SARS-CoV-2 Infection Drives a Glycan Switch of Peripheral T Cells at Diagnosis.
COVID-19 is a highly selective disease in which SARS-CoV-2 infection can result in different clinical manifestations ranging from asymptomatic/mild to severe disease that requires hospitalization. In this study, we demonstrated that SARS-CoV-2 infection results in a glycosylation reprogramming of circulating lymphocytes at diagnosis. We identified a specific glycosignature of T cells, defined upon SARS-CoV-2 infection and apparently triggered by a serological factor. This specific glycan switch of T cells is detected at diagnosis being more pronounced in asymptomatic patients. We further demonstrated that asymptomatic patients display an increased expression of a viral-sensing receptor through the upregulation of DC-SIGN in monocytes. We showed that higher levels of DC-SIGN in monocytes at diagnosis correlates with better COVID-19 prognosis. This new evidence pave the way to the identification of a novel glycan-based response in T cells that may confer protection against SARS-CoV-2 infection in asymptomatic patients, highlighting a novel prognostic biomarker and potential therapeutic target.


[Intradural extramedullary tuberculous abscess. Apropos of a case].
Intradural extramedullary tuberculous spinal abscess is rare and has a poor prognosis if not diagnosed early and treated adequately. We report the case of 13 year-old boy who presented with an 8-month history of paraplegia. MR imaging demonstrated an intradural extramedullary spinal abscess in the mid-thoracic region. At operation, an encapsulated abscess was removed completely. The tuberculous nature was confirmed with microbiological testing. Postoperative antituberculous chemotherapy resulted in complete recovery. MR imaging can prove very helpful in early diagnosis of this condition, which is particular relevant in countries where tuberculosis is endemic.


Potential for differentiation of glioma recurrence from radionecrosis using integrated 18F-fluoroethyl-L-tyrosine (FET) positron emission tomography/magnetic resonance imaging: A prospective evaluation.
To assess the utility of 18F-fluoroethyl-L-tyrosine (FET) positron emission tomography/magnetic resonance imaging (PET/MRI) in distinguishing recurrence from radionecrosis. Thirty-two patients (25 males, 7 females) of glioma who had already undergone surgery/chemoradiotherapy and had enhancing brain lesions suspicious of recurrence were evaluated using integrated 18F-FET PET/MRI, and followed up with histopathology or clinical follow-up and/or MRI/PET/MRI imaging. Manually drawn regions of interest over areas of maximal enhancement or FET uptake were used to calculate tumor to background ratios [TBRmax, TBRmean], choline: creatine ratio [Cho: Cr ratio], normalized relative cerebral blood volume [N rCBVmean] and apparent diffusion coefficient [ADCmean]. Correlations were evaluated using Pearson's coefficient. Accuracy of each parameter was calculated using independent t-test and receiver operator curve (ROC) analysis while utility of all four parameters together using multivariate analysis of variance (MANOVA) for differentiating recurrence vs. radionecrosis was evaluated. Positive histopathology and imaging/clinical follow up served as the gold standard. Twenty-four of the 32 patients were diagnosed with recurrent disease and 8 with radiation necrosis. Significant correlations were observed between TBRmaxand N rCBVmean (ρ =0.503; P = 0.003), TBRmean, and N rCBVmean (ρ =0.414; P = 0.018), TBRmaxand ADCmean (ρ = -0.52; P = 0.002), and TBRmeanand ADCmean(ρ = -0.518; P = 0.002). TBRmax, TBRmean, ADCmean, Cho: Cr ratios, and N rCBVmeanwere significant in differentiating recurrence from radiation necrosis with an accuracy of 94.1%, 88.2%, 80.4%, 96.4%, and 89.9%, respectively. MANOVA indicated that combination of all parameters demonstrated better evaluation of recurrence vs. necrosis than any single parameter. The diagnostic accuracy, sensitivity, and specificity using all MRI parameters were 93.75%, 96%, and 85.7%, and using all FET PET/MRI parameters was 96.87%, 100%, and 85.7%, respectively. Synergetic effect of multiple MR parameters evaluated together in addition to FET PET uptake highlights the fact that integrated 18F-FET PET/MRI might have the potential to impact management of patients with glioma by timely and conclusive recognition of true recurrence from radiation necrosis.


CSF B-cell expansion in opsoclonus-myoclonus syndrome: a biomarker of disease activity.
Lack of a biomarker of disease activity has hindered the therapy of childhood opsoclonus-myoclonus syndrome (OMS), which is purported to be mediated humorally. To determine if the cerebrospinal fluid (CSF) B lymphocyte, which may traffic into the central nervous system (CNS) to produce antibody locally, is one such biomarker, B lymphocytes were immunophenotyped in the CSF and blood of 56 children with OMS and 26 pediatric controls by dual-laser flow cytometry. Neurological severity was rated blindly from videotapes using a validated 12-item motor evaluation scale. Children with OMS manifested a 4- to 7-fold higher percentage of total B-cells in CSF (P < 0.0001), including CD5(+) (P = 0.001) and CD5(-) (P = 0.0004) B-cell subsets, compared with controls, in whom the percentages were negligible and unchanging with age. CSF expansion of both B-cell subsets increased with disease severity and decreased with disease duration (P </= 0.0001, ANOVA). Previous treatment with conventional immunotherapies, chemotherapy, or tumor resection had not normalized B-cell percentages in those with lingering symptoms. These studies reveal that CSF B-cell expansion in OMS is characteristic and often persistent. Presence of the autoreactive CD5(+) B-cell subset and correlations with neurological severity and disease duration suggest CSF B-cell expansion is a biomarker of disease activity and possible target for B-cell-specific therapy. Immunophenotyping of CSF lymphocytes by flow cytometry yields valuable clinical information missed by routine studies and allows crucial treatment decisions to be made rapidly.


MicroRNA 329 suppresses angiogenesis by targeting CD146.
CD146, an endothelial biomarker, has been shown to be aberrantly upregulated during pathological angiogenesis and functions as a coreceptor for vascular endothelial growth factor receptor 2 (VEGFR-2) to promote disease progression. However, the regulatory mechanisms of CD146 expression during angiogenesis remain unclear. Using a microRNA screening approach, we identified a novel negative regulator of angiogenesis, microRNA 329 (miR-329), that directly targeted CD146 and inhibited CD146-mediated angiogenesis in vitro and in vivo. Endogenous miR-329 expression was downregulated by VEGF and tumor necrosis factor alpha (TNF-α), resulting in the elevation of CD146 in endothelial cells. Upregulation of CD146 facilitated an endothelial response to VEGF-induced SRC kinase family (SKF)/p38 mitogen-activated protein kinase (MAPK)/NF-κB activation and consequently promoted endothelial cell migration and tube formation. Our animal experiments showed that treatment with miR-329 repressed excessive CD146 expression on blood vessels and significantly attenuated neovascularization in a mouse model of pathological angiogenesis. Our findings provide the first evidence that CD146 expression in angiogenesis is regulated by miR-329 and suggest that miR-329 could present a potential therapeutic tool for the treatment of angiogenic diseases.


Cell type- and time-dependent biological responses in ex vivo perfused lung grafts.
In response to the increasing demand for lung transplantation, ex vivo lung perfusion (EVLP) has extended the number of suitable donor lungs by rehabilitating marginal organs. However despite an expanding use in clinical practice, the responses of the different lung cell types to EVLP are not known. In order to advance our mechanistic understanding and establish a refine tool for improvement of EVLP, we conducted a pioneer study involving single cell RNA-seq on human lungs declined for transplantation. Functional enrichment analyses were performed upon integration of data sets generated at 4 h (clinical duration) and 10 h (prolonged duration) from two human lungs processed to EVLP. Pathways related to inflammation were predicted activated in epithelial and blood endothelial cells, in monocyte-derived macrophages and temporally at 4 h in alveolar macrophages. Pathways related to cytoskeleton signaling/organization were predicted reduced in most cell types mainly at 10 h. We identified a division of labor between cell types for the selected expression of cytokine and chemokine genes that varied according to time. Immune cells including CD4+ and CD8+ T cells, NK cells, mast cells and conventional dendritic cells displayed gene expression patterns indicating blunted activation, already at 4 h in several instances and further more at 10 h. Therefore despite inducing inflammatory responses, EVLP appears to dampen the activation of major lung immune cell types, what may be beneficial to the outcome of transplantation. Our results also support that therapeutics approaches aiming at reducing inflammation upon EVLP should target both the alveolar and vascular compartments.


Investigation of the requirements for O-glycosylation by bovine submaxillary gland UDP-N-acetylgalactosamine:polypeptide N-acetylgalactosamine transferase using synthetic peptide substrates.
Peptides containing a triprolyl sequence carboxyl to a threonine residue can be O-glycosylated by a crude Triton x-100 extract of porcine submaxillary glands (Young, J. D., Tsuchiya, D., Sandlin, D. E., and Holroyde, M. J. (1979) Biochemistry 18, 4444-4448). In the present paper, we have studied the characteristics of the O-glycosylating enzyme, UDP-N-acetylgalactosamine: polypeptide N-acetylgalactosamine transferase, from a membrane extract of bovine submaxillary glands using 11 synthetic peptide substrates in which the Thr-Pro-Pro-Pro was varied. The effect of these changes was measured by determining the apparent Km and Vmax values of the substrates. The studies thus far reveal: threonine cannot be glycosylated without a carboxyl triprolyl sequence; the alpha amino acid group of the threonine must be blocked; the nature of the group NH2-terminal to the threonine affects the kinetics of the reaction; and one residue can be between the threonyl and the triprolyl sequence. The triprolyl sequence in a protein may be an important signal for O-glycosylation.


A sensitizing d-amphetamine regimen induces long-lasting spinophilin protein upregulation in the rat striatum and limbic forebrain.
Structural studies have shown that chronic regimens of psychostimulants increase dendritic spine number in the rat striatum. The present study used Western blotting and radioimmunocytochemistry to examine psychostimulant-induced changes in the levels of spinophilin, a protein found abundantly in dendritic spines. Spinophilin determinations were conducted in striatum as well as several other subcortical regions implicated in psychostimulant-induced neuroplasticity. Rats received an escalating (1-8 mg/kg) dosing regimen of d-amphetamine (twice daily, i.p.) for 5 weeks, were tested for locomotor sensitization, and were killed 28 days later. This amphetamine dosing regimen was found to induce a significant sensitization of locomotor activity in these animals. Using both Western blotting and radioimmunocytochemistry, spinophilin protein was found to be upregulated in the striatum of amphetamine-treated rats. In addition, radioimmunocytochemistry revealed that spinophilin was increased in the septum, hippocampus, amygdala and the cingulate cortex, and was unchanged in sensorimotor cortices. Because it binds to F-actin and protein phosphatase-1, spinophilin has been proposed as a protein linking synaptic transmission to changes in spine morphology. Radioimmunocytochemistry for spinophilin provides a novel approach to identification of brain regions whose neurons undergo dendritic change after chronic exposure to drugs of abuse.


Understanding the Mode and Factors Influencing Cut-Throat Injuries in a Tribal-Dominated Population in Eastern India.
Introduction Traditionally, injuries have often been perceived as random and inevitable 'accidents'. However, in the current context, both intentional and unintentional injuries are preventable. Among these, neck injuries can be particularly complex, encompassing homicidal, suicidal, or accidental causes. Despite extensive research on the different modes and patterns of cut-throat injuries in the general population, this study aims to look deeper into this phenomenon within a unique context. Our investigation is centered in the Eastern part of India, among a tribal-dominated population who live with their traditional culture. Method In this prospective observational study, 50 cut-throat patients were included, who reported to the emergency department and then were referred to the ENT department. Parameters such as age, sex, anatomical location, mode of cut-throat injury, prior substance abuse, psychiatric issues, socioeconomic level, and length of hospital stay were considered for analysis. Results The majority (n=40, 80%) of patients belonged to tribal communities and most were young adults. Cut-throat injuries were predominantly caused by suicide (n=36, 72%) and homicide (n=12, 24%). Among tribals, 85% (n=34) of the cases were suicidal. Among suicidal cases, 86.11% (n=31) had a history of substance abuse while 22.22% (n=8) had a history of psychiatric illnesses. Conclusion In Eastern India, among the tribal-dominated population, suicide emerges as the predominant mode of cut-throat injuries, which is notably distinct from patterns observed in the general population of developing countries. These were often associated with substance abuse. Future interventions and public health efforts in these regions should consider these factors in the development of targeted strategies aimed at prevention and support for at-risk individuals.


A controlled trial on utility of oral zinc supplementation in acute dehydrating diarrhea in infants.
A controlled, randomized trial was conducted in 50 infants with acute dehydrating diarrhea to evaluate the effect of oral zinc supplementation in acute diarrhea. After completion of rehydration, 25 infants in Group A received oral zinc sulfate (20 mg elemental zinc twice daily) and an equal number in Group B were given placebo (glucose). Both groups were comparable with respect to various initial characteristics including nutritional status, diarrheal disease, serum alkaline phosphatase, and serum and rectal mucosal zinc content. During therapy all the assessed parameters of zinc status (serum alkaline phosphatase and serum and rectal zinc) recorded significant elevation and reduction in Groups A and B, respectively. At recovery the zinc status of Group A was significantly better and was nearer that of healthy controls. The diarrheal duration and frequency in the zinc-supplemented group were lower, but the differences were not significant (0.05 less than p less than 0.1). However, when only subjects with relatively severe initial zinc depletion (rectal zinc lower than the 15th percentile of healthy controls; 11 in Group A and 14 in Group B) were considered, the diarrheal duration and frequency were significantly (p less than 0.05 and p less than 0.01, respectively) lower in the zinc-supplemented cases. Weight gain in both groups was similar. It is concluded that oral zinc administration in acute diarrhea can replenish body zinc status and this may shorten the diarrheal duration and frequency in children with relatively severe zinc depletion.


A Comparative Evaluation of Three Different Dental Age Estimation Methods in India: A Test of Ethnic Variability.
The present study aimed to evaluate and compare the applicability of Demirjian, Willems, and Haavikko methods of dental age estimation in southeastern (Dravidian ethnicity) and northwestern regions (Aryan ethnicity) of the Indian population. The study includes the orthopantomographs (OPGs) of 303 individuals (173 males and 130 females) of age ranging from 5 to 14 years. The participants in the present research were evaluated under two study groups: group I: participants of the southeastern region and group II: participants of the northwestern region. Dental age was calculated using Demirjian, Willems, and Haavikko methods and compared with the chronologic age of each participant. The accuracy of dental age estimation methods was evaluated by mean absolute error. One-way analysis of variance (ANOVA) and Student's t tests were used to test the significant difference between the chronologic age and estimated dental ages. The Demirjian method showed overestimation, while Willems and Haavikko methods showed underestimation for boys and girls in both the ethnic groups of Indian population. The Willems method of dental age estimation showed comparatively more accurate and reliable results in both the ethnic groups of the Indian population. The dental age estimation by Demirjian, Willems, and Haavikko methods showed no significant variation between the different ethnicities of the Indian population. The present research will be helpful in pedodontic, orthodontic, and forensic investigations for accurate and reliable dental age estimation in different parts of Indian population. Chaudhry K, Talwar M, Vanga NRV, et al. A Comparative Evaluation of Three Different Dental Age Estimation Methods in India: A Test of Ethnic Variability. Int J Clin Pediatr Dent 2020;13(1):16-20.


Affective commitment foci as parallel mediators of the relationship between workplace romance and employee job performance: a cross-cultural comparison of the People's Republic of China and Pakistan.
The purpose of the present study is twofold. First, we examined the relationship between workplace romance and employee job performance and tested the role of affective commitment foci - namely, affective coworker commitment, affective supervisor commitment, and affective organizational commitment - as parallel mediators in the relationship between workplace romance and employee job performance. Second, we tested the moderating role of culture on the interrelationships between workplace romance, affective commitment foci, and employee job performance. A two-wave (3-month interval) survey data were collected from 312 paramedics - 162 and 150 from Pakistani and Chinese public-sector hospitals, respectively. The first and second waves of data collection took place in January and May 2017, respectively. Structural equation modeling (SEM), bootstrapping technique, and multigroup analysis were used to test the interrelationships between workplace romance, affective commitment foci, and employee job performance and to examine the cross-cultural differences in these interrelations. Results obtained using SEM show that workplace romance positively influences employee performance. Importantly, the study revealed that the three foci of affective commitment - namely, coworker affective commitment, supervisor affective commitment, and organizational affective commitment - as parallel mediators fully mediate the relationship between workplace romance and employee performance. Moreover, national culture moderates the indirect relationship between workplace romance and employee job performance, where workplace romance is stronger for the Chinese data sample. It is concluded that workplace romance is positively related to employee job performance and that affective commitment foci fully mediate the positive relationship between workplace romance and employee job performance. Moreover, culture moderates the indirect relationship between workplace romance and employee job performance. The study contributes to theory and practice by studying an essential but largely ignored aspect of the workplace and portraying it as a constructive influence on employee job performance and their affective commitment to coworkers, supervisor, and organization.


Photosensitive Graphene P-N Junction Transistors and Ternary Inverters.
We investigate the electric transport in a graphene-organic dye hybrid and the formation of p-n junctions. In the conventional approach, graphene p-n junctions are produced by using multiple electrostatic gates or local chemical doping, which produce different types of carriers in graphene. Instead of using multiple gates or typical chemical doping, a different approach to fabricate p-n junctions is proposed. The approach is based on optical gating of photosensitive dye molecules; this method can produce a well-defined sharp junction. The potential difference in the proposed p-n junction can be controlled by varying the optical power of incident light. A theoretical calculation based on the effective medium theory is performed to thoroughly explain the experimental data. The characteristic transport behavior of the photosensitive graphene p-n junction opens new possibilities for graphene-based devices, and we use the results to fabricate ternary inverters. Our strategy of building a simple hybrid p-n junction can further offer many opportunities in the near future of tuning it for other optoelectronic functionalities.


Anti-neuroinflammatory Effect of Short-Chain Fatty Acid Acetate against Alzheimer's Disease via Upregulating GPR41 and Inhibiting ERK/JNK/NF-κB.
Alzheimer's disease (AD) is a high-incidence neurodegenerative disease in the elderly. Acetate (Ace) is a short-chain fatty acid (SCFA) with neuroprotective activity. The purpose of this study was to investigate the effects and its possible mechanisms of SCFA Ace on AD. A male APP/PS1 transgenic mouse was given intragastric administration Ace for 4 weeks. Cognitive function and microglia activation in mice were assessed. Furthermore, Ace pretreated amyloid-β (Aβ)-induced BV2 microglia, and the levels of CD11b, COX-2, and G-protein-coupled receptor 41 (GPR41) and phosphorylation of ERK, JNK, and NF-κB p65 were determined. Our results revealed that Ace significantly attenuated the cognitive impairment and decreased the CD11b level in the APP/PS1 mice. Moreover, Ace inhibited the phosphorylation of NF-κB p65, ERK, and JNK and decreased the levels of COX-2 and interleukin 1β in the Aβ-stimulated BV2 microglia. Finally, Ace increased the GPR41 level in the Aβ-stimulated BV2 cells. The finding indicated that Ace exerted antineuroinflammatory effects via the upregulation of GPR41 and suppression of the ERK/JNK/NF-κB pathway, which might provide an alternative therapy strategy of AD.


Therapy of cancer metastasis by activation of the inducible nitric oxide synthase.
The process of cancer metastasis consists of multiple sequential and highly selective steps. The vast majority of tumor cells that enter the circulation die rapidly; only a few survive to produce metastases. This survival is not random. Metastases are clonal in origin and are produced by specialized subpopulations of cells that preexist in a heterogeneous primary tumor. Experimental studies concluded that metastatic cells survive in the circulation whereas nonmetastatic cells do not. In part, this difference is due to an inverse correlation between expression of endogenous inducible nitric oxide synthase (iNOS) and production of nitric oxide (NO) and metastatic potential. Direct evidence for the role of iNOS in metastasis has been provided by our data on transfection of highly metastatic murine K-1735 clone 4 (C4.P) cells which express low levels of iNOS, with a functional iNOS (C4.L8), inactive mutated iNOS (C4.S2), or neomycin resistance (C4.Neo) genes in medium containing 3 mM of the specific iNOS inhibitor NG-L-methyl arginine (NMA). C4.P, C4.Neo, and C4.S2 cells were highly metastatic, whereas C4.L8 cells were not. Moreover, C4.L8 cells produced slow-growing subcutaneous tumors in nude mice, whereas the other 3 cell lines produced fast-growing tumors. In vitro studies indicated that the expression of iNOS in C4.L8.5 cells was associated with either cytostasis or cytolysis via apoptosis, depending upon NO output. The tumor cells producing high levels of NO underwent autocytolysis and produced cytolysis of bystander cells under both in vitro and in vivo conditions. Multiple i.v. injections of liposomes containing a synthetic lipopeptide upregulated iNOS expression in murine M5076 reticulum sarcoma cells growing as hepatic metastases. The induction of iNOS was associated with the complete regression of the lesions. Transfection of interferon-beta suppressed tumor formation and eradicated metastases, which was apparently linked to iNOS expression and NO production in host cells such as macrophage. Besides mediating cell death, NO produced tumor suppression by regulating expression of genes related to metastasis, e.g., survival, invasion, and angiogenesis. Suppression of metastasis can be achieved through use of immunomodulators that induce iNOS expression in tumor lesions or by the direct delivery of the iNOS gene to tumor cells or host cells through liposome and/or viral vectors.


Efferent nerve fibers associated with the outermost supporting cells of the organ of Corti in the guinea pig.
In whold-mount preparations of the organ of Corti nerve fibers are sometimes seen peripheral to the third-row outer hair cells where they appear to wander among the Hensen cells. These fibers were studied in the guinea pig by both light and electron microscopy. In the upper second, third and fourth cochlear turns nerve fibers were seen between and on the peripheral side of the third-row Deiters cells as well as in the floor of the outer tunnel space. They were not found in the intercellular spaces between the Hensen cells. These nerve fibers are continuous with the spiral efferent fibers beneath the outer hair cells. Also their ultrastructural and histochemical characteristics indicate that they are efferent neural elements. This identification was confirmed by the finding that they degenerate following interruption of the olivo-cochlear bundle in the brain stem.


Correlation Between Choroidal Thickness and Ciliary Artery Blood Flow Velocity in Normal Subjects.
To study the correlation between the choroidal thickness (CT) measured by spectral-domain optical coherence tomography (SD-OCT) and retrobulbar blood flow measured by color Doppler flowmetry (CD) in normal subjects. Healthy subjects underwent enhanced-depth imaging SD-OCT and CD using a linear 6 MHz to 18 MHz transducer. The maximal peak systolic velocity and resistance index (RI) were obtained for the ophthalmic artery (OA), short posterior ciliary artery (SPCA), and central retinal artery (CRA) and correlated with the subfoveal CT measured by SD-OCT. Twenty-seven eyes of 27 healthy patients were enrolled (mean age: 40.6 ± 12.4 years; range: 27-68 years). An inverse proportional relationship (P = .0496) was identified between the RI of the SPCA (mean, 0.6117 ± 0.07911) and the subfoveal CT (319.9 µm ± 83.79 µm) but not between the RI and the OA (mean: 0.7019 µm ± 0.07317 µm) or the CRA (mean: 0.68843 µm ± 0.08994 µm). The results of this study suggested there is an inverse proportional relationship between the RI of the SPCA and the subfoveal CT. The data also suggested a correlation between a decrease in the CT and increased RI in the retrobulbar arteries. Therefore, lower choroidal blood flow may explain the thinner CT in normal subjects.


Novel Hybrid Input Part Using Riboswitch and Transcriptional Repressor for Signal Inverting Amplifier.
Genetic circuits are composed of input, logic, and output parts. Construction of complex circuits for practical applications requires numerous tunable genetic parts. However, the limited diversity and complicated tuning methods used for the input parts hinders the scalability of genetic circuits. Therefore, a new type of input part is required that responds to diverse signals and enables easy tuning. Here, we developed RNA-protein hybrid input parts that combine a riboswitch and orthogonal transcriptional repressors. The hybrid inputs successfully regulated the transcription of an output in response to the input signal detected by the riboswitch and resulted in signal inversion because of the expression of transcriptional repressors. Dose-response parameters including fold-change and half-maximal effective concentration were easily modulated and amplified simply by changing the promoter strength. Furthermore, the hybrid input detected both exogenous and endogenous signals, indicating potential applications in metabolite sensing. This hybrid input part could be highly extensible considering the rich variety of components.


The growth inhibitory and apoptotic effects of umbelliprenin in a mouse model of systemic candidiasis.
Umbelliprenin has shown promising biological activities, including immunoregulatory, anti-inflammatory, and anti-cancer effects. The present study investigated the growth inhibitory and apoptotic effects of umbelliprenin against Candida albicans in a BALB/c mice model of disseminated candidiasis. First, an antimicrobial assay via microdilution sensitivity test was performed. Then, twenty-five 6-week-old female BALB/c mice (20 ± 12 g) were divided into five groups of five mice, including one control group (no umbelliprenin treatment) and four experimental groups: C. albicans-infected mice treated with umbelliprenin at the doses of 5, 10, 20, and 40 mg kg -1. The brain, lung, kidney, spleen, and liver tissues were examined for fungal infection and histological lesions, and TUNEL staining was performed to assess apoptosis. The β-1, 3-glucan synthase assay was used to evaluate enzymatic activity, and gene expression analysis was also performed to investigate the transcriptional changes of ERG11, CDR1, ALS1, and HWP1 genes. The MIC of umbelliprenin was 1.5 mg mL-1. Our results showed that at the 40 mg kg -1 dose, umbelliprenin was able to eradicate fungal infection in BALB/c mice. The percentage of apoptotic cells in umbelliprenin-treated groups increased in a concentration-dependent manner. Umbelliprenin (40 mg kg -1) also inhibited the expression of β-1, 3-glucan synthase, and the genes involved in antifungal resistance (CDR1 and ERG11), as well as the expression of the genes encoding adhesins (ALS1 and HWP1). Our results showed that umbelliprenin could promote antifungal effects, partly via inducing apoptosis.


Trmt112 gene expression in mouse embryonic development.
Mouse Trmt112, the homologous gene of yeast Trm112 (tRNA methyltransferase 11-2), was initially cloned from RIKEN with uncertain function. The yeast TRM112 is now known to play important roles in RNA methylation. Here, we studied the expression of Trmt112 by in situ hybridization and quantitative real-time RT-PCR (QRT-PCR). A higher expression level of Trmt112 was observed in the brain and nervous system by whole mount in situ hybridization from embryonic day 10.5 (E10.5) to E11.5. At later developmental stages E13.5 and E16.5, abundant expression was prominently found in various organs and tissues including developing brain, nervous system, thymus, lung, liver, intestine, kidney, and cartilage. Furthermore, Trmt112 was persistently expressed from E9.5 to E18.5 on whole embryos and highly expressed in multiple organs at E12.5, E15.5 and E18.5 by QRT-PCR. These results showed that Trmt112 gene was highly and ubiquitously expressed during mouse embryonic development, implying that it might be involved in the morphogenesis of diverse organs and tissues and numerous physiological functions.


Spanish adaptation and validation of the supportive & palliative care indicators tool - SPICT-ESTM.
OBJECTIVE To culturally adapt and validate the SPICTTM to Spanish, which is a brief and simple tool to support a better identification of chronic patients who have palliative care needs. METHODS For this study, we designed a multicenter and national project between the centers of Galicia, Balearic Islands, and Andalusia. For the process of translation and cross-cultural adaptation of the SPICTTM to Spanish, we followed the steps proposed by Beaton et al. with successive translations and subsequent consensus of experts using the debriefing methodology. After the content validation was completed, the psychometric properties were validated. A prospective longitudinal study was designed with 188 patients from Galicia, the Balearic Islands, and Andalusia. The internal consistency and reliability of the test and retest was analyzed for 10 days by the same researcher. RESULTS For more than 90% of the participants of the SPICT-ESTM, it seems simple to be filled out, and they consider it written in an understandable language. The average time to apply the questionnaire without prior knowledge was 4 minutes and 45 seconds. To evaluate the internal consistency of the instrument, we used the Kuder-Richardson formula 20. Internal consistency is 0.71. The agreement index of the Kappa test is between 0.983 and 0.797 for the different items. CONCLUSIONS In this study, we demonstrate the equivalence of content with the original. In addition, the validation of the psychometric properties establishes that the SPICT-ESTM maintains adequate reliability and stability. If we add the satisfaction shown by the professionals and the ease of use, the SPICT-ESTM is an adequate tool for the identification of palliative patients with chronic diseases and palliative care needs.


Statistical correlation between cell adhesion and proliferation on biocompatible metallic materials.
Our ambition for several years is to appreciate and quantify the long-term adhesion of cells on materials at times where the interface between cells and substrate becomes more complex, more closed to the cell/matrix/substrate interface existing in vivo. With this objective, we quantified the long-term adhesion and proliferation of human osteoblasts cultured from 24 h to 21 days on pure titanium, titanium alloy, and stainless-steel substrates presenting six different surface morphologies and two different roughness amplitude. Hence, we did proceed to the statistical correlation of cell adhesion and cell proliferation on 30 different substrates. Additionally, we described surface topography not only by the roughness amplitude but also by the roughness morphology using new specific parameters. By multiple analysis of variance, we demonstrated that nor material composition nor surface roughness amplitude did influence cell proliferation, whereas a very significant influence of the process used to produce the surface was observed meaning that the main influent factor on cell proliferation was the surface morphology. The long-term adhesion and proliferation capacity of cells were positively correlated on 23 types of substrates on 30, this positive correlation being statistically asserted on 13 types of substrates on 23. This study is the first demonstration of the existence of a statistical correlation between long-term adhesion and proliferation capacity of human bone cells on substrates with various chemical composition, surface chemistry, and surface topography.


Formulation, antileukemia mechanism, pharmacokinetics, and biodistribution of a novel liposomal emodin.
Emodin is a multifunctional Chinese traditional medicine with poor water solubility. D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) is a pegylated vitamin E derivate. In this study, a novel liposomal-emodin-conjugating TPGS was formulated and compared with methoxypolyethyleneglycol 2000-derivatized distearoyl-phosphatidylethanolamine (mPEG2000-DSPE) liposomal emodin. TPGS improved the encapsulation efficiency and stability of emodin egg phosphatidylcholine/cholesterol liposomes. A high encapsulation efficiency of 95.2% ± 3.0%, particle size of 121.1 ± 44.9 nm, spherical ultrastructure, and sustained in vitro release of TPGS liposomal emodin were observed; these were similar to mPEG2000-DSPE liposomes. Only the zeta potential of -13.1 ± 2.7 mV was significantly different to that for mPEG2000-DSPE liposomes. Compared to mPEG2000-DSPE liposomes, TPGS liposomes improved the cytotoxicity of emodin on leukemia cells by regulating the protein levels of myeloid cell leukemia 1 (Mcl-1), B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein, which was further enhanced by transferrin. TPGS liposomes prolonged the circulation time of emodin in the blood, with the area under the concentration-time curve (AUC) 1.7 times larger than for free emodin and 0.91 times larger than for mPEG2000-DSPE liposomes. In addition, TPGS liposomes showed higher AUC for emodin in the lung and kidney than for mPEG2000-DSPE liposomes, and both liposomes elevated the amount of emodin in the heart. Overall, TPGS is a pegylated agent that could potentially be used to compose a stable liposomal emodin with enhanced therapeutics.


[Evolution of the Origin of Herba Schizonepetae].
Herba Schizonepetae was firstly recorded in the Sheng nong ben caojing (Shennong's Materia Medica) with the title Jiasu. It could be sure that the original plant of Jiasu is Ocimumbasilicum L. ofLabiatae based on the record of Jiasu's name, morphology, edible property before the Song Dynasty. Beginning from the Ben cao tu jing (Illustrated Classic of Materia Medica) in the Song Dynasty, the source of this drug evolved as SchizonepetatenuisfoliaBriq. ofLabiatae, and it has been in use until now. Hence, the sources of Jiasu should be both O. basilicum L. and the co-existence of S. tenuisfolia Briq in the Qing Dynasty. It is claimed that the hometowns of those herb writers who considered the source ofOcimumbasilicum L. to be the producing areas of cultivation of the edible Ocimumbasilicum L. It was found that the source of Jiasu recorded in the Sheng nong ben cao jing should be O. basilicum L. , hence, it is suggested the title Jiasu should be recorded for the source of O. basilicum L, and the original plant of Herba Schizonepetae was Schizonepetatenuisfolia Briq. of Labiatae, and this medicine should be separately recorded. In fact, Jiasu and Herba Schizonepetae were two different kinds of medicines.


[MR stress perfusion for the detection of flow-limiting stenoses in symptomatic patients with known coronary artery disease and history of stent implantation].
The aim of the present study was to determine the correlation of myocardial perfusion MR imaging (MPMRI) and coronary angiography for the detection of flow-limiting stenosis in symptomatic patients with known coronary artery disease and a history of intervention. MPMRI was performed in 51 symptomatic patients (44 male, 64.7 +/- 9.5 years) with known coronary artery disease and a history of stent implantation (between 5 years and 2 weeks prior to MRI). Malperfused myocardial regions were correlated with findings of coronary angiography. A stenosis of > 70% was regarded as hemodynamically significant. In MPMRI 37 patients (73%) showed a stress induced perfusion deficit. In 35 of these patients coronary angiography revealed a stenosis of > 70 %. A total of 38 patients (75%) showed stenoses of > 70%. MPMRI yielded a sensitivity of 92% with a specificity of 85 %. The positive predictive value was 95 % and negative predictive value was 79%. The assignment of malperfused segments to coronary artery territories was carried out according to the standardized myocardial model of the American Heart Association (sensitivity/specificity was 59/85% for RCA, 79/81% for LAD and 54/68 % for LCX). MPMRI is a suitable non-invasive method for detecting flow-limiting coronary artery stenoses in patients with a history of stent implantation.


Genitourinary skin and soft tissue infections: a prospective contemporary evaluation of causative pathogens.
Prior literature identified anaerobes as the predominant causative organisms in genitourinary skin and soft tissue infections. However, the increasing prevalence of community acquired, methicillin resistant Staphylococcus aureus infection has brought about the growing need to reevaluate these infections and their causative organisms. We examined the causative organisms and risk factors in suppurative superficial genitourinary infections, and evaluated the growing role of community acquired, methicillin resistant S. aureus. We performed a single institution, prospective assessment of 60 adults who presented between August 2008 and July 2010 with genitourinary skin and soft tissue infections requiring incision and drainage. Patients completed a standardized, nonvalidated questionnaire before undergoing débridement of the site. A total of 60 patient specimens were obtained and 92 bacterial pathogens were isolated. Of these pathogens 55% were aerobes. S. aureus was the most predominant cultured organism, representing 25% of all cultured organisms, and 65% of these isolates were community acquired, methicillin resistant S. aureus. The most commonly associated comorbidities included diabetes mellitus, tobacco smoking and heavy alcohol use. HIV/AIDS showed a statistically significant association with community acquired, methicillin resistant S. aureus infection (OR 11.00, 95% CI 1.05-115.51, p = 0.0456), as did the cumulative number of community acquired, methicillin resistant S. aureus risk factors (OR 2.64, 95% CI 1.31-5.33, p = 0.007). Aerobic organisms now account for most of these infections and community acquired, methicillin resistant S. aureus has emerged as a significant causative organism. Populations that may be at increased risk for these infections include patients with diabetes mellitus, heavy alcohol users and tobacco smokers. In patients with HIV/AIDS or multiple community acquired, methicillin resistant S. aureus risk factors the latter organism is more likely to be the causative organism.


Serotype tracking of Salmonella through integrated broiler chicken operations.
The widespread presence of Salmonella in all phases of broiler chicken production and processing is well documented. However, little information is available to indicate the identity and movement of specific serotypes of Salmonella through the different phases of an integrated operation. In this study, samples were collected from the breeder farm, from the hatchery, from the previous grow-out flock, from the flock during grow-out, and from carcasses after processing. Salmonella were recovered from 6, 98, 24, 60, and 7% of the samples, respectively, in the first trial and from 7, 98, 26, 22, and 36% of the samples, respectively, in the second trial. Seven different serotypes were identified in the first trial, and 12 different serotypes were identified in the second trial. For both trials there was poor correlation between the serotypes found in the breeder farms and those found in the hatchery. This finding and the fact that similar serotypes were found in the hatchery in both trials suggests that there was an endemic population of Salmonella in the hatchery. An association between the serotypes found in the hatchery and those found on the final processed carcasses was observed in both trials. This study confirms that a successful intervention program for broiler production operations must be multifaceted, with one component being disinfection in the hatchery.


Expanding the conservation genomics toolbox: Incorporating structural variants to enhance genomic studies for species of conservation concern.
Structural variants (SVs) are large rearrangements (>50 bp) within the genome that impact gene function and the content and structure of chromosomes. As a result, SVs are a significant source of functional genomic variation, that is, variation at genomic regions underpinning phenotype differences, that can have large effects on individual and population fitness. While there are increasing opportunities to investigate functional genomic variation in threatened species via single nucleotide polymorphism (SNP) data sets, SVs remain understudied despite their potential influence on fitness traits of conservation interest. In this future-focused Opinion, we contend that characterizing SVs offers the conservation genomics community an exciting opportunity to complement SNP-based approaches to enhance species recovery. We also leverage the existing literature-predominantly in human health, agriculture and ecoevolutionary biology-to identify approaches for readily characterizing SVs and consider how integrating these into the conservation genomics toolbox may transform the way we manage some of the world's most threatened species.


Development of a Real-Time RT-PCR for the Universal Detection of LChV1 and Study of the Seasonal Fluctuation of the Viral Titer in Sweet Cherry Cultivars.
Little cherry virus 1 (LChV1) is a sweet cherry pathogen which has lately been reported in other Prunus spp. LChV1 variability makes reliable detection a challenging undertaking. The objective of this work was to develop a rapid, sensitive, and reliable one-tube, real-time reverse-transcription polymerase chain reaction (RT-PCR) for the detection and quantification of LChV1. Primers and a TaqMan probe were designed, using conserved regions of the capsid protein gene. Detection range was evaluated using several divergent viral isolates. The amplification efficiency of the method was estimated at 96.7%, whereas the detection limit was about 100 RNA copies. The protocol was applied in the study of virus fluctuation within leaves and phloem tissue throughout the year and the best periods to test and plant tissues to sample were determined. Comparative analysis of this method with a previously published nested RT-PCR revealed the higher analytical and diagnostic sensitivity of the new test, making it a reliable tool that can be used in routine testing and certification programs.


Transcriptome analysis of genes related to gonad differentiation and development in Muscovy ducks.
Sex-related genes play a crucial role in gonadal differentiation into testes or ovaries. However, the genetic control of gonadal differentiation in Muscovy ducks remains unknown. Therefore, the objective of our study was to screen new candidate genes associated with ovarian and testicular development. In this study, 24 males before gonadal differentiation (MB), 24 females before gonadal differentiation (FB), 24 males after gonadal differentiation (MA) and 24 females after gonadal differentiation (FA) were selected from Putian Muscovy ducks, forming 4 groups. RNA-Seq revealed 101.76 Gb of clean reads and 2800 differentially expressed genes (DEGs), including 46 in MB vs FB, 609 in MA vs FA, 1027 in FA vs FB, and 1118 in MA vs MB. A total of 146 signalling pathways were enriched by KEGG analysis, among which 20, 108, 108 and 116 signalling pathways were obtained in MB vs FB, MA vs MB, MA vs FA and FA vs FB, respectively. In further GO and KEGG analyses, a total of 21 candidate genes related to gonad differentiation and development in Muscovy ducks were screened. Among these, 9 genes were involved in the differentiation and development of the testes, and 12 genes were involved in the differentiation and development of the ovaries. In addition, RNA-Seq data revealed 2744 novel genes. RNA-Seq data revealed 21 genes related to gonadal differentiation and development in Muscovy ducks. We further identified 12 genes, namely, WNT5B, HTRA3, RSPO3, BMP3, HNRNPK, NIPBL, CREB3L4, DKK3, UBE2R2, UBPL3KCMF1, ANXA2, and OSR1, involved in the differentiation and development of ovaries. Moreover, 9 genes, namely, TTN, ATP5A1, DMRT1, DMRT3, AMH, MAP3K1, PIK3R1, AGT and ADAMTSL1, were related to the differentiation and development of testes. Moreover, after gonadal differentiation, DMRT3, AMH, PIK3R1, ADAMTSL1, AGT and TTN were specifically highly expressed in males. WNT5B, ANXA2 and OSR1 were specifically highly expressed in females. These results provide valuable information for studies on the sex control of Muscovy ducks and reveal novel candidate genes for the differentiation and development of testes and ovaries.


Multicenter evaluation of an enzymatic method for glycated albumin.
The use of glycated albumin (GA) has been proposed as an additional glycemic control marker particularly useful in intermediate-term monitoring and in situation when HbA1c test is not reliable. We have performed the first multicenter evaluation of the analytical performance of the enzymatic method quantILab Glycated Albumin assay implemented on the most widely used clinical chemistry analyzers (i.e. Abbott Architect C8000, Beckman Coulter AU 480 and 680, Roche Cobas C6000, Siemens ADVIA 2400 and 2400 XPT). The repeatability of the GA measurement (expressed as CV, %) implemented in the participating centers ranged between 0.9% and 1.2%. The within-laboratory CVs ranged between 1.2% and 1.6%. A good alignment between laboratories was found, with correlation coefficients from 0.996 to 0.998. Linearity was confirmed in the range from 7.6 to 84.7%. The new enzymatic method for glycated albumin evaluated by our investigation is suitable for clinical use.


Chromosomal location by in situ hybridization of the human Sau3A family of DNA repeats.
The Sau3A family is a human, clustered, highly repetitive, GC-rich DNA family. In situ hybridization studies with a plasmid carrying a Sau3A monomer as a probe have shown that Sau3A sequences are preferentially concentrated in the heterochromatic regions of human acrocentric chromosomes (D and G groups, both in pericentromeric regions and in cytological satellites) and in pericentromeric heterochromatin of chromosome 1. The same chromosomal locations were observed by using as probes two recombinant phages which carry Sau3A-positive genomic sectors. The two sectors differ for the relative proportions of monomer and multiples of Sau3A repeats, which show different extents of homology to the cloned monomer, and for the presence, in one of the two, of a small amount of an unrelated repeat (alphoid DNA). The similarity of the results obtained with the three probes suggests that heterogeneous Sau3A repeats share the same chromosomal localizations and that the two analyzed genomic sectors may not contain significant amounts of repetitive DNAs other than the Sau3A family. A comparison between the chromosomal locations of Sau3A and EcoRI families of repeats has confirmed that each family is characterized by specific chromosomal locations and that single heterochromatic regions may contain both.


Decreased Stroke Volume and Venous Return in School Children with Postural Tachycardia Syndrome.
In postural tachycardia syndrome (POTS), a subtype of orthostatic intolerance, the changes in hemodynamics due to postural changes are poorly understood. We speculated that inappropriate venous return, which may occur in the upright position in patients with school-aged POTS, could be detected by echocardiography. Our prospective study was conducted with 100 POTS patients (45 boys and 55 girls), aged 13.1 ± 1.5 years and 52 age- and sex-matched healthy subjects (control). Echocardiography was performed in the supine and sitting positions. Cardiac parameters [stroke volume index, cardiac index, heart rate, and the maximum inferior vena cava diameter (max IVC)] were evaluated in addition to pulse pressure. Unlike the control subjects, POTS patients demonstrated decreased stroke volume index (P = 0.02) and max IVC (P < 0.01) irrespective of posture. The rates of max IVC change did not differ between control and POTS groups. The enrolled POTS patients were divided into two subgroups [dilatation (n = 57) and contraction (n = 43)] based on whether the change rate of max IVC was less than zero or not. The contraction group showed a significantly higher heart rate than the dilatation group with respect to posture (P = 0.03), indicating the poor response of peripheral vessels in the lower limbs only in the contraction group. In conclusion, echocardiographic assessment detected decreased stroke volume and venous return in POTS. The changes in max IVC in response to postural changes may indicate an underlying pathophysiology in POTS.


Cutaneous adverse effects associated with the tyrosine-kinase inhibitor cabozantinib.
Cabozantinib S-malate is a vascular endothelial growth factor receptor 2, c-MET, and RET multitargeted tyrosine kinase inhibitor that has antiangiogenic and antitumorigenic properties with potential efficacy for the treatment of several cancers. Cutaneous reactions, one of the most frequently observed adverse effects associated with tyrosine kinase inhibitors, can significantly affect patients' quality of life and drug adherence and represent a major therapeutic challenge to maximizing the efficacy of targeted cancer therapy. To describe the frequency and spectrum of skin reactions in patients with urothelial carcinoma receiving cabozantinib as monotherapy. A single-institution study at the Clinical Research Center at the National Institutes of Health included 41 consecutive adults with metastatic, progressive urothelial carcinoma enrolled in a National Cancer Institute open-label, nonrandomized, phase 2 clinical trial. Patients receiving cabozantinib were evaluated for the development of skin reactions at each treatment visit from October 2012 to June 2014 by the primary oncology team and referred for dermatologic evaluation as appropriate. A detailed history, full-body physical examination, and clinical photographs of cutaneous lesions were obtained. Of 41 consecutive patients who received cabozantinib, 30 (73%) developed 1 or more cutaneous toxic effects. Adverse events included hand-foot skin reaction (22 [54%]), generalized pigment dilution and/or hair depigmentation (18 [44%]), xerosis (8 [20%]), scrotal erythema/ulceration (6 [15%]), and nail splinter hemorrhages (5 [12%]). Eighteen patients (44%) had 2 or more cutaneous adverse events. Reactions developed in 17 of 30 patients (57%) during the first month of cabozantinib treatment and in 24 of 30 (80%) by the second month. Of patients with skin toxic effects, dose reduction was required for symptom management in 9 of 30 patients (30%), and treatment discontinuation was required in 4 of 30 (13%). Cabozantinib monotherapy is associated with 1 or more cutaneous adverse events in most patients. Early detection and prompt treatment may increase patients' adherence to tyrosine kinase inhibitor therapy. clinicaltrials.gov Identifier: NCT01688999.


Anaesthetic management of Osler-Weber-Rendu syndrome with coexisting congenital methaemoglobinaemia.
A 9-year-old cyanosed child suffering from Osler-Weber-Rendu syndrome with bilateral pulmonary arteriovenous malformations (PAVMs) was posted for cerebral angiography under general anaesthesia. Careful preanaesthetic evaluation led to the diagnosis of coexisting congenital methaemoglobinaemia. There is no previous report of Osler-Weber-Rendu syndrome coexisting with congenital methaemoglobinaemia. This report emphasizes that a second contributory cause of cyanosis must be suspected and meticulously looked for if the symptomatology in a patient cannot be explained by a single established diagnosis. Positive-pressure ventilation was associated with reduction in arterial oxygenation despite an increasing inspired oxygen concentration, which returned to preanaesthetic levels only after extubation and resumption of spontaneous respiration.


Gout in a 15-year-old boy with juvenile idiopathic arthritis: a case study.
Joint pain is a common complaint in pediatrics and is most often attributed to overuse or injury. In the face of persistent, severe, or recurrent symptoms, the differential typically expands to include bony or structural causes versus rheumatologic conditions. Rarely, a child has two distinct causes for joint pain. In this case, an obese 15-year-old male was diagnosed with gout, a disease common in adults but virtually ignored in the field of pediatrics. The presence of juvenile idiopathic arthritis (JIA) complicated and delayed the consideration of this second diagnosis. Indeed, the absence of gout from this patient's differential diagnosis resulted in a greater than two-year delay in receiving treatment. The patients' BMI was 47.4, and he was also mis-diagnosed with osteochondritis dissecans and underwent medical treatment for JIA, assorted imaging studies, and multiple surgical procedures before the key history of increased pain with red meat ingestion, noticed by the patient, and a subsequent elevated uric acid confirmed his ultimate diagnosis. With the increased prevalence of obesity in the adolescent population, the diagnosis of gout should be an important consideration in the differential diagnosis for an arthritic joint in an overweight patient, regardless of age.


Erythrocyte consumption of nitric oxide in presence and absence of plasma-based hemoglobin.
Experimental measurements have suggested a consumption rate of nitric oxide (NO) by red blood cells (RBCs) that is orders of magnitude smaller than that of an equivalent concentration of free hemoglobin in solution. This difference has been attributed to external diffusion limitations in the transport of NO from the plasma to the surface of the RBC or to resistance in the transport through the erythrocytic membrane. A detailed mathematical model is developed to quantify the resistance to NO transport around a single RBC and to predict the consumption rate in the presence and absence of extracellular hemoglobin. We provide a description for the NO consumption rate as a function of hematocrit, RBC radius, membrane permeability, and extracellular hemoglobin concentration. We predict a first-order rate constant for NO consumption in blood between 7.5 x 10(2) and 6.5 x 10(3) s(-1) at a hematocrit of 45% for membrane permeability values between 0.1 and 40 cm/s. Our results suggest that the difference in NO uptake by RBCs and free hemoglobin is smaller than previously reported and it is hematocrit dependent.


[Application of BMD models in quantitative evaluation of carcinogenic risk].
The characteristics of the relationship between the exposure level and the incidence of harmful health effects is a general objective of assessing health risk related to chemical exposure. A real dose-response relationship, particularly for low doses, is usually unknown thus it can only be deduced on the basis of biological and statistical considerations. Low dose risk estimation requires extrapolation beyond the range of data observed. Nowadays, quantitative risk assessment encounters certain duality as linear models are mostly used in evaluation of environmental exposure, and nonlinear models are most frequently applied in occupational exposure. Bearing in mind that the assumption on the dose-response linear relationship is an apparent simplification built on our lack of knowledge of carcinogenic mechanisms, it seems that the proposal of the US Environmental Protection Agency (US EPA) to use benchmark dose methods (BMD) for exposure effects manifested by neoplasms, is the compromise between a conservative approach of the EPA towards risk modelling resulting from the limited knowledge of these mechanisms and lack of criteria for selection of nonlinear models. In the case of carcinogenic risk assessment, this solution involves the identification of so called 'cut off point' by applying relevant statistical models. The cut off point indicates the exposure level that contributes to the increase in risk by 10%, 5% or 1%. Another possibility is to use interspecies extrapolation methods for the cut of point modification, and then draw a line between the cut off point and the beginning of the system of co-ordinates. Since it is not feasible to apply a complete BMD methods for certain chemicals (e.g. bezo(a)pirene), not because of chemical properties, but due to insufficient experimental experience, it is proposed to use the method of sticking together a straight line and a curve in relation to a two-grade curve and not to its confidence limitation.


Irreversible photobleaching of bacteriorhodopsin in a high-temperature intermediate state.
The photo-intermediate state of bacteriorhodopsin is a metastable state that spontaneously transforms to the ground state over the energy barrier of a local minimum. As the recovery of the photocycle to the ground state and irreversible photobleaching to the denatured state may occur from the same local energy minimum, depending on the temperature, the structural stability of bacteriorhodopsin under illumination at high temperature was measured in order to study the intra- and inter-molecular interactions that contribute to the recovery of the ground state. Visible CD spectra of bacteriorhodopsin began to change at 60 degrees C from a bilobed to positive type in accordance with an appearance of an absorption peak at 470 nm. Irreversible photobleaching, the light-induced denaturation, also started to occur at 60 degrees C, suggesting some correlation between irreversible photobleaching and the structural change to the high-temperature intermediate state. However, bacteriorhodopsin in the dark was stable up to 70 degrees C, suggesting that there is some additional factor that lends structural stability to bacteriorhodopsin in the dark. The contribution of protein-protein interactions to stability is discussed on the basis of the difference in the denaturation behaviors between light and dark conditions.


Amiloride derivatives are effective blockers of insect odorant receptors.
Heteromeric insect odorant receptors (ORs) form ligand-activated nonselective cation channels in recombinant expression systems. We performed a pharmacological characterization of Drosophila melanogaster and Bombyx mori ORs expressed in the Xenopus laevis oocyte expression system and characterized them using the 2-electrode voltage clamp. We identified amiloride derivatives as high-affinity blockers, which inhibit the ion current through the channel in a low micromolar range. For the heteromeric Drosophila Or47a + DmelOrco receptor, the potency sequence (IC(50)) is HMA [5-(N,N-hexamethylene)amiloride] (3.9 µM), MIA [5-(N-methyl-N-isobutyl)amiloride] (11.0 µM), and DMA [5-(N,N-dimethyl)amiloride] (113.3 µM). Amiloride itself is nearly ineffective. Other tested insect ORs (Drosophila Or49b + DmelOrco, B. mori BmorOr1 + BmorOrco) were blocked in a similar fashion suggesting that the amiloride derivatives were potential general blockers of all receptor combinations. Our results suggest that pyrazine derivatives of amiloride are useful probes to study the mechanism of chemosensory transduction in insects in more detail.


Angiographic diagnosis of inflammatory bowel disease in patients presenting with gastrointestinal bleeding.
The objective of our study was to review the final diagnosis and outcome in patients undergoing visceral angiography for gastrointestinal hemorrhage in whom a diagnosis of inflammatory bowel disease (IBD) had been suspected on the basis of angiographic findings. A retrospective review was performed of all visceral angiography referrals over a 10-year period. During that time, 522 visceral angiograms were obtained for the investigation of acute or chronic gastrointestinal bleeding. IBD was reported as a possible or probable diagnosis based on the angiographic findings in 43 patients (8.2%) (male-to-female ratio, 23:20; age range, 11-79 years; mean age, 48.6 years). Active IBD was confirmed in 25 (58%) of these 43 individuals (male-to-female ratio, 15:10; mean age, 46.5 years), representing 4.8% of all patients referred for the investigation of gastrointestinal bleeding. In 14 of these individuals, a diagnosis of IBD had not been suspected previously. A diagnosis other than IBD was found to be the cause of the angiographic findings in seven subjects. In the 32 patients in whom a cause for the angiographic findings was identified, IBD was the diagnosis in 25 (78%). In a group of patients referred for angiography to investigate acute or chronic gastrointestinal bleeding, IBD can be expected to be the cause in approximately 5%. Radiologists should be aware of the angiographic abnormalities seen in patients with IBD and be prepared to consider this diagnosis even if the results of other previous investigations have been reported as normal.


Phytochemical Composition and Antioxidant Activities of the Essential Oil and Extracts of Satureja subspicata Vis. Growing in Bosnia and Herzegovina.
The phytochemical composition and the antioxidant activities of the essential oil, as well as methanol and hot water extracts of endemic Satureja subspicata Vis. growing in Bosnia and Herzegovina (BiH), were described. β-Caryophyllene, cis-β-ocimene, and α-pinene, identified by GC/MS and GC-FID, were the dominant oil components. The major compound of both of extracts, identified by HPLC-DAD, was rosmarinic acid. The analyzed essential oil showed moderate antioxidant activity. In this first report on the extracts of S. subspicata growing in BiH, the obtained results showed a high content of rosmarinic acid, as well as considerable amount of total phenols and flavonoids. Compared to the hot water extract, the methanol extract exhibits higher antioxidant potential, measured by DPPH and FRAP assay (IC50 = 0.45 g/l and 1879.43 equiv. Fe2+ μm), while the hot water extract showed higher potential in inhibition of linoleic acid oxidation (51.7% and 61.5% for 1 and 10 g/l). A good antioxidant potential of the tested extracts indicates their potential use as antioxidants, particularly for lipid protection, and partly explains the justification of the use of this plant in traditional medicine of BiH.


Effects of central administration of the human Tau protein on the Bdnf, Trkb, p75, Mapt, Bax and Bcl-2 genes expression in the mouse brain.
Alzheimer's disease is the most common form of dementia, affecting millions of people worldwide. Despite intensive work by many researchers, the mechanisms underlying Alzheimer's disease development have not yet been elucidated. Recently, more studies have been directed to the investigation of the processes leading to the formation of neurofibrillary tangles consisting of hyperphosphorylated microtubule-associated Tau proteins. Pathological aggregation of this protein leads to the development of neurodegeneration associated with impaired neurogenesis and apoptosis. In the present study, the effects of central administration of aggregating human Tau protein on the expression of the Bdnf, Ntrk2, Ngfr, Mapt, Bax and Bcl-2 genes in the brain of C57Bl/6J mice were explored. It was found that five days after administration of the protein into the fourth lateral ventricle, significant changes occurred in the expression of the genes involved in apoptosis and neurogenesis regulation, e. g., a notable decrease in the mRNA level of the gene encoding the most important neurotrophic factor BDNF (brain-derived neurotrophic factor) was observed in the frontal cortex which could play an important role in neurodegeneration caused by pathological Tau protein aggregation. Central administration of the Tau protein did not affect the expression of the Ntrk2, Ngfr, Mapt, Bax and Bcl-2 genes in the frontal cortex and hippocampus. Concurrently, a significant decrease in the expression of the Mapt gene encoding endogenous mouse Tau protein was found in the cerebellum. However, no changes in the level or phosphorylation of the endogenous Tau protein were observed. Thus, central administration of aggregating human Tau protein decreases the expression of the Bdnf gene in the frontal cortex and the Mapt gene encoding endogenous mouse Tau protein in the cerebellum of C57Bl/6J mice.


[Species of Lutzomyia involved in an urban focus of visceral and cutaneous leishmaniasis].
A focus of leishmanias transmission was reported in the municipality of El Carmen de Bolívar in the province of Bolívar, Colombia, where both cutaneous and visceral leishmaniasis cases have occured. Vector identification, ecology and behavior of potential vector species have not been characterized in this region, however. Sand fly species of the genus Lutzomyia were identified, patterns of behavior were established, and their possible roles in leishmaniasis transmission were evaluated. CDC light traps were used in several different habitats; in addition, monthly collections were made with human bait as attraction inside houses as well as outdoor Shannon trap collections. The collection data were compared with independent variables including precipitation, temperature, relative humidity and wind velocity by means of a Pearson correlation matrix to estimate levels of association and to determine the influence of the climatic conditions on the density of adults of Lutzomyia evansi and L. gomezi in each of the habitats. Five species of Lutzomyia were captured: L. evansi, L. cayennensis cayennensis, L. gomezi, L. dubitansi, and L. walkeri. Lutzomyia evansi and L. gomezi presented a significant relationship in the abundance of adults indoors with respect to outdoor wind velocity. The Lutzomyia species captured showed an anthropophagic behavior with a constant activity between the 18:00 and 20:00 hrs. Lutzomyia evansi and L. gomezi are inversely proportional in relationship to wind velocity-when the wind diminishes, the activity of these species increases.


Specific IgA response, T-cell subtype and cytokine profile in experimental intravaginal trichomoniasis.
Trichomoniasis caused by Trichomonas vaginalis may lead to either a complete absence of symptoms or to severe inflammatory manifestations in infected women. Studies of the role of immune responses in the pathogenesis and varied symptomatology of this disease are lacking. Mice may prove useful as an experimental model for intravaginal trichomoniasis in developing an understanding of the role of local immune responses in the pathogenesis and varied symptomatology of this disease. The present study reports the levels of anti-Trichomonas IgA antibodies in serum and vaginal washes, and T-cell subtype and cytokine profile in vaginal cervical tissues of mice infected intravaginally with T. vaginalis isolates from 15 symptomatic and 15 asymptomatic women. It also correlates the responses with symptomatology of the patients. Successful intravaginal infection was established by inoculating T. vaginalis in BALB/c mice preinoculated with Lactobacillus acidophilus and pretreated with oestradiol. A significant increase in specific IgA antibody levels was detected with enzyme-linked immunosorbent assay in vaginal secretions and serum samples collected on the 7th post-infection day from animals infected with isolates from asymptomatic women when compared with mice infected with isolates from symptomatic women. T-cell subset analysis showed significant differences, with increased CD4+ T-cell count in animals infected with isolates from asymptomatic women compared with animals infected using isolates from symptomatic women. No difference in CD8+ T cells was observed between the two groups. Cytokine profile revealed significantly higher (P < 0.001) production of gamma-IFN and IL-2 in mice infected with asymptomatic isolates compared with animals infected with symptomatic isolates, using T. vaginalis crude antigen extract and nonspecific mitogen (ConA) as stimulants for vaginal cervical lymphocytes. However, no difference in IL-4 levels was observed in the two groups of animals. In contrast, significant increase in tumour necrosis factor (TNF-alpha) levels was observed in animals infected with asymptomatic isolates compared with those infected with isolates from symptomatic women and controls, thereby indicating that TNF-alpha may play an important role in the inflammatory response to trichomoniasis. The study further suggests that specific IgA antibodies might help to protect asymptomatic individuals from severe infection and T-lymphocytes may play an important function in the eradication of the parasite. The cytokine profile indicated the involvement of Th-1 like responses in mice infected with asymptomatic isolates, compared with those infected with symptomatic isolates.


[Fibrous epithelial polyps of the pyelo-ureteral junction in children. Presentation of 3 cases and review of the literature (33 cases)].
Primary ureteral tumors are rare and benign ones constitute only a small portion. Of the benign neoplasms, fibro epithelial polyps are probably the most common and could be considered to be an exceedingly rare cause of Hydronephrosis in children. The exact etiology of benign ureteral polyps is not certain but it is likely that they have a congenital one. They are mesodermal in origin and consist of a thick fibrous stalk covered by a layer of normal transitional epithelium. They are more commonly found in boys (80.6%), who present usually with abdominal pains or renal colics. Fibro-epithelial polyps often rise in the proximal ureter and renal pelvis, especially at the left side (69.4%). Radiographic signs are those of a non typical uretero-pelvic Junction obstruction. IVP and retrograde ureterogram usually demonstrate a long, thin, filiform, lucent filling defect within the ureteral lumen with moderate hydronephrosis. Appropriate treatment of these benign tumors is local excision with or without segmental resection. Prognosis should be considered as excellent without a report of recurrence. A review of the literature revealed 33 cases of ureteral polyps in children. We report here 3 additional cases of obstructing fibro epithelial polyps, observed in boys aged respectively 4, 8 and 9 years.


Monoclonal antibody against a tumor-associated sialoglycoprotein of superficial papillary bladder tumors and cervical condylomas.
A mouse IgG1 monoclonal antibody (MAb), 19A211, defining a tumor-associated cell-surface antigen of superficial papillary bladder tumors, was generated by immunizing with fresh bladder tumor cells mice neonatally injected with normal human urothelial cells. The reactivity of the antibody with cell lines was examined by indirect immunofluorescence staining and was restricted to 3/14 bladder cancer lines and 3/31 cancer cell lines of non-bladder origin, including HeLa cervical cancer. No normal fibroblast, kidney cells, EBV-lymphocytes, erythrocytes or leukocytes expressed the antigen. Reactivity of MAb 19A211 was well preserved on tissue paraffin sections. Immunoperoxidase staining of normal adult or fetal tissues showed no reactivity except for a patchy or uniform staining of umbrella cells in 6/23 adult and 1/4 fetal urothelium samples. Positive and often heterogeneous staining was observed on 24/38 papillary superficial tumors (Ta) and 4/5 carcinoma in situ bladder lesions but on only 4/20 infiltrating tumors. It was also observed on 5/6 cervical condylomas and one bladder condyloma, but none of 6 penile or vulvar condylomas. All other tumors tested were negative. The antigenic determinant is present on a heterogeneous group of proteins with molecular weights ranging from 90 to 200 kDa. It is sensitive to periodate treatment and to neuraminidase but only partially sensitive to proteases. MAb 19A211 is different from other reported MAbs with similar reactivity to superficial bladder tumors and umbrella cells of normal urothelium. When tested in competition assays, several of these MAbs, but not 19A211, were found to react with Lewis X blood group determinant. Our results suggest that 19A211 may be useful for detection and stratification of bladder tumors.


Polycondensation of Asparagine-comprising Dipeptides in Aqueous Media-A Simulation of Polypeptide Formation in Primordial Earth Hydrosphere.
Asparagine and aspartic acid might have mutually transformed in the primordial hydrosphere of the earth, if ammonia and aspartic acid had existed in equilibrium. These amino acids seem to contribute to polypeptides, while the simple amino acids glycine and alanine easily form cyclic dipeptides and do not achieve long peptide chains. Asparagine-comprising dipeptides contribute some kinds of activation forms of dipeptides because these can polymerize faster than asparagine only. The new finding of polypeptide formation suggests a pathway of sequential polypeptides to evolve a diversity of polypeptides.


Evaluation of a multilocus sequence typing system for Staphylococcus epidermidis.
Staphylococcus epidermidis is a significant cause of nosocomial disease. However, the taxonomy of this pathogen, particularly at subspecies level, is unclear. A multilocus sequence typing (MLST) scheme has therefore been investigated as a tool to elucidate taxonomic relationships within this group, based on genetic relatedness. DNA sequences for internal fragments of seven housekeeping genes were compared in 47 geographically and temporally diverse S. epidermidis isolates that were obtained from clinical infections. Twenty-three different allelic profiles were detected; 17 of these were represented by single strains and the largest profile group contained 17 isolates. Diversity of the same collection of isolates was investigated by using PFGE of SmaI-digested genomic DNA to test the discrimination and validity of the MLST approach. Isolates within the largest profile group were resolved into four distinct PFGE clusters on the basis of their SmaI digest patterns. Isolates within other profile groups that contained multiple isolates had matching PFGE SmaI patterns within each group. It appears that MLST is an effective method for grouping S. epidermidis strains at the subspecies level; however, it is not as discriminatory as it has been for other species for which MLST schemes have been established and, used alone, would not be a useful method for epidemiological studies. In addition, it was demonstrated that this method was effective for confirming the identity of S. epidermidis CoNS (coagulase-negative) isolates.


Preterm delivery and later maternal cardiovascular disease risk.
Women who have delivered a preterm infant are at elevated risk for cardiovascular disease (CVD), but mechanisms for this association are not understood. In a cross-sectional study we investigated whether older women with a history of preterm birth (<37 weeks) had a higher prevalence of CVD. Participants were 446 women (mean age 80 years; 47% black) enrolled in the Pittsburgh, PA field center of The Health, Aging and Body Composition Study. Women reported preterm status, birth weight, smoking status, and selected complications for each pregnancy. CVD status was determined by self-report and hospital records. Analysis was limited to first births not explicitly complicated by hypertension or preeclampsia. Women who had delivered a preterm infant (on average 57 years in the past) had a higher prevalence of CVD. After adjustment for race, age, blood pressure, pulse wave velocity, interleukin-6, high-density lipoprotein cholesterol, and statin use, the odds ratio for CVD among women who delivered a preterm infant was 2.85 (95% confidence interval = 1.19-6.85) compared with women who had delivered term infants weighing more than 2500 g. This relationship was not altered by lifetime smoking history. There was evidence of negative confounding by statin use and high-density lipoprotein cholesterol. Among women delivering infants who were both preterm and low birth weight (<2500 g), the odds ratio was 3.31 (1.06-10.37) for CVD compared with women with term, normal weight infants. These results suggest that vascular and metabolic factors account for some but not all of the increased prevalence of CVD among women many years after a preterm birth.


Claudins and alveolar epithelial barrier function in the lung.
The alveolar epithelium of the lung constitutes a unique interface with the outside environment. This thin barrier must maintain a surface for gas transfer while being continuously exposed to potentially hazardous environmental stimuli. Small differences in alveolar epithelial barrier properties could therefore have a large impact on disease susceptibility or outcome. Moreover, recent work has focused attention on the alveolar epithelium as central to several lung diseases, including acute lung injury and idiopathic pulmonary fibrosis. Although relatively little is known about the function and regulation of claudin tight junction proteins in the lung, new evidence suggests that environmental stimuli can influence claudin expression and alveolar barrier function in human disease. This review considers recent advances in the understanding of the role of claudins in the breakdown of the alveolar epithelial barrier in disease and in epithelial repair.


Pivoting to the QUAD AIM-Lessons Learned From the Central Texas Market.
Since 2009, the Military Health System (MHS) has represented its mission as that of attaining the Quadruple Aim (QUAD AIM): increased readiness, better health, better care, and low per capita costs. The journey to reach the four goals is challenging and ongoing. Leaders in the MHS's Central Texas Market (CTM) sought to understand and overcome the root-cause obstacles that interfered with achieving the QUAD AIM. This process required a self-critical and thoroughly objective review of the behavioral economics of the system. We hypothesized that two corporate behaviors fed upon each other to create a vicious downward spiral. First, as a socialized (salary-based) system, the enterprise has a built-in incentive that covertly competes with the attainment of the QUAD AIM. Because additional work does not result in any material gain for its workers, the system regulates to a comfortable flow. Second, centralized leaders defer important management controls to tactical teammates due to their special medical expertise. This corporate behavior makes overcoming the first one challenging-keeping realization of the QUAD AIM elusive. Beginning in July of 2019, CTM leaders strove to replace the two identified corporate behaviors with more productive ones. First, in place of regulating to comfort, we directed teammates to focus wholly on achieving the QUAD AIM. Second, we exerted leadership from the top down to attain the QUAD AIM's four goals. Because the vicious cycle manifested itself differently in the realms of primary, inpatient, and specialty care, we adapted the application of our virtuous behaviors to match the problem set in each realm. In primary care, we replaced fee-for-service incentives with value-based ones. In inpatient care, we eliminated hidden incentives that resulted in inappropriate and unnecessary transfers. In specialty care, we consolidated the management of referrals, templating, and scheduling-taking central control of system productivity. The interventions in each realm required the introduction of new workflows, policies, and dashboards to ensure change. Over a 2-year period, the CTM made a quantum to leap toward attaining the QUAD AIM. In our community based primary care homes, we significantly improved our operations as quantified by the value-based metrics of patient satisfaction, Healthcare Effectiveness Data and Information Set (HEDIS) quality metrics, access to care, and leakage. In the inpatient realm, we decreased monthly transfers by 73% (110 s to 30 s) resulting in higher bed censuses and multiple downstream positive impacts. In specialty care, we demonstrated our ability to return our specialty service lines quickly to high levels of production in the coronavirus disease-2019 crisis. Each of these interventions demonstrated large-scale movement toward the QUAD AIM. The CTM's actions demonstrate that the QUAD AIM can be attained in military medicine. Doing so requires the recognition of two destructive corporate behaviors. Through decades of hardening, these corporate behaviors have been imprinted upon the MHS, making them practically invisible as guiding currents in economic behavior. Counteracting them with persistent regulation to the QUAD AIM facilitated by proactive top-down leadership offers a solution.


Access To Mental Health Care Increased But Not For Substance Use, While Disparities Remain.
We assessed whether early implementation of Affordable Care Act (ACA) Medicaid expansion and state health insurance exchanges increased access to mental health and substance use treatment among those in need and whether these changes differed by racial/ethnic group. We found that mental health treatment rates increased significantly but found no evidence of a reduction in the wide racial/ethnic disparities in mental health treatment that preceded ACA expansion from 2005 to 2013.


Outcome of periocular sebaceous gland carcinoma.
To determine the long-term outcome of periocular sebaceous gland carcinoma and factors predictive of tumor recurrence. A retrospective case note review of all patients with periocular sebaceous gland carcinoma treated at the Queen's Medical Centre, Nottingham, United Kingdom, between 1992 and 1999. Patient age at time of surgery, tumor location, and treatment were recorded. The tumor dimensions and histopathologic description were correlated with tumor recurrence. The general practitioners were contacted to determine whether there had been any further tumor recurrences since the last entry in the hospital notes. A total of 11 cases (mean age, 75 years) were reviewed, of which 7 were female. The eyelids were involved in all but 2 cases, and maximum tumor dimension ranged from 6 to 25 mm. Three demonstrated pagetoid spread. Recurrence was seen in all tumors reported as incompletely excised (4 cases), of which only one demonstrated pagetoid spread. Tumour size was not predictive of recurrence. In our unit, the best prognostic factor for sebaceous gland carcinoma is a histologic report confirming complete excision of the tumor, whatever the tumor size or pattern of spread identified.


Advancing a framework to enable characterization and evaluation of data streams useful for biosurveillance.
In recent years, biosurveillance has become the buzzword under which a diverse set of ideas and activities regarding detecting and mitigating biological threats are incorporated depending on context and perspective. Increasingly, biosurveillance practice has become global and interdisciplinary, requiring information and resources across public health, One Health, and biothreat domains. Even within the scope of infectious disease surveillance, multiple systems, data sources, and tools are used with varying and often unknown effectiveness. Evaluating the impact and utility of state-of-the-art biosurveillance is, in part, confounded by the complexity of the systems and the information derived from them. We present a novel approach conceptualizing biosurveillance from the perspective of the fundamental data streams that have been or could be used for biosurveillance and to systematically structure a framework that can be universally applicable for use in evaluating and understanding a wide range of biosurveillance activities. Moreover, the Biosurveillance Data Stream Framework and associated definitions are proposed as a starting point to facilitate the development of a standardized lexicon for biosurveillance and characterization of currently used and newly emerging data streams. Criteria for building the data stream framework were developed from an examination of the literature, analysis of information on operational infectious disease biosurveillance systems, and consultation with experts in the area of biosurveillance. To demonstrate utility, the framework and definitions were used as the basis for a schema of a relational database for biosurveillance resources and in the development and use of a decision support tool for data stream evaluation.


Electroconvulsive Therapy Applications on Children in the 1940s: The Italian Case.
The existence of pediatric applications of electroconvulsive therapy (ECT) in the 1940s in Italy has been neglected by international literature. However, 2 case reports by Ferdinando Accornero and Mario Anderson, both assistants of Ugo Cerletti at the Sapienza Clinic for Nervous and Mental Diseases, should be brought to the attention of historians of ECT. The work presented therein began in Rome in September 1940, approximately at the same time of the first reported ECT administration on a child in Bristol, United Kingdom. The 2 reports described applications on 19 children and adolescents during 3 different sessions (1940-1941, 1944-1947, and 1947-1949), with a 3-year-long interruption due to the circumstances of World War II. Unfortunately, this research appeared belatedly in 2 articles from 1948 and 1950, respectively, in an Italian journal with limited distribution, when more extensive research contributions on pediatric ECT had already received international exposure. The Italian reports may cast light on the progress made by the early generation of ECT researchers in the 1940s toward the refinement of ECT techniques and the subsequent identification of diagnostic indicators for ECT among children.


Double micropipettes configuration method of scanning ion conductance microscopy.
In this paper, a new double micropipettes configuration mode of scanning ion conductance microscopy (SICM) is presented to better overcome ionic current drift and further improve the performance of SICM, which is based on a balance bridge circuit. The article verifies the feasibility of this new configuration mode from theoretical and experimental analyses, respectively, and compares the quality of scanning images in the conventional single micropipette configuration mode and the new double micropipettes configuration mode. The experimental results show that the double micropipettes configuration mode of SICM has better effect on restraining ionic current drift and better performance of imaging. Therefore, this article not only proposes a new direction of overcoming the ionic current drift but also develops a new method of SICM stable imaging.


A subtype of laminopathies: Generalized lipodystrophy-associated progeroid syndrome caused by LMNA gene c.29C>T mutation.
The term laminopathies refers to a group of congenital diseases characterized by accelerated degeneration of human tissues. Mutations in LMNA, LMNB, ZMPSTE24, and other genes lead to structural and functional abnormalities associated with lamins. One subtype of laminopathy is the generalized lipodystrophy-associated progeroid syndrome (GLPS), which occurs in patients with heterozygous mutations of the LMNA gene c.29C>T(p.T10I). This paper reports the first case of GLPS in China and compares the clinical features of other GLPS patients with literature reports. A 16-year-old male patient was treated for diabetic ketoacidosis, presenting with premature aging appearance, systemic lipodystrophy, severe fatty liver, and decreased bone density. After peripheral blood DNA extraction and second-generation sequencing, a heterozygous mutation of exon 1 of the LMNA gene c.29C>T(p.T10I) was detected. This case of GLPS may provide a diagnostic and therapeutic basis for potential patients.


Influence of breast feeding on the development of cow's milk protein antibodies and the IgE level.
In 48 infants unselected with regard to atopic heredity, the levels of serum IgG, IgA and IgM antibodies against native cow's milk proteins and IgG antibodies against beta-lactoglobulin were measured with ELISA and the total serum IgE concentration with Phadebas PRIST. Using multiple regression analysis the level of each type of antibody was related to the age at weaning, at first exposure to cow's milk and at sampling. The longer the infants were exposed to cow's milk protein without concomitant breast feeding and the younger they were at the introduction of cow's milk formula, the higher were the IgG antibody levels against native cow's milk proteins. The investigated variables explained only 17% of the variation of the antibody level, however. The IgG antibodies against beta-lactoglobulin showed significant negative correlations to the age at weaning and the age at first cow's milk exposure, explaining 8% of the variation. Specific IgA and IgM antibody levels an those of total serum IgE did not show any significant relation to the investigated independent variables.


In vivo cytotoxicity of type I CD20 antibodies critically depends on Fc receptor ITAM signaling.
Antibody-Fc receptor (FcR) interactions play an important role in the mechanism of action of most therapeutic antibodies against cancer. Effector cell activation through FcR triggering may induce tumor cell killing via antibody-dependent cellular cytotoxicity (ADCC). Reciprocally, FcR cross-linking of antibody may lead to the induction of apoptotic signaling in tumor cells. The relative importance of these bisecting pathways to in vivo antibody activity is unknown. To unravel these roles, we developed a novel mouse model with normal FcR expression but in which FcR signaling was inactivated by mutation of the associated gamma-chain. Transgenic mice showed similar immune complex binding compared with wild-type mice. In contrast, ADCC of cells expressing frequently used cancer targets, such as CD20, epidermal growth factor receptor, Her2, and gp75, was abrogated. Using the therapeutic CD20 antibodies ofatumumab and rituximab, we show that FcR cross-linking of antibody-antigen immune complexes in the absence of gamma-chain signaling is insufficient for their therapeutic activity in vivo. ADCC therefore represents an essential mechanism of action for immunotherapy of lymphoid tumors.


lncRNA MSTRG.29039.1 Promotes Proliferation by Sponging hsa-miR-12119 via JAK2/STAT3 Pathway in Multiple Myeloma.
Noncoding RNA (ncRNA) is involved in the occurrence, development, metastasis, and drug resistance of tumors and involves a variety of biological functions. In addition, miRNA can regulate proliferation and migration and even regulate epigenetics to promote the development of multiple myeloma (MM). However, the mechanism of ncRNA involved in MM is still unclear, and there are many unknown ncRNAs to be explored. This research is aimed at discovering the unknown lncRNA in MM through high-throughput sequencing and to study the mechanism and role of competitive endogenous RNA (ceRNA) involved in the pathogenesis of MM for the development of novel molecular markers and potential new targeted drugs. We screened out 262 new lncRNAs with statistical differences by RNA sequencing and selected the lncRNA MSTRG.29039.1 according to the expression and function of lncRNAs and their target genes in MM. We verified that MSTRG.29039.1 and its target gene OSMR were highly expressed in MM. After knockdown of MSTRG.29039.1 in MM cell lines, the expression of OSMR was decreased, and the expression of hsa-miR-12119 was upregulated which can also promote cell apoptosis and inhibit proliferation. Then, we knocked down hsa-miR-12119 and MSTRG.29039.1, we found that apoptosis of MM cells was reduced, and cell proliferation was increased compared with just knocking down hsa-miR-12119. We further verified the direct binding relationship between MSTRG.29039.1 and OSMR by the dual-luciferase reporter assay system. Thus, MSTRG.29039.1 can competitively bind with miRNA to counteract the inhibitory effect of miRNA on OSMR, which regulates cell proliferation and apoptosis through the JAK2/STAT3 pathway. In a conclusion, lncRNA MSTRG.29039.1 could promote proliferation by sponging hsa-miR-12119 via the JAK2/STAT3 pathway in multiple myeloma. This may be a molecular marker and a potential therapeutic target for MM.


Tpc1 is an important Zn(II)2Cys6 transcriptional regulator required for polarized growth and virulence in the rice blast fungus.
The establishment of polarity is a critical process in pathogenic fungi, mediating infection-related morphogenesis and host tissue invasion. Here, we report the identification of TPC1 (Transcription factor for Polarity Control 1), which regulates invasive polarized growth in the rice blast fungus Magnaporthe oryzae. TPC1 encodes a putative transcription factor of the fungal Zn(II)2Cys6 family, exclusive to filamentous fungi. Tpc1-deficient mutants show severe defects in conidiogenesis, infection-associated autophagy, glycogen and lipid metabolism, and plant tissue colonisation. By tracking actin-binding proteins, septin-5 and autophagosome components, we show that Tpc1 regulates cytoskeletal dynamics and infection-associated autophagy during appressorium-mediated plant penetration. We found that Tpc1 interacts with Mst12 and modulates its DNA-binding activity, while Tpc1 nuclear localisation also depends on the MAP kinase Pmk1, consistent with the involvement of Tpc1 in this signalling pathway, which is critical for appressorium development. Importantly, Tpc1 directly regulates NOXD expression, the p22phox subunit of the fungal NADPH oxidase complex via an interaction with Mst12. Tpc1 therefore controls spatial and temporal regulation of cortical F-actin through regulation of the NADPH oxidase complex during appressorium re-polarisation. Consequently, Tpc1 is a core developmental regulator in filamentous fungi, linking the regulated synthesis of reactive oxygen species and the Pmk1 pathway, with polarity control during host invasion.


Retinal pigment epithelial abnormalities in fundus flavimaculatus: a light and electron microscopic study.
Light, fluorescent, and scanning and transmission electron microscopic examinations of two postmortem eyes from a 24-year-old man with well-documented fundus flavimaculatus with atrophic macular degeneration revealed striking abnormalities in the retinal pigment epithelium (RPE). Beginning near the equator, scanning electron microscopy demonstrated a progressively marked heterogeneity in the size of the RPE cells. Surrounded by a fairly regular mosaic of relatively normal appearing cells, enormously enlarged hypomelanotic cells measuring up to 80 microns in diameter occurred in irregular aggregates that became more prevalent posteriorly. Diffusely and intensely PAS-positive, the RPE was packed with a granular substance with ultrastructural, autofluorescent, and histochemical properties consistent with an abnormal form of lipofuscin. The greatest concentration of lipopigment was noted posteriorly. Stains for acid mucopolysaccharide were only mildly positive. The clinical and fluorescein angiographic manifestations of fundus flavimaculatus are consistent with accumulation of a lipofuscin-like substance in the RPE. The massive amounts of lipopigment encountered in this young individual suggest that disordered lipopigment metabolism may play a major role in the pathogenesis of this retinal pigment epithelial disorder.