectum; the effects of tectal output on behavior is discussed also in the present review.


Efficacy and safety of pregabalin for treating neuropathic pain associated with diabetic peripheral neuropathy: a 14 week, randomized, double-blind, placebo-controlled trial.
To evaluate the efficacy, safety and pharmacokinetics of pregabalin in treating neuropathic pain associated with diabetic peripheral neuropathy in Japanese patients. A randomized, double-blind, placebo-controlled, multicentre 14 week clinical trial was conducted. Japanese patients with diabetic peripheral neuropathy (n = 317) were randomized to receive placebo or pregabalin at 300 or 600 mg/day. The primary efficacy measure was a change of mean pain score from baseline to end-point from patients' daily pain diaries. Significant reductions in pain were observed in patients treated with pregabalin at 300 and 600 mg/day vs. placebo (P < 0.05). Improvements in weekly pain scores were observed as early as week 1 and were sustained throughout the study period (300 and 600 mg/day difference from placebo at study end-point, -0.63 and -0.74, respectively). Pregabalin produced significant improvements in weekly sleep interference scores, the short-form McGill Pain Questionnaire, the Medical Outcomes Study-Sleep Scale, the 36-item Short-Form Health Survey scale, and the Patient and Clinical Global Impression of Change. Patient impressions of numbness, pain and paraesthesia were also significantly improved. Regarding treatment responders, 29.1 and 35.6% of patients treated with 300 and 600 mg/day, respectively, reported ≥ 50% improvement in mean pain scores (vs. 21.5% for placebo). Pregabalin was well tolerated; somnolence (26%), dizziness (24%), peripheral oedema (13%) and weight gain (11%) were the most common adverse events and generally were reported as mild to moderate. Pregabalin was effective in reducing pain and improving sleep disturbances due to pain, and was well tolerated in Japanese patients with painful DPN.


Luminescent and Photoredox-Active Molybdenum(0) Complexes Competitive with Isoelectronic Ruthenium(II) Polypyridines.
Ruthenium(II) complexes with chelating polypyridine ligands are among the most frequently investigated compounds in photophysics and photochemistry, owing to their favorable luminescence and photoredox properties. Equally good photoluminescence performance and attractive photocatalytic behavior is now achievable with isoelectronic molybdenum(0) complexes. The zero-valent oxidation state of molybdenum is stabilized by carbonyl or isocyanide ligands, and metal-to-ligand charge transfer (MLCT) excited states analogous to those in ruthenium(II) complexes can be established. Microsecond MLCT excited-state lifetimes and photoluminescence quantum yields up to 0.2 have been achieved in solution at room temperature, and the emission wavelength has become tunable over a large range. The molybdenum(0) complexes are stronger photoreductants than ruthenium(II) polypyridines and can therefore perform more challenging chemical reductions. The triplet nature of their luminescent MLCT states allows sensitization of photon upconversion via triplet-triplet annihilation, to convert low-energy input radiation into higher-energy output fluorescence. This review summarizes the current state of the art concerning luminescent molybdenum(0) complexes and highlights their application potential. Molybdenum is roughly 140 times more abundant and far cheaper than ruthenium, hence this research is relevant in the greater context of finding more sustainable alternatives to using precious and rare transition metals in photophysics and photochemistry.


The Asn418-linked N-glycan of ErbB3 plays a crucial role in preventing spontaneous heterodimerization and tumor promotion.
ErbB2 and ErbB3, two members of the ErbB family, form a high-affinity heregulin coreceptor that elicits potent mitogenic and transforming signals, and clinical studies indicate that these receptors play an important role in tumor incidence and progression. To determine whether N-glycosylation is involved in the function of ErbB3, a series of human ErbB3 molecules devoid of N-glycans were prepared and transfected to Flp-In-CHO cells for stable expression. A cross-linking study showed that the Asn(418) to Gln mutant (N418Q) of ErbB3 underwent autodimerization without its ligand, heregulin. The wild-type or N418Q mutant of ErbB3 was next coexpressed with ErbB2 in Flp-In-CHO cells, and the effect of N-glycan on heterodimerization was examined. The N418Q mutant of ErbB3 was autodimerized with ErbB2 without ligand stimulation, and receptor tyrosine phosphorylation and subsequent extracellular signal-regulated kinase (ERK) and Akt phosphorylation were promoted in the absence of heregulin. A cell proliferation assay and a soft agar colony formation assay showed that the N418Q mutant of ErbB3 coexpressed with ErbB2 promoted cell proliferation and colony formation in soft agar in an ERK- and Akt-dependent manner. The mutation also promoted the growth of tumors in athymic mice when injected s.c. These findings suggest that the Asn(418)-linked N-glycan in ErbB3 plays an essential role in regulating receptor heterodimerization with ErbB2 and might have an effect on transforming activity.