Thirty-Day Postoperative Outcomes Following Sugammadex Use in Colorectal Surgery Patients; Retrospective Study.
Sugammadex rapidly reverses muscle relaxation compared to acetylcholinesterase inhibitors. The long-term outcomes of sugammadex, however, are not well known. We compared 30-day postoperative outcomes following sugammadex and acetylcholinesterase inhibitor use in colorectal surgery patients. Colorectal surgical patients older than 21 were included in this retrospective study, and were dichotomized according to use of reversal agents, sugammadex (group S), and acetylcholinesterase inhibitor (group A). We assessed 30-day postoperative outcomes, including total length of hospital stay, length of postoperative hospital stay, readmission rate, and delayed discharge rate. Additional parameters included postanesthetic care unit stay time, time to first successful oral intake, unforeseen intensive care unit (ICU) admission rate, postoperative pulmonary complications, and mortality. Among a total of 585 patients, 157 patients remained in each group after propensity score matching. Total length of hospital stay, length of postoperative hospital stay, and readmission rates did not differ between the two groups, while the incidence of delayed discharge was significantly lower in group S (23 (15%) vs. 40 (25%), p = 0.017). Other outcomes did not differ between the two groups. We found no difference in 30-day postoperative outcomes following sugammadex and acetylcholinesterase inhibitor use. The only difference between these treatments was the associated incidence of delayed discharge, which was lower in group S.


Mortality traps and the dynamics of health transitions.
An examination of life expectancy in 1963 reveals twin peaks in the empirical distribution across countries: one group of countries clustered around a life expectancy of 40 years and a second group clustered around a life expectancy of 65 years. By 2003, the mode of each cluster had moved up by approximately 10 years. Although the two groups are similar in that within each of them, there is progress toward higher life expectancy, a number of countries appear to have made the jump from the high-mortality cluster to the low-mortality cluster. We reject the hypothesis that these changes reflect a simple convergence process. The data instead suggest continuous advances among many countries within clusters, with advances in life expectancy in some nations resulting in a jump from one cluster to the other.


Targeting autophagy in disease: established and new strategies.
Macroautophagy/autophagy is an evolutionarily conserved pathway responsible for clearing cytosolic aggregated proteins, damaged organelles or invading microorganisms. Dysfunctional autophagy leads to pathological accumulation of the cargo, which has been linked to a range of human diseases, including neurodegenerative diseases, infectious and autoimmune diseases and various forms of cancer. Cumulative work in animal models, application of genetic tools and pharmacologically active compounds, has suggested the potential therapeutic value of autophagy modulation in disease, as diverse as Huntington, Salmonella infection, or pancreatic cancer. Autophagy activation versus inhibition strategies are being explored, while the role of autophagy in pathophysiology is being studied in parallel. However, the progress of preclinical and clinical development of autophagy modulators has been greatly hampered by the paucity of selective pharmacological agents and biomarkers to dissect their precise impact on various forms of autophagy and cellular responses. Here, we summarize established and new strategies in autophagy-related drug discovery and indicate a path toward establishing a more efficient discovery of autophagy-selective pharmacological agents. With this knowledge at hand, modern concepts for therapeutic exploitation of autophagy might become more plausible.Abbreviations: ALS: amyotrophic lateral sclerosis; AMPK: AMP-activated protein kinase; ATG: autophagy-related gene; AUTAC: autophagy-targeting chimera; CNS: central nervous system; CQ: chloroquine; GABARAP: gamma-aminobutyric acid type A receptor-associated protein; HCQ: hydroxychloroquine; LYTAC: lysosome targeting chimera; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; NDD: neurodegenerative disease; PDAC: pancreatic ductal adenocarcinoma; PE: phosphatidylethanolamine; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol 3-phosphate; PROTAC: proteolysis-targeting chimera; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SQSTM1/p62: sequestosome 1; ULK1: unc-51 like autophagy activating kinase 1.


Seed dispersal by hornets: An unusual insect-plant mutualism.
Vespicochory, seed dispersal by hornets, is a rare seed dispersal mechanism in angiosperms and, to date, there are few records of this phenomenon. Through field investigations and behavioral assays conducted in four populations of Stemona tuberosa from 2011-2016, we demonstrate that hornets are the primary seed dispersers of S. tuberosa and play an important role in "long-distance" seed dispersal in this species. Furthermore, some ant species act as secondary dispersers and may transport the seeds to safe sites. Hornets and ants provide complementary seed dispersal at different spatial scales. This unique example of insect-plant mutualism may be an underestimated but important strategy to ensure "long-distance" seed dispersal in other myrmecochorous plants.


Food frequency questionnaire for dietary assessment among adults at a risk of coronary heart disease: A mixed-methods study.
To develop and psychometrically test a food frequency questionnaire for adults at risk of coronary heart disease (Cardio-FFQ). Comprehensive dietary assessment is critical for the prevention of cardiovascular disease, but appropriate instruments to perform this work are lacking. A sequential mixed-methods study followed the COREQ and STROBE guidelines. This study was conducted between April 2016 and November 2017. It started with dietary history interviews (Phase 1) to identify candidate food items of the Cardio-FFQ, which validity and reliability were assessed (Phase 2) through expert consultation and four seasonal measurements, including test and retest with a 2-week gap every season. Physical activity and blood glucose and lipids were assessed seasonally, while another FFQ was administered during the fourth measurement. Content analysis was used to analyse verbatim interview transcripts, while descriptive and inferential analyses were used to simplify the Cardio-FFQ and examine its psychometric properties. Phase I involved 34 participants during their first onset of acute coronary syndrome and generated 176 candidate food items (consumed by at least three participants) under 12 food categories. These food items were simplified to form the 133-item Cardio-FFQ after discarding items with trivial contributions to food commonalities or between-person variance. Further analysis showed that the simplified questionnaire had satisfactory content validity, concurrent validity, convergent validity, predictive validity, known-group validity and test-retest reliability. The 133-item Cardio-FFQ is a valid and reliable tool for a comprehensive dietary assessment appropriate for adults at risk of coronary heart disease. Nurses may use the Cardio-FFQ to conduct a dietary assessment to better support people to commit to healthy diets, aiming to reduce the risk of coronary heart disease.


Approaches to DNA/RNA Extraction and whole genome amplification.
Analysis of DNA and/or RNA is an important component of most epidemiologic studies. The methods used for their preparation vary depending on the number of samples in the study as well as the amount of tissue or cells available, the specific downstream assay, and the resources available. They range from classic phenol/chloroform extractions to robotic methods suitable for large-scale studies. Several methods are also available for the quantitation of DNA/RNA, including UV or fluorescence measurements and PCR. For DNA samples of limited quantity, it is also now possible to use whole genome amplification to increase the amount of DNA suitable for genotyping. Finally, a major issue in quality control is the careful labeling and handling of samples.


Species sensitivity distributions for two widely used anti-sea lice chemotherapeutants in the salmon aquaculture industry.
The main objective of the present study is to construct acute aquatic species sensitivity distributions (SSD) and generate proposed HC5 values (i.e. the hazardous concentration for which 5 % of species are affected or potentially affected) for two aquaculture anti-sea lice bath pesticides, azamethiphos, and hydrogen peroxide. These values could be used as the basis for the establishment of environmental quality standards (EQS). We have generated SSDs and inferred HC5 values for mortality and sublethal endpoints using LC50, EC50, and NOEC/LOEC data points separately and for each bath pesticide. Through the examination of literature data on the toxicity of both compounds, we opted to use tests with limited exposure times to ensure environmental relevance for bath pesticides. We also separated life stages for some of the sensitive taxa to account for differences in sensitivities and risk of exposure. The resulting threshold concentrations in environmental seawater are 0.10 μg/L for azamethiphos and 0.15 mg/L for hydrogen peroxide. These suggested azamethiphos and hydrogen peroxide thresholds are comparable to some previously reported EQS values. Further considerations need to be included in how to better use these thresholds in a regulatory context in relation to dispersion patterns. It is also clear that delayed mortality and sublethal effects documented in the literature require further study to fully anticipate the environmental risks of using these two bath pesticides.


Contrast sensitivity after +Gz acceleration.
This study was designed to determine the extent and duration of contrast sensitivity (CS) loss after high sustained +Gz acceleration in a centrifuge. The subjects were 12 healthy male flight surgeons between 20 and 22 (mean = 21.1) yr of age. The human centrifuge at the Aviation Physiology Research Laboratory in Tainan, Taiwan, was used to expose the subjects to an acceleration profile. Each subject experienced three centrifuge runs made up of one gradual onset and two rapid onset profiles. Contrast sensitivity (CS) was measured before, and at 5 min, 10 min, and 20 min for the right eye; and 7 min, 12 min, and 22 min for the left eye after the acceleration. Both eyes were measured with the right eye being tested first. There was a generalized depression of CS at 5-12 min for both eyes. The depression was more severe at low and medium frequencies (1.5, 3.0, 6.0 cycles per degree, cpd) than at a high spatial frequency (18.0 cpd). There was a significant decrease in CS of the right eye at 1.5 cpd (p < 0.05 between control and 5 min), and on the left eye at 3.0 cpd (p < 0.05 between control and 7 min, p < 0.05 between control and 12 min) and 6.0 cpd (p < 0.05 between control and 12 min). The CS loss was more obvious at 5-12 min for both eyes, and there was only partial recovery at 22 min after the acceleration. These results demonstrated that +Gz acceleration is associated with CS loss. The recovery time was greater than expected. Factors other than ocular blood flow may be involved in the prolonged CS loss.


A review of stem cell translation and potential confounds by cancer stem cells.
Mesenchymal stem cells (MSCs) are multipotent cells found in both fetal and adult tissues. MSCs show promise for cellular therapy for several disorders such as those associated with inflammation. In adults, MSCs primarily reside in the bone marrow (BM) and adipose tissues. In BM, MSCs are found at low frequency around blood vessels and trabecula. MSCs are attractive candidates for regenerative medicine given their ease in harvesting and expansion and their unique ability to bypass the immune system in an allogeneic host. Additionally, MSCs exert pathotropism by their ability to migrate to diseased regions. Despite the "attractive" properties of MSCs, their translation to patients requires indepth research. "Off-the-shelf" MSCs are proposed for use in an allogeneic host. Thus, the transplanted MSCs, when placed in a foreign host, could receive cue from the microenvironment for cellular transformation. An important problem with the use of MSCs involves their ability to facilitate the support of breast and other cancers as carcinoma-associated fibroblasts. MSCs could show distinct effect on each subset of cancer cells. This could lead to untoward effect during MSC therapy since the MSCs would be able to interact with undiagnosed cancer cells, which might be in a dormant state. Based on these arguments, further preclinical research is needed to ensure patient safety with MSC therapy. Here, we discuss the basic biology of MSCs, discuss current applications, and provide evidence why it is important to understand MSC biology in the context of diseased microenvironment for safe application.


Functional interaction of phospholipid hydroperoxide glutathione peroxidase with sperm mitochondrion-associated cysteine-rich protein discloses the adjacent cysteine motif as a new substrate of the selenoperoxidase.
The mitochondrial capsule is a selenium- and disulfide-rich structure enchasing the outer mitochondrial membrane of mammalian spermatozoa. Among the proteins solubilized from the sperm mitochondrial capsule, we confirmed, by using a proteomic approach, the presence of phospholipid hydroperoxide glutathione peroxidase (PHGPx) as a major component, and we also identified the sperm mitochondrion-associated cysteine-rich protein (SMCP) and fragments/aggregates of specific keratins that previously escaped detection (Ursini, F., Heim, S., Kiess, M., Maiorino, M., Roveri, A., Wissing, J., and Flohé, L. (1999) Science 285, 1393-1396). The evidence for a functional association between PHGPx, SMCP, and keratins is further supported by the identification of a sequence motif of regularly spaced Cys-Cys doublets common to SMCP and high sulfur keratin-associated proteins, involved in bundling hair shaft keratin by disulfide cross-linking. Following the oxidative polymerization of mitochondrial capsule proteins, catalyzed by PHGPx, two-dimensional redox electrophoresis analysis showed homo- and heteropolymers of SMCP and PHGPx, together with other minor components. Adjacent cysteine residues in SMCP peptides are oxidized to cystine by PHGPx. This unusual disulfide is known to drive, by reshuffling oxidative protein folding. On this basis we propose that oxidative polymerization of the mitochondrial capsule is primed by the formation of cystine on SMCP, followed by reshuffling. Occurrence of reshuffling is further supported by the calculated thermodynamic gain of the process. This study suggests a new mechanism where selenium catalysis drives the cross-linking of structural elements of the cytoskeleton via the oxidation of a keratin-associated protein.


Synthesis, Characterization and Performance of Materials for a Sustainable Future.
Today, sustainability represents the key factor for economic progress in compliance with social advancement and environmental protection, driving innovation in materials, processes and technologies [...].


Enteroaggregative Escherichia coli: epidemiology, virulence and detection.
Enteroaggregative Escherichia coli (EAEC) is a subgroup of diarrhoeagenic E. coli (DEC) that during the past decade has received increasing attention as a cause of watery diarrhoea, which is often persistent. EAEC have been isolated from children and adults worldwide. As well as sporadic cases, outbreaks of EAEC-caused diarrhoea have been described. The definition of EAEC is the ability of the micro-organism to adhere to epithelial cells such as HEp-2 in a very characteristic 'stacked-brick' pattern. Although many studies searching for specific virulence factor(s) unique for this category of DEC have been published it is still unknown why the EAEC cause persistent diarrhoea. In addition, the aggregative property of EAEC causes a lot of problems in serotyping due to the cells auto-agglutinating. The gold standard for identification of EAEC includes isolation of the agent and an adherence assay using tissue culture, viz. HEp-2 cells. This assay is in most cases reliable; however, emergence of 'atypical' EAEC has been described in several publications. In addition, the HEp-2 assay is time consuming, demands a tissue culture lab and trained staff. Several molecular biological assays have been described, however, none show 100 % specificity.


Creating healthcare cultures of patient safety.
With the release of the Institute of Medicine's report on patient safety, a national agenda was set to rebuild the public's trust and create cultures of safety within all healthcare organizations. This vision of improvement is driving changes in healthcare organizations, educational institutions, and regulatory agencies to remove the blame and improve their systems. Understanding historical events, strategies for organization change, and current patient safety initiatives will assist nursing leaders to become active participants at the local, state, and national level as cultures are changed and solutions are developed to prevent patient injuries.


An evolutionary model for the origin of modularity in a complex gene network.
Scale-free cellular networks are organized into a complex topology by massive interactions (links) between nodes, which can be typically characterized by a power-law degree. In contrast, almost all cellular networks show the feature of modularity. The popular BA model (Barabasi and Albert) demonstrated the origin of scale-free property by the attachment preference, but not for the origin of modularity. We propose a BBA model (Biological BA) by introducing the random link-loss mechanism under the original BA model, showing that scale-free and modularity can emerge as a derived property of the BBA model. Data analysis has shown that, roughly, the rate of gene network evolution can be described as a 2-2-1 pattern (adding two new genes and two new links with the cost of one link-loss).


The architecture and complete sequence of mitochondrial genome of an assassin bug Agriosphodrus dohrni (Hemiptera: Reduviidae).
The 16, 470 bp nucleotide sequence of the mitochondrial genome (mitogenome) of an assassin bug from the reduviid subfamily Harpactorinae, Agriosphodrus dohrni, has been revealed. The entire genome encodes for two ribosomal RNA genes (rrnL and rrnS), 22 transfer RNA (tRNA) genes, 13 protein-coding genes, and a control region. The nucleotide composition is biased toward adenine and thymine (A+T = 72.2%). Comparative analysis with two other reduviid species Triatoma dimidiata and Valentia hoffmanni, exhibited highly conserved genome architectures including genome contents, gene order, nucleotide composition, codon usage, amino acid composition, as well as genome asymmetry. All protein-coding genes use standard mitochondrial initiation codons (methionine and isoleucine), except that nad1 starts with GTG. All tRNAs have the classic clover-leaf structure, except that the dihydrouridine (DHU) arm of tRNA(Ser(AGN)) forms a simple loop. Secondary structure comparisons of the two mitochondrial ribosomal subunits among sequenced assassin bugs show that the sequence and structure of rrnL is more conservative than that of rrnS. The presence of structural elements in the control region is also discussed, with emphasis on their implications in the regulation of replication and/or transcription of the reduviid mitogenome. The phylogenetic analyses indicated that within Reduviidae, Harpactorinae is a sister group to the Salyavatinae + Triatominae clade.


[Alteration of bronchomotor tone after deep inhalation. Mechanisms and pediatric data].
There is significant alteration of airway calibre after deep inhalation (DI). An increase of airway calibre has been evidenced in children in case of mild asthmatic obstruction and after a positive response to methacholine or exercise challenge. Such an increase is blunted in the presence of a moderate to severe asthmatic airway obstruction and no bronchodilatory effect of DI has been found in infants. Bronchial hyperreactivity and airway inflammation strongly influence post-DI alterations of bronchomotor tone. Airways and lung parenchyma are interdependent but both exhibit imperfect elasticity. Hysterisis characterizes imperfect elasticity of pressure-volume relationship. The mechanical theory of relative hysteresis between airway and lung parenchyma is the main mechanism implicated in the induced changes of airway calibre. DI may influence results of lung function testing in children. The technique may be of interest to increase sensibility of routine lung function testing in children.


Impulsivity and Cognitive Flexibility as Neuropsychological Markers for Suicidality: A Multi-Modal Investigation Among Military Veterans with Alcohol Use Disorder and PTSD.
To examine relations between self-report and behavioral measures of impulsivity and cognitive flexibility with suicidal ideation and self-harm and suicide attempt history. Methods: Eighty-seven military veterans who met DSM-5 diagnostic criteria for alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD) were evaluated for current suicidal ideation and self-harm, suicide attempt history, impulsivity, and cognitive flexibility. Results: Higher levels of self-reported impulsivity were associated with greater suicidal ideation and self-harm and lower behavioral inhibition was associated with greater likelihood of endorsing a suicide attempt. Conclusion: Use of multi-modal assessment of impulsivity and cognitive flexibility may aid in suicide screening and intervention among vulnerable and high-risk populations.


Induction of apoptosis by phenylisocyanate derivative of quercetin: involvement of heat shock protein.
Quercetin, a widely distributed bioflavonoid, inhibits the growth of various tumor cells. The present study was designed to investigate whether a novel quercetin derivative [phenylisocyanate of quercetin (PHICNQ)] exerts antitumor activity against K562 and CT26 tumor cell lines by inducing apoptosis, and to examine the possible mechanism in the phenomenon. The cell proliferation assay of K562 and CT26 tumor cells was determined by the trypan blue dye exclusion test. Apoptosis of PHICNQ-treated cells was determined by morphological analysis, agarose gel DNA electrophoresis and quantitated by flow cytometry after staining with propidium iodide. Cell cycle was evaluated by flow cytometry. The expression of heat shock protein 70 was checked by Western blot analysis. Our results showed that PHICNQ inhibited the proliferation of K562 and CT26 cells in a dose-dependent and time-dependent manner. PHICNQ was 308- and 73-fold more active on CT26 and K562 cells than quercetin, respectively. In addition to this cytostatic effect, treatment of K562 and CT26 tumor cells with PHICNQ induced apoptosis. PHICNQ treatment downregulated the expression of heat shock protein 70 more dramatically than quercetin treatment. These results suggest that PHICNQ is a more powerful antiproliferative derivative than quercetin, with cytostatic and apoptotic effects on K562 and CT26 tumor cells. PHICNQ may trigger apoptosis in tumor cells through inhibition of heat shock protein 70 synthesis and expression.


Functional neuroimaging of hallucinations in schizophrenia: toward an integration of bottom-up and top-down approaches.
Hallucinations in schizophrenia represent an important clinical problem, an interesting neuropsychological enigma, and a significant challenge for neuroscientific research. Functional neuroimaging techniques allow the in vivo, systems-level study of brain dysfunction underlying this debilitating symptom. Clinical and scientific vantage points that can inform the design and interpretation of functional neuroimaging studies of schizophrenic hallucinations are outlined. These include considerations of the phenomenology of hallucinations, the relationship of hallucinations to other symptoms of schizophrenia, and the neuropsychological functions that are thought to be disrupted in hallucinations. They also include the anatomical and chemical brain systems in which abnormalities are implicated in schizophrenia, the neurologic conditions in which hallucinations may occur, the neurochemical contexts that are associated with hallucinations, and the methodologic details of the functional neuroimaging techniques employed. Bottom-up and top-down functional neuroimaging strategies for the investigation of schizophrenic hallucinations with positron emission tomography (PET), single photon emission computed tomography (SPECT) and functional magnetic resonance imaging (fMRI) are reviewed. Bottom-up approaches start with or measure the biology associated with hallucinations. Top-down approaches start from the specific neuropsychological dysfunctions thought to be associated with hallucinations. The distributed brain regions, systems and functions implicated in schizophrenic hallucination formation are then discussed in the context of an integration of bottom-up and top-down approaches. Focus is placed upon abnormalities in the functions of, and interactions among, auditory-linguistic association cortices, caudal and rostral limbic/paralimbic systems, prefrontal cortices, ventral striatum and (non-specific projection and associative) thalamic nuclei, as well as upon the glutamatergic, GABAergic and ventral tegmental dopaminergic modulation of these systems.


Listeria monocytogenes Inoculation Impedes the Development of Brain Pathology in Experimental Cerebral Malaria by Inhibition of Parasitemia.
Cerebral malaria (CM) is a serious central nervous system dysfunction caused by Plasmodium falciparum infection. In this study, we investigated the effect of Listeria monocytogenes (Lm) inoculation on experimental cerebral malaria (ECM) using Plasmodium berghei ANKA (PbA)-infected C57BL/6 mice. Live Lm inoculation inhibited the parasitemia and alleviated ECM symptoms. The protective effect against ECM symptoms was connected with improved brain pathology manifested as a less-damaged blood-brain barrier, decreased parasite sequestration, and milder local inflammation. Meanwhile, Lm inoculation decreased expression of cell adhesion molecules (ICAM-1 and VCAM-1) and accumulation of pathogenic CD8+ T cells in the brain. In keeping with the suppression of parasitemia, there was an upregulation of IFN-γ, IL-12, MCP-1, and NO expression in the spleen by Lm inoculation upon PbA infection. Early treatment with exogenous IFN-γ exhibited a similar effect to Lm inoculation on PbA infection. Taken together, Lm inoculation impedes the development of brain pathology in ECM, and early systemic IFN-γ production may play a critical role in these protective effects.


Doppler sonographic evaluation of left atrial function after cardioversion of atrial fibrillation.
Restoration of sinus rhythm is not always followed by immediate return of effective atrial contraction. Left atrial mechanical function can be assessed by Doppler echocardiography; in the present study we measured the atrial ejection force, which is a noninvasive Doppler-derived parameter that measures the strength of atrial contraction. The aim of the present study was to evaluate the influence of clinical and echocardiographic parameters: duration and cause of atrial fibrillation, different modality of cardioversion, and left atrial size with respect to the delay in the return of effective atrial contraction after cardioversion. Seventy patients were randomly chosen to undergo cardioversion by either direct current shock or intravenously administered procainamide hydrochloride. The 52 patients who had sinus rhythm restored underwent a complete Doppler echocardiographic examination 1 h after the restoration of sinus rhythm and after 1 day, 7 days, and 1 month. The relation between clinical variables and atrial ejection force was tested. Atrial ejection force was greater immediately and 24 h after cardioversion in patients who underwent pharmacologic therapy compared to patients treated with direct current shock (11.3+/-3 versus 5+/-2.9 dynes; P<0.001). In both groups atrial ejection force increased over time. The mode of cardioversion was significantly associated with recovery of left atrial mechanical function by day 1 in univariate and multivariate analysis (odds ratio, 0.14; 95% confidence interval, 0.02-1.2). The other variable associated with the delay in the recovery of atrial function was a dilated left atrium (odds ratio, 0.16; 95% confidence interval, 0.12-1.6). Atrial ejection force is a noninvasive parameter that can be easily measured after cardioversion and gives accurate information about the recovery of left atrial mechanical function. The recovery of left atrial function was influenced by the mode of cardioversion and left atrial size.


Rituximab-associated infections.
After more than 10 years of use, rituximab has proven to be remarkably safe. However, accumulated evidence now suggests that under some circumstances it may significantly increase the risk of infections. This risk is difficult to quantify because of confounding factors (namely, concomitant use of immunosuppressive or chemotherapeutic agents and underlying conditions), as well as under-reporting. Increased number of infections has been documented in patients treated with maintenance rituximab for low-grade lymphoma and in patients with concomitant severe immunodeficiency, whether caused by human immunodeficiency virus (HIV) infection or immunosuppressive agents like fludarabine. From the practical standpoint, the most important infection is hepatitis B reactivation, which may be delayed and result in fulminant liver failure and death. Special care should be placed on screening for hepatitis B virus (HBV) and preemptive antiviral treatment. Some investigators have reported an increase in Pneumocystis pneumonia. Finally, there is increasing evidence of a possible association with progressive multifocal leukoencephalopathy (PML), a lethal encephalitis caused by the polyomavirus JC. This review enumerates the described infectious complications, summarizes the possible underlying mechanisms of the increased risk, and makes recommendations regarding prevention, diagnosis and management.


The Power of Simplicity: Sea Urchin Embryos as in Vivo Developmental Models for Studying Complex Cell-to-cell Signaling Network Interactions.
Remarkably few cell-to-cell signal transduction pathways are necessary during embryonic development to generate the large variety of cell types and tissues in the adult body form. Yet, each year more components of individual signaling pathways are discovered, and studies indicate that depending on the context there is significant cross-talk among most of these pathways. This complexity makes studying cell-to-cell signaling in any in vivo developmental model system a difficult task. In addition, efficient functional analyses are required to characterize molecules associated with signaling pathways identified from the large data sets generated by next generation differential screens. Here, we illustrate a straightforward method to efficiently identify components of signal transduction pathways governing cell fate and axis specification in sea urchin embryos. The genomic and morphological simplicity of embryos similar to those of the sea urchin make them powerful in vivo developmental models for understanding complex signaling interactions. The methodology described here can be used as a template for identifying novel signal transduction molecules in individual pathways as well as the interactions among the molecules in the various pathways in many other organisms.


Leiomyomatosis peritonealis disseminata associated with endometriosis and multiple uterus-like mass: report of two cases.
Leiomyomatosis peritonealis disseminate (LPD) is a rare benign disease of unknown etiology of women in reproductive age. A few reported cases of association with endometriosis have been described suggesting a possible origin from submesothelial multipotential cells. We present two cases of LPD associated with endometriosis expressing smooth muscle metaplasia, and some of the nodules with aspects of uterus-like mass. Laparoscopy, gross findings, and the pathological and immunohistochemical study of the surgical specimens were described. Our findings suggest an endometriotic origin for the LPD and indicate that the therapeutic approach might contemplate the surgical reduction of the nodules and endometriosis treatment.


Highly efficient photosensitizers with aggregation-induced emission characteristics obtained through precise molecular design.
We herein report a new strategy to obtain highly efficient photosensitizers (PSs) by reducing the singlet-triplet energy gap (ΔEST) and blocking the non-radiative decay pathways. Through precise molecular design, TP1-8 were synthesized to exhibit predictable properties including moderate to high photosensitizing efficacy, tunable absorption and emission wavelengths and aggregation-induced emission characteristics.


Myor/ABF-1 mRNA [corrected] Expression Marks Follicular Helper T Cells but Is Dispensable for Tfh Cell Differentiation and Function In Vivo.
Follicular T helper cells (Tfh) are crucial for effective antibody responses and long term T cell-dependent humoral immunity. Although many studies are devoted to this novel T helper cell population, the molecular mechanisms governing Tfh cell differentiation have yet to be characterized. MyoR/ABF-1 is a basic helix-loop-helix transcription factor that plays a role in the differentiation of the skeletal muscle and Hodgkin lymphoma. Here we show that MyoR mRNA is progressively induced during the course of Tfh-like cell differentiation in vitro and is expressed in Tfh responding to Alum-precipitated antigens in vivo. This expression pattern suggests that MyoR could play a role in the differentiation and/or function of Tfh cells. We tested this hypothesis using MyoR-deficient mice and found this deficiency had no impact on Tfh differentiation. Hence, MyoR-deficient mice developed optimal T-dependent humoral responses to Alum-precipitated antigens. In conclusion, MyoR is a transcription factor selectively up-regulated in CD4 T cells during Tfh cell differentiation in vitro and upon response to alum-protein vaccines in vivo, but the functional significance of this up-regulation remains uncertain.


Getting axons onto the right path: the role of transcription factors in axon guidance.
The normal function of the nervous system requires that the constituent neurons are precisely 'wired together'. During embryogenesis, each neuron extends an axonal process, which can navigate a considerable distance to its target. Although a number of the receptors and guidance signals that direct axonal growth have been identified, less is known about the transcription factors that regulate the expression of these molecules within the neuron and its environment. This review examines recent studies in vertebrates and Drosophila that address the identity of the transcription factors that either control the repertoire of guidance receptors and signals that permits an axon to take a particular trajectory or act themselves as novel extracellular guidance factors.


Development of EST Intron-Targeting SNP Markers for Panax ginseng and Their Application to Cultivar Authentication.
Panax ginseng is one of the most valuable medicinal plants in the Orient. The low level of genetic variation has limited the application of molecular markers for cultivar authentication and marker-assisted selection in cultivated ginseng. To exploit DNA polymorphism within ginseng cultivars, ginseng expressed sequence tags (ESTs) were searched against the potential intron polymorphism (PIP) database to predict the positions of introns. Intron-flanking primers were then designed in conserved exon regions and used to amplify across the more variable introns. Sequencing results showed that single nucleotide polymorphisms (SNPs), as well as indels, were detected in four EST-derived introns, and SNP markers specific to "Gopoong" and "K-1" were first reported in this study. Based on cultivar-specific SNP sites, allele-specific polymerase chain reaction (PCR) was conducted and proved to be effective for the authentication of ginseng cultivars. Additionally, the combination of a simple NaOH-Tris DNA isolation method and real-time allele-specific PCR assay enabled the high throughput selection of cultivars from ginseng fields. The established real-time allele-specific PCR assay should be applied to molecular authentication and marker assisted selection of P. ginseng cultivars, and the EST intron-targeting strategy will provide a potential approach for marker development in species without whole genomic DNA sequence information.


Closed loop stimulation is effective in improving heart rate and blood pressure response to mental stress: report of a single-chamber pacemaker study in patients with chronotropic incompetent atrial fibrillation.
Closed-loop stimulation (CLS) is a form of rate-adaptive pacing capable of providing an effective pacing rate profile not only during physical exercise but also during mental stress. To test its effectiveness, CLS and accelerometer sensor (AS) rate response were compared intraindividually during a mental stress test (MST). Thirty-six patients (mean age 78.9 ± 6.4 years) implanted with a pacemaker with the CLS algorithm (Cylos, Biotronik, Berlin, Germany) underwent MSTs in different pacing configurations: nonrate-adaptive mode (VVI), AS mode (VVIR), and CLS mode, respectively. A modified Stroop test was used in order to induce mental stress. Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure, and pacing percentage burden were collected for 5 minutes before, during, and 5 minutes after the test. Mean peak-HR during MST was significantly higher in CLS configuration than in VVIR and VVI modes (92.8 ± 12.6 vs 78.9 ± 6.5 vs 77.8 ± 7.5; P ≤ 0.001). The average HR increase during MST was also higher in CLS configuration than in VVIR and VVI modes (22.7 ± 16.7 vs 8.2 ± 8.6 vs 6.6 ± 6.3; P ≤ 0.001). The percentage of pacing beats during MST was higher in CLS configuration than with the other two algorithms (48.4 ± 17.9 vs 27.4 ± 17.5 vs 25.8 ± 17.6; P ≤ 0.001). The average peak-SBP was significantly higher during MST in CLS mode than in VVIR and VVI configurations (172.6 ± 15.5 vs 156.7 ± 12.2 vs 145.5 ± 13.7; P ≤ 0.001). The mean SBP increase showed a similar behavior (51.8 ± 24.7 vs 18.4 ± 13.7 vs 16.4 ± 10.3; P ≤ 0.001). CLS algorithm in a single-chamber device is more effective than AS in detecting an hemodynamic demand due to an emotional stress and supplying a proper HR increase. These results are even more surprising compared to previous data in dual-chamber pacemakers, because they imply that CLS algorithm can provide an appropriate rate-modulation in patients with AF and chronotropic incompetence.


Molecular mechanisms of corticotropin-releasing factor stimulation of calcium mobilization and adrenocorticotropin release from anterior pituitary tumor cells.
In a tumor cell line of the mouse anterior pituitary (AtT-20/D16-16) consisting of a homogeneous population of corticotrophs, corticotropin-releasing factor (CRF) activates adenylate cyclase and cAMP-dependent protein kinase. In addition, CRF induces a rise in cytosolic calcium levels in AtT-20/D16-16 cells and stimulates adrenocorticotropin hormone release. To determine whether activation of cAMP-dependent protein kinase is essential for CRF to stimulate calcium mobilization and trigger adrenocorticotropin hormone release, an inhibitor of cAMP-dependent protein kinase was inserted into AtT-20/D16-16 cells using a liposome technique. In control cells, CRF, forskolin (a direct activator of adenylate cyclase) and potassium increased cytosolic calcium levels. Insertion of the protein kinase inhibitor into AtT-20/D16-16 cells greatly attenuated CRF and forskolin-stimulated calcium mobilization although it did not alter the rise in cytosolic calcium induced by potassium. Treatment of the cells with liposomes lacking protein kinase inhibitor (but containing an equivalent amount of bovine serum albumin) had no effect upon the calcium mobilization elicited by any of the agents tested. These results reveal an essential role for cAMP-dependent protein kinase in mediating CRF-stimulated calcium mobilization and suggest that its activation may be an essential molecular event for CRF to evoke adrenocorticotropin hormone secretion.


Controlled Drug Delivery Systems for Oral Cancer Treatment-Current Status and Future Perspectives.
Oral squamous cell carcinoma (OSCC), which encompasses the oral cavity-derived malignancies, is a devastating disease causing substantial morbidity and mortality in both men and women. It is the most common subtype of the head and neck squamous cell carcinoma (HNSCC), which is ranked the sixth most common malignancy worldwide. Despite promising advancements in the conventional therapeutic approaches currently available for patients with oral cancer, many drawbacks are still to be addressed; surgical resection leads to permanent disfigurement, altered sense of self and debilitating physiological consequences, while chemo- and radio-therapies result in significant toxicities, all affecting patient wellbeing and quality of life. Thus, the development of novel therapeutic approaches or modifications of current strategies is paramount to improve individual health outcomes and survival, while early tumour detection remains a priority and significant challenge. In recent years, drug delivery systems and chronotherapy have been developed as alternative methods aiming to enhance the benefits of the current anticancer therapies, while minimizing their undesirable toxic effects on the healthy non-cancerous cells. Targeted drug delivery systems have the potential to increase drug bioavailability and bio-distribution at the site of the primary tumour. This review confers current knowledge on the diverse drug delivery methods, potential carriers (e.g., polymeric, inorganic, and combinational nanoparticles; nanolipids; hydrogels; exosomes) and anticancer targeted approaches for oral squamous cell carcinoma treatment, with an emphasis on their clinical relevance in the era of precision medicine, circadian chronobiology and patient-centred health care.


Medical pluralism in action? A case study of community pharmacies in Johannesburg, South Africa.
The main aim of this study was to examine whether, and to what extent, community pharmacies have become sites for the practice of complementary and alternative medicine (CAM) as an example of "medical pluralism." Qualitative as well as quantitative methods such as a telephone survey of all pharmacies in Johannesburg, observations, and in-depth interviews with pharmacists and CAM healers were used. The evidence presented in this paper, although based on a study of community pharmacies in Johannesburg only, can be interpreted as an indication of a general trend in urban areas in South Africa, that of involvement with CAM in the form of dispensing and sales of CAM products, provision of advice, and, in a few cases, employment of CAM practitioners to consult on their premises. Thus the two systems of CAM and allopathic medicine are being practiced within the same premises. However, the manner in which they operate, as portrayed in this study, is that of two separate systems existing in relative harmony side-by-side. Because of the constraints of the study, it is difficult to ascertain to what extent this is a first step toward the development of a more meaningful integration between the systems. It is much easier to demonstrate that this growth is driven by the pharmacists' response to the growing demand from the public and their readiness to seize the opportunity to expand their responsibilities and increase their profits. This is supported by the willingness of CAM healers to participate in the endeavor.


Nut and peanut butter intake are not directly associated with the risk of endometrial or ovarian cancer: Results from a Dutch prospective cohort study.
Nut intake has been associated with reduced cancer-related mortality and cancer risk. However, very few studies investigated the association between nut consumption and the risk of endometrial and ovarian cancer, with inconclusive results. We prospectively examined the relation between total nut, tree nut, peanut, and peanut butter intake and the risk of endometrial and ovarian cancer in the prospective Netherlands Cohort Study (NLCS). In 1986, 62,573 women aged 55-69 years were included in the NLCS. At baseline, all participants filled in a questionnaire and a subcohort of 2589 women was randomly selected. After 20.3 years of follow-up, 389 endometrial and 347 ovarian cancer cases with complete data were included in the analysis. Hazard ratios (HRs) were calculated in multivariable-adjusted Cox regression analyses, using a case-cohort approach. Compared to nonconsumers, the HRs (95% confidence intervals) for women consuming 10 + g total nuts/day were 1.23 (0.82-1.87) for endometrial cancer and 0.84 (0.57-1.24) for ovarian cancer. For tree nut, peanut, and peanut butter intake, also no significant relations with endometrial or ovarian cancer were observed. In the endometrial cancer analyses, significant interactions of total nut intake with body mass index and cigarette smoking status were found. The results of this study suggest that intake of total nuts, tree nuts, peanuts, and peanut butter is not related to the risk of endometrial or ovarian cancer. The observed interactions in the endometrial cancer analyses, in particular with cigarette smoking status, require confirmation in other studies.


Free radicals, antioxidants and international nutrition.
The oxidative degradation of polyunsaturated fatty acids is the primary factor in limiting the shelf-life of most manufactured foods. Free radical mechanisms are implicated in the pathogenesis of human diseases and in the process of ageing. This has led to the suggestion that antioxidants, and plant diet-derived antioxidants in particular, might have health benefits as prophylactic agents. Delineating the in vivo contribution of plant extracts and/or plant-derived antioxidants (the pure active principles in plant extracts with antioxidant indications) to the modulation of the pathological consequences of oxidative stress in the human body is complicated by the fact that antioxidant actions may be achieved through more than one mechanism. The interest in the health promoting qualities of plant foods may be ascribed to the observation that various compounds present in these foods possess antioxidant properties in vitro. From a food stability perspective, one would be interested in the integrity of the food and the effects of storage on the molecular components of the food. For humans, the emphasis is on the importance of nutritional antioxidants in health and disease management.


Cautioning Health-Care Professionals.
Science and practice seem deeply stuck in the so-called stage theory of grief. Health-care professionals continue to "prescribe" stages. Basically, this perspective endorses the idea that bereaved people go through a set pattern of specific reactions over time following the death of a loved one. It has frequently been interpreted prescriptively, as a progression that bereaved persons must follow in order to adapt to loss. It is of paramount importance to assess stage theory, not least in view of the current status of the maladaptive "persistent complex bereavement-related disorder" as a category for further research in DSM-5. We therefore review the status and value of this approach. It has remained hugely influential among researchers as well as practitioners across recent decades, but there has also been forceful opposition. Major concerns include the absence of sound empirical evidence, conceptual clarity, or explanatory potential. It lacks practical utility for the design or allocation of treatment services, and it does not help identification of those at risk or with complications in the grieving process. Most disturbingly, the expectation that bereaved persons will, even should, go through stages of grieving can be harmful to those who do not. Following such lines of reasoning, we argue that stage theory should be discarded by all concerned (including bereaved persons themselves); at best, it should be relegated to the realms of history. There are alternative models that better represent grieving processes. We develop guidelines to enhance such a move beyond the stage approach in both theory and practice.


Trimethoprim-sulfamethoxazole v. amoxicillin in the treatment of acute otitis media.
Although amoxicillin has long been the preferred drug for treatment of acute otitis media, resistant strains of two relatively common causal organisms have emerged, prompting a search for other antibiotics. We performed a randomized double-blind trial comparing amoxicillin and trimethoprim-sulfamethoxazole in 221 children in whom acute otitis media was diagnosed in an outpatient setting. Diagnosis was on the basis of symptoms, otoscopic examination and acoustic reflectometry. No culture specimens were taken. A research nurse, using the same methods, evaluated patients in a follow-up home visit at around 14 days and measured compliance by examination of the medicine bottle. Equal proportions of children in the two groups were cured or improved (88% and 87%). Therapeutic efficacy was related to compliance in both groups, and there were few side effects in either group. This study had statistical power of 80% to detect a difference of 15%. We conclude that trimethoprim-sulfamethoxazole can be considered a first-line antibiotic in the treatment of acute otitis media.


Investigation on Ammonia-Biodiesel Fueled RCCI Combustion Engine Using a Split Injection Strategy.
Advanced combustion concepts in compression ignition are emerging as one of the most promising solutions to reduce nitrogen oxides (NOx) and particle emissions without sacrificing fuel efficiency. Among many advanced combustion concepts, reactive controlled compression ignition (RCCI) can achieve a wider working range. In this study, to implement RCCI operation, ammonia gas is introduced through the manifold as a low-reactive fuel, and biodiesel is injected directly as a high-reactivity fuel with a 40:60 energy ratio. The effect of biodiesel split ratio in a split injection strategy (pre- and main injections) is examined under varied load conditions, and the results are compared with ammonia/biodiesel single injection. Results indicate that the use of the 45% biodiesel split ratio at full load boosts the peak in-cylinder pressure and heat release rate and shifts the peak occurrence toward the top dead center (TDC). An increase in brake thermal efficiency (BTE) to 36.22% and reduced brake specific energy consumption (BSEC) to 8.75 MJ/kWh are 12.33% higher and 19.31% lower than ammonia/biodiesel single injection. Emissions of HC, CO, and smoke opacity were reduced to 50 ppm, 0.098% vol, and 15.6%, which are 34.21, 39.13, and 33.89% lower, while the emission of NOx was increased to 615 ppm, which is 36.06% higher than the single-injection ammonia/biodiesel RCCI combustion.


Two natural eudesmane-type sesquiterpenes from Laggera alata inhibit angiogenesis and suppress breast cancer cell migration through VEGF- and Angiopoietin 2-mediated signaling pathways.
Eudesmane-type sesquiterpenes are natural sesquiterpenes with anti-inflammatory properties, but their anti-angiogenic activities are not known. The present study demonstrated that 5α-hydroxycostic acid and hydroxyisocostic acid, two eudesmane-type sesquiterpenes (ETSs), isolated from the herb Laggera alata, possessed anti-angiogenic effects. Under non-toxic dosage, ETSs suppressed VEGF‑induced proliferation in human umbilical vein endothelial cells (HUVECs) and vessel formation in zebrafish embryos. Moreover, ETSs inhibited VEGF-stimulated HUVEC migration, stress fibers and tube formation. Results from real‑time PCR analysis involving in vivo and in vitro experiments indicated that pro-angiogenic-related mRNA levels were downregulated, including VEGFA, VEGFR2 and Tie2 genes after ETS treatments. Western blot analysis showed that ETSs suppressed VEGF-stimulated VEGFR2 phosphorylation and activation of its downstream molecules, such as Src/AKT/eNOS, FAK, PLCγ/ERK1/2 and p38. Moreover, the VEGF-stimulation of angiopoietin 2 (Ang2) mRNA level increase was significantly downregulated in the presence of ETSs. ETSs inhibited Ang2-induced phosphorylation of the receptor Tie2 in HUVECs, which indicated that ETSs not just suppressed VEGF/VEGFR2 axis, but also the Ang2/Tie2 one. Furthermore, the wound-healing assay revealed that ETSs reduced the migration of Ang2-stimulated human breast cancer (MCF-7) cells. Mechanistically, the anti-migration effect of ETSs correlated with the blockade of Ang2-induced E-cadherin loss and AKT activation. Collectively, the present study suggests that ETSs possess anti-angiogenic ability by interfering the VEGF- and Ang2-related pathways, and they may be good drug candidates.


Cobalt-Catalyzed Decarboxylative Allylations: Development and Mechanistic Studies.
In recent years, there has been a concerted drive to develop methods that are greener and more sustainable. Being an earth-abundant transition metal, cobalt offers an attractive substitute for commonly employed precious metal catalysts, though reactions engaging cobalt are still less developed. Herein, we report a method to achieve the decarboxylative allylation of nitrophenyl alkanes, nitroalkanes, and ketones employing cobalt. The reaction allows for the formation of various substituted allylated products in moderate-excellent yields with a broad scope. Additionally, the synthetic potential of the methodology is demonstrated by the transformation of products into versatile heterocyclic motifs. Mechanistic studies revealed an in situ activation of the Co(II)/dppBz precatalyst by the carboxylate salt to generate a Co(I)-species, which is presumed to be the active catalyst.


Unique Features of Aeromonas Plasmid pAC3 and Expression of the Plasmid-Mediated Quinolone Resistance Genes.
A highly fluoroquinolone-resistant isolate of Aeromonas species was isolated from a wastewater treatment plant and found to possess multiple resistance mechanisms, including mutations in gyrA and parC, efflux pumps, and plasmid-mediated quinolone resistance (PMQR) genes. Complete sequencing of the IncU-type plasmid, pAC3, present in the strain revealed a circular plasmid DNA 15,872 bp long containing two PMQR genes [qnrS2 and aac(6')-Ib-cr]. A mobile insertion cassette element containing the qnrS2 gene and a typical miniature inverted-repeat transposable element (MITE) structure was identified in the plasmid. The present study revealed that this MITE sequence appears in other Aeromonas species plasmids and chromosomes. Plasmid pAC3 was introduced into Escherichia coli, and its PMQR genes were expressed, resulting in the acquisition of resistance. Proteome analysis of the recipient E. coli strain harboring the plasmid revealed that aac(6')-Ib-cr expression was constitutive and that qnrS2 expression was dependent upon fluoroquinolone stress through regulation by regulator of sigma D (Rsd). To the best of our knowledge, this is the first report to characterize a novel MITE sequence upstream of the PMQR gene within a mobile insertion cassette, as well as the regulation of qnrS2 expression. Our results suggest that this mobile element may play an important role in qnrS2 dissemination. IMPORTANCE In the present study, plasmid pAC3 isolated from a highly fluoroquinolone-resistant isolate of Aeromonas species was sequenced and found to contain two fluoroquinolone resistance genes, aac(6')-Ib-cr and qnrS2. Comparative analyses of plasmid pAC3 and other Aeromonas sp. IncU-type plasmids revealed a mobile insertion cassette element with a unique structure containing a qnrS2 gene and a typical miniature inverted-repeat transposable element (MITE) structure. This study also revealed that this MITE sequence appears in other Aeromonas species plasmids and chromosomes. Our results also demonstrate that the fluoroquinolone-dependent expression of qnrS2 is associated with rsd in E. coli DH5α harboring plasmid pAC3. Our findings suggest that the mobile element may play an important role in qnrS2 dissemination and that Aeromonas species constitute an important reservoir of fluoroquinolone resistance determinants in the environment.


Sensitive and high resolution in situ hybridization to human chromosomes using biotin labelled probes: assignment of the human thymocyte CD1 antigen genes to chromosome 1.
A method for in situ hybridization originally developed for mapping genes in the nematode, Caenorhabditis elegans has been adapted for high resolution cytological mapping of genes in the human. The probe DNAs are labelled by incorporation of biotin dUTP and the site of hybridization detected by immunofluorescence. For the accurate assignment of the hybridization signal to chromosome bands, visualized by staining with Hoechst 33258, a heterologous ribosomal DNA probe is also included in the hybridization reaction. These rDNA signals are used as fiducial markers when aligning the two fluorescent images. We demonstrate the method by assignment of the human thymocyte CD1 antigen genes to human chromosome 1q22-23.


Selecting the donor liver: risk factors for poor function after orthotopic liver transplantation.
Initial poor function and primary nonfunction are important problems in clinical transplantation. The incidence of primary nonfunction is about 6% and that of initial poor function is about 15%. Grafts with initial poor function have a higher graft failure rate in the first 3 mo after transplantation. Severe steatosis and cold preservation in University of Wisconsin solution for over 30 hr will alone cause primary nonfunction. However, primary nonfunction is probably most often caused by the presence of multiple relative risk factors. The major donor-relative risk factors are moderate steatosis, cold preservation over 12 hr and donor age over 50 yr, whereas retransplantation, high (United Network of Organ Sharing class 4) medical status and kidney failure are recipient relative risk factors. The most important perioperative risk factor is warm ischemia time. Rates of primary nonfunction and initial poor function might be reduced by avoidance of combinations of risk factors. Several tests have been developed to predict primary nonfunction and initial poor function, but none is yet clinically efficient.


Domain differences in the weights of perceptual and conceptual information in children's categorization.
Visual appearance is one of the main cues children rely on when categorizing novel objects. In 3 studies, testing 128 3-year-olds and 192 5-year-olds, we investigated how various kinds of information may differentially lead children to overlook visual appearance in their categorization decisions across domains. Participants saw novel animals or artifacts of varying degrees of similarity to target categories and were asked to place them in 1 of 2 categories. Manipulated across studies was the kind of information pitted against visual similarity: internal information (Study 1, both 3- and 5-year-olds), intentional information (Study 2, both 3- and 5-year-olds), or labels (Study 3, only 5-year-olds). Overall, we found that for 5-year-olds, but not so for 3-year-olds, internal information had a stronger effect on the categorization of animals than of artifacts. Intentional information, in turn, had a stronger effect on both age groups' categorization of artifacts than of animals. Labels too had a stronger effect on 5-year-olds' categorization of artifacts than of animals. These findings are consistent with a domain-specific account of categorization, according to which the weight of different kinds of information on categorization decisions depends on children's developing understanding of domains.


HPV types and E6/E7 mRNA expression in cervical samples from Turkish women with abnormal cytology in Ankara, Turkey.
Human papillomaviruses have been established as a risk factor for invasive carcinoma of the uterine cervix. HPV E6/E7 oncogene expression has recently emerged as a promising biomarker to determine the risk for progression to high-grade cervical lesions. The aim of this study was to evaluate HPV mRNA and DNA detection in samples with abnormal cytology. Cervical specimens were obtained at the Department of Obstetrics and Gynecology via cervical brushes during January-October 2011. Liquid-based cytology slides were evaluated according to the 2001 Bethesda System. Cytology specimens from a total of 81 women with abnormal cytology were included. Real-time PCR and NASBA assays were performed to detect HPV DNA and E6/E7 mRNA, respectively. HPV DNA was identified in 73 samples (90.1%). HPV E6/E7 mRNA expression was observed in 45 samples (55.6%). A statistically significant difference was observed among cytological diagnosis groups. In 25 patients, a biopsy was performed during the follow-up. HPV DNA was detected in all of these patients. HPV E6/E7 expression was present only in CIN I-III diagnosed patients. The E6/E7 mRNA test is a robust indicator of cytological atypia and correlates better with progressive lesions than DNA assays.


Fabrication of nano-hydroxyapatite using a novel ultrasonic atomization precipitation method.
A novel technique to synthesize hydroxyapatite (HAP) with nanocrystalline structure was developed in this study. Nanocrystalline HAP was prepared by a precipitation method with aid of ultrasonic atomization using Ca(NO3)2 x 4H2O and (NH4)2HPO4 as raw materials. The crystallization and the morphology of the prepared nanopowder were characterized by X-ray diffraction (XRD) and scanning electron microscopy (SEM). The obtained powder was 30-40 nm in size and homogenous. The effect of some surfactants on the crystallization and morphology of HAP nanoparticles was also investigated. The results showed that the synthesis method used in this study can effectively shorten the reaction time while improving the homogeneity of the powder when compared to other published methods. It was also found that the addition of a small amount of surfactant glycine during the precipitation synthesis can reduce the agglomeration of the HAP nanoparticles.


Lactococcus insecticola sp. nov. and Lactococcus hodotermopsidis sp. nov., isolated from the gut of the wood-feeding lower termite Hodotermopsis sjostedti.
Two strains of lactic acid bacteria, designated Hs20B0-1T and Hs30E4-3T, were isolated from the gut of the damp-wood termite Hodotermopsis sjostedti. These strains were characterized genetically and phenotypically. Strain Hs20B0-1T was related to Lactococcus piscium DSM 6634T showing 96.3 and 84.2 % sequence similarity in 16S rRNA gene and rpoB gene sequences, respectively. Strain Hs30E4-3T was related to Lactococcus plantarum DSM 20686T showing 94.8 and 82.2 % sequence similarity in 16S rRNA gene and rpoB gene sequences, respectively. The 16S rRNA gene sequence similarity between strains Hs20B0-1T and Hs30E4-3T was 95.7 %. Furthermore, genomic comparisons using pairwise average nucleotide identity (ANI) and digital DNA-DNA hybridization (DDH) analyses between strain Hs20B0-1T and L. piscium DSM 6634T resulted in values of 73.5 and 20.1 %, respectively. Strain Hs30E4-3T had 72.8 % ANI similarity and 21.3 % DDH similarity to L. plantarum DSM 20686T. Strains Hs20B0-1T and Hs30E4-3T had 75.4 % ANI similarity and 21.1 % DDH similarity to each other. The cell-wall peptidoglycan types of strains Hs20B0-1T and Hs30E4-3T were A4α, Lys-Asp and A3α, Lys-Thr-Ala, respectively. The two strains, Hs20B0-1T and Hs30E4-3T, are distinguishable from each other and other established Lactococcus species phylogenetically and phenotypically. In conclusion, two novel species of the genus Lactococcus are proposed, namely Lactococcus insecticola Hs20B0-1T (=JCM 33485T=DSM 110147T) and Lactococcus hodotermopsidis Hs30E4-3T (=JCM 33486T=DSM 110148T), respectively.


Effects of capsaicin on corneal wound healing.
This study examined whether the depletion of neuropeptides from sensory nerve terminals induced by capsaicin modifies the healing rate of experimental corneal wounds in adult rabbits. Capsaicin (33 or 3.3 mM solutions) was administered topically and/or by a single retrobulbar injection to one eye while the fellow eye, treated with the vehicle, served as a control. After 1-3 weeks of treatment, an epithelial wound was made in the center of the cornea of both eyes with n-heptanol. Migration rates of epithelial cells surrounding the wound and estimated wound closure times were calculated by measuring the reduction in wound size. Combined treatment with 33 mM retrobulbar and 3.3 mM topical capsaicin for 3 weeks induced a significant delay in epithelial migration rates and in wound closure times (P less than 0.05). Topical or retrobulbar capsaicin alone for 3 weeks and combined treatment lasting only 1 week were not sufficient to modify wound healing times. The substance P antagonist, spantide (3 mM), applied topically for 1-3 weeks before or immediately after corneal wounding was also ineffective in changing wound closure rates. These findings suggest that the delayed wound healing observed after prolonged treatment with capsaicin could be due to a sustained depletion of neuropeptides from corneal sensory endings, supporting the hypothesis that trophic effects of sensory nerves on corneal epithelium are, at least in part, mediated by neuropeptides contained in peripheral nerve terminals.


Iron Acquisition Pathways as Targets for Antitubercular Drugs.
Tuberculosis nowadays ranks as the second leading cause of death from an infectious disease worldwide. In the last twenty years, this disease has again started to spread mainly for the appearance of multi-drug resistant forms. Therefore, new targets are needed to address the growing emergence of bacterial resistance and for antitubercular drug development. Efficient iron acquisition is crucial for the pathogenesis of Mycobacterium tuberculosis, because it serves as cofactor in many essential biological processes, including DNA biosynthesis and cellular respiration. Bacteria acquire iron chelating non-heme iron from the host using the siderophore mycobactins and carboxymycobactins and by the uptake of heme iron released by damaged red blood cells, through several acquisition systems. Drug discovery focused its efforts on the inhibition of MbtI and MbtA, which are are two enzymes involved in the mycobactin biosynthetic pathway. In particular, MbtI inhibitors have been studied in vitro, while MbtA inhibitors showed activity also in infected mice. Another class of compounds, MmpL3 inhibitors, showed antitubercular activity in vitro and in vivo, but their mechanism of action seems to be off-target. Some compounds inhibiting 4'-phosphopantetheinyl transferase were discovered but not tested on in vivo assays. The available data reported in this study based on inhibitors and gene deletion studies, suggest that targeting iron acquisition systems could be considered a promising antitubercular strategy. Due to their redundancy, the relative importance of each pathway for Mycobacterium tuberculosis survival has still to be determined. Thus, in vivo studies with new, potent and specific inhibitors are needed to highlight target selection.


Optical and Chemical Characterization of Uranium Dioxide (UO2) and Uraninite Mineral: Calculation of the Fundamental Optical Constants.
Uranium dioxide (UO2) is a material with historical and emerging applications in numerous areas such as photonics, nuclear energy, and aerospace electronics. While often grown synthetically as single-crystal UO2, the mineralogical form of UO2 called uraninite is of interest as a precursor to various chemical processes involving uranium-bearing chemicals. Here, we investigate the optical and chemical properties of a series of three UO2 specimens: synthetic single-crystal UO2, uraninite ore of relatively high purity, and massive uraninite mineral containing numerous impurities. An optical technique called single-angle reflectance spectroscopy was used to derive the optical constants n and k of these uranium specimens by measuring the specular reflectance spectra of a polished surface across the mid- and far-infrared spectral domains (ca. 7000-50 cm-1). X-ray diffractometry, scanning electron microscopy, and energy-dispersive X-ray spectroscopy were further used to analyze the surface composition of the mineralogical forms of UO2. Most notably, the massive uraninite mineral was observed to contain significant deposits of calcite and quartz in addition to UO2 (as well as other metal oxides and radioactive decay products). Knowledge of the infrared optical constants for this series of uranium chemicals facilitates nondestructive, noncontact detection of UO2 under a variety of conditions.


Unusual presentation and treatment of biliary ileus with long term follow up: case report and review of the literature.
Gallstone ileus is a rare complication of cholelithiasis. It accounts for 25% of nonstrangulated small bowel obstructions in patients over the age of 65 years. The morbidity and mortality rate of gallstone ileus remains very high, partly because of misdiagnosis or delayed diagnosis. The two surgical options are: a) enterolithotomy with removal of impacted stone, cholecystectomy, and fistula repair at the same surgical operation (i.e., "one-stage" procedure) and b) enterolithotomy with stone extraction followed or not by elective biliary surgery. The latter is the most popular surgical approach, whereas enterolithotomy combined with cholecistectomy and fistulectomy is indicated only in selected cases. In this article, a case of biliary ileus with unusual presentation treated by entherolithotomy alone with long term follow up is described, and the literature on this subject is reviewed and discussed.


Uniportal video-assisted thoracoscopic resection of anterior segment of the left upper lobe.
Anatomical segment resections are often technically more demanding than lobectomies. Anterior segment of the left upper lobe (S3) is usually removed within the standard resection of the upper three segments. Our patient in this case was a 56-year-old with a known oropharyngeal carcinoma, otherwise amenable to curative treatment, who was admitted to our clinic with a 1-cm nodule in the anterior segment of the left upper lobe. Distant metastases were excluded, and a decision was made to proceed with a uniportal video-assisted thoracoscopic segmentectomy and lymphadenectomy. The procedure was successfully conducted without any adverse effects and the patient's postoperative course was uneventful. The tumor was diagnosed as a primary solid 1-cm adenocarcinoma and the final stage was pT1aN0M0.


Artificial environments for the co-translational stabilization of cell-free expressed proteins.
An approach for designing individual expression environments that reduce or prevent protein aggregation and precipitation is described. Inefficient folding of difficult proteins in unfavorable translation environments can cause significant losses of overexpressed proteins as precipitates or inclusion bodies. A number of chemical chaperones including alcohols, polyols, polyions or polymers are known to have positive effects on protein stability. However, conventional expression approaches can use such stabilizing agents only post-translationally during protein extraction and purification. Proteins that already precipitate inside of the producer cells cannot be addressed. The open nature of cell-free protein expression systems offers the option to include single chemicals or cocktails of stabilizing compounds already into the expression environment. We report an approach for systematic screening of stabilizers in order to improve the solubility and quality of overexpressed proteins co-translationally. A comprehensive list of representative protein stabilizers from the major groups of naturally occurring chemical chaperones has been analyzed and their concentration ranges tolerated by cell-free expression systems have been determined. As a proof of concept, we have applied the method to improve the yield of proteins showing instability and partial precipitation during cell-free synthesis. Stabilizers that co-translationally improve the solubility and functional folding of human glucosamine 6-phosphate N-acetyltransferase have been identified and cumulative effects of stabilizers have been studied.


On the cause of the variation in tissue-maximum ratio values with source-to-detector distance.
While tissue-maximum ratios (TMR) for 60cobalt treatment units have been shown to be independent of source-to-axis distance (SAD), high-energy photon beams demonstrate variations in their TMR as a function of SAD. Some authors have asserted that the distance dependence of the TMR stems from electron contamination in the beams, while others have suggested low-energy, scattered photons as the cause. Using a magnet to sweep contaminant electrons out of the photon treatment beam eliminates any variation in TMR with distance. Thus, electron contamination accounts for all of the distance dependence, and any low-energy, scattered photons behave indistinguishably like the high-energy photons.


Fourth-degree burn of the brain from friction burn of scalp: an unusual injury from a golf cart.
Intracranial injury has been reported secondary to not only blunt and penetrating trauma but also thermal and high-voltage electrical injury. Reconstruction can be challenging, especially in the face of necrosis of large areas of the cranium. The authors present a novel case of fourth-degree thermal burn to the head caused by a rotating tire. Initial wound debridement exposed dura, prompting a dural patch and Integra® for temporary coverage. Definitive coverage was accomplished with a latissimus dorsi free flap. The injury was complicated by associated neurologic defects and seizure activity. However, management was effective, and at 1 year, the patient is alive and well.


[Melanoma and dysplastic nevus after 8 years of topical Caryolysine].
A 48-year-old woman with poikiloderma atrophicans vasculare was treated with topical mechlorethamine, applied three times weekly, for eight years. After five years treatment she developed nine melanocytic naevi on covered skin. The naevi spread for the next three years and a surgical excision was performed. Pathological examination revealed one level II SSM, one level I SSM and seven junctional naevi with focal dysplasia or melanocytic hyperplasia. The development of melanoma and dysplastic naevi after topical mechlorethamine has not been previously reported. However it seems likely that mechlorethamine was the causative agent. As for the mechlorethamine's imputability in this case, we have used a method combining intrinsic identification of adverse drug responsibility's score, based on the clinical case and on extrinsic identification based on literature evaluation. We suggest that mechlorethamine could act as UV light.


Dual Action of Mexiletine and Its Pyrroline Derivatives as Skeletal Muscle Sodium Channel Blockers and Anti-oxidant Compounds: Toward Novel Therapeutic Potential.
Mexiletine (Mex) has been recently appointed as an orphan-drug in myotonic-syndromes, being a potent use-dependent blocker of skeletal-muscle sodium channels (NaV1.4). Available evidences about a potential anti-oxidant effect of Mex and its tetramethyl-pyrroline-derivatives in vivo, suggest the possibility to further enlarge the therapeutic potential of Mex-like compounds in myopathies in which alteration of excitation-contraction coupling is paralleled by oxidative stress. In line with this and based on our previous structure-activity-relationship studies, we synthesized new compounds with a tetramethyl-pyrroline-ring on the amino-group of both Mex (VM11) and of its potent use-dependent isopropyl-derivative (CI16). The compounds were tested for their ability to block native NaV1.4 and to exert cyto-protective effects against oxidative-stress injury in myoblasts. Voltage-clamp-recordings on adult myofibers were performed to assess the tonic and use-dependent block of peak sodium-currents (INa) by VM11 and CI16, as well as Mex, VM11 and CI16 were 3 and 6-fold more potent than Mex in producing a tonic-block of peak sodium-currents (INa), respectively. Interestingly, CI16 showed a 40-fold increase of potency with respect to Mex during high-frequency stimulation (10-Hz), resulting the strongest use-dependent Mex-like compound so far. The derivatives also behaved as inactivated channel blockers, however the voltage dependent block was modest. The experimental data fitted with the molecular-modeling simulation based on previously proposed interaction of main pharmacophores with NaV1.4 binding-site. CI16 and VM11 were then compared to Mex and its isopropyl derivative (Me5) for the ability to protect C2C12-cells from H2O2-cytotoxicity in the concentration range effective on Nav1.4. Mex and Me5 showed a moderate cyto-protective effect in the presence of H2O2, Importantly, CI16 and VM11 showed a remarkable cyto-protection at concentrations effective for use-dependent block of NaV1.4. This effect was comparable to that of selected anti-oxidant drugs proved to exert protective effect in preclinical models of progressive myopathies such as muscular dystrophies. Then, the tetramethyl-pyrroline compounds have increased therapeutic profile as sodium channel blockers and an interesting cyto-protective activity. The overall profile enlarges therapeutic potential from channelopathies to myopathies in which alteration of excitation-contraction coupling is paralleled by oxidative-stress, i.e., muscular dystrophies.


TGF-β1 signaling pathway serves a role in HepG2 cell regulation by affecting the protein expression of PCNA, gankyrin, p115, XIAP and survivin.
The transforming growth factor-β (TGF-β) signaling pathway serves a key role in the pathogenesis of liver cancer. To investigate the association between TGF-β1 and the following proteins: Proliferating cell nuclear antigen (PCNA), gankyrin, general vesicular transport factor p115 (p115), X-linked inhibitor of apoptosis protein (XIAP) and survivin, HepG2 liver cancer cells were transfected with small interfering RNA (siRNA) directed against TGF-β1, or were treated with exogenous TGF-β1. TGF-β1 protein expression levels were assessed at 72 and 96 h using western blotting, cell growth was evaluated using a Cell Counting kit-8 assay, and flow cytometry was used to examine cell cycle distribution and apoptosis. In addition, PCNA, gankyrin, p115, XIAP and survivin protein levels were evaluated using western blotting. TGF-β1 protein expression levels were decreased at 72 and 96 h following siRNA transfection, indicating that the siRNA against TGF-β1 was effective. In the TGF-β1-knockdown group, the HepG2 cells exhibited G1 or S-phase cell cycle arrest; therefore, the number of G2-phase cells was decreased, cell growth was inhibited and apoptotic peaks were observed. By contrast, no significant alteration in cell cycle distribution or apoptosis was observed in the cells treated with exogenous TGF-β1. In the exogenous TGF-β1 group, PCNA and XIAP protein expression levels were increased, whereas gankyrin, p115 and survivin protein expression was observed to be dependent on the duration of treatment. By contrast, PCNA, gankyrin, XIAP and survivin protein expression decreased following TGF-β1 knockdown; however, p115 protein expression increased. In conclusion, the TGF-β1 signaling pathway may affect cell growth, cell cycle distribution and apoptosis through the regulation of PCNA, gankyrin, p115, XIAP and survivin protein expression in liver cancer. The results of the present study may improve the current understanding of the role of the TGF-β signaling pathway during the pathogenesis of liver cancer.


Factors to consider when choosing long-term care insurance.
New policies regarding long-term care insurance offer access to a variety of care options and services. This information can initiate discussions about long-term care needs and financial options for you and your patient population. This article provides an overview of long-term care and factors to consider when choosing insurance programs and benefits.


Innate immunity, assessed by plasma NO measurements, is not suppressed during the incubation fast in eiders.
Immunity is hypothesized to share limited resources with other physiological functions and may mediate life history trade-offs, for example between reproduction and survival. However, vertebrate immune defense is a complex system that consists of three components. To date, no study has assessed all of these components for the same animal model and within a given situation. Previous studies have determined that the acquired immunity of common eiders (Somateria mollissima) is suppressed during incubation. The present paper aims to assess the innate immune response in fasting eiders in relation to their initial body condition. Innate immunity was assessed by measuring plasma nitric oxide (NO) levels, prior to and after injection of lipopolysaccharides (LPS), a method which is easily applicable to many wild animals. Body condition index and corticosterone levels were subsequently determined as indicators of body condition and stress level prior to LPS injection. The innate immune response in eiders did not vary significantly throughout the incubation period. The innate immune response of eiders did not vary significantly in relation to their initial body condition but decreased significantly when corticosterone levels increased. However, NO levels after LPS injection were significantly and positively related to initial body condition, while there was a significant negative relationship with plasma corticosterone levels. Our study suggests that female eiders preserve an effective innate immune response during incubation and this response might be partially determined by the initial body condition.


Differential effects of saturated versus unsaturated dietary fatty acids on weight gain and myocellular lipid profiles in mice.
In conditions of continuous high-fat (HF) intake, the degree of saturation of the fatty acids (FAs) in the diet might have a crucial role in the onset of obesity and its metabolic complications. In particular, the FA composition of the diet might influence the storage form of lipids inside skeletal muscle. The aim of the present study was to examine whether the FA composition of HF diets differentially affects weight gain and accumulation of myocellular triacylglycerol (TAG) and diacylglycerol (DAG). Furthermore, we examined whether the FA composition of the diet was reflected in the composition of the myocellular lipid intermediates. C57Bl6 mice were fed HF diets (45% energy) mainly containing palm oil (PO), cocoa butter (CB), olive oil (OO) or safflower oil (SO; n=6 per group) for 8 weeks. A low-fat diet (10% energy, PO) was used as control. Body weight was monitored weekly. At the end of the dietary intervention, myocellular TAG and DAG content and profiles were measured. We here show that HF_CB prevented weight gain after 8 weeks of HF feeding. Furthermore, the HF diet rich in SO prevented the accumulation of both myocellular TAG and DAG. Interestingly, the FA composition of DAG and TAG in skeletal muscle was a reflection of the dietary FA composition. Already after a relatively short period, the dietary FA intake relates to the FA composition of the lipid metabolites in the muscle. A diet rich in polyunsaturated FAs seems to prevent myocellular lipid accumulation.


Induced parturition in cattle. 1. Clinical studies.
Parturition was induced in 17 Friesland heifers to decrease the possible occurrence of dystocia. The heifers were given 39 mg dexamethasone intra-muscularly on the 267th day of pregnancy and were observed for signs of impending parturition. The time of foetal membrane expulsion was noted. Parturition occurred on an average of 57 hours after corticosteroid administration. Three heifers required assistance during parturition. In one case a second injection of dexamethazone had to be given. The incidence of retained placenta was 68,8%. Rectal examination five to seven months after induction revealed that 76,5% of all animals were again pregnant. Of the four non-pregnant animals three had received assistance during parturition.


[Effect of Helicobacter pylori Infection on Autonomic Nervous Function and Calcitonin Gene-related Peptide in Patients with Functional Dyspepsia].
Objective To investigate the effects of Helicobacter pylori(H.pylori)infection on autonomic nervous function and calcitonin gene-related peptide in patients with functional dyspepsia(FD). Methods Thirty-one patients with FD matching Rome Ⅳ criteria were included and divided into H.pylori-positive group and H.pylori-negative group.All patients were evaluated by Symptom Index of Dyspepsia(SID),Nepean Dyspepsia Index(NDI),and Hospital Anxiety and Depression Scale(HADS).Their heart rate variability(HRV)and calcitonin gene-related peptide(CGRP)level were also measured. Results There were no significant differences in SID(Z=-0.858, P=0.858),NDI(Z=-1.464, P=0.143),and Hospital Depression Scale score(Z=0.699, P=0.485).However,the Hospital Anxiety Scale score was significantly higher in H.pylori-positive group than the H.pylori-negative group(Z=-2.470, P=0.014).The level of CGRP in H.pylori-positive group[(0.999±0.274)ng/ml]was significantly higher than that in the H.pylori-negative group[(0.812±0.172)ng/ml;t=2.238, P=0.033].HRV data showed no significant difference between these two groups at very low frequency(t=-1.210, P=0.236),low frequency(LF)(t=0.419, P=0.678),high frequency(HF)(t=0.612, P=0.546),LF/HF(t=-0.882, P=0.399),and total power(t=-0.963, P=0.344). Conclusion In FD patients,patients with H.pylori-positive FD patients have higher depression and CGRP levels than those without H.pylori infection,although their dyspepsia symptoms and HRV show no notable changes.


Cryptococcal meningitis after transnasal transsphenoidal pituitary microsurgery of ACTH-secreting pituitary adenoma: A case report.
Microbial infection should be regarded in the differential diagnosis of neurosurgical complications after transnasal transsphenoidal pituitary microsurgery, albeit cryptococcal meningitis is rare. This article will discuss the risk factors of cryptococcal meningitis in patients underwent transnasal transsphenoidal pituitary microsurgery, and summary the potential origins of infection. Here, we report a case of 37-year-old male who had cryptococcal meningitis after transnasal transsphenoidal pituitary microsurgery of a relapsing ACTH-secreting pituitary adenoma. Standard therapy for Cryptococcus neoformans (fluconazole [400 mg per day] and flucytosine) was administered and followed by maintenance dose. The patient had been on treatment for one and a half years during follow-up and reported neurologically well with repeated negative cerebrospinal fluid (CSF) culture until sudden death of heart arrest. C neoformans can be a possible cause of meningitis in immunocompetent patients after transnasal transsphenoidal pituitary microsurgery. Risk factors, such as pre-existed pulmonary infection and Cushing-associated hypercortisolemia, should be stressed. Promising preventive measures may include preoperative routine sputum smear and India-ink stain for screening, preoperative treatment of cryptococcal pneumonia, postoperative antibiotic management, and a more secure skull base reconstruction. Radiation and pharmaceutical treatment may be alternative for recurrent Cushing disease.


Peptide-based vaccine for cancer therapies.
Different strategies based on peptides are available for cancer treatment, in particular to counter-act the progression of tumor growth and disease relapse. In the last decade, in the context of therapeutic strategies against cancer, peptide-based vaccines have been evaluated in different tumor models. The peptides selected for cancer vaccine development can be classified in two main type: tumor-associated antigens (TAAs) and tumor-specific antigens (TSAs), which are captured, internalized, processed and presented by antigen-presenting cells (APCs) to cell-mediated immunity. Peptides loaded onto MHC class I are recognized by a specific TCR of CD8+ T cells, which are activated to exert their cytotoxic activity against tumor cells presenting the same peptide-MHC-I complex. This process is defined as active immunotherapy as the host's immune system is either de novo activated or restimulated to mount an effective, tumor-specific immune reaction that may ultimately lead to tu-mor regression. However, while the preclinical data have frequently shown encouraging results, therapeutic cancer vaccines clinical trials, including those based on peptides have not provided satisfactory data to date. The limited efficacy of peptide-based cancer vaccines is the consequence of several factors, including the identification of specific target tumor antigens, the limited immunogenicity of peptides and the highly immunosuppressive tumor microenvironment (TME). An effective cancer vaccine can be developed only by addressing all such different aspects. The present review describes the state of the art for each of such factors.


Targeting Prostate Cancer, the 'Tousled Way'.
Androgen deprivation therapy (ADT) has been the mainstay of prostate cancer (PCa) treatment, with success in developing more effective inhibitors of androgen synthesis and antiandrogens in clinical practice. However, hormone deprivation and AR ablation have caused an increase in ADT-insensitive PCas associated with a poor prognosis. Resistance to ADT arises through various mechanisms, and most castration-resistant PCas still rely on the androgen axis, while others become truly androgen receptor (AR)-independent. Our research identified the human tousled-like kinase 1 (TLK1) as a crucial early mediator of PCa cell adaptation to ADT, promoting androgen-independent growth, inhibiting apoptosis, and facilitating cell motility and metastasis. Although explicit, the growing role of TLK1 biology in PCa has remained underrepresented and elusive. In this review, we aim to highlight the diverse functions of TLK1 in PCa, shed light on the molecular mechanisms underlying the transition from androgen-sensitive (AS) to an androgen-insensitive (AI) disease mediated by TLK1, and explore potential strategies to counteract this process. Targeting TLK1 and its associated signaling could prevent PCa progression to the incurable metastatic castration-resistant PCa (mCRPC) stage and provide a promising approach to treating PCa.


Percutaneous left main coronary artery stent for acute myocardial ischemia after repaired ALCAPA.
Percutaneous coronary artery stent angioplasty is rare in the pediatric population but can be a life-saving by rapidly reestablishing flow to an obstructed coronary artery. It is a technically challenging and high-risk procedure in infants and further limited by the need for future surgical intervention. We report of an infant with anomalous left coronary artery from the pulmonary artery who underwent acutely successful surgical reimplantation of the left coronary artery onto the ascending aorta. One month later, she developed acute myocardial ischemia and emergent catheterization diagnosed near-total occlusion of the left coronary artery. We implanted a 2.5 mm coronary stent in the left main coronary artery with reestablishment of flow. The patient's left ventricular systolic function recovered within 4 weeks and repeat angiography 3 months later showed complete normalization of the entire left coronary artery system. The patient weighed 3 kg and was < 6 weeks of age at the time of stent implantation which to our knowledge is the smallest and youngest reported patient to undergo coronary stent angioplasty. This case supports the feasibility of this procedure in infants as a temporizing solution to hemodynamic instability from myocardial ischemia due to coronary artery stenosis. The left ventricular systolic function remained normal at 7 months after stent placement and the patient was clinically well from a cardiac perspective.


Nucleotide sequences of cDNAs encoding four complete nuclear-encoded plastid ribosomal proteins.
The nucleotide sequences of four pea nuclear-encoded plastid ribosomal protein cDNAs have been determined. These cDNAs were shown to encode the complete precursor proteins. The transit sequences of the encoded proteins are similar to the transit sequences of other imported proteins being rich in serine and/or threonine and lacking aspartic and glutamic acid. The transit sequences do not, however, have any apparent amino acid sequence similarity with one another or with the transit sequences of other imported proteins. The derived amino acid sequences of the plastid ribosomal proteins were compared to the amino acid sequences of other ribosomal proteins. Significant amino acid sequence similarity was found between Escherichia coli ribosomal proteins L9 and L24 and two of the nuclear-encoded pea plastid ribosomal proteins.


Inflammatory myopathy in adults, health-related quality of life, and wellbeing: a round trip between immune disease and wellness.
Health-related quality of life (HRQoL) and wellbeing are poorer in patients with chronic conditions than in the general population, and this is the case of individuals with myositis. Research has shown a negative relationship between this disease and wellbeing, but there is little data on the effect that enhanced wellbeing has on the disease course. HRQoL, wellbeing, and other related concepts are examined here with special emphasis on the benefits of positive status in the physical, environmental, psychological, and social function areas for reducing the severity of the clinical course and organ damage in a chronic condition such as myositis. The factors affecting HRQoL, and wellbeing are analyzed to delineate specific strategies that will lead to improvements in the life of adult patients with myositis. The mechanisms implicated in these changes are also discussed. Myositis refers to a heterogeneous group of chronic systemic autoimmune diseases. HRQoL and wellbeing are poor in these patients, and evidence suggests that improvements in this line can have positive repercussions on the course and outcome of the disease. Strategies to improve HRQoL and wellbeing should be designed for adults with myositis.


Current Issues in Duodenoscope-Associated Infections: Now Is the Time to Take Action.
A duodenoscope has a very complex structure that contains many small parts which make reprocessing more challenging. The difficulty in cleaning duodenoscopes contributes to a higher risk of infection than that of conventional gastrointestinal endoscopes. However, a duodenoscope shares similar disinfection process with other gastrointestinal endoscopes. Recent outbreaks of carbapenem-resistant Enterobacteriaceae (CRE) infections associated with duodenoscopes used for endoscopic retrograde cholangiopancreatography procedures have raised many concerns worldwide. Duodenoscope-associated infections involving CRE or other multidrug-resistant bacteria pose a great threat to patients undergoing procedures using duodenoscopes and should be dealt with a great concern. Updated guidelines regarding cleaning and disinfection of duodenoscope needs to be developed urgently to prevent transmission of infection and ensure patient safety. Meanwhile, healthcare staff should pay special attention to thorough cleaning and disinfection of duodenoscopes.


Meta-analyses of gabapentinoids for pain management after knee arthroplasty: A caveat emptor? A narrative review.
The use of gabapentinoids for perioperative pain management after total knee arthroplasty has been the subject of nine systematic reviews and meta-analyses. A critical analysis of the clinical aspects of the methodology of these publications shows major flaws which limit the interpretation for the recommended use of perioperative gabapentinoids in pain management for unilateral primary total knee arthroplasty. Consequently, readers and authors of systematic reviews and meta-analyses should critically assess the clinical aspects of the included studies.


Prokaryotic Response to Phytodetritus-Derived Organic Material in Epi- and Mesopelagic Antarctic Waters.
Particulate organic matter (POM) export represents the underlying principle of the biological carbon pump, driving the carbon flux from the sunlit to the dark ocean. The efficiency of this process is tightly linked to the prokaryotic community, as >70% of POM respiration is carried out by particle-associated prokaryotes. In the Ross Sea, one of the most productive areas of the Southern Ocean, up to 50% of the surface primary production is exported to the mesopelagic ocean as POM. Recent evidence suggests that a significant fraction of the POM in this area is composed of intact phytoplankton cells. During austral summer 2017, we set up bottle enrichment experiments in which we amended free-living surface and deep prokaryotic communities with organic matter pools generated from native microplankton, mimicking the particle export that may derive from mild (1 μg of Chlorophyll a L-1) and intense (10 μg of Chlorophyll a L-1) phytoplankton bloom. Over a course of 4 days, we followed free-living and particle-attached prokaryotes' abundance, the degradation rates of polysaccharides, proteins and lipids, heterotrophic production as well as inorganic carbon utilization and prokaryotic community structure dynamics. Our results showed that several rare or undetected taxa in the initial community became dominant during the time course of the incubations and that different phytodetritus-derived organic matter sources induced specific changes in microbial communities, selecting for peculiar degradation and utilization processes spectra. Moreover, the features of the supplied detritus (in terms of microplankton taxa composition) determined different colonization dynamics and organic matter processing modes. Our study provides insights into the mechanisms underlying the prokaryotic utilization of phytodetritus, a significant pool of organic matter in the dark ocean.