Combinatorial actions of Tgfβ and Activin ligands promote oligodendrocyte development and CNS myelination.
In the embryonic CNS, development of myelin-forming oligodendrocytes is limited by bone morphogenetic proteins, which constitute one arm of the transforming growth factor-β (Tgfβ) family and signal canonically via Smads 1/5/8. Tgfβ ligands and Activins comprise the other arm and signal via Smads 2/3, but their roles in oligodendrocyte development are incompletely characterized. Here, we report that Tgfβ ligands and activin B (ActB) act in concert in the mammalian spinal cord to promote oligodendrocyte generation and myelination. In mouse neural tube, newly specified oligodendrocyte progenitors (OLPs) are first exposed to Tgfβ ligands in isolation, then later in combination with ActB during maturation. In primary OLP cultures, Tgfβ1 and ActB differentially activate canonical Smad3 and non-canonical MAP kinase signaling. Both ligands enhance viability, and Tgfβ1 promotes proliferation while ActB supports maturation. Importantly, co-treatment strongly activates both signaling pathways, producing an additive effect on viability and enhancing both proliferation and differentiation such that mature oligodendrocyte numbers are substantially increased. Co-treatment promotes myelination in OLP-neuron co-cultures, and maturing oligodendrocytes in spinal cord white matter display strong Smad3 and MAP kinase activation. In spinal cords of ActB-deficient Inhbb(-/-) embryos, apoptosis in the oligodendrocyte lineage is increased and OLP numbers transiently reduced, but numbers, maturation and myelination recover during the first postnatal week. Smad3(-/-) mice display a more severe phenotype, including diminished viability and proliferation, persistently reduced mature and immature cell numbers, and delayed myelination. Collectively, these findings suggest that, in mammalian spinal cord, Tgfβ ligands and ActB together support oligodendrocyte development and myelin formation.


Rearrangement moves on rooted phylogenetic networks.
Phylogenetic tree reconstruction is usually done by local search heuristics that explore the space of the possible tree topologies via simple rearrangements of their structure. Tree rearrangement heuristics have been used in combination with practically all optimization criteria in use, from maximum likelihood and parsimony to distance-based principles, and in a Bayesian context. Their basic components are rearrangement moves that specify all possible ways of generating alternative phylogenies from a given one, and whose fundamental property is to be able to transform, by repeated application, any phylogeny into any other phylogeny. Despite their long tradition in tree-based phylogenetics, very little research has gone into studying similar rearrangement operations for phylogenetic network-that is, phylogenies explicitly representing scenarios that include reticulate events such as hybridization, horizontal gene transfer, population admixture, and recombination. To fill this gap, we propose "horizontal" moves that ensure that every network of a certain complexity can be reached from any other network of the same complexity, and "vertical" moves that ensure reachability between networks of different complexities. When applied to phylogenetic trees, our horizontal moves-named rNNI and rSPR-reduce to the best-known moves on rooted phylogenetic trees, nearest-neighbor interchange and rooted subtree pruning and regrafting. Besides a number of reachability results-separating the contributions of horizontal and vertical moves-we prove that rNNI moves are local versions of rSPR moves, and provide bounds on the sizes of the rNNI neighborhoods. The paper focuses on the most biologically meaningful versions of phylogenetic networks, where edges are oriented and reticulation events clearly identified. Moreover, our rearrangement moves are robust to the fact that networks with higher complexity usually allow a better fit with the data. Our goal is to provide a solid basis for practical phylogenetic network reconstruction.


Neutralization of Sindbis virus by antisera to antigens of vector mosquitoes.
Sindbis virus harvested from infected cultures of Vero cells and from Aedes aegypti mosquitoes was used in neutralization tests with sera obtained from guinea pigs immunized with ground A. aegypti and from guinea pigs repetitively bitten by mosquitoes. Employing these antisera, more mosquito-propagated virus was neutralized than was virus grown in cultures of Vero cells. The neutralizing activity resided in the immune globulin fraction and may reflect the production of antibody to vector antigens on the viral envelope.


An iron responsive element-like stem-loop regulates alpha-hemoglobin-stabilizing protein mRNA.
Hemoglobin production during erythropoiesis is mechanistically coupled to the acquisition and metabolism of iron. We discovered that iron regulates the expression of alpha-hemoglobin-stabilizing protein (AHSP), a molecular chaperone that binds and stabilizes free alpha-globin during hemoglobin synthesis. In primates, the 3'-untranslated region (UTR) of AHSP mRNA contains a nucleotide sequence resembling iron responsive elements (IREs), stem-loop structures that regulate gene expression post-transcriptionally by binding iron regulatory proteins (IRPs). The AHSP IRE-like stem-loop deviates from classical consensus sequences and binds IRPs poorly in electrophoretic mobility shift assays. However, in cytoplasmic extracts, AHSP mRNA co-immunoprecipitates with IRPs in a fashion that is dependent on the stem-loop structure and inhibited by iron. Moreover, this interaction enhances AHSP mRNA stability in erythroid and heterologous cells. Our findings demonstrate that IRPs can regulate mRNA expression through non-canonical IREs and extend the repertoire of known iron-regulated genes. In addition, we illustrate a new mechanism through which hemoglobin may be modulated according to iron status.


A high speed string correction method using a hierarchical file.
This paper describes a high speed string correction method using a hierarchical file. After reviewing a string correction method based on the Levenshtein distance, a hierarchical file construction method is introduced. A multistage string correction method using this file is proposed. The lower bound of computational complexity is estimated, and it is shown that a multistage method using a special type of a hierarchical file can reduce computational labor greatly. The larger the number of strings considered is, the more efficient the method becomes. The results of computer simulations on 5374 phoneme sequences using two and three stage correction methods are stated. The condition for a multistage string correction method to obtain higher correction rates than an ordinary dictionary method is included.


Medical student perspectives on conducting patient experience debrief interviews with hospitalized children and their families.
To explore how medical students completing a pediatric clerkship viewed the benefits and barriers of debrief interviews with hospitalized patients and families. In this study, focus groups were conducted with pediatric clerkship students after completion of a debrief interview. The constant comparative method was used with Mezirow's transformative learning theory as a lens to explore perceptions of the benefits and challenges of performing the interview. Focus groups revealed five benefits and two challenges. The benefits were that the debrief interviews helped students (1) humanize patients and appreciate social and environmental influences on patient health, (2) assess caregiver/patient understanding about care to correct misunderstandings, (3) actively involve caregivers/patients in treatment plan development, (4) engage patients in active expression of questions/concerns, and (5) recognize the value of their own role on the healthcare team. The challenges were that students felt (1) a lack of knowledge to answer caregivers'/patients' questions about diagnoses and (2) discomfort responding to caregiver/patient frustration, anxiety, or sadness. Student feedback on feasibility and implementation led to guidelines for selecting patients and conducting small group discussions after the debrief interviews. Debrief interviews offer a unique approach for learners to explore patient perspectives during hospitalization through direct patient engagement and dialogue, contributing to professional development, empathy, and potentially more positive patient care experiences.


Regression models for linkage heterogeneity applied to familial prostate cancer.
Linkage heterogeneity frequently occurs for complex genetic diseases, and statistical methods must account for it to avoid severe loss in power to discover susceptibility genes. A common method to allow for only a fraction of linked pedigrees is to fit a mixture likelihood and then to test for linkage homogeneity, given linkage (admixture test), or to test for linkage while allowing for heterogeneity, using the heterogeneity LOD (HLOD) score. Furthermore, features of the families, such as mean age at diagnosis, may help to discriminate families that demonstrate linkage from those that do not. Pedigree features are often used to create homogeneous subsets, and LOD or HLOD scores are then computed within the subsets. However, this practice introduces several problems, including reduced power (which results from multiple testing and small sample sizes within subsets) and difficulty in interpretation of results. To address some of these limitations, we present a regression-based extension of the mixture likelihood for which pedigree features are used as covariates that determine the probability that a family is the linked type. Some advantages of this approach are that multiple covariates can be used (including quantitative covariates), covariates can be adjusted for each other, and interactions among covariates can be assessed. This new regression method is applied to linkage data for familial prostate cancer and provides new insights into the understanding of prostate cancer linkage heterogeneity.


Encapsulation of the topoisomerase I inhibitor GL147211C in pegylated (STEALTH) liposomes: pharmacokinetics and antitumor activity in HT29 colon tumor xenografts.
The topoisomerase I inhibitor GL147211C [7-[(4-methylpiperazino)methyl]-10,11-(ethylenedioxy)-(20S)-campto thecin trifluoroacetate], a camptothecin analogue, has significant activity in tumor cell cytotoxicity assays in vitro and antitumor activity in both animal tumor models and human patients. Its toxicity is significant, however, effectively limiting the amount of drug that can be administered and its clinical utility. To determine whether the therapeutic index of GL147211C could be improved, the drug was encapsulated in long-circulating, pegylated (STEALTH) liposomes (SPI-355). The pharmacokinetics and antitumor activity of SPI-355 were compared to those of nonliposomal GL147211C. The plasma pharmacokinetics of SPI-355 in rats were typical of those of other pegylated liposomal formulations, with significantly increased blood circulation time; the dose-corrected area under the curve and Cmax of SPI-355 (10 mg/kg) were 1250- and 35-fold higher, respectively, than those of nonliposomal GL14711C (8.72 mg/kg). The comparative antitumor activity of SPI-355 and nonliposomal GL1472211C was evaluated in nude mice implanted with HT29 colon carcinoma xenografts. SPI-355 was 20-fold more effective than GL147211C in inhibiting tumor growth (1 mg/kg SPI-355 and 20 mg/kg GL147211C) and produced durable complete remissions of tumors at well-tolerated dose levels that were >5-fold lower than the maximally tolerated dose of GL147211C, which induced no durable complete responses. Signs of toxicity were similar between the two drugs, but liposome encapsulation increased the toxicity of drug approximately 4-fold, with increased weight loss and several deaths with SPI-355 (5 mg/kg SPI-355 versus 20 mg/kg GL147211C). Despite the increased toxicity seen with SPI-355, the therapeutic index of the liposomal formulation was increased approximately 5-fold over that of nonliposomal GL147211C, suggesting that such a pegylated liposomal formulation could demonstrate increased therapeutic index in human patients.


Experiences and perspectives of nurses infected with COVID-19: A qualitative systematic review and meta-synthesis.
This qualitative systematic review aims to comprehensively understand the experiences and perspectives of nurses infected with COVID-19, addressing a significant gap in the current literature. Following the JBI meta-synthesis approach, a rigorous search was conducted across nine electronic databases and references until January 16, 2023. Seventeen eligible studies underwent quality assessment using the JBI critical checklist. Data were synthesized using standardized tools, and the ConQual tool evaluated confidence in the findings. Seven key findings emerged, providing valuable insights into emotional experiences, adaptation to COVID-19 challenges, influence of support systems, coping strategies, posttraumatic growth perceptions, and effects on professional identity and career advancement. The findings highlight emotional toll, adaptive strategies, and professional implications for nurses. Moreover, they emphasize the importance of support systems, coping mechanisms, and posttraumatic growth in promoting nurses' well-being and resilience. These insights have practical implications for targeted interventions and support mechanisms to enhance infected nurses' well-being and improve healthcare outcomes.


Continuous nursing intervention on recovery of diabetic patients.
The aim of this study was to probe the influence of continuous nursing intervention on recovery of diabetic patients. From October 2016 to June 2017, 80 diabetic patients who received treatment in our hospital were selected and randomly divided into an intervention group and a control group. The intervention group received continuous nursing care including indirect follow-up, health education and home visit. The self-care ability and blood sugar of the two groups were compared three months later. The score of self-care ability in the intervention group was 89.64±1.64 and that in control group was 72.68±2.47, and a significant difference was observed (P less than 0.001). The fasting blood glucose level in the intervention group was 6.62±0.86 MMOL/L, and the 2-hour post-meal blood glucose level was 8.47±1.32 MMOL/L, which were both lower than those in the control group. Continuous nursing can help monitor the recovery of patients after discharge. It is helpful to improve the self-care ability of patients, control blood sugar level, and promote recovery. It is worth wide promotion.


The interleukin-8-251 AA genotype is associated with angiogenesis in gastric carcinogenesis in Helicobacter pylori-infected Koreans.
Helicobacter pylori (H. pylori) is an important risk factor of gastric adenocarcinoma. Interleukin (IL)-8 is a potent angiogenic factor and plays an important role in inflammation of gastric mucosa by H. pylori. Host susceptibility may help to predict H. pylori-infected individuals with a higher risk of gastric adenocarcinoma. The aim of this study was to clarify the effect of IL-8 polymorphism on angiogenesis in the process of gastric carcinogenesis in H. pylori-infected Koreans. The IL-8-251A/T polymorphism was genotyped by PCR-RFLP from a total of 395 subjects; 92 normal controls, 87 H. pylori-infected controls, 108 chronic atrophic gastritis and/or intestinal metaplasia and 108 adenocarcinoma. The gastric mucosal concentrations of IL-8, membrane metalloproteinase (MMP)-9, angiopoietin (Ang)-1, and vascular endothelial growth factor (VEGF) were measured by ELISA. MMP-9 concentrations were increased with disease progression. There was significant correlation between MMP-9 and disease progression in AA (r=0.42, p<0.01) and AT genotype (r=0.43, p<0.01). Ang-1 concentrations were increased in AA genotype (r=0.40, p=0.01). However, there was no significant correlation between VEGF and disease progression in AA genotype. In conclusion, IL-8-251 AA genotype may be associated with angiogenesis in gastric carcinogenesis in H. pylori-infected Koreans.


Allicin alleviated learning and memory deficits caused by lead exposure at developmental stage.
It is a promising approach to search the therapeutic strategies for treating lead (Pb) toxicity. Allicin, a natural compound extracted from Allium sativum (garlic), has been reported to have many beneficially biological properties. In this study, we investigated the protective effects of allicin on learning and memory function of rats exposed by lead acetate at developmental stage. Rats received lead acetate for inducing toxicity, and gavaged with allicin to ameliorate this toxicity. Morris water maze test was performed to determine learning and memory function. Superoxide dismutase (SOD), glutathione (GSH) and methane dicarboxylic aldehyde (MDA) was measured to determine oxidative stress. Immunofluorescence was carried out to analyze GFAP-positive cells. The protein expression of ERK, p-ERK, EGFR and p-EGFR were detected using western blot. We found that allicin ameliorated lead acetate-caused learning and memory deficits by promoting hippocampus astrocyte differentiation, which mainly through EGFR/ERK signaling. Moreover, allicin attenuated the increased ROS level by regulating the oxidative defense system. These results suggest that allicin is a potent agent able to ameliorate lead acetate-induced learning and memory deficits during early development, and may thus be useful for defeating lead acetate toxicity.


Management of eosinophilic esophagitis associated food impaction in Europe and the United States.
Eosinophilic esophagitis (EoE) is the most common cause of esophageal food impaction (EFI). Approaches to management of EFI due to EoE have not been well characterized. We conducted a web-based survey to understand approaches to management of EFI due to EoE among endoscopists. Questions focused on management of patients from presentation to post-endoscopy follow-up. The survey was administered to a list of eligible candidates provided by societies of gastroenterology. A total of 308 endoscopists completed the questionnaire. The majority (83%) practiced in Europe and treated adults (78%). Most agreed patients should be advised to seek emergency care (66%) within 1 to 2 hours (41% agreement). There was agreement that medications to induce vomiting should be avoided (84%) and that blood tests or imaging studies were usually not required before endoscopy. By contrast, there was more variability in the type of sedation recommended and the need for endotracheal intubation, especially when comparing more experienced with less experienced EoE-endoscopists. Overall, fewer than half (43%) respondents recommended obtaining esophageal biopsies during the initial endoscopy. However, there were significant differences in the proportion who recommended biopsies based on level of EoE-experience (25, 52, 77%, P < 0.001; less vs. moderate vs. very experienced) and comparing pediatric and adult endoscopists (32, vs. 79%, P < 0.001; adult vs. pediatric). There exists heterogeneity among endoscopists in recommendations to manage EFI in patients with EoE. These findings support development of clinical guidelines and new studies to clarify the rationale for best practices. Key summary: Established knowledge-The optimal management of patients with esophageal food impaction due to eosinophilic esophagitis from presentation at the emergency department to postendoscopy care is unclear. New findings-Considerable recommendation variation exists in the management of EFI in patients with EoE. Our findings provide a rationale for the creation of consensus practice guidelines and further study into best practices.


Evaluation of a Clinical Platform to Promote Chronic Disease Management.
Self-reported data suggest American adults with multiple chronic conditions account for 25.7% to 60% of the population. Despite emphasis on information technology to improve quality in health care, data addressing outcomes of clinically focused, provider-oriented dashboards are limited. To explore integrating performance platforms into clinical care, the authors designed a platform-based intervention to address 2 prevalent chronic conditions with significant long-term burden. This study used a performance platform to enhance clinicians' management of patients with diabetes and osteoporosis. Descriptive statistics were used to summarize patients' surveys and quality metrics, and to analyze clinicians' knowledge, attitudes, and beliefs in the pre and post time frames. The frequency of screening for osteoporosis in women improved post intervention (40% vs. 44%, P < 0.0001), whereas other quality metrics did not. Clinician respondents were primarily physicians (82%), white (73%), internal medicine specialists (58%), with an average of 18 years' experience, and nearly equally male and female. Their percent of correctly answered knowledge questions increased slightly in the postintervention phase for osteoporosis and hypoglycemia (0.53 and 1.74, respectively); however, results were not statistically significant (P > 0.4). Post intervention, clinicians reported that their attitudes and beliefs regarding disease management had changed in the past 6 months in a positive direction. Although few outcomes studied changed over time, results suggest that performance platforms may have a role to play in managing chronic conditions. However, their efficacy must continue to be evaluated in order to improve understanding of optimal approaches to integrating technology into patient care.


Peptide inhibition of the Prausnitz-Küstner reaction.
A pentapeptide was synthesized with the same amino acid sequence that occurs in a unique region of the chaim of immunoglobulin E near the cysteine residue participating in the linkage between the two heavy chains. This pentapeptide has the capacity to block a standard Prausnitz-Küstner reaction as well as to inhibit a known positive skin test reaction. Other similar synthetic polypeptides had less or no inhibitory activity. The likelihood that this pentapeptide amino acid sequence does in fact represent the structure of the specific immunoglobulin E binding site for the mast cell and basophil is considered.


Nano Spray Drying Technique as a Novel Approach To Formulate Stable Econazole Nitrate Nanosuspension Formulations for Ocular Use.
The effect of using methyl-β-cyclodextrin and hydroxypropyl-β-cyclodextrin as carriers for econazole nitrate nanoparticles prepared by nano spray dryer was explored in this work. Stabilizers, namely, poly(ethylene oxide), polyvinylpyrrolidone k30, poloxamer 407, Tween 80, and Cremophor EL, were used. The nano spray dried formulations revealed almost spherical particles with an average particle size values ranging from 121 to 1565 nm and zeta potential values ranging from -0.8 to -2.5 mV. The yield values for the obtained formulations reached 80%. The presence of the drug in the amorphous state within the nanosuspension matrix system significantly improved drug release compared to that for pure drug. Combination of hydroxypropyl-β-cyclodextrin with Tween 80 achieved an important role for preserving the econazole nanosuspension from aggregation during storage for one year at room temperature as well as improving drug release from the nanosuspension. This selected formulation was suspended in chitosan HCl to increase drug release and bioavailability. The in vivo evaluation on albino rabbit's eyes demonstrated distinctly superior bioavailability of the selected formulation suspended in chitosan compared to its counterpart formulation suspended in buffer and crude drug suspension due to its mucoadhesive properties and nanosize. The nano spray dryer could serve as a one step technique toward formulating stable and effective nanosuspensions.


Tamoxifen induces stem-like phenotypes and multidrug resistance by altering epigenetic regulators in ERα+ breast cancer cells.
To understand the mechanism underlying tamoxifen-induced multidrug resistance (MDR) and stem-like phenotypes in breast cancer cells, we treated the MCF-7 cells with 4-hydroxy-tamoxifen (TAM) for 6 months continuously and established MCF-7 tamoxifen resistance (TR) phenotypes. In the present study, the following methods were used: cell viability assay, colony formation, cell cycle analysis, ALDEFLUOR assay, mammosphere formation assay, chromatin immunoprecipitation (ChIP) assay, PCR array, western blot analysis and quantitative reverse transcription polymerase chain reaction (QRT-PCR). The expression of ERα was significantly higher in MCF7-TR cells when compared with parental MCF-7 cells. MCF7-TR cells exposed to TAM showed a significant increase in the proliferation and rate of colony formation. The number of cancer stem cells was higher in MCF7-TR cells as observed by the increase in the number of ALDH+ cells. Furthermore, the number of mammospheres formed from the FACS-sorted ALDH+ cells was higher in MCF7-TR cells. Using PCR array analysis, we were able to identify that the long-term exposure of TAM leads to alterations in the epigenetic and MDR stem cell marker genes. Furthermore, western blot analysis demonstrated elevated levels of Notch-1 expression in MCF-TR cells compared with MCF-7 cells. Chromatin immunoprecipitation (ChIP) assay revealed that Notch-1 enhanced the cyclin D1 expression significantly in these cells. In addition, we observed that MCF7-TR cells were resistant to doxorubicin but not the MCF-7 cells. In the present study, we conclude that the treatment with tamoxifen induces multiple epigenetic alterations that lead to the development of MDR and stem-like phenotypes in breast cancers. Therefore, our study provides better insights to develop novel treatment regime to control the progression of breast cancer.


An RNA aptamer restores defective bone growth in FGFR3-related skeletal dysplasia in mice.
Achondroplasia is the most prevalent genetic form of dwarfism in humans and is caused by activating mutations in FGFR3 tyrosine kinase. The clinical need for a safe and effective inhibitor of FGFR3 is unmet, leaving achondroplasia currently incurable. Here, we evaluated RBM-007, an RNA aptamer previously developed to neutralize the FGFR3 ligand FGF2, for its activity against FGFR3. In cultured rat chondrocytes or mouse embryonal tibia organ culture, RBM-007 rescued the proliferation arrest, degradation of cartilaginous extracellular matrix, premature senescence, and impaired hypertrophic differentiation induced by FGFR3 signaling. In cartilage xenografts derived from induced pluripotent stem cells from individuals with achondroplasia, RBM-007 rescued impaired chondrocyte differentiation and maturation. When delivered by subcutaneous injection, RBM-007 restored defective skeletal growth in a mouse model of achondroplasia. We thus demonstrate a ligand-trap concept of targeting the cartilage FGFR3 and delineate a potential therapeutic approach for achondroplasia and other FGFR3-related skeletal dysplasias.


NME4/nucleoside diphosphate kinase D in cardiolipin signaling and mitophagy.
Mitophagy is an emerging paradigm for mitochondrial quality control and cell homeostasis. Dysregulation of mitophagy can lead to human pathologies such as neurodegenerative disorders and contributes to the aging process. Complex protein signaling cascades have been described that regulate mitophagy. We have identified a novel lipid signaling pathway that involves the phospholipid cardiolipin (CL). CL is synthesized and normally confined at the inner mitochondrial membrane. However, upon a mitophagic trigger, ie, collapse of the inner membrane potential, CL is rapidly externalized to the mitochondrial surface with the assistance of the hexameric nucleoside diphosphate kinase D (NME4, NDPK-D, or NM23-H4). In addition to its NDP kinase activity, NME4/NDPK-D shows intermembrane phospholipid transfer activity in vitro and in cellular systems, which relies on NME4/NDPK-D interaction with CL, CL-dependent crosslinking of inner and outer mitochondrial membranes by symmetrical, hexameric NME4/NDPK-D, and a putative NME4/NDPK-D-based CL-transfer pathway. CL exposed at the mitochondrial surface then serves as an 'eat me' signal for the mitophagic machinery; it is recognized by the LC3 receptor of autophagosomes, targeting the dysfunctional mitochondrion to lysosomal degradation. Similar NME4-supported CL externalization is likely also involved in apoptosis and inflammatory reactions.


Human herpesvirus-6 in human lymphomas: identification of specific sequences in Hodgkin's lymphomas by polymerase chain reaction.
In search of a possible involvement of the human herpesvirus type 6 (HHV-6) in human Hodgkin's and non-Hodgkin's lymphomas, we studied the levels of anti-HHV-6 antibodies in the sera of 94 cases by an immunofluorescence assay, as well as the presence of HHV-6 sequences in the affected tissues of 66 cases by polymerase chain reaction, using one set of primer oligonucleotides. Our results showed higher anti-HHV-6 antibody titers in human lymphomas than in normal blood donors, but the difference is statistically significant only when normal donors are compared with Hodgkin's lymphoma cases. HHV-6 sequences were detected in 3 of 25 Hodgkin's lymphomas and 0 of the 41 cases of non-Hodgkin's lymphomas studied. The three cases positive for HHV-6 sequences belong to the nodular sclerosis-lymphocyte depletion histologic subtype and share remarkable similarities in their clinical features. Furthermore, Southern blot analysis of total genomic DNA obtained from the neoplastic tissues of two of the three patients showed the same restriction fragment length polymorphism. Our results suggest that: (1) the high level of anti-HHV-6 antibodies in Hodgkin's disease is due to an activation of the immune system not related to the presence of HHV-6 sequences in affected lymph nodes; (2) the presence of HHV-6 sequences in human lymphoid tissues is not a frequent event, rather it is in fact a very rare event in non-Hodgkin's lymphomas, while in Hodgkin's cases it is more frequent than previously reported on the basis of Southern blot analysis; and (3) the presence of HHV-6 sequences in Hodgkin's lymphomas may have a relation with the clinical presentation of the disease.


Threshold level of protein kinase A activity and polarized growth in Mucor rouxii.
A model system to study the involvement of cAMP-mediated regulation of a cellular process such as hyphal morphogenesis was investigated. Impairment of polarized growth was observed when Mucor rouxii sporangiospores were grown in the presence of N(6)-cAMP analogues and of SQ 65,442, a cAMP phosphodiesterase inhibitor. Together with an effect on isodiametric growth, there was increased pigmentation, increased cell fragility and loss of cell adhesiveness. The total effect on morphology was attained even after adding the compounds shortly before germ-tube emergence; when added after this time growth continued in a non-polarized form and rounding of the germ tip was observed. The morphological effect was observed under all the nutritional and environmental conditions studied (aerobic conditions and defined medium with maltose or glucose, Casamino acids medium with glucose, or rich medium; anaerobic conditions with rich medium; and following a shift from anaerobiosis to aerobiosis). The time of germ-tube emergence, and the size of the cell at this time, was dependent on the growth medium. Protein kinase A (PKA) specific activity was followed during the germination process under three growth conditions. It was found that the total activity of PKA correlated with differentiation and not with growth, and that the total specific activity at the time of germination was the same, independent of the culture medium. The time of germ-tube emergence correlated with the time of attainment of a threshold level of PKA total specific activity. The concentration of dibutyryl-cAMP needed to promote isodiametric growth correlated with the total units of activity of PKA to be activated per cell. It was concluded that PKA is involved in the morphogenetic process of the fungus grown under all the nutritional and ambient conditions tested.


Development of a LC-MS/MS Method for the Multi-Mycotoxin Determination in Composite Cereal-Based Samples.
The analytical scenario for determining contaminants in the food and feed sector is constantly prompted by the progress and improvement of knowledge and expertise of researchers and by the technical innovation of the instrumentation available. Mycotoxins are agricultural contaminants of fungal origin occurring at all latitudes worldwide and being characterized by acute and chronic effects on human health and animal wellness, depending on the species sensitivity. The major mycotoxins of food concern are aflatoxin B1 and ochratoxin A, the first for its toxicity, and the second for its recurrent occurrence. However, the European legislation sets maximum limits for mycotoxins, such as aflatoxin B1, ochratoxin A, deoxynivalenol, fumonisins, and zearalenone, and indicative limits for T-2 and HT-2 toxins. Due to the actual probability that co-occurring mycotoxins are present in a food or feed product, nowadays, the availability of reliable, sensitive, and versatile multi-mycotoxin methods is assuming a relevant importance. Due to the wide range of matrices susceptible to mycotoxin contamination and the possible co-occurrence, a multi-mycotoxin and multi-matrix method was validated in liquid chromatography-tandem mass spectrometry (LC-MS/MS) with the purpose to overcome specific matrix effects and analyze complex cereal-based samples within the Italian Total Diet Study project.


Mapping potential Anopheles gambiae s.l. larval distribution using remotely sensed climatic and environmental variables in Baringo, Kenya.
Anopheles gambiae s.l. (Diptera: Culicidae) is responsible for the transmission of the devastating Plasmodium falciparum (Haemosporida: Plasmodiidae) strain of malaria in Africa. This study investigated the relationship between climate and environmental conditions and An. gambiae s.l. larvae abundance and modelled the larval distribution of this species in Baringo County, Kenya. Mosquito larvae were collected using a 350-mL dipper and a pipette once per month from December 2015 to December 2016. A random forest algorithm was used to generate vegetation cover classes. A negative binomial regression was used to model the association between remotely sensed climate (rainfall and temperature) and environmental (vegetation cover, vegetation health, topographic wetness and slope) factors and An. gambiae s.l. for December 2015. Anopheles gambiae s.l. was significantly more frequent in the riverine zone (P < 0.05, r = 0.59) compared with the lowland zone. Rainfall (b = 6.22, P < 0.001), slope (b = - 4.81, P = 0.012) and vegetation health (b = - 5.60, P = 0.038) significantly influenced the distribution of An. gambiae s.l. larvae. High An. gambiae s.l. abundance was associated with cropland and wetland environments. Effective malaria control will require zone-specific interventions such as a focused dry season vector control strategy in the riverine zone.


[Hepatobiliary and pancreatic disorders as risk factors for fat-soluble vitamin deficiencies].
The aim of this article is to describe the fat-soluble vitamin status in patients with hepatobiliary and pancreatic diseases, and the contribution of these vitamin deficiency or excess to hepatic injury. A considerable number of patients with advanced liver disease and cholestasis might actually be fat-soluble vitamin deficient, although clinical signs of deficiency are uncommonly seen in patients with vitamin A and E deficiency. Increased bone resorption may be the predominant cause of hepatic osteodystrophy. On the other hand, the possible causes of vitamin K deficiency seen in patients with hepatobiliary disease are the decrease of vitamin K absorption from intestine, the disturbance of vitamin K cycle and the decrease of pool area for vitamin K storage. The intake of vitamin A may be associated with the risk of liver cirrhosis in lifetime teetotalers, although the retinyl palmitate reduces hepatic fibrosis in rats.


Early Sign Language Exposure and Cochlear Implantation Benefits.
Most children with hearing loss who receive cochlear implants (CI) learn spoken language, and parents must choose early on whether to use sign language to accompany speech at home. We address whether parents' use of sign language before and after CI positively influences auditory-only speech recognition, speech intelligibility, spoken language, and reading outcomes. Three groups of children with CIs from a nationwide database who differed in the duration of early sign language exposure provided in their homes were compared in their progress through elementary grades. The groups did not differ in demographic, auditory, or linguistic characteristics before implantation. Children without early sign language exposure achieved better speech recognition skills over the first 3 years postimplant and exhibited a statistically significant advantage in spoken language and reading near the end of elementary grades over children exposed to sign language. Over 70% of children without sign language exposure achieved age-appropriate spoken language compared with only 39% of those exposed for 3 or more years. Early speech perception predicted speech intelligibility in middle elementary grades. Children without sign language exposure produced speech that was more intelligible (mean = 70%) than those exposed to sign language (mean = 51%). This study provides the most compelling support yet available in CI literature for the benefits of spoken language input for promoting verbal development in children implanted by 3 years of age. Contrary to earlier published assertions, there was no advantage to parents' use of sign language either before or after CI.


Vanadium aminophenolates in catechol oxidation: conformity with Finke's common catalyst hypothesis.
Six known aminophenolate vanadium complexes V1-V6 were examined in 3,5-di-tert-butylcatechol (1, 3,5-DTBC) oxidation. From the complexes V1-V5 have been previously shown to demonstrate catechol oxidase (catecholase) like behavior, catalytically oxidizing 1 to 3,5-di-tert-butyl-1,2-benzoquinone (2, 3,5-DTBQ). A critical re-evaluation of V1-V5, including V6 not assessed earlier, in the aerobic oxidation of 1 has revealed that several catechol dioxygenase products are obtained in addition to 2, which is produced partly by autoxidation. Mechanistic investigations into the V1-V6 catalyzed oxidation of 1 by EPR, negative mode ESI-MS and 51V NMR, in addition to semi-quantitative product distribution analyses with GC and column chromatography afford compelling evidence in support of the "common catalyst hypothesis" earlier proposed by Finke and co-workers. During the reaction, V1-V6 are partially converted in situ by H2O2 assisted leaching to vanadium catecholate complexes [V(3,5-DTBC)2(3,5-DTBSQ˙)] and [VO(3,5-DTBC)(3,5-DTBSQ˙)], where 3,5-DTBSQ˙ = 3,5-di-tert-butyl-1,2-semiquinone, the latter of which has been implicated as the common true active catalyst in catechol dioxygenation as per the common catalyst hypothesis. The results herein suggest that vanadium aminophenolate complexes are sensitive to H2O2 mediated leaching in the presence of strong σ and π donating ligands such as 1 and 2. Furthermore, based on these results, the use of vanadium aminophenolate complexes as catechol oxidase mimics is not as warranted as previously understood.


Motor control characteristics of upper limbs in response to assistive forces during bilateral tasks.
Most research on power assist suits (PASs) that concerned PAS-human interactions has used human physical reactions as criteria to evaluate the mechanical function, however, with minimal emphasis on human reactions in response to PASs. In this study, we focused on the physiological responses of the upper limbs including muscle activity of the biceps brachii and the triceps brachii, co-activation, force steadiness (CV) and rated perceived exertion (RPE) to various patterns of bilateral assistive force, such as unilateral assistance (L0% & R67% [% = percentage of workload force, L = left arm, R = right arm], L67% & R0%, L0% & R33%, L33% & R0%), symmetrical (L0% & R0%, L33% & R33%, L67% & R67%) and asymmetrical bilateral assistance (L33% & R67%, L67% & R33%), during bilateral isometric force-matching tasks. The results showed a similar muscular response of the two arms to bilateral assistive conditions, and the muscle activity of the arm that was being observed decreased only when the assistive force that applied on itself increased, indicating that both arms may have adopted similar but independent motor control mechanisms to acclimate to the bilateral assistive forces. Comparison between the two unilateral assistances (L0% & R33% and L33% & R0%) and the two asymmetrical bilateral assistances (L33% & R67%, L67% & R33%) showed no significant differences in muscular responses, CV and RPE, indicating that bilateral assistances with bilateral interchanged assistive levels may be equally effective regardless of which arm the higher assistive force is applied to. Comparison between unilateral and symmetrical assistive conditions that have similar overall workloads (L67% & R0%, L33% & R33%, L0% & R67%) showed a lower CV and RPE score at symmetrical assistance compared with unilateral assistance, suggesting that assisting both arms with the same level simultaneously improves task performances compared with applying the assistive force to only one arm.


Presentation, management, and outcome of posterior urethral valves in a Nigerian tertiary hospital.
Posterior urethral valves (PUV) remain the most common cause of bladder outlet obstruction and renal insufficiency in male children. The aim of this study was to evaluate the presentation, management, challenges, and outcome of the disease in a Nigerian tertiary health institution. Retrospectively, medical records of male children with a diagnosis of PUVs over a 10 year period (2003-2012) were retrieved. All data in relation to the study objectives were recorded and analyzed. A total of 44 patients was managed for PUV within the period. The mean age of presentation was 3.95 years with 56.8% of the patients presenting after the age of 1 year. Voiding dysfunction noted in 40 (91.0%) patients was the most common mode of presentation. The most common finding on physical examination was a palpable bladder while urinary tract infection noted in 23 (52.3%) patients was the most common complication noted. Abdominal ultrasonography revealed dilated posterior urethra in 16 (36.4%) cases, while micturating cystourethrogram revealed a dilated proximal urethra in all 35 cases in which it was done, diverticulum in 6 and vesicoureteric reflux in 9. The creatinine value at presentation ranged between 0.4 mg/dl and 4.0 mg/dl with a mean of 1.02 ± 0.93 mg/dl. Urethroscopy in 37 patients confirmed type I and type III PUV in 35 and 2 patients, respectively. Valve ablation with a diathermy bugbee electrode provided relief of obstructions in the 37 patients who underwent the procedure without any significant immediate complication. The period of follow-up ranged between 2 weeks and 3 years with a mean of 10.2 months. There was sustained improvement in urine stream, reduction in the mean creatinine concentration and incidence of UTI during follow-up. However, patients with significantly impaired renal function had a poorer outcome. Many patients with PUV presented late within the reviewed period. Valve ablation provided relief of obstruction in most of the cases. There is a need to counsel parents/guardians on the need for long-term follow-up.


Across Species "Natural Ablation" Reveals the Brainstem Source of a Noninvasive Biomarker of Binaural Hearing.
The binaural interaction component (BIC) of the auditory brainstem response is a noninvasive electroencephalographic signature of neural processing of binaural sounds. Despite its potential as a clinical biomarker, the neural structures and mechanism that generate the BIC are not known. We explore here the hypothesis that the BIC emerges from excitatory-inhibitory interactions in auditory brainstem neurons. We measured the BIC in response to click stimuli while varying interaural time differences (ITDs) in subjects of either sex from five animal species. Species had head sizes spanning a 3.5-fold range and correspondingly large variations in the sizes of the auditory brainstem nuclei known to process binaural sounds [the medial superior olive (MSO) and the lateral superior olive (LSO)]. The BIC was reliably elicited in all species, including those that have small or inexistent MSOs. In addition, the range of ITDs where BIC was elicited was independent of animal species, suggesting that the BIC is not a reflection of the processing of ITDs per se. Finally, we provide a model of the amplitude and latency of the BIC peak, which is based on excitatory-inhibitory synaptic interactions, without assuming any specific arrangement of delay lines. Our results show that the BIC is preserved across species ranging from mice to humans. We argue that this is the result of generic excitatory-inhibitory synaptic interactions at the level of the LSO, and thus best seen as reflecting the integration of binaural inputs as opposed to their spatial properties.SIGNIFICANCE STATEMENT Noninvasive electrophysiological measures of sensory system activity are critical for the objective clinical diagnosis of human sensory processing deficits. The binaural component of sound-evoked auditory brainstem responses is one such measure of binaural auditory coding fidelity in the early stages of the auditory system. Yet, the precise neurons that lead to this evoked potential are not fully understood. This paper provides a comparative study of this potential in different mammals and shows that it is preserved across species, from mice to men, despite large variations in morphology and neuroanatomy. Our results confirm its relevance to the assessment of binaural hearing integrity in humans and demonstrates how it can be used to bridge the gap between rodent models and humans.


An IkappaB-beta COOH terminal region protein is essential for the proliferation of CHO cells under acidic stress.
CHO-K1 cells were able to proliferate and maintain pHi homeostasis at pH 6.3. A novel acidic sensitive mutant, AS-5B, which proliferated at pH 7.4 but failed to either proliferate or maintain pHi homeostasis at pH 6.3, was derived from CHO-K1 using a replica method. The acidic-sensitivity of AS-5B was not due to deficiencies in sodium proton exchangers, HCO3- (co)transporters or H+-ATPases. A cDNA clone encoding a COOH terminal region of IkappaB-beta conferred partial acidic-resistance on AS-5B, and the encoded protein was present in CHO-K1, but was nearly absent from AS-5B. Our data demonstrated that the expression of this small protein was essential for the proliferation of CHO cells under acidic stress.


Potential Causal Association between Elevated Gamma-Glutamyl Transferase Level and Stroke: A Two-Sample Mendelian Randomization Study.
Researchers have suggested a potential relationship between gamma-glutamyl transferase (GGT) level and stroke. We investigated a potential causal relationship between GGT level as exposures and stroke and stroke subtypes (cardioembolic, small vessel, and large artery) in a European population. We performed a two-sample Mendelian randomization (MR) study using the genome-wide association study (GWAS) data from the UK Biobank as the exposure set. For the outcome set, we used stroke in the GWAS data from the GIGASTROKE Consortium. We considered alcohol consumption, atrial fibrillation, and body mass index as confounders. We used PhenoScanner searches for removal of SNPs and multivariable MR analysis for assessing confounders. We observed significant causal associations between GGT level and stroke (odds ratio [OR] = 1.23, 95% CI = [1.05-1.44], and p = 0.012 with IVW; OR = 1.19, 95% CI= [1.02-1.39], and p = 0.031 with MR-PRESSO). These results were consistent after removing SNPs related to confounding factors. Similarly, in multivariable MR, GGT was associated with stroke after adjusting for confounding factors (OR = 1.30, 95% CI 1.07-1.60), p = 0.010). Because GGT level has a causal relationship with stroke, researchers should test its significance as a potential risk factor for stroke. Additional research is required to validate these results.


Structure and function relationships of the respiratory muscles.
Potential relationships between the structure of the diaphragm and external intercostals and several indices of respiratory muscle function, lung function and nutrition in 27 patients (61+/-10 yrs of age) subjected to thoracotomy as a result of a lung neoplasm have been investigated. Prior to surgery the nutritional status of the patients was assessed and lung function (spirometry, lung volumes, transfer factor of the lungs for carbon monoxide, arterial blood gases) and respiratory muscle function (maximal inspiratory pressure (MIP) and diaphragmatic function were measured). Biopsies of the diaphragm (and external intercostals) were obtained during surgery. On average, patients showed mild airflow limitation (forced expiratory volume in one second (FEV1), 70+/-14% of predicted value, FEV1/forced vital capacity (FVC), 70+/-9%) with some air trapping (residual volume (RV), 139+/-50% pred) and normal gas exchange (arterial oxygen tension (Pa,O2), 11.3+/-1.33 kPa (85+/-10 mmHg)) and arterial carbon dioxide tension (Pa,CO2) 5.4+/-0.5 kPa (40.6+/-4 mmHg). MIP was 77+/-25% pred; maximal transdiaphragmatic pressure was 90+/-27 cmH2O. Most morphometric measurements of the diaphragm and external intercostals were within the range of values reported previously in other skeletal muscles. The size of the fibres of these two respiratory muscles was positively related (p<0.05) to MIP (% pred). There were no significant relationships between the structure of both muscles and nutritional status or any index of lung function. In conclusion, in the population studied, the fibre size of the diaphragm and external intercostals appears to relate to their ability to generate force.


Nonrainfall water origins and formation mechanisms.
Dryland ecosystems cover 40% of the total land surface on Earth and are defined broadly as zones where precipitation is considerably less than the potential evapotranspiration. Nonrainfall waters (for example, fog and dew) are the least-studied and least-characterized components of the hydrological cycle, although they supply critical amounts of water for dryland ecosystems. The sources of nonrainfall waters are largely unknown for most systems. In addition, most field and modeling studies tend to consider all nonrainfall inputs as a single category because of technical constraints, which hinders prediction of dryland responses to future warming conditions. This study uses multiple stable isotopes (2H, 18O, and 17O) to show that fog and dew have multiple origins and that groundwater in drylands can be recycled via evapotranspiration and redistributed to the upper soil profile as nonrainfall water. Surprisingly, the non-ocean-derived (locally generated) fog accounts for more than half of the total fog events, suggesting a potential shift from advection-dominated fog to radiation-dominated fog in the fog zone of the Namib Desert. This shift will have implications on the flora and fauna distribution in this fog-dependent system. We also demonstrate that fog and dew can be differentiated on the basis of the dominant fractionation (equilibrium and kinetic) processes during their formation using the 17O-18O relationship. Our results are of great significance in an era of global climate change where the importance of nonrainfall water increases because rainfall is predicted to decline in many dryland ecosystems.


Differential effect of nanoparticle and standard forms of ZnO on serum zinc and magnesium levels in rats.
This study examined the effect of chronic (2 weeks) administration of zinc oxide nanoparticles (NPs-ZnO) and standard zinc oxide (S-ZnO) on the levels of zinc (Zn), magnesium (Mg) and calcium (Ca) in rat serum. S-ZnO and NPs-ZnO were administered either per os (p.o.) or intraperitoneally (i.p.) at doses of 7 mg/kg or 14 mg/kg. Neither form of ZnO administered p.o. altered serum zinc concentration. However, different effects dependent upon either S-ZnO or NPs-ZnO forms were noticed after i.p. administration. Namely, while S-ZnO increased serum zinc concentration (by 136%) only at the higher dose (14 mg/kg), both doses of NPs-ZnO increased zinc concentration (by 97% at 7 mg/kg and by 564% at 14 mg/kg). The form-dependence of the ZnO effect was also demonstrated in the effect on the serum magnesium level. Only the S-ZnO form (at the dose of 14 mg/kg) reduced serum magnesium concentration (by 14% p.o., 6% i.p.). No influence of NPs-ZnO on the serum calcium level was observed. The present study demonstrated effects on the serum Zn and Mg levels, which differed between the standard and nanoparticle forms of ZnO. This may contribute to the different functional effects of these ZnO forms shown previously.


Natural cycle frozen-thawed embryo transfer in young women with regular menstrual cycles increases the live-birth rates compared with hormone replacement treatment: a retrospective cohort study.
To determine the optimal endometrial preparation protocols of frozen-thawed embryo transfer (FET) in young women with regular menstrual cycles. Retrospective cohort study. Public fertility center. Infertile women with regular menstrual cycles undergoing FET. Natural cycle (NC) treatment for patients with proven ovulation in previous cycles or who refused medication (n = 308), or hormone treatment (HT) for patients who could not be frequently monitored (n = 1,538). Live-birth rates. The live-birth rates were 61.73% in the NC group and 55.11% in the HT group. The effect size of the endometrial preparation on live-birth rates was evaluated in prespecified and exploratory subgroups in each subgroup, and multivariable logistic regression analysis was used to determine which variables could be independently associated with the live-birth rate. The HT patients had a lower chance of live birth in all subgroups: endometrial thickness on the day of progesterone administration, triple-line endometrial pattern, female age at embryo transfer, fertilization type, and protocol in the fresh cycle. Multivariable analysis showed NC to be associated with an increased likelihood of live birth compared with HT. Natural cycle treatment has a higher chance of live birth than HT for endometrial preparation in young women with regular menstrual cycles.


Antiplatelet therapy: new pharmacological agents and changing paradigms.
Recurrent atherothrombotic events in patients with acute coronary syndromes (ACS) and/or those undergoing percutaneous coronary intervention (PCI) are essentially platelet-driven processes, underscoring the need for effective pharmacological platelet inhibition. Dual antiplatelet therapy with aspirin and clopidogrel has been, for over a decade, the mainstay of antiplatelet management in ACS/PCI. However, atherothrombotic events continue to occur in a relevant proportion of subjects despite the benefit of this combination, which has led to the clinical development of newer and more potent antiplatelet drugs. Two of these, prasugrel and ticagrelor, have been recently approved for clinical use. The scope of this manuscript is to provide an up-to-date overview on new antiplatelet drugs in the setting of ACS and PCI, including the most recent advances on newly approved agents as well as on emerging compounds in clinical development.


Confocal microscopy with a radially polarized focused beam.
Rigorous vectorial focusing theory is used to study the imaging of small adjacent particles with a confocal laser scanning system. We consider radially polarized illumination with an optimized amplitude distribution and an annular lens to obtain a narrower distribution of the longitudinal component of the field in focus. A polarization convertor at the detector side is added to transform radial polarization to linear polarization in order to make the signal detectable with a single mode fiber.


Lack of association of HLA B27 with radiographic sacroiliitis in inflammatory bowel disease.
In 89 patients with inflammatory bowel disease, only one out of 11 patients with radiographic sacroiliitis was found to possess the HLA B27 antigen, while three out of four patients with ankylosing spondylitis were B27 positive. This suggests that sacroiliitis in inflammatory bowel disease may not always be a precursor of ankylosing spondylitis.


Partitioning the sources of demographic variation reveals density-dependent nest predation in an island bird population.
Ecological factors often shape demography through multiple mechanisms, making it difficult to identify the sources of demographic variation. In particular, conspecific density can influence both the strength of competition and the predation rate, but density-dependent competition has received more attention, particularly among terrestrial vertebrates and in island populations. A better understanding of how both competition and predation contribute to density-dependent variation in fecundity can be gained by partitioning the effects of density on offspring number from its effects on reproductive failure, while also evaluating how biotic and abiotic factors jointly shape demography. We examined the effects of population density and precipitation on fecundity, nest survival, and adult survival in an insular population of orange-crowned warblers (Oreothlypis celata) that breeds at high densities and exhibits a suite of traits suggesting strong intraspecific competition. Breeding density had a negative influence on fecundity, but it acted by increasing the probability of reproductive failure through nest predation, rather than through competition, which was predicted to reduce the number of offspring produced by successful individuals. Our results demonstrate that density-dependent nest predation can underlie the relationship between population density and fecundity even in a high-density, insular population where intraspecific competition should be strong.


Major bleeding complicating deep sternal infection after cardiac surgery.
This study was undertaken to determine the incidence and outcome of major bleeding complicating deep sternal infection after cardiac surgery, to identify predisposing factors and means of prevention, and to clarify management options. This was a retrospective study of 10,863 consecutive patients, of whom 213 (2.18%) acquired deep sternal infection. With 43 additional referrals, the total number of patients with deep sternal infection was 280. Deep sternal infection was managed by a two-stage scheme. Major bleeding was considered to be bleeding that occurred during or after operation for deep sternal infection from the heart, great vessels, or grafts, or bleeding requiring urgent exploration. Fifteen patients (5.36%) had major bleeding. The incidences of deep sternal infection and bleeding were highest among patients undergoing coronary artery bypass grafting. Thirteen patients had underlying diseases (type 2 diabetes in 9 cases). Deep sternal infection was diagnosed a median of 15 days after reoperation. Bleeding originated from the right ventricle in 9 patients. In 4 patients bleeding was iatrogenic during surgery for wire removal (n = 2) or reconstruction (n = 2). In 11 it occurred 15 minutes to 15 days (median 2 days) after wire removal, as a result of shearing forces in 7 cases and of infection only in 4 cases. Three patients died immediately. The other 12 were operated on, 6 with complete cardiopulmonary bypass, 2 with femoral cannulation, and 4 without cardiopulmonary bypass. The immediate mortality was 26.7%; the overall mortality was 53.3%. The median length of hospitalization of surviving patients was 38 days. The probability of development of major bleeding in patients with deep sternal infection was unrelated to the primary operation. The mortality associated with this complication was high. Meticulous technique during wire removal may decrease the risk of major bleeding. The impacts of cardiopulmonary bypass and of the technique and timing of sternal reconstruction remain undetermined.


A multiobjective evolutionary algorithm toolbox for computer-aided multiobjective optimization.
This paper presents an interactive graphical user interface (GUI) based multiobjective evolutionary algorithm (MOEA) toolbox for effective computer-aided multiobjective (MO) optimization. Without the need of aggregating multiple criteria into a compromise function, it incorporates the concept of Pareto's optimality to evolve a family of nondominated solutions distributing along the tradeoffs uniformly. The toolbox is also designed with many useful features such as the goal and priority settings to provide better support for decision-making in MO optimization, dynamic population size that is computed adaptively according to the online discovered Pareto-front, soft/hard goal settings for constraint handlings, multiple goals specification for logical "AND"/"OR" operation, adaptive niching scheme for uniform population distribution, and a useful convergence representation for MO optimization. The MOEA toolbox is freely available for download at http://vlab.ee.nus.edu.sg/-kctan/moea.htm which is ready for immediate use with minimal knowledge needed in evolutionary computing. To use the toolbox, the user merely needs to provide a simple "model" file that specifies the objective function corresponding to his/her particular optimization problem. Other aspects like decision variable settings, optimization process monitoring and graphical results analysis can be performed easily through the embedded GUIs in the toolbox. The effectiveness and applications of the toolbox are illustrated via the design optimization problem of a practical ill-conditioned distillation system. Performance of the algorithm in MOEA toolbox is also compared with other well-known evolutionary MO optimization methods upon a benchmark problem.


Comparison of commercially available target enrichment methods for next-generation sequencing.
Isolating high-priority segments of genomes greatly enhances the efficiency of next-generation sequencing (NGS) by allowing researchers to focus on their regions of interest. For the 2010-11 DNA Sequencing Research Group (DSRG) study, we compared outcomes from two leading companies, Agilent Technologies (Santa Clara, CA, USA) and Roche NimbleGen (Madison, WI, USA), which offer custom-targeted genomic enrichment methods. Both companies were provided with the same genomic sample and challenged to capture identical genomic locations for DNA NGS. The target region totaled 3.5 Mb and included 31 individual genes and a 2-Mb contiguous interval. Each company was asked to design its best assay, perform the capture in replicates, and return the captured material to the DSRG-participating laboratories. Sequencing was performed in two different laboratories on Genome Analyzer IIx systems (Illumina, San Diego, CA, USA). Sequencing data were analyzed for sensitivity, specificity, and coverage of the desired regions. The success of the enrichment was highly dependent on the design of the capture probes. Overall, coverage variability was higher for the Agilent samples. As variant discovery is the ultimate goal for a typical targeted sequencing project, we compared samples for their ability to sequence single-nucleotide polymorphisms (SNPs) as a test of the ability to capture both chromosomes from the sample. In the targeted regions, we detected 2546 SNPs with the NimbleGen samples and 2071 with Agilent's. When limited to the regions that both companies included as baits, the number of SNPs was ∼1000 for each, with Agilent and NimbleGen finding a small number of unique SNPs not found by the other.


Stanford University Network for Diagnosis of Retinopathy of Prematurity (SUNDROP): five years of screening with telemedicine.
To report the 5-year results of the Stanford University Network for Diagnosis of Retinopathy of Prematurity (SUNDROP) telemedicine initiative. Infants requiring retinopathy of prematurity (ROP) screening at six neonatal intensive care units from December 1, 2005, to November 30, 2010, were evaluated with remote retinal photography by an ROP specialist. Every infant received outpatient binocular indirect ophthalmoscope examinations until termination criteria were achieved or until treatment. Outcomes were treatment-warranted ROP (TW-ROP, ETROP type 1) and adverse anatomical events. Five hundred eleven infants (1,022 eyes) were screened. Fifteen infants had TW-ROP and underwent laser photocoagulation. The TW-ROP cohort had significantly lower birth weight and gestational age (both P < .001). No patient progressed to adverse anatomical outcomes and no case of TW-ROP was missed. Tele-medicine had 100% sensitivity, 99.8% specificity, 93.8% positive predictive value, and 100% negative predictive value for detection of TW-ROP. Telemedicine demonstrates high diagnostic accuracy for detection of TW-ROP and can complement ROP screening.


Emergence of Lyme Disease on Treeless Islands, Scotland, United Kingdom.
Lyme disease is usually associated with forested habitats but has recently emerged on treeless islands in the Western Isles of Scotland. The environmental and human components of Lyme disease risk in open habitats remain unknown. We quantified the environmental hazard and risk factors for human tick bite exposure among treeless islands with low and high Lyme disease incidence in the Western Isles. We found a higher prevalence of Borrelia burgdorferi sensu lato-infected ticks on high-incidence than on low-incidence islands (6.4% vs. 0.7%); we also found that residents of high-incidence islands reported increased tick bite exposure. Most tick bites (72.7%) occurred <1 km from the home, including many in home gardens. Residents of high Lyme disease incidence islands reported increasing problems with ticks; many suggested changing deer distribution as a potential driver. We highlight the benefits of an integrated approach in understanding the factors that contribute to Lyme disease emergence.


Brain and brain-heart Granger causality during wakefulness and sleep.
In this exploratory study we apply Granger Causality (GC) to investigate the brain-brain and brain-heart interactions during wakefulness and sleep. Our analysis includes electroencephalogram (EEG) and electrocardiogram (ECG) data during all-night polysomnographic recordings from volunteers with apnea, available from the Massachusetts General Hospital's Computational Clinical Neurophysiology Laboratory and the Clinical Data Animation Laboratory. The data is manually annotated by clinical staff at the MGH in 30 second contiguous intervals (wakefulness and sleep stages 1, 2, 3, and rapid eye movement (REM). We applied GC to 4-s non-overlapping segments of available EEG and ECG across all-night recordings of 50 randomly chosen patients. To identify differences in GC between the different sleep stages, the GC for each sleep stage was subtracted from the GC during wakefulness. Positive (negative) differences indicated that GC was greater (lower) during wakefulness compared to the specific sleep stage. The application of GC to study brain-brain and brain-heart bidirectional connections during wakefulness and sleep confirmed the importance of fronto-posterior connectivity during these two states, but has also revealed differences in ipsilateral and contralateral mechanisms of these connections. It has also confirmed the existence of bidirectional brain-heart connections that are more prominent in the direction from brain to heart. Our exploratory study has shown that GC can be successfully applied to sleep data analysis and captures the varying physiological mechanisms that are related to wakefulness and different sleep stages.


Two decades of circadian time.
Circadian rhythms coordinate our physiology at a fundamental level. Over the last 20 years, we have witnessed a paradigm shift in our perception of what the clocks driving such rhythms actually are, moving from 'black boxes' to talking about autoregulatory transcriptional/post-translational feedback loops with identified molecular components. We also now know that the pacemaker of the suprachiasmatic nuclei (SCN) is not our only clock but quite the opposite because circadian clocks abound in our bodies, driving local rhythms of cellular metabolism, and synchronised to each other and to solar time, by cues from the SCN. This discovery of dispersed local clocks has far-reaching implications for understanding our physiology and the pathological consequences of clock dysfunction, revealing that clocks are critical in a variety of metabolic and neurological conditions, all of which have long-term morbidity attributable to them. Without the currently available molecular framework, these insights would have not have been possible. In the circadian future, a growing appreciation of the systems-level functioning of these clocks and their various cerebral and visceral outputs, will likely stimulate the development of novel therapies for major illnesses.


Regeneration of the transected rat sciatic nerve after suturing or adhesion with cyanoacrylate glue.
Traditional treatment of transected peripheral nerves has been by suturing the nerve ends to each other. Because this approach is not widely available and is technically demanding, the authors evaluated an easier method for end-to-end anastomosis using cyanoacrylate-based glue. The authors used a rat sciatic nerve model. The sciatic nerve was transected in one hind limb in each of 40 rats. In 20 rats, end-to-end anastomosis was performed with suturing, while in the other 20 it was performed using only cyanoacrylate glue. The outcome variables were incapacitance test results; the functional sciatic index; somatosensory evoked potentials; axon counts and sizes at the proximal, anastomotic, and distal levels; local adhesions; and automutilation injuries. Outcomes were measured in a manner blinded to the anastomotic technique. Only the somatosensory evoked potentials and degree of local adhesions were significantly better in the Suture Group than in the Glue Group. With respect to the remaining outcomes (automutilation injuries, counts of large and medium axons combined, and counts of small axons), either the results were significantly better in the Glue Group or the between-groups difference was not statistically significant. There were no consistent significant correlations between the various outcome measures. Using cyanoacrylate-based glue for microanastomosis of cut nerves appears to be as effective as microsuturing the nerve ends. Despite more local adhesions in the glued nerves, most functional outcomes were not influenced by the anastomotic technique. Validation of these findings awaits studies of larger groups of animals.


A different look at the quality of modeled three-dimensional protein structures.
Measuring the accuracy of protein three-dimensional structures is one of the most important problems in protein structure prediction. For structure-based drug design, the accuracy of the binding site is far more important than the accuracy of any other region of the protein. We have developed an automated method for assessing the quality of a protein model by focusing on the set of residues in the small molecule binding site. Small molecule binding sites typically involve multiple regions of the protein coming together in space, and their accuracy has been observed to be sensitive to even small alignment errors. In addition, ligand binding sites contain the critical information required for drug design, making their accuracy particularly important. We analyzed the accuracy of the binding sites on two sets of protein models: the predictions submitted by the top-performing CASP7 groups, and the models generated by four widely used homology modeling packages. The results of our CASP7 analysis significantly differ from the previous findings, implying that the binding site measure does not correlate with the traditional model quality measures used in the structure prediction benchmarks. For the modeling programs, the resolution of binding sites is extremely sensitive to the degree of sequence homology between the query and the template, even when the most accurate alignments are used in the homology modeling process.


Skin lesions on common bottlenose dolphins (Tursiops truncatus) from three sites in the Northwest Atlantic, USA.
Skin disease occurs frequently in many cetacean species across the globe; methods to categorize lesions have relied on photo-identification (photo-id), stranding, and by-catch data. The current study used photo-id data from four sampling months during 2009 to estimate skin lesion prevalence and type occurring on bottlenose dolphins (Tursiops truncatus) from three sites along the southeast United States coast [Sarasota Bay, FL (SSB); near Brunswick and Sapelo Island, GA (BSG); and near Charleston, SC (CHS)]. The prevalence of lesions was highest among BSG dolphins (P = 0.587) and lowest in SSB (P = 0.380), and the overall prevalence was significantly different among all sites (p<0.0167). Logistic regression modeling revealed a significant reduction in the odds of lesion occurrence for increasing water temperatures (OR = 0.92; 95%CI:0.906-0.938) and a significantly increased odds of lesion occurrence for BSG dolphins (OR = 1.39; 95%CI:1.203-1.614). Approximately one-third of the lesioned dolphins from each site presented with multiple types, and population differences in lesion type occurrence were observed (p<0.05). Lesions on stranded dolphins were sampled to determine the etiology of different lesion types, which included three visually distinct samples positive for herpesvirus. Although generally considered non-fatal, skin disease may be indicative of animal health or exposure to anthropogenic or environmental threats, and photo-id data provide an efficient and cost-effective approach to document the occurrence of skin lesions in free-ranging populations.


Return to Activity After SARS-CoV-2 Infection: Cardiac Clearance for Children and Adolescents.
Sedentary behavior and inability to participate in organized physical activity has negatively affected the physical and mental health of children and adolescents; however, cardiac injury and associated risk for sudden cardiac death with return to activity remains a major concern. Guidelines have been proposed for return to activities; however, these fail to address the needs of younger children and those participating in more casual activities. Guidance is needed for primary care providers to facilitate safe return to everyday activity and sports and to help direct appropriate laboratory, electrocardiographic, and anatomical assessment. Review of computerized databases of available literature on SARS-CoV-2 infection in children and postinfection sequelae, risk factors for sudden cardiac death, and previous return to play recommendations. Clinical guidelines based on available evidence and expert consensus. Level 4. In this report, we review the literature on return to activity after SARS-CoV-2 infection and propose recommendations for cardiac clearance for children and adolescents. Though severe disease and cardiac injury is less common in children than in adults, it can occur. Several diagnostic modalities such as electrocardiography, echocardiography, cardiac magnetic resonance imaging, and serologic testing may be useful in the cardiac evaluation of children after SARS-CoV-2 infection. Gradual return to activity is possible in most children and adolescents after SARS-CoV-2 infection and many of these patients can be cleared by their primary care providers. Providing education on surveillance for cardiopulmonary symptoms with return to sports can avoid unnecessary testing and delays in clearance.


Dual regulation of insulin-like growth factor binding protein-1 levels by insulin and cortisol during fasting.
Insulin-like growth factor (IGF) binding protein-1 (IGFBP-1) gene transcription is known to be inhibited by insulin in vivo and in vitro. Levels of IGFBP-1 typically rise during fasting but also rise after acute hypoglycemia, including that induced by insulin, through an unknown mechanism that may involve counterregulatory hormones such as cortisol. To study the regulation of IGFBP-1 secretion during fasting, we measured IGFBP-1, insulin, cortisol, GH, and glucose during the course of standardized fasting studies in a total of 21 children. The fasting studies lasted 13-32 h and were terminated for a whole-blood glucose concentration of less than 50 mg/dL (2.8 mmol). Of the children studied, 9 children had no disorder, 8 had ketotic hypoglycemia, 2 had isolated GH deficiency, and 2 had fatty acid oxidation disorders. During fasting, IGFBP-1 rose above the mean baseline levels of 28+/-5 ng/mL to a mean level+/-SEM of 336+/-59 ng/mL at the time of hypoglycemia (P=0.001). IGFBP-1 was strongly associated with serum insulin and cortisol levels over the entire course of fasting (P < 0.0001)). The interaction of the 2 hormones across time was also strongly significant (P < 0.0001). There was no statistically significant association between IGFBP-1 and GH or glucose. At the time of hypoglycemia, insulin levels were suppressed to 1.7 microU/mL or less, and there was no correlation between IGFBP-1 levels at the end of fasting and final insulin level. In contrast, cortisol levels correlated with IGFBP-1 in the final hypoglycemic sample (r=0.56, P < 0.01). Partial correlation analysis revealed that the relationship between IGFBP-1 and cortisol was unchanged when the data was controlled for insulin levels. These data show that insulin and cortisol both regulate IGFBP-1 secretion during fasting; the effects of insulin and cortisol are strong during the course of fasting. Significant hypoglycemia stimulates a further rise in IGFBP-1, which seems to be regulated, in part, by cortisol. The cortisol-induced rise in IGFBP-1 during fasting and during hypoglycemia potentially serves to prevent the hypoglycemic effects of free IGFs.


A Formal Account of Structuring Motor Actions With Sensory Prediction for a Naive Agent.
For naive robots to become truly autonomous, they need a means of developing their perceptive capabilities instead of relying on hand crafted models. The sensorimotor contingency theory asserts that such a way resides in learning invariants of the sensorimotor flow. We propose a formal framework inspired by this theory for the description of sensorimotor experiences of a naive agent, extending previous related works. We then use said formalism to conduct a theoretical study where we isolate sufficient conditions for the determination of a sensory prediction function. Furthermore, we also show that algebraic structure found in this prediction can be taken as a proxy for structure on the motor displacements, allowing for the discovery of the combinatorial structure of said displacements. Both these claims are further illustrated in simulations where a toy naive agent determines the sensory predictions of its spatial displacements from its uninterpreted sensory flow, which it then uses to infer the combinatorics of said displacements.


Rib stress fractures among rowers: a systematic review on return to sports, risk factors and prevention.
Rib stress fractures (RSFs) are injuries frequently sustained by elite rowers with an injury rate of 8-16% over the course of a rowing career, resulting in negative effects on training and performance. For clinical management, the aim of this review was to describe time to return to sports, summarize potentially preventive measures and appraise the evidence on risk factors. A search strategy was performed in PubMed, SportDiscus, Web of Science and Embase till June 1st 2015. All studies were graded on their quality. The search resulted in 124 studies, of which 17 were included: Ten reported on return to sports, 17 reported on risk factors and nine on preventive measures. For return to sports, nine studies mentioned a loss of training of 4-6 weeks. The shortest period was one week and the longest 16 weeks. For risk factors, insufficient or conflicting evidence was found for changes in the training program, incorrect rowing technique, female gender, low bone mineral density, inadequate equipment, and training type. For prevention, gradual changes in the training program, alertness on the part of coaches and clinicians, and supplementation of diet and hormones are suggested as effective measures. However, no effect studies have been found. The main outcome of this review on RSFs is that little evidence is available on return to sports, risk factors and preventive measures. Coaches and clinicians should carefully guide and assist rowers suffering from RSFs in off training and in the subsequent training period to regain their pre-injury level.


Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia.
Both axon and myelin degeneration have significant impact on the long-term disability of patients with white matter disorder. However, the clinical manifestations of the neurological dysfunction caused by white matter disorders are not sufficient to determine the origin of neurological deficits. A noninvasive biological marker capable of detecting and differentiating axon and myelin degeneration would be a significant addition to currently available tools. Directional diffusivities derived from diffusion tensor imaging (DTI) have been previously proposed by this group as potential biological markers to detect and differentiate axon and myelin degeneration. To further test the hypothesis that axial (lambdaparallel) and radial (lambdaperpendicular) diffusivities reflect axon and myelin pathologies, respectively, the optic nerve was examined serially using DTI in a mouse model of retinal ischemia. A significant decrease of lambdaparallel, the putative DTI axonal marker, was observed 3 days after ischemia without concurrently detectable changes in lambdaperpendicular, the putative myelin marker. This result is consistent with histological findings of significant axonal degeneration with no detectable demyelination at 3 days after ischemia. The elevation of lambdaperpendicular observed 5 days after ischemia is consistent with histological findings of myelin degeneration at this time. These results support the hypothesis that lambdaparallel and lambdaperpendicular hold promise as specific markers of axonal and myelin injury, respectively, and, further, that the coexistence of axonal and myelin degeneration does not confound this utility.


Understanding and promoting resilience in children and youth.
In a context of global concern about the consequences of stress and extreme adversities, advances in theory and methods for studying human resilience have ushered in a new era of integrative, biopsychosocial research. This review highlights recent theory, findings, and implications of resilience research on young people. Resilience research has shifted toward dynamic system models with multiple levels of interaction, including research on the neurobiology of stress and adaption, epigenetic processes, and disasters. Growing evidence indicates individual differences in biological sensitivity to negative and positive experiences, including interventions. Early experiences show enduring programming effects on key adaptive systems, underscoring the importance of early intervention. Studies of developmental cascades demonstrate spreading effects of competence and symptoms over time, with important implications for the timing and targeting of interventions. Disaster research suggests guidelines for planning to protect children in the event of large-scale trauma. Research is integrating the study of resilience across system levels, with implications for promoting positive adaptation of young people faced with extreme adversity. However, studies on neurobiological and epigenetic processes are just beginning, and more research is needed on efficacy, as well as strategic timing and targeting, of interventions.


Partial characterization of ribonuclease (RNase) activity from the isolated and solubilized brush border of Hymenolepis diminuta.
The isolated brush border membrane of Hymenolepis diminuta contained ribonuclease (RNase) activity which was demonstrable using yeast RNA or synthetic homopolymers of adenylic, cytidylic, inosinic, or uridylic acids as substrates. Polyguanylic acid was not hydrolyzed by worm RNase. RNase activity was inhibited by EDTA and divalent cations as well as sulfhydryl blocking and reducing agents. Polyguanylic acid and DNA were also inhibitors of RNase activity; these compounds were not hydrolyzed, but inhibited the hydrolysis of other substrates, possibly by nonproductive substrate binding. Data suggested that RNase (endonuclease) was probably the major enzyme activity in the degradation of long chain polyribonucleotides at the work's surface, while phosphodiesterase (exonuclease) activity did not contribute significantly to the hydrolysis of these compounds.


Inter-rater Reliability of Videofluoroscopic Dysphagia Scale.
To investigate the inter-rater agreement using the Videofluoroscopic Dysphagia Scale (VDS). The present study was designed as a multicenter, single-blind trial. A Videofluoroscopic Swallowing Study (VFSS) was performed using the protocol described by J.A Logemann. Thick-fluid, pureed food, mechanically altered food, regularly textured food, and thin-fluid boluses were sequentially swallowed. Each participant received a 3 ml bolus followed by a 5 ml bolus of each food material, in the order mentioned above. All study procedures were video recorded. Discs containing these video recordings in random order were distributed to interpreters who were blinded to the participant information. The video recordings were evaluated using a standardized VDS sheet and the inter-rater reliability was calculated. In total, 100 patients participated in this study and 10 interpreters analyzed the findings. Inter-rater reliability was fair in terms of lip closure (κ: 0.325), oral transit time (0.253), delayed triggering of pharyngeal swallowing (0.300), vallecular residue (0.275), laryngeal elevation (0.345), pyriform sinus residue (0.310), coating of the pharyngeal wall (0.310), and aspiration (0.393). However, other parameters of the oral phase were lower than those of the pharyngeal phase (0.06-0.153). Moreover, the summation of VDS reliability (intraclass correlation coefficient: 0.556) showed moderate agreement. VDS shows a moderate rate of agreement for evaluating the swallowing function. However, many of the parameters demonstrated a lower rate of agreement, particularly the oral phase parameters.


Brucella Hijacks Host-Mediated Palmitoylation To Stabilize and Localize PrpA to the Plasma Membrane.
Brucellaceae are a group of pathogenic intracellular bacteria with the ability to modulate the host response, both at the individual cell level and systemically. One of the hallmarks of the virulence process is the capacity of the bacteria to downregulate the adaptive and acquired host immune response through a plethora of virulence factors that directly impact several key signaling cascades. PrpA is one of those virulence factors that alters, via its polyclonal B-cell activity, the humoral and cellular immune responses of the host, ultimately favoring the establishment of a chronic infection. Even though PrpA affects B cells, it directly targets macrophages, triggering a response that ultimately affects B lymphocytes. In the present article we report that PrpA is S-palmitoylated in two N-terminal cysteine residues by the host cell and that this modification is necessary for its biological activity. Our results demonstrate that S-palmitoylation promotes PrpA migration to the host cell plasma membrane and stabilizes the protein during infection. These findings add a new mechanism exploited by this highly evolved pathogen to modulate the host immune response.


Treatment of rheumatoid arthritis with prostaglandin E1 precursors cis-linoleic acid and gamma-linolenic acid.
20 patients with active rheumatoid arthritis were treated for 12 weeks with the prostaglandin E1 precursors cis-linoleic acid and gamma-linolenic acid in the form of primrose evening oil (Efamol) and the co-factors zinc, ascorbic acid, niacin, and pyridoxin (Efavit). There was a slight fall in skin reactivity to UV light during the treatment, but no effect on plasma or urine concentrations of PGE1, cAMP or cGMP. There was no effect of the treatment on ESR, P-fibrinogen, number of tender joints, number of swollen joints, the duration of morning stiffness, or on the patient's estimation of pain.


[Analysis of anti-proliferation of curcumin on human breast cancer cells and its mechanism].
To study the suppressive effects of curcumin on breast carcinoma cells and the mechanism. Estrogen receptor (ER) positive human breast cancer line MCF-7 and ER negative human breast cancer line MDA-MB-231 were cultured 17-beta estradiol and curcumin were added into the culture. Northern blot hybridization and Western blots were performed to detect the expression of mRNA and protein. The human ERE promoter activity was analyzed by transient transfection with CAT-reporter constructs. Invasion experiments were conducted with a Matrigel invasion chamber. Curcumin inhibit the proliferation in both estrogen receptor (ER) positive MCF-7 cells and ER negative MDA-MB-231 cells. Curcumin's antiproliferative effects are estrogen dependent in ER positive MCF-7 cells. Curcumin inhibits the expression of ER downstream genes including pS2 and TGF-alpha (transforming growth factor-alpha) in ER-positive MCF-7 cells, and this inhibition is also dependent on the presence of estrogen. In addition, curcumin exerts strong anti-invasive effects in vitro which was not estrogen dependent in the ER-negative MDA-MB-231 breast cancer cells. These anti-invasive effects appeared to be mediated through the down-regulation of MMP-2 (matrix metalloproteinase) and the up-regulation of TIMP-1 (tissue inhibitor of metalloproteinase). Curcumin inhibited the transcript levels of two major angiogenesis factors VEGF (vascular endothelial growth factor) and b-FGF (basic fibroblast growth factor) in ER-negative MDA-MB-231 cells. Curcumin exerts multiple suppressive effects on breast carcinoma cells;it's mechanism of chemoprevention is pleiotropic.


Lyotropic liquid crystal-based transcutaneous peptide delivery system: Evaluation of skin permeability and potential for transcutaneous vaccination.
Transcutaneous drug delivery is a promising method in terms of drug repositioning and reformulation because of its non-invasive and easy-to-use features. To overcome the skin barrier, which is the biggest challenge in transcutaneous drug delivery, a number of techniques, such as microemulsion, solid-in-oil dispersions and liposomes, have been studied extensively. However, the low viscosity of these formulations limits drug retention on the skin and reduces patient acceptability. Although viscosity can be increased by adding a thickening reagent, such an addition often alters formulation nanostructures and drug solubility, and importantly, decreases skin permeability. In this study, a gel-like lyotropic liquid crystal (LLC) was used as a tool to enhance skin permeability. In particular, we prepared 1-monolinolein (ML)-based LLCs with different water contents. All LLCs significantly enhanced skin permeation of a peptide drug, an epitope peptide of melanoma, despite their high viscoelasticity. Fourier transform infra-red spectroscopic analysis of the skin surface treated with the LLCs revealed that the gyroid geometry more strongly interacted with the lamellar structure inside the stratum corneum (SC) than the diamond geometry. Finally, as the result of the in vivo tumor challenge experiment using B16F10 melanoma-bearing mice, the LLC with the gyroid geometry showed stronger vaccine effect against tumor than a subcutaneous injection. Collectively, ML-based LLCs, especially with the gyroid geometry, are a promising strategy to deliver biomacromolecules into skin. STATEMENT OF SIGNIFICANCE: Transcutaneous drug delivery is a promising method for drug repositioning and reformulation because of its non-invasive and easy-to-use features. To overcome the skin barrier, which is the biggest challenge in transcutaneous drug delivery, we used a gel-like lyotropic liquid crystal (LLC) as a novel tool to enhance skin permeability. In this paper, we demonstrated that an LLC with a specific liquid crystalline structure has the highest skin permeation enhancement effect for a peptide antigen as a model drug. Moreover, the peptide antigen-loaded LLC showed a vaccine effect that was comparable to a subcutaneous injection in vivo. This study provides a basis for designing a transcutaneous delivery system of peptide drugs with LLC.


The effects of corticosteroids and related compounds on the histamine and 5-hydroxy-tryptamine content of rat tissues.
Daily intramuscular injections of cortisone, prednisolone, triamcinolone, dexamethasone, fludrocortisone and 2-methylfludrocortisone markedly reduced the histamine and 5-hydroxytryptamine contents of the skin and small intestine of rats; there was an increase however, in the amine contents of the stomach. The sex hormones were weaker in these effects while deoxycortone and corticotrophin were inactive. When the skin was depleted of half of its 5-hydroxytryptamine by prolonged treatment with polymyxin B, the rate of recovery of this amine was retarded by the glucocorticoids. The glucocorticoid activity of a steroid and its ability to produce changes in the histamine and 5-hydroxytryptamine contents of tissues are related.


Establishment of local adaptation in partly self-fertilizing populations.
Populations often inhabit multiple ecological patches and thus experience divergent selection, which can lead to local adaptation if migration is not strong enough to swamp locally adapted alleles. Conditions for the establishment of a locally advantageous allele have been studied in randomly mating populations. However, many species reproduce, at least partially, through self-fertilization, and how selfing affects local adaptation remains unclear and debated. Using a two-patch branching process formalism, we obtained a closed-form approximation under weak selection for the probability of establishment of a locally advantageous allele (P) for arbitrary selfing rate and dominance level, where selection is allowed to act on viability or fecundity, and migration can occur via seed or pollen dispersal. This solution is compared to diffusion approximation and used to investigate the consequences of a shift in a mating system on P, and the establishment of protected polymorphism. We find that selfing can either increase or decrease P, depending on the patterns of dominance in the two patches, and has conflicting effects on local adaptation. Globally, selfing favors local adaptation when locally advantageous alleles are (partially) recessive, when selection between patches is asymmetrical and when migration occurs through pollen rather than seed dispersal. These results establish a rigorous theoretical background to study heterogeneous selection and local adaptation in partially selfing species.


3D Bioprinting of Tumor Models for Cancer Research.
The exact mechanistic understanding of cancer metastasis continues to be unknown, although it is a major cause of death worldwide. Along with the tumor mass, the tumor microenvironment also contributes to pathogenesis and treatment resistance. Tumors are characterized by a high degree of heterogeneity and complexity. However, the fabrication of suitable in vitro models of the microenvironment is difficult as two-dimensional (2D) models do not completely recapitulate the biochemical and biophysical signals of the tumor environment. Thus, three-dimensional (3D) tumor models are emerging as vital tools for the comprehensive understanding of the sophisticated disease. Among different 3D models such as spheroid cultures, biopolymer scaffolds, organ on chip, and ex vivo tissue slices, 3D bioprinting has a competitive advantage due to the ability to precisely control and define the desired structure and position of multiple types of cells in a high-throughput manner. In this Review, we discussed the 3D bioprinted tumor models that integrate their microenvironment with different cell types, substrates, and bioprinting modalities and their application in drug screening and therapy. Finally, we highlighted the comprehensive understanding of the cancer microenvironment by 3D printed tumor models that are more physiologically relevant than the other models and expounded the challenges that need to be addressed for the clinical translation.


Psychological pathways between type D personality and COVID-19.
Patients with a type D personality have worse social functioning and mental health and more affective constraints than non-type D personalities. They have a negative outlook on life and health-related issues. The aim of this study was to examine the mediating role of stress and anxiety in the relationship between type D personality and COVID-19 by adjustment of the effect of demographic characteristics and perceived symptoms as confounder variables. A total of 196 patients out of those suspected of having COVID-19 and visiting the reference hospitals were selected. They had completed the type D personality and the anxiety and stress scales along with their hospital admission form before undergoing COVID-19 testing. After their COVID-19 test, the participants were divided into two groups based on their disease, an infected group (n = 90) and a non-infected group (n = 106). Type D personality has no significant direct effect on infection with the disease, but taking into account the mediating variable of stress, the odds of an event in those with type D personality is 2.21 times higher than those without this personality (p = .027) and, taking into account the mediating variable of anxiety, having a type D personality increases the odds of an event by 2.62 times (p = .011), holding demographic characteristics and perceived symptoms constant. Given the indirect relationship between COVID-19 and type D personality, the mediating variables of stress and anxiety can be considered full mediating variables.