Alterations induced by titanium dioxide nanoparticles (nano-TiO2) in fertilization and embryonic and larval development of the tropical sea urchin Lytechinus variegatus.
The release of nanomaterials into the environment is the cause of an emerging concern. Titanium dioxide nanoparticles (nano-TiO2) among the most produced nanomaterials, has been documented in marine coastal areas posing a threat on marine biota. Sea urchin embryos are recognized as suitable bioindicators in ecological risk assessment and recently for nanomaterials. This study investigated the impact of nano-TiO2 on fertilization, embryonic and larval development of the tropical sea urchin Lytechinus variegatus in a range of concentrations (0.005-5 μg/mL) which includes environmentally relevant ones. The behavior of nano-TiO2 in tropical natural seawater was determined by dynamic light scattering (DLS) and toxicity was evaluated through fertilization and embryotoxicity tests, and morphological/morphometric analyses of sea urchin's larvae. Limited toxicity was recorded for nano-TiO2 in tropical sea urchin embryos and larvae, except for effects at the gastrula stage at 0.005 μg/mL. Large agglomerates of nano-TiO2 (5 μg/mL) were observed adhering onto sea urchin larvae thus probably preventing nanoparticles uptake at the highest concentrations (>0.005 μg/mL). Environmental levels of nano-TiO2 are able to cause toxicity on tropical sea urchin L. variegatus embryos with potential consequences on populations and their ecological role in tropical coastal areas.


Field incidence of mycotoxins in commercial popcorn and potential environmental influences.
Popcorn ear damage by insects and mycotoxin levels in kernels were monitored in several commercial popcorn fields in central Illinois over a 4-year period. Aflatoxin was rare, but fumonisin and deoxynivalenol (DON) were commonly encountered each year, and occurred at mean levels in fields up to 1.7 mg/kg (sample max. 2.77 mg/kg) and 1.9 mg/kg (sample max. 2.66 mg/kg), respectively. Neither fumonisin nor DON levels were significantly correlated with the percent of ears with visibly moldy insect-damaged kernels. Significant correlations were noted for the percent of ears with early caterpillar damage and both fumonisin and DON levels overall for some years and at specific sites in other years. Fumonisin levels were generally more highly correlated with insect damage than DON levels. Insect damaged kernels had 100- to 500-fold or greater levels of fumonisin compared to noninsect-damaged kernels, while DON levels were closer to 10- to 30-fold higher in insect damaged versus nondamaged kernels. A high percentage of DON-contaminated kernels were not insect damaged in 2007 and 2008. In some cases, differing mycotoxin levels for the same hybrid and same year planted at different locations appeared to be due to the prior crop. Higher DON levels in 2008 than other years were most likely associated with higher levels of rainfall and cooler temperatures than average during ear fill. While kernel sorters are reported to remove mycotoxin-contaminated popcorn kernels to acceptible levels, consideration of environmental factors that promote mycotoxins in popcorn should result in more effective control measures in the field.


'The 39 steps' in gene expression profiling: critical issues and proposed best practices for microarray experiments.
Gene expression microarrays have been used widely to address increasingly complex biological questions and to produce an unprecedented amount of data, but have yet to realize their full potential. The interpretation of microarray data remains a major challenge because of the complexity of the underlying biological networks. To gather meaningful expression data, it is crucial to develop standardized approaches for vigilant study design, controlled annotation of resources, careful quality control of experiments, robust statistics, and data registration and storage. This article reviews the steps needed in the design and execution of valid microarray experiments so that global gene expression data can play a major role in the pursuit of future biological discoveries that will impact drug development.


Validation of the German version of the Vertigo Symptom Scale (VSS) in patients with organic or somatoform dizziness and healthy controls.
The objective of this study was to validate the German version of the Vertigo Symptom Scale (VSS) and to determine its ability to differentiate the type, frequency, and severity of balance disorders. The scale (34 items) was designed by Yardley and coworkers and has been already validated in its English and Spanish versions. 98 patients with organic vertigo syndromes, 90 patients with somatoform (psychogenic) dizziness and 56 healthy controls were evaluated with the VSS and additional standardized questionnaires regarding distress (SCL-90R), quality of life (SF-36), anxiety and depression (HADS). In order to differentiate organic from somatoform dizziness all patients underwent detailed clinical neurological and vestibular neurophysiological testing. The two identified subscales 'vertigo and related symptoms' (VER) and 'somatic anxiety and autonomic arousal' (AA) had good internal consistencies (Cronbach's alpha: VER 0.79; AA 0.89). Test-retest correlations were r = 0.75 for VER and r = 0.75 for AA. VER could discriminate well between dizziness patients and healthy controls. AA discriminated moderately between somatoform and organic dizziness. We found close relations between the AA scale and different measures of emotional distress. Correlations between VER and measures of emotional distress were weaker. The German version of the VSS has good reliability and validity in the detection of different vertigo syndromes. Measurement of anxiety symptoms can be helpful to identify patients with somatoform dizziness.


The Venezuelan diaspora: Migration-related experiences and mental health.
Since 2015, the Venezuelan diaspora has poured forth from the Venezuelan sending context into an array of (mostly) middle-income receiving countries and into the United States (US) as well. For many Venezuelan migrants, post-migration reception has been mixed, and multiple studies suggest that mental health is an important challenge with discrimination and negative context reception contributing to mental health burden in terms of depression, anxiety, and posttraumatic stress. Cross-national research points to important sociodemographic differences between Venezuelan migrants resettled in South American contexts and in the US, and suggests that-on average-migration-related cultural stress is lower and mental health outcomes are better among those resettling in South Florida and elsewhere in the US.


A role for microsomal glutathione transferase 1 in melanin biosynthesis and melanoma progression.
Recent advancements in the treatment of melanoma are encouraging, but there remains a need to identify additional therapeutic targets. We identify a role for microsomal glutathione transferase 1 (MGST1) in biosynthetic pathways for melanin and as a determinant of tumor progression. Knockdown (KD) of MGST1 depleted midline-localized, pigmented melanocytes in zebrafish embryos, while in both mouse and human melanoma cells, loss of MGST1 resulted in a catalytically dependent, quantitative, and linear depigmentation, associated with diminished conversion of L-dopa to dopachrome (eumelanin precursor). Melanin, especially eumelanin, has antioxidant properties, and MGST1 KD melanoma cells are under higher oxidative stress, with increased reactive oxygen species, decreased antioxidant capacities, reduced energy metabolism and ATP production, and lower proliferation rates in 3D culture. In mice, when compared to nontarget control, Mgst1 KD B16 cells had less melanin, more active CD8+ T cell infiltration, slower growing tumors, and enhanced animal survival. Thus, MGST1 is an integral enzyme in melanin synthesis and its inhibition adversely influences tumor growth.


Negative regulation of the Apaf-1 apoptosome by Hsp70.
Release of cytochrome c from mitochondria by apoptotic signals induces ATP/dATP-dependent formation of the oligomeric Apaf-1-caspase-9 apoptosome. Here we show that the documented anti-apoptotic effect of the principal heat-shock protein, Hsp70, is mediated through its direct association with the caspase-recruitment domain (CARD) of Apaf-1 and through inhibition of apoptosome formation. The interaction between Hsp70 and Apaf-1 prevents oligomerization of Apaf-1 and association of Apaf-1 with procaspase-9. On the basis of these results, we propose that resistance to apoptosis exhibited by stressed cells and some tumours, which constitutively express high levels of Hsp70, may be due in part to modulation of Apaf-1 function by Hsp70.


N1-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism.
Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers and is characterized by high recurrence and heterogeneity, yet its mechanism is not well understood. Here we show that N1-methyladenosine methylation (m1A) in tRNA is remarkably elevated in hepatocellular carcinoma (HCC) patient tumour tissues. Moreover, m1A methylation signals are increased in liver cancer stem cells (CSCs) and are negatively correlated with HCC patient survival. TRMT6 and TRMT61A, forming m1A methyltransferase complex, are highly expressed in advanced HCC tumours and are negatively correlated with HCC survival. TRMT6/TRMT61A-mediated m1A methylation is required for liver tumourigenesis. Mechanistically, TRMT6/TRMT61A elevates the m1A methylation in a subset of tRNA to increase PPARδ translation, which in turn triggers cholesterol synthesis to activate Hedgehog signaling, eventually driving self-renewal of liver CSCs and tumourigenesis. Finally, we identify a potent inhibitor against TRMT6/TRMT61A complex that exerts effective therapeutic effect on liver cancer.


Heat shock mRNA in mouse epidermis after UV irradiation.
Total RNA from murine epidermis was extracted at different times after irradiation with erythemogenic doses of ultraviolet light (UVB or UVB/UVA) and hybridized to a DNA probe from the gene of a heat shock protein (hsp 70). An intense and transitory enrichment in RNA molecules hybridizing to the DNA probe was found between 15 and 120 min after irradiation, followed by a return to control levels over the next 70 h. Dose-response analysis indicates that 30 min after the irradiation, the relative amount of RNA hybridizing to the hsp 70 DNA probe increases with the dose (within the range explored: 0-180 mJ/cm2) up to values greater than 5 times the control.


Revealing the conversion mechanism of CuO nanowires during lithiation-delithiation by in situ transmission electron microscopy.
Being promising candidates for anodes in lithium-ion batteries (LIBs), transition metal oxide anodes utilizing the so-called conversion mechanism principle typically suffer from the severe capacity fading during the 1st cycle of lithiation-delithiation. Herein, we directly investigated these processes using an individual CuO nanowire anode and constructed a lithium ion battery (LIB) prototype within a transmission electron microscope.


Optimizing human in vivo dosing and delivery of β-alanine supplements for muscle carnosine synthesis.
Interest into the effects of carnosine on cellular metabolism is rapidly expanding. The first study to demonstrate in humans that chronic β-alanine (BA) supplementation (~3-6 g BA/day for ~4 weeks) can result in significantly augmented muscle carnosine concentrations (>50%) was only recently published. BA supplementation is potentially poised for application beyond the niche exercise and performance-enhancement field and into other more clinical populations. When examining all BA supplementation studies that directly measure muscle carnosine (n=8), there is a significant linear correlation between total grams of BA consumed (of daily intake ranges of 1.6-6.4 g BA/day) versus both the relative and absolute increases in muscle carnosine. Supporting this, a recent dose-response study demonstrated a large linear dependency (R2=0.921) based on the total grams of BA consumed over 8 weeks. The pre-supplementation baseline carnosine or individual subjects' body weight (from 65 to 90 kg) does not appear to impact on subsequent carnosine synthesis from BA consumption. Once muscle carnosine is augmented, the washout is very slow (~2%/week). Recently, a slow-release BA tablet supplement has been developed showing a smaller peak plasma BA concentration and delayed time to peak, with no difference in the area under the curve compared to pure BA in solution. Further, this slow-release profile resulted in a reduced urinary BA loss and improved retention, while at the same time, eliciting minimal paraesthesia symptoms. However, our complete understanding of optimizing in vivo delivery and dosing of BA is still in its infancy. Thus, this review will clarify our current knowledge of BA supplementation to augment muscle carnosine as well as highlight future research questions on the regulatory points of control for muscle carnosine synthesis.


Spinal nerve root injuries in brachial plexus lesions: basic science and clinical application of new surgical strategies. A review.
This paper reviews studies aimed at developing novel surgical means to correct functional deficits after spinal nerve root injuries in brachial plexus lesions. In a long series of animal experiments it has been possible to demonstrate re-established connectivity between severed roots and the damaged spinal cord segment. This encouraging functional recovery by a new surgical strategy of managing ventral root avulsion injuries prompted clinical application, with restoration of activity.


Adiponectin receptor agonist AdipoRon blocks skin inflamm-ageing by regulating mitochondrial dynamics.
Skin is susceptible to senescence-associated secretory phenotype (SASP) and inflamm-ageing partly owing to the degeneration of mitochondria. AdipoRon (AR) has protective effects on mitochondria in metabolic diseases such as diabetes. We explored the role of AR on mitochondria damage induced by skin inflamm-ageing and its underlying mechanism. Western blot, immunofluorescence and TUNEL staining were used to detect inflammatory factors and apoptosis during skin ageing. Transmission electron microscopy, ATP determination kit, CellLight Mitochondria GFP (Mito-GFP), mitochondrial stress test, MitoSOX and JC-1 staining were used to detect mitochondrial changes. Western blot was applied to explore the underlying mechanism. Flow cytometry, scratch test, Sulforhodamine B assay and wound healing test were used to detect the effects of AR on cell apoptosis, migration and proliferation. AR attenuated inflammatory factors and apoptosis that increased in aged skin, and improved mitochondrial morphology and function. This process at least partly depended on the suppression of dynamin-related protein 1 (Drp1)-mediated excessive mitochondrial division. More specifically, AR up-regulated the phosphorylation of Drp1 at Serine 637 by activating AMP-activated protein kinase (AMPK), thereby inhibiting the mitochondrial translocation of Drp1. Moreover, AR reduced mitochondrial fragmentation and the production of superoxide, preserved the membrane potential and permeability of mitochondria and accelerated wound healing in aged skin. AR rescues the mitochondria in aged skin by suppressing its excessive division mediated by Drp1.


The mucin MUC16 (CA125) binds to NK cells and monocytes from peripheral blood of women with healthy pregnancy and preeclampsia.
MUC16 (CA125) released from ovarian tumors binds to NK cells and monocytes via the inhibitory receptor Siglec-9. Here, we investigate whether MUC16 also binds to circulating immune cells during pregnancy and in women with preeclampsia. MUC16 binding was monitored by flow cytometry and immunoprecipitation, and RT-PCR was used to monitor indigenous expression in immune cells. Serum CA125 levels were measured by a clinical assay. MUC16 was equally distributed on Siglec-9(pos) CD16(pos)/CD56(dim) and CD16(neg)/CD56(br) NK cells in the healthy pregnant and preeclampsia groups. While serum CA125 levels and number of NK and monocytes were similar, increased binding of MUC16 was observed on these immune cells in the preeclampsia cohort as compared to the healthy pregnant samples. MUC16 binding to NK cells and monocytes likely contributes to tolerance of the fetal allograft from maternal responses and may also serve as a novel biomarker for preeclampsia.


Excess Mortality in Aspirin and Dipyrone (Metamizole) Co-Medicated in Patients With Cardiovascular Disease: A Nationwide Study.
Background Pain is a major issue in our aging society. Dipyrone (metamizole) is one of the most frequently used analgesics. Additionally, it has been shown to impair pharmacodynamic response to aspirin as measured by platelet function tests. However, it is not known how this laboratory effect translates to clinical outcome. Methods and Results We conducted a nationwide analysis of a health insurance database in Germany comprising 9.2 million patients. All patients with a cardiovascular event in 2014 and subsequent secondary prevention with aspirin were followed up for 36 months. Inverse probability of treatment weighting analysis was conducted to investigate the rate of mortality, myocardial infarction, and stroke/transient ischemic attack between patients on aspirin-dipyrone co-medication compared with aspirin-alone medication. Permanent aspirin-alone medication was given to 26,200 patients, and 5946 patients received aspirin-dipyrone co-medication. In the inverse probability of treatment weighted sample, excess mortality in aspirin-dipyrone co-medicated patients was observed (15.6% in aspirin-only group versus 24.4% in the co-medicated group, hazard ratio [HR], 1.66 [95% CI, 1.56-1.76], P<0.0001). Myocardial infarction and stroke/transient ischemic attack were increased as well (myocardial infarction: 1370 [5.2%] versus 355 [5.9%] in aspirin-only and co-medicated groups, respectively; HR, 1.18 [95% CI, 1.05-1.32]; P=0.0066, relative risk [RR], 1.14; number needed to harm, 140. Stroke/transient ischemic attack, 1901 [7.3%] versus 506 [8.5%] in aspirin-only and co-medicated groups, respectively; HR, 1.22 [95% CI, 1.11-1.35]; P<0.0001, RR, 1.17, number needed to harm, 82). Conclusions In this observational, nationwide analysis, aspirin and dipyrone co-medication was associated with excess mortality. This was in part driven by ischemic events (myocardial infarction and stroke), which occurred more frequently in co-medicated patients as well. Hence, dipyrone should be used with caution in aspirin-treated patients for secondary prevention.


Healing presence.
Since the introduction of presence as a concept in nursing literature in the early 1960s, nurse philosophers, theorists, and researchers have attempted to define and describe presence as it relates to nursing practice. Understanding of nursing presence and its link, if any, to nurse-patient interaction is basically subjective and intuitive. This article is based on the assumption that nursing presence fully understood may result in greater patient satisfaction and healing potential. A three-stage, hierarchical model culminating in healing presence is used to understand the nurse-patient dyad. The model is calibrated in terms of nursing maturity using Benner's novice nurse/expert nurse idea, Hanneman's expert nurse/nonexpert nurse view, Zaner's vivid-presence/copresence, and Doona, Chase, and Haggerty's nursing presence.


High-resolution diffusion-weighted MR imaging of the human lumbosacral plexus and its branches based on a steady-state free precession imaging technique at 3T.
3D diffusion-weighted steady-state free precession imaging (3D DW-SSFP) with isotropic resolution was performed to delineate structures of the human lumbosacral plexus (LSP). 3D DW-SSFP clearly revealed detailed anatomy of the LSP and its branches. Our data suggest that the sequence based on 3D DW-SSFP can be used for high-resolution MR imaging of the peripheral nervous system.


A small molecule screen in stem-cell-derived motor neurons identifies a kinase inhibitor as a candidate therapeutic for ALS.
Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease, characterized by motor neuron (MN) death, for which there are no truly effective treatments. Here, we describe a new small molecule survival screen carried out using MNs from both wild-type and mutant SOD1 mouse embryonic stem cells. Among the hits we found, kenpaullone had a particularly impressive ability to prolong the healthy survival of both types of MNs that can be attributed to its dual inhibition of GSK-3 and HGK kinases. Furthermore, kenpaullone also strongly improved the survival of human MNs derived from ALS-patient-induced pluripotent stem cells and was more active than either of two compounds, olesoxime and dexpramipexole, that recently failed in ALS clinical trials. Our studies demonstrate the value of a stem cell approach to drug discovery and point to a new paradigm for identification and preclinical testing of future ALS therapeutics.


The imaging findings of Peliosis hepatis on gadoxetic acid enhanced MRI.
Peliosis hepatis involves multiple blood-filled cystic spaces in the hepatic parenchyma. Using conventional imaging, distinguishing PH from other malignancies can be difficult. The findings of Peliosis hepatis on gadoxetic acid (Gd-EOB) enhanced magnetic resonance imaging are not well reported. Therefore, we report the imaging features of pathologically proven PH. On the hepatobiliary phase of Gd-EOB magnetic resonance imaging, most lesions showed unenhanced areas, but some lesions showed central enhancement "halo sign."


Pathways and polarities of synaptic interactions in the inner retina of the mudpuppy: II. Insight revealed by an analysis of latency and threshold.
Intracellular recording experiments in the mudpuppy (Necturus maculosus) have demonstrated that depolarizing bipolars show a one-half to one log unit higher threshold to light stimuli and a longer latency when compared to hyperpolarizing bipolars. This threshold difference cannot be ascribed to differences in rod and cone connections. Experimentally it was possible to use these differences to evaluate postbipolar cell connections; such experiments support the idea that some neurons are connected to one or the other bipolar cell type, while on-off cells receive input from both.


Secretory activity and histoenzymological characteristics in the subcommissural organ of hormone-injected ducks, Anas platyrhynchos.
Gonadotrophin and gonadal hormone injections performed on male ducks induce some changes in the activity of the subcommissural organ (SCO). Particularly LH, FSH and testosterone propionate injections are followed by a depletion of secretory material accompanied by increased activities of investigated dehydrogenases and acid phosphatase in SCO cells.


Successful Fidaxomicin Hospital Discharges of Adult Patients With Clostridioides difficile Infections Post-2021 Guidelines: Are Economic Barriers Finally Coming Down?
We reviewed Clostridioides difficile-positive patients discharged on fidaxomicin after local adoption of 2021 C. difficile infection (CDI) guidelines. From 14 June to 3 October 2021, 80% (12/15) had copayments of $0-$35 and 27% (4/15) required prior authorization. The 30-day CDI recurrence was 7%.


Improvement of Supramine and development of new food mixtures for the young. I. Improvement of Supramine.
Supramine, a food mixture produced in Egypt by El-Nil Pharmaceutical Company supported by UNICEF. The product suffers from two problems: It is not well liked by the children, and its shelf life is relatively short. Studies were made to overcome these problems. Pretreatment of the ingredients such as cooking, autoclaving or roasting markedly improved palatability of the product. Adjustment of the conditions of the enzyme action increased hydrolysis of the starchy material making the product more soft and digestible. Formulation of new mixtures gave the chance to the produce to satisfy the wish of a wide sector of the consumers. The heat treatment made to the ingredients minimized contamination and prolonged shelf life of the product.


Transvaginal ovarian cystectomy for adnexal torsion during pregnancy.
Ovarian torsion requiring surgical intervention in pregnancy is rare. Herein is reported a case of ovarian torsion that was managed by transvaginal ovarian cystectomy in a 27 week gravid patient.


[Child obesity in Navarra: evolution, tendency and relation between child and adult obesity. Pecna study].
Excess of weight at an adult age is linked to an increased risk of dying. Obesity during childhood has been increasing in recent years in the developed countries. The aim of this study is to determine the prevalence of obesity in an infant-youth population of Navarra and its follow up over six years. Longitudinal study of a cohort formed by 1,164 children of both sexes of 4, 10 and 17 years of age at the start of the study, with data collection in 1987 and 1993. Obesity was calculated using the Index of Corporal Mass or Quetelet Index (QI) higher than percentile 90 for their age and sex. The rate of response obtained was 63.3% (n=737). Between 1987 and 1993 there was an increase of 5% in the obese population (p<0.01). There is a significant correlation (r=0.72) between the values of the QI at the start of the study and those obtained at its conclusion. Some 61.4% of the individuals belonging to the higher quintile of the sample at the start of the study continued belonging to this quintile after six years of follow up. There was an increase in obesity, in correspondence with the findings of similar studies. There is good "tracking" between obesity during childhood and its presence at an adult age. The strategies for prevention of obesity must start from infancy.


Self-Reported Distress: Adult Acute Leukemia Survivors During and After Induction Therapy.
Data suggest that acute leukemia survivors experience moderate to severe distress that does not significantly decline from diagnosis through survivorship. . The purpose of this study is to assess acute leukemia survivors' level and source of self-reported distress from active cancer treatment through six months post-treatment. . A cross-sectional group-comparison design was used. Male (n = 60) and female (n = 40) survivors aged 19-84 years were accrued from a National Cancer Institute-designated cancer center. Patients were sampled at four time points. Self-reported distress was elevated for all groups. Highest distress scores were found during induction therapy.


A Primer on Meta-Analytic Structural Equation Modeling: the Case of Depression.
In this paper, we show how the methods of systematic reviewing and meta-analysis can be used in conjunction with structural equation modeling to summarize the results of studies in a way that will facilitate the theory development and testing needed to advance prevention science. We begin with a high-level overview of the considerations that researchers need to address when using meta-analytic structural equation modeling (MASEM) and then discuss a research project that brings together theoretically important cognitive constructs related to depression to (a) show how these constructs are related, (b) test the direct and indirect effects of dysfunctional attitudes on depression, and (c) test the effects of study-level moderating variables. Our results suggest that the indirect effect of dysfunctional attitudes (via negative automatic thinking) on depression is two and a half times larger than the direct effect of dysfunctional attitudes on depression. Of the three study-level moderators tested, only sample recruitment method (clinical vs general vs mixed) yielded different patterns of results. The primary difference observed was that the dysfunctional attitudes → automatic thoughts path was less strong for clinical samples than it was for general and mixed samples. These results illustrate how MASEM can be used to compare theoretically derived models and predictions resulting in a richer understanding of both the empirical results and the theories underlying them.


Spatio-temporal heterogeneity of the coupling between digital economy and green total factor productivity and its influencing factors in China.
The synergy of the digital economy and green total factor productivity (TFP) is the foundation for achieving beneficial outcomes for both the economy and environment. This synergy is also the catalyst for high-quality development and sustainable economic growth in China. The study applied a modified Ellison-Glaeser (EG) index, super-efficiency slacks-based measure (SBM) with a Malmquist-Luenberger (ML) index, coupling coordination degree, and other models to explore the spatiotemporal heterogeneity of the coupling between the digital economy and green TFP from 2011 to 2020 and also analyzed the influencing factors of the coupling. The results show that the coupling between the digital economy and green TFP showed an overall upward trend from imbalance to synergy during the study period. The distribution of the synergistic coupling expanded from point-like to band-like, and there was a significant spreading pattern from the east to the center or west China. The number of cities in a transition state decreased significantly. Spatial jumps, a coupling linkage effect, and evolution in time were prominent. Additionally, the absolute difference among cities expanded. Although coupling in the west experienced the fastest growth rate, the coupling in the east and resource-based cities showed significant benefits. Coupling did not reach an ideal coordinated state, and a neutral interaction pattern remains to be formed. Industrial collaboration, industrial upgrading, government support, economic foundation, and spatial quality all positively impacted the coupling; technological innovation had a lagged effect; and environmental regulation has not reached its full potential. Further, the positive effects of government support and spatial quality performed better in the east and in non-resource-based cities. Due to the optimization of industrial structure, the coupling of the west and resource-based cities achieved better dividends; however, spatial quality needs further improvement. Therefore, the efficient coordination of China's digital economy and green TFP requires a scientific, reasonable, localized, and distinctive approach.


Apparent diffusion coefficient correlates with different histopathological features in several intrahepatic tumors.
To investigate associations between apparent diffusion coefficient (ADC) and cell count, Ki 67, tumor-stroma ratio (TSR), and tumoral lymphocytes in different hepatic malignancies. We identified 149 cases with performed liver biopsies: hepatocellular cancer (HCC, n = 53), intrahepatic cholangiocarcinoma (iCC, n = 29), metastases of colorectal cancer (CRC, n = 24), metastases of breast cancer (BC, n = 28), and metastases of pancreatic cancer (PC, n = 15). MRI was performed on a 1.5-T scanner with an axial echo-planar sequence. MRI was done before biopsy. Biopsy images of target lesions were selected. The cylindrical region of interest was placed on the ADC map of target lesions in accordance with the needle position on the biopsy images. Mean ADC values were estimated. TSR, cell counts, proliferation index Ki 67, and number of tumor-infiltrating lymphocytes were estimated. Spearman's rank correlation coefficients and intraclass correlation coefficients were calculated. Inter-reader agreement was excellent regarding the ADC measurements. In HCC, ADC correlated with cell count (r = - 0.68, p < 0.001) and with TSR (r = 0.31, p = 0.024). In iCC, ADC correlated with TSR (r = 0.60, p < 0.001) and with cell count (r = - 0.54, p = 0.002). In CRC metastases, ADC correlated with cell count (r = - 0.54 p = 0.006) and with Ki 67 (r = - 0.46, p = 0.024). In BC liver metastases, ADC correlated with TSR (r = 0.55, p < 0.002) and with Ki 67 (r = - 0.51, p = 0.006). In PC metastases, no significant correlations were found. ADC correlated with tumor cellularity in HCC, iCC, and CRC liver metastases. ADC reflects TSR in BC liver metastases, HCC, and iCC. ADC cannot reflect intratumoral lymphocytes. The present study shows that the apparent diffusion coefficient can be used as a surrogate imaging marker for different histopathological features in several malignant hepatic lesions. • ADC reflects different histopathological features in several hepatic tumors. • ADC correlates with tumor cellularity in HCC, iCC, and CRC metastases. • ADC strongly correlates with tumor-stroma ratio in BC metastases and iCC.


G1359A polymorphism in the cannabinoid receptor-1 gene is associated with metabolic syndrome in the Chinese Han population.
Recent studies suggest that endocannabinoids modulate food intake and lipogenesis through cannabinoid receptor-1 (CNR1). This study aims to determine the association between G1359A polymorphism of CNR1 and metabolic syndrome (MetS) in the Chinese Han population. A total of 382 subjects at risk for MetS and 136 healthy subjects from Tianjin, China were genotyped for the G1359A polymorphism of CNR1 using TaqMan assay. Anthropometric measurements and serum analyses were done for body mass index (BMI), waist circumference, blood pressure, serum triglycerides (TG), serum total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fasting plasma glucose, and plasma insulin levels. GG genotype of CNR1 has a higher incidence in MetS subjects than in control subjects. Logistic regression analysis shows that the GG genotype was significantly associated with the increased risk of developing MetS (OR 2.204, 95% CI 1.277-3.803, p = 0.005). Compared with CNR1 GG genotype in MetS subjects, CNR1 GA and AA genotypes in subjects with MetS had relatively lower levels of BMI, waist circumference, homeostasis model assessment of insulin resistance (HOMA-IR) and TG. Results suggest that the G1359A polymorphism of the CNR1 gene may contribute to MetS susceptibility in the Chinese Han population.


Regulation of Chylomicron Secretion: Focus on Post-Assembly Mechanisms.
Rapid and efficient digestion and absorption of dietary triglycerides and other lipids by the intestine, the packaging of those lipids into lipoprotein chylomicron (CM) particles, and their secretion via the lymphatic duct into the blood circulation are essential in maintaining whole-body lipid and energy homeostasis. Biosynthesis and assembly of CMs in enterocytes is a complex multistep process that is subject to regulation by intracellular signaling pathways as well as by hormones, nutrients, and neural factors extrinsic to the enterocyte. Dysregulation of this process has implications for health and disease, contributing to dyslipidemia and a potentially increased risk of atherosclerotic cardiovascular disease. There is increasing recognition that, besides intracellular regulation of CM assembly and secretion, regulation of postassembly pathways also plays important roles in CM secretion. This review examines recent advances in our understanding of the regulation of CM secretion in relation to mobilization of intestinal lipid stores, drawing particular attention to post-assembly regulatory mechanisms, including intracellular trafficking of triglycerides in enterocytes, CM mobilization from the lamina propria, and regulated transport of CM by intestinal lymphatics.


Sensitivity to chemoradiation predicts development of metastasis in muscle-invasive bladder cancer patients.
In bladder-sparing approaches for muscle-invasive bladder cancer (MIBC) involving transurethral resection of the bladder tumor (TURBT) and chemoradiation, survival outcomes are excellent for patients who achieve tumor-free state after TURBT and chemoradiation but poor for those with persistent disease. Since metastatic disease accounts for most bladder cancer deaths, we hypothesized that tumor sensitivity to chemoradiation may reflect metastatic potential in MIBC. From 1997 to 2010, 179 cT2-4aN0M0 bladder cancer patients underwent TURBT and induction chemoradiation (40 Gy with cisplatin 20 mg/d for 5 days × 2). Study subjects were 73 patients who had had macroscopic disease after TURBT and were evaluated for tumor sensitivity to the induction chemoradiation; of the 73 patients, chemoradiation response was evaluated pathologically in partial and radical cystectomy specimens for 8 and 44 patients, respectively, and clinically for the remaining 21 who did not undergo cystectomy. Tumors were defined as chemoradiation-sensitive when they regressed to T0 pathologically for the 52 patients undergoing cystectomy or clinically for the 21 undergoing no cystectomy; otherwise, they were defined as chemoradiation-resistant. Primary and secondary endpoints were metastasis-free and cancer-specific survival, respectively. The association between chemoradiation sensitivity and development of metastasis was investigated in MIBC patients. Of the 73 patients, 21 (29%: 13 pathologic and 8 clinical T0) had chemoradiation-sensitive tumors while 52 (71%) had chemoradiation-resistant tumors. Median follow-up was 53 months. Multivariate analysis identified chemoradiation resistance as the strongest independent predictor for the development of metastasis (hazard ratio (HR) 18.9, P < 0.0001). When stratified by chemoradiation sensitivity, 5-year metastasis-free and cancer-specific survival rates were 94.7% and 100%, respectively, for patients with chemoradiation-sensitive tumors, and 45.7% (P = 0.0005) and 41.0% (P < 0.0001), respectively, for patients with chemoradiation-resistant tumors. Chemoradiation sensitivity predicts the development of metastasis in bladder cancer. Clinical and translational research results indicate that chemoradiation sensitivity is likely to reflect metastatic potential.


The complete mitochondrial genome of the Anas platyrhynchos Linnaeus, 1758 breed Longshengcui and its phylogenetic analyses.
Duck breed Longshengcui (Anas platyrhynchos Linnaeus, 1758 breed Longshengcui, LSC) is one of the famous native breed of the Guangxi Zhuang Nationality Autonomous Region in China. In this study, we report the complete mitochondrial genome of LSC. The mitogenome (GenBank accession no. MZ895120) has 16,602 bp in length and consisted of the well-known 13 protein-coding genes, 22 tRNA genes, two rRNA genes, and the control region. The phylogenetic analysis showed that LSC and Zhijiang duck have highly similar genetic relationship. These results are helpful for the conservation of genetic resources and phylogeny of this species.


Effects of riboflavin and amotosalen photoactivation systems for pathogen inactivation of fresh-frozen plasma on fibrin clot structure.
Fresh-frozen plasma (FFP) transfusion carries a risk of viral transmission from donor to recipient. Riboflavin (Mirasol) and amotosalen (Intercept) are two pathogen inactivation (PI) methods that may enhance the safety of FFP for transfusion. Our study investigated the effects of Mirasol and Intercept treatment on fibrin formation and clot structure. FFP underwent either Mirasol or Intercept treatment, and aliquots were taken before addition of the compound, before illumination (after addition of compound only), and after treatment (addition of compound plus illumination). All samples underwent turbidimetric analysis, lysis analysis, assessment of clot permeation, and analysis by laser scanning confocal microscopy. After treatment, there was a decrease in optical density of the fibrin network for Mirasol and Intercept, lag time to fibrin formation was prolonged for Mirasol and lysis time for Intercept, clot permeability was significantly decreased, and clot density was increased for both. Our study shows that plasma treated with Mirasol and Intercept produces denser clots consisting of thinner fibers and warrants further studies to evaluate the clinical significance of these structural changes in fibrin clot formation.


Digitally reconstructed severe trauma-induced oro-maxillofacial defects with free vascularised composite tissue flaps.
The aim of this study was to outline the characteristics of severe trauma-induced oro-maxillofacial defects and explore the application of microsurgical reconstruction of these defects by selecting appropriate free vascularised composite tissue flaps. A retrospective analysis was performed in 11 cases with severe trauma-induced oromaxillofacial defects from 2005 to 2018, All cases were reconstructed with free vascularised composite flaps using a supermicro-surgical/micro-surgical and digital technology. This study consisted of 11 patients (8 men, 3 women) with a median age (range) of 28 (6-64) years. Patients with long-standing trauma experienced severe scars and displacements. The trauma-induced oro-maxillofacial defects ranged in size from 4.0 × 5.0 cm2 to 7 × 15 cm2. Six radial forearm flaps, three fibular osteocutaneous flaps, a lateral thoracic flap, and an anterolateral thigh flap were harvested individually. All patients were treated effectively and followed up for over two years, with a 100% survival rate of these free vascularised composite tissue flaps. No uncontrollable complications occurred, and all patients were satisfied with the postoperative shape and function. The trauma-induced oro-maxillofacial defects display unique features, and microsurgical techniques play an important role in the reconstruction of shapes and function. In addition, some patients may need multi-stage surgeries to attain aesthetic refinement.


C-reactive protein and alpha-1-acid glycoprotein in monitoring of patients with chronic arterial occlusion of the lower limbs.
C-reactive protein (CRP) and alpha-1-acid glycoprotein (AGP) levels were studied in the sera of 107 patients with chronic arterial ischaemia of the lower limbs. Depending on the degree of ischaemia, patients were divided into four groups: (i) intermittent claudication--20 patients; (ii) rest pain and ankle pressure above 50 mmHg--12 patients; (iii) rest pain and ankle pressure below 50 mmHg--25 patients; (iv) peripheral necrosis--50 patients. Reconstructive surgery was performed in 84 patients and primary major amputation in 23 cases. Levels of CRP and AGP increased with the severity of ischaemia. In uncomplicated cases, CRP and AGP concentrations decreased to normal values 7-10 days after surgery. In a group of 23 patients with postoperative necrotic complications, significant increases in CRP and AGP levels were found 7-10 days after surgery. These proteins, especially CRP, may be clinically useful in monitoring patients during the postoperative period with a CRP level greater than 50 mg/l predictive of complications with a sensitivity of 83% and a specificity of 94%.


Optimizing the gonadoliberin dosage and evaluating the egg quality in the preseason and seasonal artificial reproduction of pond-reared sterlet Acipenser ruthenus.
Sterlet Acipenser ruthenus is the smallest in size, early maturing, yet third in production scale among the sturgeon species and as such presents a good model to study reproductive biology. The present study aimed to evaluate the effects of preseason artificial reproduction and reduction of hormonal dosage on the egg quality in pond-reared sterlet. Therefore, a series of three trials were conducted in the period 2021 and 2022 (21 and 22) that evaluated three dosages of mammalian gonadotropin releasing hormone analog des-Gly10-(d-Ala6)-GnRH (40, 20, and 10 µg/kg) in both preseason (January) and seasonal (April) spawning batches (PRE and SEA). The greatest embryo survival was achieved in SEA-21-10 (84.8 ± 5.8 %) and the lowest in PRE-21-40 (31.0 ± 40.7 %). Overall results indicated that a dosage of 10 µg/kg leads to the highest embryo survival. Considering the season, latency time was significantly longer in preseason reproduction being on average about 6 h prolonged (35.1 ± 2.8 h vs. 41.4 ± 2.9 h) and it directly affected the embryo survival (linear correlation r = - 0.769, P = 0.003). Likewise, preseason reproduction yields more variable egg quality, due to impaired performance of later ovulating fish most likely due to lower oocyte maturation competence. The present study found expected latency time at 14 °C to be 37-41 h in the preseason and 31-41 h in season, while the recommended dosage is 10 µg/kg des-Gly10-(d-Ala6)-GnRH. Future studies should develop in vitro tools to evaluate the oocyte maturational competence to improve the egg quality in the preseason.


Effects of cicloxilic acid on secretory function of the liver. I. Effect on bile flow and on biliary secretion of bilirubin and glucuronic acid in anesthetised bileduct-cannulated rat.
Both in normal and experimentally jaundiced rats cis-2-hydroxy-2-phenyl-cyclohexanecarboxilic acid (cicloxilic acid) induces a greater and longer lasting increase in bile flow and a greater increase in bilirubin and glucuronic acid secretion than do the choleretics sodium 2-(2-hydroxy-3n hexoxy-propoxy)-benzoate and dehydrocholic acid. The intense increase in bilirubin secretion is interpreted as the outcome of stimulation of the biliary secretion mechanisms whilst the effect on bile flow and on the biliary secretion of glucuronic acid are attributed to the kinetics of biliary secretion of cicloxilic acid.


Evidence supporting zoonotic transmission of Cryptosporidium in rural New South Wales.
Cryptosporidium hominis, which has an anthroponotic transmission cycle and Cryptosporidium parvum, which is zoonotic, are the primary species of Cryptosporidium that infect humans. The present study identified the species/genotypes and subgenotypes of Cryptosporidium in 7 human and 15 cattle cases of sporadic cryptosporidiosis in rural western NSW during the period from November 2005 to January 2006. The species/genotype of isolates was determined by PCR sequence analysis of the 18S rRNA and C. parvum and C. hominis isolates were subgenotyped by sequence analysis of the GP60 gene. Fourteen of 15 cattle-derived isolates were identified as C. parvum and 1 as a C. bovis/C. parvum mixture. Of the human isolates, 4 were C. parvum and 3 were C. hominis. Two different subgenotypes were identified with the human C. hominis isolates and six different subgenotypes were identified within the C. parvum species from humans and cattle. All four of the C. parvum subtypes found in humans were also found in the cattle, indicating that zoonotic transmission may be an important contributor to sporadic human cases cryptosporidiosis in rural NSW.


Meta-Analysis of Simultaneous versus Staged Decompression of Stenotic Regions in Patients with Tandem Spinal Stenosis.
Tandem spinal stenosis (TSS) refers to simultaneous spinal canal stenosis of noncontiguous regions. There is no consensus in the surgical strategies for patients with symptomatic TSS because of the confusing clinical manifestations. This meta-analysis aimed to compare the outcomes of 1-stage and 2-stage decompression of all stenotic regions (cervical and lumbar/thoracic segments) in patients with TSS. A systematic review was conducted, and a comprehensive literature search with the Japanese Orthopedic Association score, was carried out using MEDLINE, Web of Science, and PubMed databases from inception to September 13, 2022. Observational studies reporting the outcomes after 1-stage or 2-stage decompression of all symptomatic regions were included. Possible heterogeneity among studies was assessed by the Higgins I2 test, and heterogeneity was statistically investigated using the Q statistic. Thirteen retrospective observational studies were included in this meta-analysis. Meta-analysis showed that there was no significant difference in the Japanese Orthopedic Association score improvement in patients with TSS involving either the cervical-thoracic or cervical-lumbar segments. Regarding the surgical parameters and complications, 1-stage decompression showed comparable operation time, blood loss, and major complications to 2-stage decompression in patients with cervical and lumbar TSS. In patients with cervical and thoracic TSS, 1-stage decompression had significant advantages compared with 2-stage decompression in operation time, blood loss, and major complications. For patients with cervical and lumbar TSS, 2-stage decompression showed slight advantages in clinical outcome without exposing patients to unnecessary surgical risks. For patients with cervical and thoracic TSS, 1-stage decompression showed comparable clinical outcome, although with better operative parameters and lower complication rate than in simultaneous decompression.


Multifaceted regulation of the sumoylation of the Sgs1 DNA helicase.
Homologous recombination repairs DNA breaks and sequence gaps via the production of joint DNA intermediates such as Holliday junctions. Dissolving Holliday junctions into linear DNA repair products requires the activity of the Sgs1 helicase in yeast and of its homologs in other organisms. Recent studies suggest that the functions of these conserved helicases are regulated by sumoylation; however, the mechanisms that promote their sumoylation are not well understood. Here, we employed in vitro sumoylation systems and cellular assays to determine the roles of DNA and the scaffold protein Esc2 in Sgs1 sumoylation. We show that DNA binding enhances Sgs1 sumoylation in vitro. In addition, we demonstrate the Esc2's midregion (MR) with DNA-binding activity is required for Sgs1 sumoylation. Unexpectedly, we found that the sumoylation-promoting effect of Esc2-MR is DNA independent, suggesting a second function for this domain. In agreement with our biochemical data, we found the Esc2-MR domain, like its SUMO E2-binding C-terminal domain characterized in previous studies, is required for proficient sumoylation of Sgs1 and its cofactors, Top3 and Rmi1, in cells. Taken together, these findings provide evidence that while DNA binding enhances Sgs1 sumoylation, Esc2-based stimulation of this modification is mediated by two distinct domains.


Polyamine requirement for prolactin action on macromolecular synthesis in the MCF-7 human mammary epithelial cell line.
The actions of insulin, hydrocortisone, prolactin and growth hormone on the synthesis of macromolecules in MCF-7 cells was determined in a serum-free defined medium. The inclusion of the polyamine spermidine in the medium was shown to enhance the insulin stimulation of the rate of [3H]uridine incorporation into RNA in a manner similar to that demonstrated for hydrocortisone. Spermidine, in addition to insulin and hydrocortisone, was also essential for prolactin to manifest a stimulation of the rate of [3H]uridine incorporation; this effect of spermidine was optimal with spermidine concentrations between 1 and 5 mM. Prolactin also stimulated the rate of [3H]leucine incorporation into total cellular protein and into an isoelectrically precipitable (pH 4.6) phosphoprotein fraction. The actions of prolactin on total protein and phosphoprotein synthesis were only expressed if spermidine, in addition to insulin and hydrocortisone, was contained in the culture medium. All of the prolactin responses were observed employing physiological concentrations of prolactin. Specificity of the prolactin responses was established by demonstrating that porcine growth hormone had no effects on RNA or phosphoprotein synthesis in the MCF-7 cells.


The hemK gene in Escherichia coli encodes the N(5)-glutamine methyltransferase that modifies peptide release factors.
Class 1 peptide release factors (RFs) in Escherichia coli are N(5)-methylated on the glutamine residue of the universally conserved GGQ motif. One other protein alone has been shown to contain N(5)-methylglutamine: E.coli ribosomal protein L3. We identify the L3 methyltransferase as YfcB and show that it methylates ribosomes from a yfcB strain in vitro, but not RF1 or RF2. HemK, a close orthologue of YfcB, is shown to methylate RF1 and RF2 in vitro. hemK is immediately downstream of and co-expressed with prfA. Its deletion in E.coli K12 leads to very poor growth on rich media and abolishes methylation of RF1. The activity of unmethylated RF2 from K12 strains is extremely low due to the cumulative effects of threonine at position 246, in place of alanine or serine present in all other bacterial RFs, and the lack of N(5)-methylation of Gln252. Fast-growing spontaneous revertants in hemK K12 strains contain the mutations Thr246Ala or Thr246Ser in RF2. HemK and YfcB are the first identified methyltransferases modifying glutamine, and are widely distributed in nature.


Age-related changes in adenosine in rat coronary resistance vessels.
1. The vasodilator effects of adenosine receptor agonists, isoprenaline and histamine were examined in perfused heart preparations from young (4-6 weeks) and mature (12-20 weeks) rats. 2. Adenosine induced a biphasic concentration-dependent decrease in KCl (35 mM) raised coronary perfusion pressure in hearts from young and mature rats, suggesting the presence of both high- and low-affinity sites for adenosine receptors in the two age groups tested. In heart preparations from mature rats, vasodilator responses to adenosine were significantly reduced compared with responses observed in young rats. 3. Responses to 5'-N-ethylcarboxamidoadenosine (NECA) and 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS-21680) were reduced in preparations from mature rats, whereas the vasodilator actions of N6-cyclopentyladenosine (CPA) and N6-2-(4-aminophenyl)ethyladenosine (APNEA) did not change with age. 4. The results presented in this study suggest that several adenosine receptor subtypes mediate vasodilator responses in the coronary circulation of the rat and that a reduction in response to adenosine with age may be due to changes in the high-affinity receptor site.


Laterally nanostructured adsorbed layers of surfactant/surfmer mixtures before and after polymerisation.
The adsorbed layer structure of mixed films of the polymerisable cationic surfactant dodecyldimethyl(ethylmethacrylate)ammonium bromide (MEDDAB) with the cationic and non-ionic surfactants dodecyltrimethylammonium bromide (DTAB) and polyoxyethylene-23-lauryl ether (C12E23) has been investigated by AFM soft-contact imaging before and after solution polymerisation of MEDDAB. MEDDAB alone adsorbs on mica as a planar bilayer, but the adsorbed layer structure can be modified by mixing with DTAB or C12E23 to yield an adsorbed mesh or cylinders. The equilibrium adsorbed film structure after solution polymerisation of the methacrylate group on MEDDAB was found to depend on the solubilising ability of the non-polymerisable surfactant. C12E23 effectively prevented precipitation of polymerised MEDDAB, retaining the unpolymerised adsorbed layer structure, whereas DTAB mixtures became cloudy above 23 mol% MEDDAB. The resultant structure remained similar to the adsorbed rods formed prior to polymerisation, but had a diameter several times larger.


Update on multiple sclerosis therapy.
Multiple sclerosis is a demyelinating disorder of the central nervous system characterized by exacerbations and remissions of symptoms. This article deals with symptomatic therapy involving treatment of spasticity, fatigue, neurobehavioral disorders, paroxysmal disorders, pain, bladder dysfunction, and cerebellar dysfunction. This article also reviews immunosuppressive therapies including treatment of acute exacerbations or overall progression of the disorder with resultant accumulation of disability.


Prevalence of selected species of internal parasites in equids at necropsy in central Kentucky (1995-1999).
A survey to determine current prevalence of several species of endoparasites in equids (n=350) at necropsy was conducted at the Livestock Disease Diagnostic Center in central Kentucky (1995-1999). Thelazia lacrymalis were found in 42% of the 1- to 4-year olds (n=132), which was the only age group examined for these parasites. Five- to 30-year olds (n=157), examined for Onchocerca spp. worms/lesions, had a prevalence of 24%. In > or =1-year olds (n=324), the infection rate for Gasterophilus intestinalis was 12% for second instars and 14% for third instars and for Gasterophilus nasalis was 2% for second instars and 2% for third instars. For Anoplocephala perfoliata (n=268 equids), prevalence was 52%. Data were compiled for the equids according to breed, age, sex, month of necropsy, and number of parasites. Arterial lesions caused by migrating Strongylus vulgaris larvae were observed in a low number (3 of 52) of equids. Specific examination for Parascaris equorum revealed that 46% of 13 weanlings and 10% of 20 older horses were infected. Anoplocephala magna were found in one of the weanlings. Compared to previous studies (about 15-25 years ago) in Kentucky, the present survey indicated the genera Onchocerca and Gasterophilus greatly declined but Thelazia, Anoplocephala, and Parascaris did not.


Seasonal variation in the effects of artificial light at night on the occurrence of nocturnally migrating birds in urban areas.
Urban areas often contain large numbers of migratory bird species during seasonal migration, many of which are nocturnal migrants. How artificial light at night (ALAN) and urban landcover are associated with the diurnal occurrence of nocturnal migrants within urban areas across seasons has not been explored. Here, we use eBird bird occurrence information to estimate the seasonal species richness of nocturnally migrating passerines (NMP) within 333 well surveyed urban areas within the contiguous USA. We model the relationship between seasonal NMP species richness and ALAN, proportion of tree canopy cover, and proportion of impervious surface. NMP species richness reached its highest levels during spring and autumn migration and lowest during the winter and summer. Greater tree canopy cover was associated with higher NMP species richness during spring and autumn migration and the summer. A 10% increase in the proportion of tree canopy cover was associated with a 2.0% increase in NMP species richness during spring migration, a 1.8% increase during autumn migration, and a 0.9% increase during the summer. More impervious surface was associated with higher NMP species richness during the winter. A 10% increase in the proportion of impervious surface was associated with a 6.1-9.8% increase in NMP species richness. Higher ALAN was associated with lower NMP species richness during the winter and summer, and higher NMP species richness during spring and autumn migration. A 50% increase in ALAN was associated with a 3.0-3.6% decrease in NMP species richness during the winter, a 1.7% increase during spring migration, a 2.1% decrease during the summer, and a 5.0% increase during autumn migration. These findings highlight the variable effects of ALAN and urban landcover on the seasonal occurrence of NMP species in urban areas, the value of tree canopy cover during migration and the breeding season, and the importance of reducing ALAN during migration.


The critical gap for pediatric reference intervals of complete blood count in China.
We examined the critical gap for pediatric reference intervals in China byvalidating 3 existing pediatric reference intervals (RIs) of complete blood count(CBC) respectively. A total of 2255 healthy children attended physical examination in Beijing Children's Hospital. Fasted blood was sampled and CBC, including red blood cell (RBC) count, hemoglobin (HGB), hematocrit (HCT), platelet count (PLT) and white blood cell (WBC) count were measured by automated hematological analyzer Sysmex Xs-800i. The observed proportions of out-of-range (OOR) values were calculated by three RIs in order to examine its applicability. Compared with RIs of CBC recommended by Zhu Futang Practice of Pediatrics, the upper side OORs of RBC count, HGB, WBC count, and PLT deviated from upper reference limit, which ranged from 10% to 91.9%. On the contrary, the lower side OOR of WBC count was 64%. Compared with Chinese adult RIs, the upper side OORs of WBC count and PLT were >10%. While the lower sides OORs of RBC count, HGB and HCT were >10% among boys <14y. It appears that the RIs validated by Beijing Children's Hospital were relatively accurate RIs for children. There is a gap for pediatric RIs in China. It is imperative to initiate research on establishing and validating pediatric RIs in China.


Film coating based on native starch and cationic starch blend improved postharvest quality of mangoes.
This work focused on the preparation and characterization of films and coatings based on native cassava starch cationic cassava starch and a blend of the two. The films and coatings are intended for application as coating materials for mango fruits. Due to the good miscibility between native cassava starch and cationic cassava starch, the starch blend film was more hydrophobic than films produced from unblended native cassava starch and unblended cationic cassava starch. In addition, after storage for 10 days, the mangoes coated with the starch blend film had lost the least weight and exhibited only slight changes in physical appearance. Therefore, the coating of native and cationic cassava starch blend is a promising alternative coating that presents no hazard to consumer health or the environment.


Ligand-based autotaxin pharmacophore models reflect structure-based docking results.
The autotaxin (ATX) enzyme exhibits lysophospholipase D activity responsible for the conversion of lysophosphatidyl choline to lysophosphatidic acid (LPA). ATX and LPA have been linked to the initiation of atherosclerosis, cancer invasiveness, and neuropathic pain. ATX inhibition therefore offers currently unexploited therapeutic potential, and substantial interest in the development of ATX inhibitors is evident in the recent literature. Here we report the performance-based comparison of ligand-based pharmacophores developed on the basis of different combinations of ATX inhibitors in the training sets against an extensive database of compounds tested for ATX inhibitory activity, as well as with docking results of the actives against a recently reported ATX crystal structure. In general, pharmacophore models show better ability to select active ATX inhibitors binding in a common location when the ligand-based superposition shows a good match to the superposition of actives based on docking results. Two pharmacophore models developed on the basis of competitive inhibitors in combination with the single inhibitor crystallized to date in the active site of ATX were able to identify actives at rates over 40%, a substantial improvement over the <10% representation of active site-directed actives in the test set database.


Minimizing physical restraints in acute care.
The use of restraints to protect patients and insure continuation of care is an accepted fact in today's medical practice. However over the last 20 years a growing body of evidence supports the idea that restraints are harmful and should be used as the last resort. Since 1987, federal law requires long term care facilities to be restraint free. This article describes the use of restraints in the acute care setting, complications of using restraints and efforts to minimize restraint use in order to compliant with national policies.


Signet-ring cell carcinoma of the stomach metastasizing to renal cell carcinoma: a case report and review of the literature.
Metastasis of one neoplasm to another is also known as metastasis of "tumor to tumor", "cancer to cancer", "tumor in tumor", and "one to another". We describe the case of a 75-year-old woman with the metastasis of signet-ring cell carcinoma of the stomach to clear cell renal cell carcinoma. Six years earlier, the patient had undergone gastrectomy for early gastric cancer. She complained of lumbago, and a mass was found in her left kidney. Examination of a partial nephrectomy revealed clear cell renal cell carcinoma containing signet-ring cells. Morphological and immunohistochemical findings of the signet-ring cells found in kidney cancer and gastric cancer were identical. Subsequent examinations revealed the patient had multiple bone metastases. The diagnosis of carcinoma metastasizing to renal cell carcinoma can be challenging; therefore, additional clinical information and immunohistochemical panel studies are requisite.


The effect of rider weight and additional weight in Icelandic horses in tölt: part I. Physiological responses.
This study examined the effect of increasing BW ratio (BWR) between rider and horse, in the BWR range common for Icelandic horses (20% to 35%), on heart rate (HR), plasma lactate concentration (Lac), BWR at Lac 4 mmol/l (W4), breathing frequency (BF), rectal temperature (RT) and hematocrit (Hct) in Icelandic horses. In total, eight experienced school-horses were used in an incremental exercise test performed outdoors on an oval riding track and one rider rode all horses. The exercise test consisted of five phases (each 642 m) in tölt, a four-beat symmetrical gait, at a speed of 5.4±0.1 m/s (mean±SD), where BWR between rider (including saddle) and horse started at 20% (BWR20), was increased to 25% (BWR25), 30% (BWR30), and 35% (BWR35) and finally decreased to 20% (BWR20b). Between phases, the horses were stopped (~5.5 min) to add lead weights to specially adjusted saddle bags and a vest on the rider. Heart rate was measured during warm-up, the exercise test and after 5, 15 and 30 min of recovery and blood samples were taken and BF recorded at rest, and at end of each of these aforementioned occasions. Rectal temperature was measured at rest, at end of the exercise test and after a 30-min recovery period. Body size and body condition score (BCS) were registered and a clinical examination performed on the day before the test and for 2 days after. Heart rate and BF increased linearly (P0.05), but negative correlations (P<0.05) existed between body size measurements and Hct. While HR, Hct and BF recovered to values at rest within 30 min, Lac and RT did not. All horses had no clinical remarks on palpation and at walk 1 and 2 days after the test. In conclusion, increasing BWR from 20% to 35% resulted in increased HR, Lac, RT and BF responses in the test group of experienced adult Icelandic riding horses. The horses mainly worked aerobically until BWR reached 22.7%, but considerable individual differences (17.0% to 27.5%) existed that were not linked to horse size, but to back BCS.


Morning vs evening dosing of the cathepsin K inhibitor ONO-5334: effects on bone resorption in postmenopausal women in a randomized, phase 1 trial.
The cathepsin K inhibitor, ONO-5334, improves bone mineral density in postmenopausal women with osteoporosis. The effects of morning versus evening administration of ONO-5334 were investigated by measuring bone turnover marker levels in healthy postmenopausal women. Morning administration of ONO-5334 showed a more consistent suppressive effect on bone resorption than evening administration. Bone turnover is thought to be subject to circadian variation, and the efficacy of osteoporosis treatments may be optimized by regulating the time of dosing. This study assessed whether evening administration of the cathepsin K inhibitor, ONO-5334, had a differential effect on the bone turnover marker, C-terminal telopeptide of type I collagen (CTX-I), compared with morning administration. This was a single-center, single blind crossover study. Fourteen healthy postmenopausal women were assigned to receive ONO-5334 150 mg once daily for 5 days in each period; they were randomized to receive either evening doses in the first period and morning doses in the second or vice versa. Serum and urinary levels of CTX-I were measured throughout the study. Both regimens showed similar patterns of reduction in serum and urinary CTX-I; however, CTX-I suppression was more consistently >60% over 24 h following morning administration. Morning administration led to 6% greater suppression of 24-h serum CTX-I area under the effect curve (AUE; 69 vs 63%; P < .05) and 7% greater suppression of urinary CTX-I/creatinine AUE (93 vs 86%; P < .01) than evening administration. Higher plasma ONO-5334 concentrations were observed between 12 and 24 h postdose following morning administration, with mean trough concentrations for the morning and evening regimens at 9.4 and 4.0 ng/mL, respectively. There were no safety findings of concern. Morning dosing of ONO-5334 is more efficacious at reducing markers of bone turnover in healthy postmenopausal women than evening dosing. ClinicalTrials.gov: NCT01384188 , registered on June 27, 2011 EudraCT: 2008-006284-37.


Transplantation of human umbilical cord-derived endothelial progenitor cells promotes re-endothelialization of the injured carotid artery after balloon injury in New Zealand white rabbits.
Cell transplantation has great potential for promoting endothelial repair and reducing the complications of percutaneous coronary intervention (PCI). The aim of this study was to investigate the effect of transplantation of human umbilical cord blood endothelial progenitor cells (EPCs) on injured arteries. Umbilical cord blood mononuclear cells were obtained from post-partum lying-in women, and EPCs were isolated, cultured, expanded and identified by immunofluorescence. The carotid arterial endothelium of New Zealand white rabbits was injured by dilatation with a 3F balloon, and the EPCs were injected into the lumen of the injured artery in the transplanted group (n = 16), while an equal volume of phosphated buffered saline (PBS) was injected into the control group after balloon injury (n = 16). The animals were sacrificed after either 2 or 4 weeks, and the grafted cells were identified by double immunofluorescence staining with human nuclear antigen (HNA) and CD31 antibodies. Arterial cross sections were analyzed by pathology, immunohistochemistry and morphometry to evaluate the reparative effects of EPCs. Proliferating cell nuclear antigen (PCNA) and transforming growth factor (TGF)-β1 mRNA expression were detected by reverse transcription-polymerase chain reaction (RT-PCR). Fluorescence-labeled EPCs were found in the neointima. The neointimal area and the neointimal/medial area ratio were significantly lower in the transplanted group than in the control group (P < 0.05). von Willebrand factor (vWF) immunohistostaining showed more VWF-positive cells in the transplanted animals than in the controls (8.75 ± 2.92 vs. 4.50 ± 1.77, P < 0.05). Compared with the control group, the transplanted group had lower expression of PCNA mRNA (0.67 ± 0.11 vs. 1.25 ± 0.40, P < 0.01) and higher expression of TGF-β1 mRNA (1.10 ± 0.21 vs. 0.82 ± 0.07, P < 0.05). EPCs derived from human umbilical cord blood were successfully transplanted into injured vessels. The transplanted EPCs inhibited neointimal hyperplasia and promoted vascular re-endothelialization.


A new sequenced allelic ladder marker for D1S80 typing.
A sequenced allelic ladder marker that contains 32 alleles consisting of alleles 13-44 was developed for D1S80 ( MCT118) typing. Each allele, after amplification with D1S80 primers, was cloned to the pT7Blue T-Vector. The plasmid DNAs of these clones were mixed and amplified with D1S80 primers to construct the allelic ladder marker. All the alleles prepared in this study were sequenced in both directions, using two types of forward primers and one reverse primer. The sequencing results revealed that all the alleles in our allelic ladder marker had the correct length corresponding to the allele number. This marker can be used for more effectively typing D1S80.


Projections from the inferior olive to the cerebellar nuclei in the cat demonstrated by retrograde transport of horseradish peroxidase.
The method of intracerebral injections of horseradish peroxidase has been applied to demonstrate a projection from the inferior olivary nucleus to the intracerebellar nuclei in the cat. Cells labeled by the transported enzyme can be observed in different regions of the olive according to the localization of the injection. The caudal half of the medial and dorsal accessory subdivisions, the dorsal cap and nucleus beta project to the fastigial nucleus. In the rostral half of the olive, the accessory subdivisions of that nucleus and the dorsomedial cell column send fibers to the interposed nuclei while the principal olive and the ventrolateral outgrowth are connected with the dentate nucleus. It is likely that these fibers are collaterals of the climbing fibers.


Low accuracy of tumor markers for diagnosing pancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1 patients.
The assessment of tumor markers for diagnosing pancreatic neuroendocrine tumors (pNET) in multiple endocrine neoplasia type 1 (MEN1) patients is advised in the current guidelines but has never been validated for this purpose. The objective of the study was to assess the diagnostic accuracy of chromogranin A (CgA), pancreatic polypeptide (PP), and glucagon for pNET in MEN1. This was a diagnostic study. The study was conducted at Dutch university medical centers from 2008 to 2011, representing 90% of the total Dutch MEN1 population. Patients for whom data on tumor markers in combination with the reference standard (ie, radiological imaging) were available between 2008 and 2011 were included. The reference standard for the presence of pNET was pathology or detection on magnetic resonance imaging, computed tomography, or endoscopic ultrasound confirmed on subsequent imaging, irrespective of modality at follow-up. The area under the receiver-operating characteristic curve (AUC), positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio, sensitivity, and specificity were calculated for each marker. For the analysis of PP, CgA, and glucagon, 73, 81, and 94 patients were available, respectively. The AUC for CgA was 0.48 [95% confidence interval (CI) 0.35-0.61] with a sensitivity 0.33 and a specificity 0.73; the AUC for glucagon was 0.58 (95% CI 0.46-0.70) with a sensitivity 0.43 and a specificity 0.73; and the AUC for PP was 0.64 (95% CI 0.50-0.77) with a sensitivity 0.36 and a specificity 0.74. Age, imaging modality, tumor size, and number did not influence the outcomes. The diagnostic accuracy of the tumor markers CgA, PP, and glucagon for pNET in MEN1 is low.


The adaptation of soldiers to post-service life - the mediating impact of political views on the relationship between violence and adaptation.
The current research explores the association between political views, combat experiences, and the adaptation of soldiers to post-service life. Violent experiences in military service were explored as contributors to both positive and negative dimensions of adaptation, while political views served as possible mediators. Three hundred and twenty Israeli veterans participated in the study. Political views were correlated with adaptation, especially left-to-right voting and anti-militarism. The results support the mediating role of political beliefs (left-right voting and militarism) in the relationship between combat experience and adaptation to post-service life. We contend that political perceptions affect adaptation through sense-making of the combat experiences and the individual processing of these experiences, and the willingness to continue in reserve service, which allows social support and recognition. In addition, they are linked to a sense of bitterness following the reduction of public participation in military and reserve service.


A perspective of dental education in the twenty-first century.
With the beginning of the twenty-first century only twelve years away, it is clearly not too early for dental educators to be planning for it. If one compares the practice of dentistry and the nature of dental education in 1888 with that of 1988, and then tries to project what they will be like in the year 2088, we have a difficult task indeed. As Alvin Toffler has pointed out in his book Future Shock, we are in an ever escalating period of change. Dentistry and dental education will change much more in the next one hundred years than they have in the last one hundred years.


Endotoxemia and endotoxin tolerance in patients with ARDS.
The significance of endotoxemia in man is controversial, induces cytokine release and stimulates the immune system. Exaggerated cytokine release of mononuclear cells was observed in acute lung injury/acute respiratory distress syndrome (ALI/ARDS). However, repetitive administration of endotoxin can cause tolerance. To investigate endotoxemia, plasma TNFalpha, IL-1beta, IL-6, the liberation capacity of those cytokines from mononuclear cells after LPS challenge (Delta values), and plasma antibodies to endotoxins and alpha-hemolysin of Staphylococcus aureus in ALI/ARDS. A prospective clinical study was conducted. The study was carried out at the University Hospital Ulm, Ulm, Germany. The respondents were 23 patients with ALI/ARDS. ALI/ARDS was defined according to the American-European Consensus Conference on ARDS. Blood was collected periodically. Parameters were measured by LAL or ELISA. ARDS (P(a)O(2)/F(i)O(2) < 200) revealed higher endotoxemia (0.22-0.46 [0.06-1.15] EU/mL vs 0.05-0.14 [0.02-0.63] EU/mL) than ALI (P(a)O(2)/F(i)O(2) > 200) but lower DeltaIL-6 (124-209 [10-1214] pg/mL vs 298-746 [5-1797] pg/mL), DeltaTNFalpha (50-100 [6-660] pg/mL vs 143-243 [12-2795] pg/mL), and DeltaIL-1 (2-3 [0-26] pg/mL vs 2-14 [0-99] pg/mL). Endotoxemia correlated negative with P(a)O(2)/F(i)O(2) (r, -0.44 to -0.50). All patients presented antibodies to lipopolysaccharides and alpha-hemolysin, but the level did not correlate with P(a)O(2)/F(i)O(2). ALI/ARDS is associated with endotoxemia. The more severe the disease, the more intense is endotoxemia but the lower is the capacity of mononuclear cells to release cytokines (tolerance). Antibodies against Gram-positive and Gram-negative bacteria are detectable in the plasma but without relation to P(a)O(2)/F(i)O(2).


Standard automated perimetry and algorithms for monitoring glaucoma progression.
Despite increasingly sophisticated techniques for the computerized analysis of the optic nerve and retinal nerve fiber layer, standard automated perimetry (SAP) is still the primary test for assessing functional damage in glaucoma. Most of the diseases affecting the visual field can be studied analyzing the central visual field with a fixed grid of points set at 6 degrees or at a variable density within central 30 degrees, using a III white target stimulus (program 30/2 or 24/2 Humphrey, G1/G2 or 30/2 Octopus). Although there is lack of a true gold standard for glaucoma, SAP results were the primary endpoint in most of the clinical trials in glaucoma. New thresholding strategies allowed a considerable reduction of examination time without substantial loss of accuracy. Moreover, recent findings on structure-function correlation in glaucoma validate the clinical role of this well-known and widespread method of examination.


Area deprivation, perceived neighbourhood cohesion and mental health at older ages: A cross lagged analysis of UK longitudinal data.
Previous research on neighbourhood influences on older adults' mental health shows inconsistent evidence for effects of neighbourhood deprivation but stronger evidence for effects of perceived neighbourhood social cohesion, often proposed as a mediator of the link between neighbourhood deprivation and mental well-being. However, it is possible that mental health influences perceptions of neighbourhoods; this has rarely been considered. We use data from a large UK longitudinal study to investigate these associations. Results from cross-lagged models indicate that greater neighbourhood deprivation is associated with worse perceived social cohesion and worse mental health. Associations between change in perceived social cohesion and in mental health were reciprocal-lower perceived cohesion predicted poorer mental health and vice versa. Further research including three waves of data is needed to further unravel underlying directions of association.


Solitary metastasis of the patella as the first manifestation of lung cancer. A case report.
A man of 71 was seen with a solitary metastasis in the patella as the first presentation of carcinoma of the lung.


Human Umbilical Cord Tissue-Derived Multipotent Mesenchymal Stromal Cells Exhibit Maximum Secretory Activity in the Presence of Umbilical Cord Blood Serum.
Using multiplex analysis, we performed a comparative study of cytokine and growth factor production by human umbilical cord tissue-derived multipotent mesenchymal stromal cells (UC-MSC) cultured under standard conditions and in the presence of human umbilical cord blood serum (UCBS). It was found that the secretion of most studied molecules, including well-known inductors of regeneration HGF, G-CSF, GM-CSF, and VEGF by UCMSC considerably increased in the presence of 5% UCBS. The use of UCBS allows not only obtaining xenogenic-free cellular and cell-free therapeutic products, but also increasing the secretion of most biologically active molecules capable of stimulating repair processes.


'Acupuncture for antenatal depression: It's worth giving it a go' - A qualitative study.
Treatment strategies for the management of antenatal depression are limited by varied and often modest response rates, unpleasant medication side effects and uncertainty regarding foetal safety. Consequently, many pregnant women experiencing depression seek alternative non-pharmaceutical options. Acupuncture may provide a safe and potentially effective additional treatment, however further investigation is required. In this qualitative study, we explored the views of health professionals regarding the possible incorporation of acupuncture into mainstream care. Two separate focus groups were run with 16 midwives. In-depth interviews were conducted with two maternity service managers and nine doctors (3 obstetricians, 2 psychiatrists and 4 general practitioners). Data was analysed using thematic analysis. Participants were generally positive about acupuncture and open to its possible inclusion in conventional care, on the proviso that it was safe and could be shown to be effective. The overarching theme to emerge was 'acupuncture for antenatal depression: it's worth giving it a go', which participants concluded after considering 'the dilemma of mental health' treatment during the antenatal period and the additional limitations this presented, along with the belief that 'if it doesn't do any harm, I'm not against it'. Practical considerations regarding potential 'barriers' and facilitators' to implementation were additionally explored in 'making it mainstream', whereby the different 'philosophical beliefs' held by participants were seen to influence perspectives. Participants expressed an overall positive attitude towards the possible inclusion of acupuncture into mainstream care for antenatal depression, suggesting various hospital barriers could be overcome with further safety and effectiveness evidence.


[Keloid scars on black skin: myth or reality].
The keloid scar is a thick skin or the cornea of man, due to excessive accumulation of type I collagen in the dermis. Morbidity of the keloid is high, given the frequent recurrences and unpredictable. African blacks and Asians are most affected. The purpose of this study was to analyze the results of treatment of 149 cases of keloids and discuss the reality of keloids in the dark. From 1990 to 2011, 98 patients were supported for 149 keloid tumors. Seventy-eight adults (79.6%) and 20 children (20.4%) were received. Sixty-four women (65.3%) and 34 men (34.7%) were supported, including 94 blacks (96%) and four redheads (4%). The average age was 25 years with extremes of 2 years and 54 years. The trauma was the dominant etiology in 63.1% of cases. The infection, burns and surgery were implicated in 16.8%, respectively, 15% and 4.7% of cases. The cephalic end, was the seat of choice for keloids, with 84 cases or 56.4%. The ear has been the preferred unit in 38 cases, or 25.5%. The body, legs and genital area were the site of keloids, respectively, in 22.8%, 17.5%) and 3.3% of cases. Keloidal field was found in 24.5% of our cases. The reasons for consultation were the disgrace aesthetics (56.4%), pain (65%), households suppurative intrakeloidal (44.9%), functional impairment (40.8%), and the psychological impact minor (15.3%) and no major suicide attempt (66.3%). Two surgical techniques were used: total excision (TE), with total skin graft immediate or deferred, or not expanded, and intrakeloid excision (IKE) with suture surgery was associated with intra-lesional steroids. Many complications have favored the occurrence of early or late recurrence in 100% of our cases. The keloid is not a homogenous biological entity. Its prevalence is higher among black and yellow, and lowest among whites. The research results are still being evaluated. The best prevention is to avoid the scar itself.


Using large organic cations to probe the nature of ryanodine modification in the sheep cardiac sarcoplasmic reticulum calcium release channel.
We have reported that the large impermeant organic cations tetrabutyl ammonium (TBA+), tetrapentyl ammonium, and the charged local anesthetic QX314 produce unique reduced conductance states in the purified sheep cardiac sarcoplasmic reticulum Ca2+ release channel when present at the cytoplasmic face of the channel. We have interpreted this as a form of partial occlusion by the blocking cation in wide vestibules of the conduction pathway. Following modification with ryanodine, which causes the channel to enter a reduced conductance state with long open dwell time, these cations block the receptor channel to a level that is indistinguishable from the closed state. The voltage dependence of TBA+'s interaction with the Ca2+ release channel is the same before and after ryanodine modification. The concentration dependence is different, in that the ryanodine-modified channel has one-third the affinity for TBA+, which is accounted for predominantly by changes in the TBA+ on rate. The data are compatible with a structural change in the vestibule of the conduction pathway consequent upon ryanodine binding that reduces the capture radius for blocking ion entry.


Potential value of serum brain-derived neurotrophic factor, vascular endothelial growth factor, and S100B for identifying major depressive disorder in knee osteoarthritis patients.
The chronic pain and functional limitations in osteoarthritis (OA) patients can increase risk of psychiatric disorders, e.g., major depression disorder (MDD), which may further aggravate the clinical symptoms of OA. Early detection of MDD is essential in the clinical practice of OA. Two hundred and fifteen participants with knee OA were recruited, including 134 MDD patients (i.e., MDD group) and 81 ones without MDD (i.e., control group). Among them, 81 OA participants in the control group received a 3-year follow-up and were divided into trans-MDD group (who transforming into MDD; N = 39) and non-MDD group (who keeping non-MDD; N = 42) at the end of the follow-up. The 17-item Hamilton Depression Scale (HAMD-17), Self-Rating Depression Scale (SDS), and Visual Analogue Scale (VAS) were performed. Furthermore, serum levels of brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), S100B, and IGF-1 were detected. (1) Compared with OA participants without MDD, there were significant decrease in serum BDNF and significant increase in serum VEGF and S100B and VAS scores in OA participants with MDD. (2) A mediation of the association was found between the VAS scores and the HAMD-17 scores through the BDNF as mediator in OA participants with MDD. (3) Significantly lower baseline BDNF levels and higher baseline S100B levels were detected in OA participants who transforming to MDD after a 3-year follow-up when compared with those who keeping non-MDD. (4) In the trans-MDD group, significant associations of the change of serum BDNF levels with rate of change of HAMD-17 scores were found, and baseline serum S100B levels positively correlated with the HAMD-17 scores at the end of the follow-up. (5) In OA participants, the composite indicator of BDNF, VEGF, and S100B differentiated MDD patients from controls with the area under the curve (AUC) value of 0.806, and the combined indicator of baseline BDNF and S100B distinguished trans-MDD participants from non-MDD ones with an AUC value of 0.806. Serum BDNF, VEGF, and S100B may be potential biomarkers to identify MDD in OA patients. Meanwhile, serum BDNF and S100B shows great potential to predict the risk of MDD for OA.


The management of anticoagulants in patients with atrial fibrillation and history of falls or risk of falls: protocol for a systematic review and meta-analysis.
Atrial fibrillation affects an estimated 33 million individuals worldwide and is a major cause of stroke, heart failure, and death. Anticoagulants substantially reduce the risk of stroke but are also associated with an increased risk of bleeding and especially intracranial hemorrhage which is the most concerning complication. Because of this, many patients are not offered anticoagulants, particularly patients at risk of falls or with a history of falls. It is unclear what anticoagulant treatment these patients should be offered. The Liverpool AF-Falls project aims to investigate this area, and this protocol for a systematic review and meta-analysis aims to define what is the most appropriate anticoagulant treatment option for the management of atrial fibrillation patients at risk of falls or with a history of falls. This systematic review and meta-analysis will include randomized and non-randomized studies evaluating the safety and efficacy of different anticoagulant treatments (vitamin K antagonist and non-vitamin K antagonist oral anti-coagulant). Bibliographic databases (Cochrane Central Register of Controlled Trials, CINAHL, ClinicalTrials.gov , Embase, MEDLINE, Scopus and Web of Science) will be searched according to a pre-specified search strategy. Titles, abstracts, and full texts will be assessed by two independent reviewers and disagreements resolved with a third independent reviewer. The Cochrane Risk of Bias tool 2 (RoB 2) will be used to assess the risk of bias in randomized trials, and the Risk Of Bias In Non-randomized Studies - of Interventions (ROBINS-I) tool will be used for non-randomized studies. A pairwise meta-analysis based on the fixed and random-effects models will be conducted. Publication bias will be evaluated with a funnel plot and Egger's test. Heterogeneity will be assessed with the I2 statistic. If conditions for indirect comparison are met and sufficient data are available, a network meta-analysis will be conducted using frequentist and Bayesian methodologies. This review will be the first to summarize direct and indirect evidence on the safety and efficacy of anticoagulant treatments in atrial fibrillation patients at risk of falls or with a history of falls. The findings will be important to patients, clinicians, and health policy-makers to inform best practices in the use of these treatments. PROSPERO registry number: CRD42020201086.


The present and potential impact of research on animal models for clinical treatment of stimulus deprivation amblyopia.
With the benefit of hindsight based on an additional 20 years of research, we review a question posed originally by Marg of whether animal models for stimulus deprivation amblyopia in children are valid or useful for clinical application. Following a review of relevant research on animal models, the human clinical literature on treatment of stimulus deprivation amblyopia has been reviewed with respect to past and current impact of animal research on clinical treatment. In addition, we speculate on the potential future clinical impact of animal work on developmental plasticity in the visual cortex that is directed towards an understanding of its underlying molecular basis. Animal research that has begun to define the timing, nature and sites of critical periods in the central visual pathways with greater precision than was known 20 years ago has had a demonstrable impact on clinical practice. In turn, these changes in clinical practice have produced far better outcomes than prior to 1980, for both the acuity of the amblyopic eye and for binocular functions such as stereopsis.


Heart failure in women.
Heart failure (HF) has steadily increased in prevalence and affects both males and females equally. Despite this, there has been a significant underrepresentation of women in large scale HF trials. This disparity has lead to a deficit in understanding important gender-based differences in pathophysiology, diagnosis and treatment strategies. We review these gaps and explore a biological basis for varying outcomes. Endogenous estrogen plays an important role in epidemiology and outcome. The administration of exogenous estrogen has had varied success in treatment and is outlined extensively below. Additionally, we highlight unique HF syndromes through pregnancy and important sex-specific issues concerning transplant and mechanical circulatory support. A central theme remains: there is a clear need for increased female recruitment in clinical trials, and more studies exploring the role of gender-based biology in HF treatment.


Directed evolution of retroviruses activatable by tumour-associated matrix metalloproteases.
Protease-activatable retroviral vectors offer the possibility of targeted gene transfer into cancer cells expressing a unique set of proteases as, for example, the matrix metalloproteases (MMPs). However, it is difficult to predict which substrate sequence will be optimally cleaved by a given tumour cell type. Therefore, we developed a novel approach that allows the selection of MMP-activatable retroviruses from libraries of viruses displaying combinatorially diversified protease substrates. Starting from a virus harbouring a standard MMP-2 substrate motif, after only two consecutive cycles of diversification and in vivo selection, MMP-activatable viruses were recovered. Biochemical characterization of the selected viruses revealed that their linker peptides showed a considerably increased sensitivity for MMP-2 cleavage, and interestingly also improved the particle incorporation rate of the Env protein. Owing to the optimized linker peptide, the selected viruses exhibited a greatly enhanced spreading efficiency through human fibrosarcoma cells, while having retained the dependency on MMP activation. Moreover, cell entry efficiency and virus titres were considerably improved as compared to the parental virus displaying the standard MMP-2 substrate. The results presented imply that retroviral protease substrate libraries allow the definition of MMP substrate specificities under in vivo conditions as well as the generation of optimally adapted tumour-specific viruses.


Partial reduction in neural cell adhesion molecule (NCAM) in heterozygous mice induces depression-related behaviour without cognitive impairment.
The neural cell adhesion molecule (NCAM) plays an important role in brain plasticity. Using mice deficient in all isoforms of NCAM we have previously demonstrated that constitutive deficiency in the NCAM gene (NCAM-/-) resulted in cognitive impairment, anhedonic behaviour and a reduced ability to cope with stress. This was accompanied by reduced basal phosphorylation of the fibroblast growth factor receptor 1 (FGFR1) and reduced phosphorylation of calcium-calmodulin kinase (CaMK) II and IV and cAMP response element binding protein (CREB). The present study was aimed to investigate how partial deficiency in NCAM in mice (NCAM+/-) affected phenotype. We found that NCAM+/- mice showed a longer period of immobility in the tail suspension test, increased latency to feed in the novelty-suppressed feeding test and reduced preference for sucrose in sucrose preference test. Both NCAM+/- and NCAM-/- mice showed reduced extinction of contextual fear. In contrast to NCAM-/- mice, NCAM+/- mice did not demonstrate memory impairment in either object recognition or contextual fear conditioning tests. Levels of phosphorylated FGFR1 in the hippocampus and prefrontal/frontal cortex of NCAM+/- mice were partially reduced and no changes in the phosphorylation of CaMKII, CaMKIV or CREB in the hippocampus were found. We conclude that a constitutive partial reduction in NCAM proteins results in a behavioural phenotype related to depression without impairment in cognitive functions, also affecting the level of FGFR1 phosphorylation without major alterations in CaMKII and CaMKIV intracellular signalling. Partial reduction in FGFR1 phosphorylation might explain the observed behavioural phenotype in NCAM+/- mice.


Young children's knowledge of their memory span: effects of task and experience.
This study investigated the hypothesis that young children have knowledge about their memory that they may be unable to articulate, but are able to reflect on and use in problem-solving. Forty-eight kindergarteners made one of two types of judgments about their memory span for words. Half of the children made prospective verbal predictions about the number of words they thought they could recall from a list of 10. The other half made concurrent, nonverbal predictions by listening to words on a tape and manually stopping the tape when they heard as many words as they thought they could recall. Children's actual recall for words was then assessed. All children participated in multiple trials to assess the effect of task experience on their predictions. Analyses revealed that predictions made in the concurrent task were significantly more accurate than those made in the prospective task. All children lowered their predictions across trials, although only in the concurrent task were children's final-trial predictions not significantly greater than their actual recall. No meaningful effects or interactions were associated with actual recall scores. These results revealed that young children manifested greater memory knowledge when this knowledge was assessed through their concurrent problem-solving behavior rather than through their prospective verbal predictions.