Management of reproductive tract infections in rural Bangladesh.
This study was undertaken to identify existing reproductive tract infection (RTI) treatment practices of the government family planning (FP) paramedics in rural Bangladesh. It also assessed the knowledge and perceptions of the clients about RTIs as well as the service-seeking behaviour of the clients and their husbands. Data on paramedic treatment practices were collected by observing paramedic-client interactions at the family welfare centres (FWCs) and satellite clinics (SCs). One hundred clients seeking RTI treatment were observed. The same clients were interviewed at departure from the health-care facility to assess their knowledge and perceptions about RTIs as well as service-seeking behaviour of the clients and their husbands. Twenty-four village practitioners were also interviewed to assess their knowledge on the subject. Results of the study showed that in the treatment of RTI, paramedics of government FP services commonly: (i) did not do a physical examination, (ii) used a substandard dosage of drugs, and (iii) made no attempt to notify or treat male partners. Thirty-one of the 97 clients reported that their husbands had some kind of genital problem. It was revealed from the study that as an alternative to the government FP services, the clients and their husbands often seek RTI treatment from the village practitioners though the village practitioners' knowledge concerning RTI is poor. Based on the findings of this study, it is recommended that the knowledge and skills of the paramedics and village practitioners for RTI treatment be strengthened. Prevention of RTI through awareness campaigns is essential for the control of RTIs, and especially of STDs.


CRISPR/Cas9-mediated knockout of Rag-2 causes systemic lymphopenia with hypoplastic lymphoid organs in FVB mice.
Recombination activating gene-2 (RAG-2) plays a crucial role in the development of lymphocytes by mediating recombination of T cell receptors and immunoglobulins, and loss of RAG-2 causes severe combined immunodeficiency (SCID) in humans. RAG-2 knockout mice created using homologous recombination in ES cells have served as a valuable immunodeficient platform, but concerns have persisted on the specificity of RAG-2-related phenotypes in these animals due to the limitations associated with the genome engineering method used. To precisely investigate the function of RAG-2, we recently established a new RAG-2 knockout FVB mouse line (RAG-2 -/-) manifesting lymphopenia by employing a CRISPR/Cas9 system at Center for Mouse Models of Human Disease. In this study, we further characterized their phenotypes focusing on histopathological analysis of lymphoid organs. RAG-2 -/- mice showed no abnormality in development compared to their WT littermates for 26 weeks. At necropsy, gross examination revealed significantly smaller spleens and thymuses in RAG-2 -/- mice, while histopathological investigation revealed hypoplastic white pulps with intact red pulps in the spleen, severe atrophy of the thymic cortex and disappearance of follicles in lymph nodes. However, no perceivable change was observed in the bone marrow. Moreover, our analyses showed a specific reduction of lymphocytes with a complete loss of mature T cells and B cells in the lymphoid organs, while natural killer cells and splenic megakaryocytes were increased in RAG-2 -/- mice. These findings indicate that our RAG-2 -/- mice show systemic lymphopenia with the relevant histopathological changes in the lymphoid organs, suggesting them as an improved Rag-2-related immunodeficient model.


Interleukin-4 induces specific pp-GalNAc-T expression and alterations in mucin O-glycosylation in colonic epithelial cells.
Mucus hypersecretion occurs as a consequence of the Th2 immune response in epithelia, yet it was not previously known whether the degree of O-glycosylation was modulated under such conditions. A colonic carcinoma cell line LS174T was used to assess the effect of interleukin (IL)-4 on the mRNA levels of eight pp-GalNAc-Ts. A three- to four-fold increase in pp-GalNAc-T1, T4, and T7 levels was observed. Lysates of untreated or IL-4-treated cells were examined for their ability to transfer GalNAc residues onto a peptide corresponding to the tandem repeat portion of human MUC2. The number of incorporated GalNAc residues was greater after incubation with lysates of IL-4-treated cells than with lysates of untreated cells. Mucin-like large glycoproteins secreted by IL-4-treated cells had higher binding capacity to PNA and VVA-B(4) than those secreted by untreated cells. The results indicated that IL-4-treated LS174T cells are able to produce mucins with a higher degree of O-glycosylation than untreated counterparts.


Human herpesvirus 8 and pulmonary hypertension.
Human herpesvirus 8 (HHV-8) antibodies were detected in 1 of 33 patients with pulmonary hypertension (including in 1 of 16 with idiopathic pulmonary arterial hypertension), 5 of 29 with cystic fibrosis, and 3 of 13 with interstitial lung disease. No relationship between HHV-8 infection and pulmonary hypertension was found.


Coexistence of bistable multi-pulse chaotic motions with large amplitude vibrations in buckled sandwich plate under transverse and in-plane excitations.
This paper researches the dynamic snap-through phenomena and the coexistence of the multi-pulse jumping chaotic dynamics in bistable equilibrium positions and the large amplitude nonlinear vibrations for a simply supported buckled 3D-kagome truss core sandwich rectangular plate under combined transverse and in-plane excitations based on the extended high-dimensional Melnikov method. According to the two-degree-of-freedom non-autonomous nonlinear dynamical system of the buckled truss core sandwich rectangular plate and the theory of normal form, it is found that some nonlinear terms have less effects on the nonlinear dynamic responses than other nonlinear terms. The extended high-dimensional Melnikov method is employed to investigate the dynamic snap-through phenomena and the bistable multi-pulse jumping chaotic vibrations around the upper-mode and the lower-mode for two different cases of buckling in the truss core sandwich rectangular plate. A numerical method is used to detect the bistable multi-pulse jumping chaotic vibrations around two stable equilibrium positions for the non-autonomous buckled truss core sandwich rectangular plate. The obtained theoretical and numerical results indicate that there exists the coexistence of the bistable multi-pulse jumping chaotic vibrations and the large amplitude nonlinear vibrations in the buckled truss core sandwich rectangular plate under combined transverse and in-plane excitations.


Human CTLA-4 is expressed in situ on T lymphocytes in germinal centers, in cutaneous graft-versus-host disease, and in Hodgkin's disease.
Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4, CD152) is a molecule expressed on in vitro activated T cells. CTLA-4 shares important sequence homology with CD28 and binds to the same ligands, CD80 (B7-1) and CD86 (B7-2). CTLA-4 probably functions as a negative regulator of T lymphocyte activation in the mouse, although this remains to be proven for human T lymphocytes. We have developed new monoclonal antibodies against human CTLA-4 and have investigated the in situ expression of CTLA-4 in a wide variety of normal and pathological human tissues expressing CD80 and CD86. As revealed in this study, CTLA-4 is expressed on thymocytes in thymic medulla, on a subset of CD4+ T lymphocytes in germinal centers of follicular hyperplasia, on T cells, mainly CD8+, infiltrating skin affected by graft-versus-host disease, and on T cells, mainly CD4+, infiltrating Hodgkin's disease lesions. In immunoelectron microscopy, CTLA-4 was found on the plasma membrane as well as in the hyaloplasm and cytoplasmic vesicles, in agreement with its pattern of expression on in vitro activated T cells. Interestingly, no or at most scarce expression of CTLA-4 was found in granulomatous lymph nodes, T-cell-mediated inflammatory diseases, or non-Hodgkin's lymphomas, regardless of their expression of CD80 or CD86. Thus, expression of CTLA-4 appears to be induced in selective pathological conditions in vivo. The pathways leading to selective induction of CTLA-4 and its role in the pathophysiology of these conditions need to be further investigated.


Quantifying effects of habitat heterogeneity and other clustering processes on spatial distributions of tree species.
Spatially explicit consideration of species distribution can significantly add to our understanding of species coexistence. In this paper, we evaluated the relative importance of habitat heterogeneity and other clustering processes (e.g., dispersal limitation, collectively called the non-habitat clustering process) in explaining the spatial distribution patterns of 341 tree species in three stem-mapped 25-50 ha plots of tropical, subtropical, and temperate forests. Their relative importance was estimated by a method that can take one mechanism into account when estimating the effects of the other mechanism and vice versa. Our results demonstrated that habitat heterogeneity was less important in explaining the observed species patterns than other clustering processes in plots with flat topography but was more important in one of the three plots that had a complex topography. Meanwhile, both types of clustering mechanisms (habitat or non-habitat) were pervasive among species at the 50-ha scale across the studied plots. Our analyses also revealed considerable variation among species in the relative importance of the two types of mechanism within each plot and showed that this species-level variation can be partially explained by differences in dispersal mode and growth form of species in a highly heterogeneous environment. Our findings provide new perspectives on the formation of species clustering. One important finding is that a significant species-habitat association does not necessarily mean that the habitat heterogeneity has a decisive influence on species distribution. The second insight is that the large species-level variation in the relative importance of the two types of clustering mechanisms should not be ignored. Non-habitat clustering processes can play an important role on species distribution.


Early Prediction of Left Ventricular Reverse Remodeling in First-Diagnosed Idiopathic Dilated Cardiomyopathy: A Comparison of Linear Model, Random Forest, and Extreme Gradient Boosting.
Introduction: Left ventricular reverse remodeling (LVRR) is associated with decreased cardiovascular mortality and improved cardiac survival and also crucial for therapeutic options. However, there is a lack of an early prediction model of LVRR in first-diagnosed dilated cardiomyopathy. Methods: This single-center study included 104 patients with idiopathic DCM. We defined LVRR as an absolute increase in left ventricular ejection fraction (LVEF) from >10% to a final value >35% and a decrease in left ventricular end-diastolic diameter (LVDd) >10%. Analysis features included demographic characteristics, comorbidities, physical sign, biochemistry data, echocardiography, electrocardiogram, Holter monitoring, and medication. Logistic regression, random forests, and extreme gradient boosting (XGBoost) were, respectively, implemented in a 10-fold cross-validated model to discriminate LVRR and non-LVRR, with receiver operating characteristic (ROC) curves and calibration plot for performance evaluation. Results: LVRR occurred in 47 (45.2%) patients after optimal medical treatment. Cystatin C, right ventricular end-diastolic dimension, high-density lipoprotein cholesterol (HDL-C), left atrial dimension, left ventricular posterior wall dimension, systolic blood pressure, severe mitral regurgitation, eGFR, and NYHA classification were included in XGBoost, which reached higher AU-ROC compared with logistic regression (AU-ROC, 0.8205 vs. 0.5909, p = 0.0119). Ablation analysis revealed that cystatin C, right ventricular end-diastolic dimension, and HDL-C made the largest contributions to the model. Conclusion: Tree-based models like XGBoost were able to early differentiate LVRR and non-LVRR in patients with first-diagnosed DCM before drug therapy, facilitating disease management and invasive therapy selection. A multicenter prospective study is necessary for further validation. Clinical Trial Registration:http://www.chictr.org.cn/usercenter.aspx (ChiCTR2000034128).


[The venous ulcer therapy in use of the selected physical methods (Part 2)--The comparison analysis].
The aim of the study was to evaluate the influence of a high voltage stimulation, sonotherapy and laser biostimulation on the process of healing of venous leg ulcers. Four comparative groups--A, B, C and D--were made at a random from 92 patients with venous leg ulcers. The group A consisted of 26 patients, the group B--21 patients, the group C--21 patients, and the group D--24 patients. The patients in all comparative groups were treated pharmacologically. Ulcerations at the patients in the group A were additionally treated with the high voltage stimulation. However, ulcerations at the patients in the group B were treated with the sonotherapy. Ulcerations at the patients in the group C were treated with the laser biostimulation. Changes of the area, length, width and volume of the tissue defekt after above physical therapies were assessed. Changes of the pus decontamination and granulation processes were observed too. After treatment concluded, high voltage stimulation and ultrasound therapy had been more efficient at enhancing healing of venous leg ulcers than topical pharmacology. No significant effect of laser biostimulation on healing process was observed.


Periodontal management and root extrusion of traumatized teeth.
Traumatically induced coronal fractures frequently extend below the free gingival margin. Diagnostic criteria are presented to differentiate those for which crown lengthening alone is appropriate from those that also require orthodontic extrusion. A simplified crown-lengthening technique is described for the exposure of a fracture margin.


Sera of IgA nephropathy patients contain a heterogeneous population of relatively cationic alpha-heavy chains.
Sera of IgA nephropathy (IgAN) patients and normal subjects were analysed by two-dimensional (2-D) gel electrophoresis. Densitometric analysis of the 2-D gels of IgAN patients and normal subjects revealed that their protein maps were comparable. There was no shift of pI values in the major alpha-heavy chain spots. However, the volume of the alpha-heavy chain bands were differently distributed. Distribution was significantly lower at the anionic region in IgAN patients (mean anionic:cationic ratio of 1.184 +/- 0.311) as compared to normal healthy controls (mean anionic:cationic ratio of 2.139 +/- 0.538). Our data are in support of the previously reported findings that IgA1 of IgAN patients were lacking in sialic acid residues.


Variety of rumen microbial populations involved in biohydrogenation related to individual milk fat percentage of dairy cows.
Our objective was to investigate the contribution of the rumen microbiome on the individual milk fat percentage (MFP) of Holstein dairy cows under the same nutritional and management conditions. From 92 early lactation dairy cows, the top 10 with the highest MFP (HF; n = 10) and the last 10 with the lowest MFP (LF; n = 10) were selected for the study. As a result, the milk trans-10, cis-12 C18:2 content was significant lower in the HF group than that in the LF group (P < 0.001). The rumen acetate to propionate ratio was significant higher in the HF group than that in the LF group (P = 0.035). According to the results of 16S rRNA gene sequencing, a minor but significant difference existed between the groups (P = 0.040). Three genera of the family Lachnospiraceae and four genera of the order Bacteroidales were identified to be the biomarkers for the LF group and HF group in the LEfSe analysis, respectively. Three microbial modules enriched by the family Lachnospiraceae were positively related to the milk trans-10, cis-12 C18:2 content (r s > 0.60, P < 0.05). According to the results of shotgun metagenome sequencing, three kinds of linoleic acid (LA) isomerase genes were present in the gene pools of the rumen microbiome. Among them, the relative abundance of Bifidobacterium LA isomerase (BBI) was higher in the HF group than that in the LF group (P = 0.007). Three metagenome-assembled genomes (MAGs) with LA isomerase genes were positively correlated to the milk trans-10, cis-12 C18:2 content (r s > 0.40, P < 0.05). Furthermore, all of these three MAGs were found to be able to produce lactate. Taken together, these results indicate that the increased relative abundance of microbial population with the trans-10 biohydrogenation pathway within the rumen microbiome contributes to the decrease of MFP via the increase of rumen trans-10, cis-12 C18:2 production. This study provides a new perspective for the development of measures for improving the milking performance of dairy cows.


Electronic spectroscopy of the jet-cooled arsenic dicarbide (C2As) free radical.
The (2)Delta(r)-X (2)Pi(r) band system of the jet-cooled arsenic dicarbide (C(2)As) free radical has been recorded by laser-induced fluorescence (LIF) techniques in the 685-588 nm region. The radical was produced in a pulsed electric discharge jet using a precursor mixture of AsCl(3) vapor and methane in high pressure argon. A series of weak bands involving all three excited state vibrations was observed for both (12)C(2)As and (13)C(2)As. High-resolution spectra of the (2)Pi(12) component of the 0(0)(0) bands of both isotopomers were rotationally analyzed, leading to the conclusion that the upper state is (2)Delta with a small spin-orbit splitting (A = 2.78 cm(-1)). Ground and excited state molecular structures of r(0)(")(CC,ab initio) = 1.2933 A, r(0)(")(CAs) = 1.734(4) A and r(0)(')(CC,ab initio) = 1.2276 A, r(0)(')(CAs) = 1.830(3) A were derived from the B values and our density functional predictions of the C-C bond lengths. Single vibronic level emission spectra were recorded for many of the LIF bands and these were used to obtain the ground state vibrational frequencies and spin-orbit splittings. These data were satisfactorily fitted to a Renner-Teller model which gave (12)C(2)As parameters of epsilon = 0.695(8), omega(1) = 1704.8(20) cm(-1), omega(2) = 161.6(8) cm(-1), omega(3) = 663.6(12) cm(-1), and a spin-orbit constant A = 857.7(11) cm(-1).


The role of carbonyl reductase 1 in drug discovery and development.
Carbonyl reductase 1 (CBR1) plays a critical role in drug metabolism of ketones and aldehydes. CBR1 has broad substrate specificity and is involved in metabolizing a number of clinically important drugs. Areas covered: The impact of CBR1 in drug metabolism and disposition are discussed. The CBR1 enzyme is covered in detail including discussion on topics such as tissue distribution, species difference, individual variability, the effect of genetic polymorphism and disease state, iGnducibility and drug-drug interaction potential. The structure and function of CBR1 and CBR3 are also compared. In addition, the formation of chiral alcohols from CBR1 reduction and MIST coverage are reviewed. Expert Opinion: As CBR1 is an emerging enzyme in drug discovery and development, much research is needed to further understand its role in drug metabolism and disposition. In vitro-in vivo correlation for CBR1-mediated clearance is mostly unknown. Selective CBR1 inhibitors and substrates are not well enough characterized for reaction phenotyping of the CBR1 pathway. Multiple pathways appear to be involved in the regulation of CBR1. Future investigation will also help reveal their impact on drug-drug interaction potentials and the influence of individual variability.


Black Phosphorus-Based Drug Nanocarrier for Targeted and Synergetic Chemophotothermal Therapy of Acute Lymphoblastic Leukemia.
As one of the novel two-dimensional nanomaterials, black phosphorus nanosheets (BP NS) have been proven to be excellent carrier materials for drugs, owing to their fine optical properties and biocompatibility. In this work, a composite drug nanocarrier based on BP NS is proposed, which can perform a synergetic and targeted chemophotothermal therapy of acute lymphoblastic leukemia (ALL). First, BP NS were prepared by an improved liquid exfoliation technique. Then, polyethylene glycol (PEG) was modified on the surfaces of BP NS through electrostatic adsorption. Drug molecules can also be loaded onto the BP NS via electrostatic adsorption. The PEG layer can effectively protect the interior BP NS from water and air to enhance their physiological stability. The obtained PEGylated BP NS (BP NS@PEG) not only demonstrated an excellent photothermal conversion efficiency and photothermal stability but also exhibited a good pH and photothermal dual-responsive drug release behavior. In addition, the BP NS@PEG were further modified with Sgc8 aptamers through covalent bonding. The aptamers provided an efficient specificity toward ALL cells (CCRF-CEM) and greatly increased the endocytosis of the nanocarriers through a receptor-mediated manner, which can further improve the therapeutic effect. Hence, the presented BP NS-based multifunctional nanocarrier can achieve a targeted and synergetic chemophotothermal therapy of ALL, which shows a promising potential in improving the curative efficiency.


Accurate estimate of the critical exponent nu for self-avoiding walks via a fast implementation of the pivot algorithm.
We introduce a fast implementation of the pivot algorithm for self-avoiding walks, which we use to obtain large samples of walks on the cubic lattice of up to 33x10{6} steps. Consequently the critical exponent nu for three-dimensional self-avoiding walks is determined to great accuracy; the final estimate is nu=0.587 597(7). The method can be adapted to other models of polymers with short-range interactions, on the lattice or in the continuum.


Circadian rhythms of alcohol dehydrogenase and MEOS in the rat.
The circadian peak in alcohol dehydrogenase (ADH) activity fell near the time of maximal blood ethanol clearance rates both in groups of rats injected with a single ethanol dose (acute group) and in rats continuously exposed to ethanol for 22 weeks (chronic group). However, at all timepoints investigated ADH activity levels were lower and fluctuated less in the chronic group than in either the acute or control (ethanol naive) groups. In contrast, activity levels of the microsomal ethanol oxidizing system (MEOS) revealed a prominent rhythm that was 180 degrees out of phase with the ADH rhythm in the chronic group, while MEOS activity showed very low levels in the acute and control groups and did not vary over the circadian span.


Two new megastigmanes from the leaves of Cucumis sativus.
Two new megastigmane, cucumegastigmanes I (1) and II (2), together with a known megastigmane, (+)-dehydrovomifoliol (3), and five other known compounds were isolated from the leaves of Cucumis sativus. The structures of the new compounds were elucidated from spectroscopic analysis and their absolute stereochemistries were determined in detail using the chemical conversion and a modified Mosher's method.


Different dimensions of religiousness/spirituality are associated with health behaviors in breast cancer survivors.
Religiousness/spirituality (R/S) may influence cancer survivors' health through multiple pathways. We aimed to examine one potentially key pathway that has seldom been examined: relationships between survivors' R/S and their health behaviors. The present study investigated links between four core dimensions of R/S (beliefs, behaviors, identity, and coping) and three health behaviors (fruit/vegetable consumption, physical activity, and maintenance of a healthy weight) in 172 breast cancer survivors. Both spiritual identity and use of religious coping were positively related to fruit and vegetable intake, while private prayer was marginally positively related. Both service attendance and religious identity (marginally) were related to engaging in less physical activity, while private prayer was positively related. Afterlife beliefs and private prayer were positively associated with BMI. R/S has complex but meaningful associations with health behaviors in breast cancer survivors. More research is needed to understand these relationships and to determine whether different dimensions of R/S may play useful roles in lifestyle change interventions.


Potential therapeutic target discovery by 2D-DIGE proteomic analysis in mouse models of asthma.
As asthma physiopathology is complex and not fully understood to date; it is expected that new key mediators are still to be unveiled in this disease. The main objective of this study was to discover potential new target proteins with a molecular weight >20 kDa by using two-dimensional differential in-gel electrophoresis (2D-DIGE) on lung parenchyma extracts from control or allergen-exposed mice (ovalbumin). Two different mouse models leading to the development of acute airway inflammation (5 days allergen exposure) and airway remodeling (10 weeks allergen exposure) were used. This experimental setting allowed the discrimination of 33 protein spots in the acute inflammation model and 31 spots in the remodeling model displaying a differential expression. Several proteins were then identified by MALDI-TOF/TOF MS. Among those differentially expressed proteins, PDIA6, GRP78, Annexin A6, hnRPA3, and Enolase display an increased expression in lung parenchyma from mice exposed to allergen for 5 days. Conversely, Apolipoprotein A1 was shown to be decreased after allergen exposure in the same model. Analysis on lung parenchyma of mice exposed to allergens for 10 weeks showed decreased calreticulin levels. Changes in the levels of those different mediators were confirmed by Western blot and immunohistochemical analysis. Interestingly, alveolar macrophages isolated from lungs in the acute inflammation model displayed enhanced levels of GRP78. Moreover, intratracheal instillation of anti-GRP78 siRNA in allergen-exposed animals led to a decrease in eosinophilic inflammation and bronchial hyperresponsiveness. This study unveils new mediators of potential importance that are up- and down-regulated in asthma. Among up-regulated mediators, GRP-78 appears as a potential new therapeutic target worthy of further investigations.


[Hepatitis C epidemiology in the world].
Development of screening tests for hepatitis C virus (HCV) has enabled study to ascertain hypotheses concerning the epidemiology of non-A, non-B hepatitis. Phylogenic analysis shows that HCV genotypes 1, 2, and 3 are responsible for most cases of chronic hepatitis C in developing countries whereas genotypes 4, 5, and 6 are involved in other areas of the world. Our understanding of the transmission of this virus is also improving and transfusion and addiction-related transmission have now been confirmed. However many questions remain about other routes involving sex, intrafamilial contact, and mother-to-infant transmission. After transfusion there is a period of serological latency during which infection cannot be detected by PCR and which raises the problem of post-transfusion seronegative hepatitis. Current knowledge of the natural history of the disease is limited to the chronic hepatitis stage. New methods must be developed to detect and study the disease in cohorts with early stage disease. Since knowledge about worldwide prevalence is also limited, further studies are needed in the general population in different geographical areas taking into account the fact that southern and eastern Europe, Japan, and Black Africa are high prevalence zones with rates above 1.5%.


Whole-exome sequencing identified genetic risk factors for asparaginase-related complications in childhood ALL patients.
Allergy, pancreatitis and thrombosis are common side-effects of childhood acute lymphoblastic leukemia (ALL) treatment that are associated with the use of asparaginase (ASNase), a key component in most ALL treatment protocols. Starting with predicted functional germline variants obtained through whole-exome sequencing (WES) data of the Quebec childhood ALL cohort we performed exome-wide association studies with ASNase-related toxicities. A subset of top-ranking variants was further confirmed by genotyping (N=302) followed by validation in an independent replication group (N=282); except for thrombosis which was not available for that dataset. SNPs in 12 genes were associated with ASNase complications in discovery cohort including 3 that were associated with allergy, 3 with pancreatitis and 6 with thrombosis. The risk was further increased through combined SNPs effect (p≤0.002), suggesting synergistic interactions between the SNPs identified in each of the studied toxicities. Interestingly, rs3809849 in the MYBBP1A gene was associated with allergy (p= 0.0006), pancreatitis (p=0.002), thrombosis (p=0.02), event-free survival (p=0.02) and overall survival (p=0.003). Furthermore, rs11556218 in IL16 and rs34708521 in SPEF2 were both associated with thrombosis (p=0.01 and p=0.03, respectively) and pancreatitis (p=0.02). The association of SNPs in MYBBP1A, SPEF2 and IL16 geneswith pancreatitis was replicated in the validation cohort (p ≤0.05) as well as in combined cohort (p=0.0003, p=0.008 and p=0.02, respectively). The synergistic effect of combining risk loci had the highest power to predict the development of pancreatitis in both cohorts and was further potentiated in the combined cohort (p=1x10-8).The present work demonstrates that using WES data is a successful "hypothesis-free" strategy for identifying significant genetic markers modulating the effect of the treatment in childhood ALL.


The superiority of combination chemotherapy including etoposide based on in vivo cell cycle analysis in the treatment of extensive small-cell lung cancer: a randomized trial of 288 consecutive patients.
Two hundred and eighty-eight patients with extensive small-cell carcinoma of the lung (SCCL) were entered into a three-arm prospective randomized trial. The purpose was both to compare etoposide with methotrexate (MTX) in a combination chemotherapy regimen otherwise consisting of vincristine (VCR), lomustine (CCNU), and cyclophosphamide (CTX) and to evaluate a treatment design based on cell kinetic observations suggesting enhanced sensitivity to etoposide three to six days after administration of VCR, CCNU, and CTX. In all three treatment arms, VCR, CCNU, and CTX were administered on day 1 of a 28-day cycle. In arm A, MTX was administered on days 14 and 17, while in arm B, MTX was replaced by etoposide administered on days 14 through 17. In arm C, MTX was also replaced by etoposide, but administered on days 3 through 6. Overall survival was significantly longer for patients treated with "early" etoposide (arm C; median, 33 weeks) as compared with arm A (MTX; median, 23 weeks) (P less than .05), but not statistically different from "late" etoposide administration (arm B; median, 27 weeks). However, for patients with initial favorable performance status (0 + 1), a significantly longer survival was obtained for those treated with early etoposide (arm C. median, 51 weeks) as compared with patients in arm A (median, 32 weeks) and arm B (median, 36 weeks) (P less than .05). Two-year survival was obtained in six patients (7%) in arm C compared with three patients (3%) in arm B and none in arm A. The study confirmed that etoposide is an active drug in the treatment of SCCL and when combined with CTX, CCNU, and VCR, the cell kinetic approach of an early administration yields the best results.


Physical therapy on trial: the rationale, organization, and impact of a mock trial on physical therapy students' attitudes toward and confidence in research.
A learning activity, debate with a mock trial format, provides opportunities for physical therapy students to develop skill and confidence in learning to evaluate research critically, to formulate opinions regarding the credibility of the available evidence for a therapeutic approach to patient care, and to substantiate their choice of treatments with persuasive arguments and analytic rebuttals. The purposes of this study were to (1) describe the mock trial learning activity within a professional physical therapy curriculum and (2) determine whether the mock trial positively influenced students' attitudes toward research and confidence in their ability to interpret and apply research findings to clinical practice. A structured questionnaire was distributed to the 48 students at key points during the academic program to measure the overall effects of the physical therapy curriculum and the specific effects of the mock trial learning activity. There was an increase (p < 0.05) in the students' confidence in their ability to interpret and apply research after participating in the mock trial. The overall responses to the modified Attitudes-to-Research scale indicated that the physical therapy students generally held positive and optimistic attitudes toward research. These attitudes were maintained over the entire experience within the curriculum. If attitudes predict behavior, these future practitioners are more likely to be physical therapists who critically appraise and use evidence to determine practice.


[Regulation of the ubiquitin-proteasome system in spermiogenesis].
The ubiquitin-proteasome system (UPS) is an adenosine triphosphate (ATP)-dependent enzymatic machinery that targets substrate proteins for degradation by the 26S proteasome by tagging them with an isopeptide chain composed of covalently linked molecules of ubiquitin, a small chaperone protein. UPS is the main pathway of protein degradation in eukaryotic cells, and plays an important role in spermatogenesis. The dysfunction of various ubiquitin systems results in impaired sperm development with abnormal morphology and function, which is highly associated with male infertility. This review focuses on the roles of UPS in histone-to-protamine exchange, acrosome formation, sperm mitochondrial degradation and regulation of sperm function and quality.


The Inhibitory Effect of WenxinKeli on H9C2 Cardiomyocytes Hypertrophy Induced by Angiotensin II through Regulating Autophagy Activity.
We investigated the role of cardiomyocyte autophagy and its regulatory mechanisms by WenxinKeli (WXKL) in cells subjected to hypertrophy. H9C2 cardiomyocytes were divided into 8 groups. Cytoskeletal proteins as well as endogenously expressed autophagy marker proteins were studied by confocal imaging. Western blotting was used to assess the levels of light chain-3 (LC3) and mechanistic target of rapamycin (mTOR). The cell viability assay was used to detect the content of ATP. Flow cytometry was used to detect apoptotic cardiomyocytes. (1) Compared with the control group, the length and width of cells in the Angiotensin II (AngII) group were significantly increased, while those in the 3-methyladenine (3-MA) and the WXKL groups were decreased. (2) Compared with AngII group, the expression of LC3 II/I protein in the 3-MA and WXKL groups was downregulated, while the expression of mTOR protein was upregulated. (3) Compared with the AngII group, the cardiomyocytes in the WXKL group showed increased ATP and decreased apoptosis rate and number of autophagosome. We propose a novel role of WXKL as a likely inhibitor of cardiac hypertrophy by regulation of pathological autophagy.


Carotenogenesis diversification in phylogenetic lineages of Rhodophyta.
Carotenoid composition is very diverse in Rhodophyta. In this study, we investigated whether this variation is related to the phylogeny of this group. Rhodophyta consists of seven classes, and they can be divided into two groups on the basis of their morphology. The unicellular group (Cyanidiophyceae, Porphyridiophyceae, Rhodellophyceae, and Stylonematophyceae) contained only β-carotene and zeaxanthin, "ZEA-type carotenoids." In contrast, within the macrophytic group (Bangiophyceae, Compsopogonophyceae, and Florideophyceae), Compsopogonophyceae contained antheraxanthin in addition to ZEA-type carotenoids, "ANT-type carotenoids," whereas Bangiophyceae contained α-carotene and lutein along with ZEA-type carotenoids, "LUT-type carotenoids." Florideophyceae is divided into five subclasses. Ahnfeltiophycidae, Hildenbrandiophycidae, and Nemaliophycidae contained LUT-type carotenoids. In Corallinophycidae, Hapalidiales and Lithophylloideae in Corallinales contained LUT-type carotenoids, whereas Corallinoideae in Corallinales contained ANT-type carotenoids. In Rhodymeniophycidae, most orders contained LUT-type carotenoids; however, only Gracilariales contained ANT-type carotenoids. There is a clear relationship between carotenoid composition and phylogenetics in Rhodophyta. Furthermore, we searched open genome databases of several red algae for references to the synthetic enzymes of the carotenoid types detected in this study. β-Carotene and zeaxanthin might be synthesized from lycopene, as in land plants. Antheraxanthin might require zeaxanthin epoxydase, whereas α-carotene and lutein might require two additional enzymes, as in land plants. Furthermore, Glaucophyta contained ZEA-type carotenoids, and Cryptophyta contained β-carotene, α-carotene, and alloxanthin, whose acetylenic group might be synthesized from zeaxanthin by an unknown enzyme. Therefore, we conclude that the presence or absence of the four enzymes is related to diversification of carotenoid composition in these three phyla.


The incidence of venous thromboembolism is not lowin Korean patients with advanced pancreatic cancer [corrected]
Pancreatic cancer is among the most common malignancies associated with venous thromboembolism (VTE). Asian patients are known to have a lower incidence of VTE compared to Caucasian patients. However, few studies have investigated the incidence of VTE in Asian patients with pancreatic cancer. This retrospective review of medical records was performed on 505 patients with histopathologically proven advanced stage pancreatic cancer, from January 2006 to December 2012, at Soonchunhyang University Hospitals. Ninety-four patients (18.6%) had at least one pulmonary embolism (PE), deep vein thrombosis (DVT), or splanchnic vein thrombosis (SVT); 38 patients had isolated SVT; and 56 patients (11.1%) had at least one classic VTE (PE and/or DVT of lower extremities). Patients with more advanced stages of pancreatic cancer (distant metastatic stage, recurrence) or who had received chemotherapy had a higher incidence of classic VTE. Patients who were simultaneously diagnosed with pancreatic cancer and classic VTE had a poorer prognosis than patients with subsequent VTEs. There was a significant difference in overall survival (OS) between the presence and absence of a concurrent classic VTE diagnosis (median: OS, 2.1 mo vs. 10.7 mo; P<0.001). Even when VTE included SVT, the result was similar (P<0.001). In Korean patients with advanced pancreatic cancer, the incidence of VTEs is comparable to that of Caucasian patients. We also found that pancreatic cancer patients with concurrent VTEs had a poor prognosis compared to patients who developed VTEs later.


[Effects of Chansu injection on transplanting-tumor models S180 in mice and human colon cancer HT-29 in nude mice].
To study the antitumor effects of Chansu injection on transplanting- tumor of S(180 ) in mice and human colon cancer HT-29 in nude mice. Using transplanting- tumor models of S(180 ) in mice and human colon cancer HT-29 in nude mice,the tumor inhibitive ratio(IR) of Chansu injection was determined and apoptosis was microscopically observed. Compared with tumor-negative control groups, IR at different dosage of Chansu in models of S(180) and HT-29 was 19.1% - 38.2% and 9.5% - 15.8% respectively,there was a dose-dependent relationship in models of S ( 180) (P< 0.05) and HT- 29 (P> 0.05). The tumor growth was markedly inhibited by cyclophosphamide (CTX) in model of S( 180) with IR of 70.7% and in model of HT-29 with IR of 67.1%, compared with control groups, both P< 0.01; apoptosis induced by CTX was markedly observed by in microscope examination. No significant side effects were shown in the study group. Chansu injection can significantly inhibit tumor growth in model of S(180), but not in model of HT- 29. Different type of tumor has different drug-sensitivity.


Fluorine-18 fluorodeoxyglucose positron emission tomography (PET) to detect vital retinoblastoma in the eye: preliminary experience.
To report our first experience with FDG-PET in the detection of vital retinoblastoma. Four newly diagnosed retinoblastoma patients, two treated retinoblastoma patients, and four control patients were enrolled in this pilot study. F18-FDG uptake was assessed in the light of clinical and histopathological features. PET discriminated between new patients and controls, although tumor uptake varied widely. PET added no useful information with regard to possible vital tissue in tumor scars in the eye of the two treated retinoblastoma patients. Moreover, PET findings did not correlate with clinical or histopathological features. Based on this small pilot study, F18-PET shows little promise in the detection of retinoblastoma. More research on other radiofarmacons is recommended.


Objective evaluation of clinical performance and correlation with knowledge.
In certifying competence of anesthesiologists who have finished residency training, knowledge and judgment are evaluated objectively using written and oral examinations. Clinical motor skills, however, are not routinely assessed by objective techniques. This implicitly assumes that knowledge and judgment correlate with performance of motor skills. This study was designed to evaluate whether performance of a particular motor skill correlates with performance on a knowledge test related to that skill. To do this, we developed a criterion-referenced Spinal Anesthesia Skill Test and a knowledge test using multiple-choice questions related to spinal anesthesia. Both the skill and knowledge tests were administered to 44 residents at various levels of training at five major anesthesia teaching programs. Scores on the skill test were significantly higher than in the knowledge test, suggesting that proficiency in this essential motor skill is achieved earlier in training. There was no correlation between scores on the skill test and knowledge test. There were institution-linked differences in the scores on the skill test, suggesting that teaching of motor skills is not uniform. The advantages of developing criteria of performance of motor skills is discussed.


Managing substance use for clients with serious mental illnesses: Knowledge, attitude, and training challenges among outpatient behavioral health providers in California, Ohio, and New York.
Individuals with serious mental illness have high rates of substance use. The most commonly used substances among this population are alcohol and cannabis, and whether clinical providers delivering mental health services feel adequately prepared to address substance use is unclear. While information about the effects of alcohol are well established, the effects of cannabis are less well known and staff may feel less confident in their abilities to assess its use and may rely on more informal sources to learn about it. Mental health agencies in three states (California, Ohio, and New York) surveyed their staff (n =717) to explore their knowledge, training, and expertise in assessment of substance use generally as well as cannabis and alcohol specifically. Overall, providers felt more prepared to address their clients' alcohol use than cannabis use. In between-state comparisons, California providers felt significantly less well prepared to assess, discuss, and refer their clients to treatment compared to Ohio and New York providers. Using a series of multi-categorical mediation models, we confirmed that deficits in training for these specific substances largely accounted for between-state differences in assessment, capacity, and treatment. Substance use training to address the service needs of individuals with co-occurring disorders is insufficient and a significant need exists for systemic changes to workforce training of community mental health providers.


The multiple causal pathways between performance measures' use and effects.
In recent decades, there has been a growing interest in the design and implementation of systems using public reporting of performance measures to improve performance. In their simplest form, such interventions rest on the market-based logic of consumers using publicly released information to modify their behavior, thereby penalizing poor performers. However, evidence from large-scale efforts to use public reporting of performance measures as an instrumental performance improvement tool suggests that the causal mechanisms involved are much more complex. This article offers a typology of four different plausible causal pathways linking public reporting of performance measures and performance improvement. This typology rests on a variety of conceptual models and a review of available empirical evidence. We then use this typology to discuss the core elements that need to be taken into account in efforts to use public reporting of performance measures as a performance improvement tool.


Toxicity and use of over-the-counter cough and cold medication in the pediatric population.
Discussions of the efficacy and toxicity of over-the-counter cough and cold medication have been circulating in the pediatric literature for years. Adverse effects of these medications and the lack of evidence of their efficacy in children make their use a serious matter. An additional consideration for physicians is the recreational use of over-the-counter medications, including adolescent abuse of dextromethorphan. The recent increase in media attention to these issues warrants further review.


Effect of tissue inhibitor of the matrix metalloproteinases-2 expression on the growth and spontaneous metastasis of a human melanoma cell line.
In this study, we examined the effect of expression of tissue inhibitor of metalloproteinases-2 (TIMP-2) on the growth and dissemination of a highly metastatic human melanoma cell line (M24net). M24net melanoma cells express a number of matrix metalloproteinases (MMPs), including gelatinase A and B (MMP-2 and MMP-9) and interstitial collagenase (MMP-1) (A. M. P. Montgomery et al., Cancer Res., 53: 693-700, 1993). The activity of these proteases was effectively down-regulated by transfecting M24net cells with complementary DNA-encoding human TIMP-2. Overexpression of TIMP-2 markedly reduced melanoma growth in the skin of immunodeficient mice but did not prevent these highly malignant cells from spontaneously metastasizing to the lungs and lymph nodes of inoculated mice. We provide a mechanism to account for the growth inhibitory property of TIMP-2 based on its ability to regulate M24net cell growth in three-dimensional interstitial collagen. In the presence of this matrix, M24net cells assume a differentiated morphology and have a reduced growth rate. We present evidence that overexpression of TIMP-2 increases the susceptibility of M24net cells to growth inhibition and morphological differentiation by occluding interstitial collagen.


Isolation of Aspergillus nidulans from a case of fungal rhinosinusitis: a case report.
A rare species i.e. A. nidulans is reported as a causative agent of allergic fungal rhinosinusitis in this study. It is an increasingly recognized type of chronic recurring hypertrophic sinus disease. There are more than 185 species of aspergillus and over 95% of all infections are caused by A. fumigatus, A. flavus and A. niger. A. fumigatus alone accounts for the large majority of cases of both invasive and non invasive aspergillosis. A young immunocompetent lady presented with bilateral nasal obstruction due to multiple polypoid mass at Sheth Vadilal Sarabhai General Hospital, Ahmedabad. Provisional diagnosis of sinonasal polyposis possibly due to fungal cause with infiltration in to nasal cavity was made. Bilateral functional endoscopic sinus surgery with polypectomy was done. The specimen was examined by standard methods and the fungus was identified as A. nidulans by slide culture.


Using Statistical Parametric Mapping as a statistical method for more detailed insights in swimming: a systematic review.
Swimming is a time-based sport and hence strongly dependent from velocity. Most studies about swimming refer to velocity as discrete variable, i.e., 0-D (no time dimension). However, it was argued that using swimming velocity as a continuous variable (1-D, with time dimension) with Statistical Parametric Mapping (SPM) can bring deeper and detailed insights about swimming performance. Therefore, the aim of this study was to perform a systematic review about the current body of knowledge of using Statistical Parametric Mapping in a swimming context. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to identify relevant articles. After screening, nine articles related to Statistical Parametric Mapping (SPM) analysis in swimming were retained for synthesis. Results showed that four articles (44.4%) aimed to understand the kinematics, isokinetic joint torque or electromyographic (EMG) pattern of the swimmer's shoulder either on land or during front crawl trials. Two articles (22.2%) focused on understanding the swimming velocity while performing the breaststroke stroke. One article (11.1%) analyzed the swimmers' propulsion at front-crawl stroke, another one (11.1%) compared swimming velocity during a complete stroke cycle in young swimmers of both sexes as a discrete variable and as a continuous variable. Also, one article (11.1%) analyzed the underwater undulatory velocity. In an EMG context, some findings verified in SPM are not possible to be discovered with traditional 0-D statistical methods. Studies about swimming velocity (breaststroke, freestyle, and underwater undulatory velocity) and propulsion (front-crawl) also highlighted the SPM advantages in comparison to traditional statistical methods. By using SPM, researchers were able to verify specifically where within the stroke cycle significant differences were found. Therefore, coaches can get more detailed information to design specific training drills to overcome hypothetical handicaps.


Composition of sodium cholate micellar solutions.
To study the composition of sodium cholate solutions, an investigation was carried out at 25 degrees C and in N(CH3)4Cl, as a constant ionic medium, at three different concentrations (W = 0.100; 0.500 and 0.800 mol dm(-3)). Electromotive force measurements of three different galvanic cells, the first involving a glass electrode for hydrogen ions, the second an electrode for sodium ions and the third a lead amalgam electrode, were performed. Independently, lead (II) cholate solubility measurements in the presence of sodium ions were performed, as well. The experimental results obtained from both approaches were explained by assuming the formation of aggregates in cholate and sodium of different composition depending on W and on the cholate concentration. The maximum aggregation found number for cholate was 24 and even aggregation numbers were markedly predominant. Only two species with odd aggregation number were found, but at a low percentage. The assumed species and the relative constants were compared with those found for the other sodium salt of cholanic acids.


Genetic Analysis of Syndromic and Nonsyndromic Patients With Craniosynostosis Identifies Novel Mutations in the TWIST1 and EFNB1 Genes.
Craniosynostosis, the premature fusion of cranial sutures, is usually divided into 2 major categories: syndromic and nonsyndromic. Mutations in the FGFR1, FGFR2, FGFR3, TWIST1, and EFNB1 genes cause the common craniosynostosis syndromes Muenke, Crouzon and Crouzon with acanthosis nigricans, Apert, Pfeiffer, Saethre-Chotzen, and Craniofrontonasal. Overlapping features among craniosynostosis syndromes, phenotypic heterogeneity even within the same syndrome, especially in the case of Muenke syndrome, and inadequate clinical evaluation can lead to misdiagnosis, which molecular testing can help clarify. The aim of this study is to investigate the underlying genetic cause in 46 patients with syndromic or nonsyndromic craniosynostosis by direct sequencing and/or microdeletion/microduplication analysis of the FGFR1-3, TWIST1, and EFNB1 genes. Genetic analysis identified 3 novel mutations, c.413T>C - p.(Leu138Pro) [p.(L138P)] in TWIST1, the previously reported c.373G>A - p.(Glu125Lys) [p.(E125K)], and c.717dupA - p.(Leu240IlefsTer79) [p.(L240fs)] mutation in EFNB1 gene as well as 6 previously known mutations and a heterozygous TWIST1 gene deletion. The 2 novel mutations within EFNB1 gene arose de novo, but the novel mutation p.(L138P) within TWIST1 gene was inherited from the patient's father, who was found to be mosaic for the mutation. To our knowledge, this is the first case of mosaicism described for TWIST1 gene. The contribution of molecular genetic analysis to the diagnosis of patients with syndromic craniosynostosis was useful because some were originally misdiagnosed. Conversely, thorough clinical evaluation can guide molecular testing and result in a correct diagnosis.


Combining global land cover datasets to quantify agricultural expansion into forests in Latin America: Limitations and challenges.
While we know that deforestation in the tropics is increasingly driven by commercial agriculture, most tropical countries still lack recent and spatially-explicit assessments of the relative importance of pasture and cropland expansion in causing forest loss. Here we present a spatially explicit quantification of the extent to which cultivated land and grassland expanded at the expense of forests across Latin America in 2001-2011, by combining two "state-of-the-art" global datasets (Global Forest Change forest loss and GlobeLand30-2010 land cover). We further evaluate some of the limitations and challenges in doing this. We find that this approach does capture some of the major patterns of land cover following deforestation, with GlobeLand30-2010's Grassland class (which we interpret as pasture) being the most common land cover replacing forests across Latin America. However, our analysis also reveals some major limitations to combining these land cover datasets for quantifying pasture and cropland expansion into forest. First, a simple one-to-one translation between GlobeLand30-2010's Cultivated land and Grassland classes into cropland and pasture respectively, should not be made without caution, as GlobeLand30-2010 defines its Cultivated land to include some pastures. Comparisons with the TerraClass dataset over the Brazilian Amazon and with previous literature indicates that Cultivated land in GlobeLand30-2010 includes notable amounts of pasture and other vegetation (e.g. in Paraguay and the Brazilian Amazon). This further suggests that the approach taken here generally leads to an underestimation (of up to ~60%) of the role of pasture in replacing forest. Second, a large share (~33%) of the Global Forest Change forest loss is found to still be forest according to GlobeLand30-2010 and our analysis suggests that the accuracy of the combined datasets, especially for areas with heterogeneous land cover and/or small-scale forest loss, is still too poor for deriving accurate quantifications of land cover following forest loss.


Determination of genotoxic and other effects in mice following short term repeated-dose and subchronic inhalation exposure to phosphine.
Phosphine is an important fumigant in the grain industry and has been reported to be genotoxic in occupationally exposed fumigators. This study reports on the effects of phosphine inhalation exposure at up to, and exceeding, occupational relevant levels in a subchronic (0.3, 1.0 and 4.5 ppm, 13 weeks) and a short term repeated-dose (5.5 ppm, 2 weeks) study in both sexes of Balb-c mice. The following end-points were examined: micronucleus induction in bone marrow, peripheral blood, spleen lymphocytes and skin keratinocytes, mutations at the hypoxanthine-guanine phosphoribosyl transferase locus in lymphocytes, and weight gain and relative organ weights (kidneys, lungs, liver, heart, brain and spleen). After subchronic exposure, there was a highly significant negative linear correlation between proportional weight gain and exposure in both sexes (multiple linear regression, r = -0.56, P < 0.0001), with female mice showing a greater effect. Females also showed an increase in relative organ weights at the highest test dose, in contrast to males where there was a slight decrease. A statistically significant increase in micronucleus frequency was seen in the bone marrow and spleen lymphocytes of both sexes, but only at the highest concentration. The short term repeated-dose study revealed a slight decrease in weight gain in both sexes, with a greater effect in females. It is concluded that phosphine is weakly genotoxic in both sexes of mice, and has an effect on weight gain. However, the weak genotoxic effect may not be biologically significant as it was seen only in the subchronic study and only at the highest test concentration of 4.5 +/- 0.8 ppm (approaching the LD50). Although such exposure conditions are unlikely to be encountered in an occupational environment, caution should continue to be exercised in the use of phosphine until more data become available.


[Pathogenesis of pyoderma gangraenosum].
Pyoderma gangraenosum (Pg) is regarded as an indicator of internal primary diseases of mainly auto-immunological character. Gammopathies as basic diseases are very often of the IgA-type. In contrast to the characteristic clinical picture we have observed unspecific, cellular traits. New investigations have reported immunological findings such as deposition of IgG and IgM as well as C3-complexes at the vascular walls. A decreased function of T-cells is described. Pg often develops in consequence of minor traumata. In these cases the disproportion between the primary lesion and the ulcerous process becomes obvious. By presentation of a typical case in addition to a literature survey, it is discussed whether the primary disease is responsible for this development. Because of the close relationship between Pg and the underlying immunopathology it is proposed that Pg - in analogy to the neoplastic cutaneous syndrome - be classified dipolar-like as a paraimmunological syndrome.


Design of multidirectional multiscroll chaotic attractors based on fractional differential systems via switching control.
This paper proposes a saturated function series approach for generating multiscroll chaotic attractors from the fractional differential systems, including one-directional (1-D) n-scroll, two-directional (2-D) nxm-grid scroll, and three-directional (3-D) nxmxl-grid scroll chaotic attractors. Our theoretical analysis shows that all scrolls are located around the equilibria corresponding to the saturated plateaus of the saturated function series on a line in the 1-D case, a plane in the 2-D case, and a three-dimensional space in the 3-D case, respectively. In particular, each saturated plateau corresponds to a unique equilibrium and its unique scroll of the whole attractor. In addition, the number of scrolls is equal to the number of saturated plateaus in the saturated function series. Finally, some underlying dynamical mechanisms are then further investigated for the fractional differential multiscroll systems.


Efficient generation of functional Schwann cells from adipose-derived stem cells in defined conditions.
Schwann cells (SCs) are hitherto regarded as the most promising candidates for viable cell-based therapy to peripheral nervous system (PNS) injuries or degenerative diseases. However, the extreme drawbacks of transplanting autologous SCs for clinical applications still represent a significant bottleneck in neural regenerative medicine, mainly owing to the need of sacrificing a functional nerve to generate autologous SCs and the nature of slow expansion of the SCs. Thus, it is of great importance to establish an alternative cell system for the generation of sufficient SCs. Here, we demonstrated that adipose-derived stem cells (ADSCs) of rat robustly give rise to morphological, phenotypic and functional SCs using an optimized protocol. After undergoing a 3-week in vitro differentiation, almost all of treated ADSCs exhibited spindle shaped morphology similar to genuine SCs and expressed SC markers GFAP and S100. Most importantly, apart from acquisition of SC antigenic and biochemical features, the ADSC-derived SCs were functionally identical to native SCs as they possess a potential ability to form myelin, and secret nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and glia-derived neurotrophic factor (GDNF). The current study may provide an ideal strategy for harvesting sufficient SCs for cell-based treatment of various peripheral nerve injuries or disorders.


The path of helpseeking: perceptions of law enforcement among American Indian victims of sexual assault.
The longstanding history of violence and oppression toward American Indians (AI) by the United States has created numerous problems for native communities, including high crime rates. AI women are sexually victimized more than other U.S. racial groups, but often receive very limited services. Secondary analyses of National Violence Against Women Survey data indicate that AI women's reasons for not reporting rape suggest ongoing suspicion of law enforcement. AI women, compared to others, more often said law enforcement would not believe or would blame them, and more often reported that they or their family dealt with the perpetrator. Many other barriers to helpseeking persist, including prejudice, conflict between Western and native values, language barriers, and poverty. AI communities also possess numerous resources that are specific to their cultures and their sovereign relationships with the U.S. government. More needs to be done to minimize barriers and make full use of community assets.


Evolution of flowering time in a selfing annual plant: Roles of adaptation and genetic drift.
Resurrection studies are a useful tool to measure how phenotypic traits have changed in populations through time. If these trait modifications correlate with the environmental changes that occurred during the time period, it suggests that the phenotypic changes could be a response to selection. Selfing, through its reduction of effective size, could challenge the ability of a population to adapt to environmental changes. Here, we used a resurrection study to test for adaptation in a selfing population of Medicago truncatula, by comparing the genetic composition and flowering times across 22 generations. We found evidence for evolution toward earlier flowering times by about two days and a peculiar genetic structure, typical of highly selfing populations, where some multilocus genotypes (MLGs) are persistent through time. We used the change in frequency of the MLGs through time as a multilocus fitness measure and built a selection gradient that suggests evolution toward earlier flowering times. Yet, a simulation model revealed that the observed change in flowering time could be explained by drift alone, provided the effective size of the population is small enough (<150). These analyses suffer from the difficulty to estimate the effective size in a highly selfing population, where effective recombination is severely reduced.


Influence of genistein isoflavone on matrix metalloproteinase-2 expression in prostate cancer cells.
We investigated the expression of matrix metalloproteinase (MMP)-2 in human LNCaP and PC3 prostate cancer cell lines in response to genistein exposure. Initially we studied the phytosensitivity of the cells to genistein using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay to determine percentage cell viability/inhibition and the terminal deoxynucleotidyl transferase-mediated fluorescein-dUTP nick end-labeling apoptosis assay to assess the type of cell death. The results revealed that genistein inhibited growth and proliferation in both PC3 (hormone-dependent) and LNCaP (hormone-independent) prostate cancer cell lines, that there was no significant difference in sensitivity to genistein between PC3 and LNCaP cells, and that the effect of genistein on the cells was dose- and time-dependent. The results also revealed that inhibition of cell growth in both PC3 and LNCaP cells was predominantly due to apoptotic cell death. These results were consistent with data in previous studies. This was followed by determination of the MMP-2 profile in response to genistein treatment. The results indicated a significant dose- and time-dependent inhibition of MMP-2 expression levels in both cells, with a highly significant negative correlation between MMP-2 levels and concentration of genistein. This is of phytotherapeutic significance in view of the pivotal role of MMP-2 expression in the pathogenesis of prostate cancer. Increasing expression of MMPs has been identified in many human cancers, including prostate cancer. Our findings indicate that genistein could be a potent therapeutic inhibitor of MMP-2 in line with current concepts of targeted treatment.


Food consumption diversity and nutritional status among children aged 6-23 months in Indonesia: The analysis of the results of the 2018 Basic Health Research.
Stunting among children under five years of age is among the highest in Indonesia. The objective of this study was to investigate the association between food consumption diversity and nutritional status among children aged 6-23 months in Indonesia. The data used came from the results of the 2018 Basic Health Research. The main independent variable was the diversity of food consumption. Control variables included breastfeeding practices and demographic and socioeconomic factors. Using ordinal logistic regression, the role of food consumption diversity in influencing nutritional status was examined after controlling for breastfeeding practices and demographic and socioeconomic factors. The results of the study showed that the diversity of food consumption (AOR = 1.15; 95%CI: 1.07-1.24) significantly and statistically influenced nutritional status of children age 6-23 months in Indonesia even after controlling for the effects of breastfeeding practices and demographic and socioeconomic factors. Higher odds of having normal nutritional status compared to being stunted or severely stunted was associated with consuming food according to the dietary diversity. Higher odds of having normal nutritional status compared to being stunted or severely stunted was also significantly and statistically associated with being ever breastfed (AOR = 1.33; 95%CI: 1.22-1.46), aged 6-11 months (AOR = 3.07; 95%CI: 2.79-3.38), female (AOR = 1.35; 95%CI: 1.25-1.46), children of non-working mothers (AOR = 1.12; 95%CI: 1.04-1.21), children of higher educated mothers (AOR = 1.50; 95%CI: 1.30-1.72), children from higher wealth quintile households (AOR = 1.65; 95%CI: 1.44-1.85), children from smaller size family (AOR = 1.07; 95%CI: 1.05-1.10), and urban children (AOR = 1.16; 95%CI:1.08-1.25). A profound percentage of children aged 6-23 months in Indonesia experienced stunting and severely stunting. Children who did not receive minimum dietary diversity were more likely to suffer from stunting. The findings from this study suggest that to ensure the achievement of national goal of preventing stunting and sustainable development goal of ending all forms of malnutrition in Indonesia, the strategy should promote the fulfillment of minimum food consumption diversity.


Disruption of fos causes craniofacial anomalies in developing zebrafish.
Craniofacial development is a complex and tightly regulated process and disruptions can lead to structural birth defects, the most common being nonsyndromic cleft lip and palate (NSCLP). Previously, we identified FOS as a candidate regulator of NSCLP through family-based association studies, yet its specific contributions to oral and palatal formation are poorly understood. This study investigated the role of fos during zebrafish craniofacial development through genetic disruption and knockdown approaches. Fos was expressed in the periderm, olfactory epithelium and other cell populations in the head. Genetic perturbation of fos produced an abnormal craniofacial phenotype with a hypoplastic oral cavity that showed significant changes in midface dimensions by quantitative facial morphometric analysis. Loss and knockdown of fos caused increased cell apoptosis in the head, followed by a significant reduction in cranial neural crest cells (CNCCs) populating the upper and lower jaws. These changes resulted in abnormalities of cartilage, bone and pharyngeal teeth formation. Periderm cells surrounding the oral cavity showed altered morphology and a subset of cells in the upper and lower lip showed disrupted Wnt/β-catenin activation, consistent with modified inductive interactions between mesenchymal and epithelial cells. Taken together, these findings demonstrate that perturbation of fos has detrimental effects on oral epithelial and CNCC-derived tissues suggesting that it plays a critical role in zebrafish craniofacial development and a potential role in NSCLP.


Dynamic measurements of speed and risk perception during driving: Evidence of speed misestimation from continuous ratings and video analysis.
Investigating the factors underlying perceived speed and risk is crucial to ensure safe driving. However, existing studies on this topic usually measure speed and risk perception indirectly after a driving session, which makes it difficult to trace dynamic effects and time points of potential misestimates. To address this problem, we developed and validated a novel continuous method for dynamically measuring risk and speed perceptions. To study the factors affecting risk and speed perception, we presented participants with videos captured on the same racing track from the same point of view but with different drivers who varied in their speed and risk profiles. During the experiment, participants used a joystick to continuously rate the subjectively perceived risk of driving in the first block and the perceived speed in the second block. Our analysis of these dynamic ratings indicates that risk and speed estimates were decoupled, with curves resulting in decreased speeds but increased risk ratings. However, a close distance to the car in front increased both speed and risk. Based on actual and estimated speed data, we found that overtaking cars on curves resulted in participants overestimating their own speed, whereas an increase in the distance to the car in front on a straight course led to underestimations of their own speed. Our results showcase the usefulness of dynamic rating profiles for in-depth investigations into situations that could result in drivers misjudging speed or risk and will thus help the development of more intelligent, human-centered driving assistance systems.


Clinical pharmacology profile of care in Hepatology clinic.
Since 2010, the Clinical Gastroenterology and Hepatology Division of the Central Institute of Hospital das Clínicas of the University of São Paulo Medical School (HC-FMUSP, in the Portuguese acronym) has been developing specialized electives assistance activities in the Outpatient Specialty Clinic, Secondary Level, in São Paulo NGA-63 Várzea do Carmo. The objective of this study was to analyze the pharmacotherapeutic profile of patients. This is a cross-sectional and retrospective study in which patients were seen at the Hepatology sector and the results were submitted to descriptive statistics. During the study period, 492 patients were treated at the clinic, with a mean age of 58.9 years and frequency of 61.2% female and 74.8% living in São Paulo. This population was served by various other medical specialties (cardiology and endocrine among others) and the major liver diagnoses were: chronic hepatitis B and C and fatty liver. Comorbidities were also identified, such as diabetes, hypertension and dyslipidemia. Most patients took their medication in the Basic Health Units. We found that 30% of patients use of more than five medications and the most prescribed were omeprazole 208 (42.3%), metformin 132 (26.8%) and losartan 80 (16.3%). Because it is an adult/elderly population, with several comorbidities and polymedication, it is important to be aware of the rational use of medication. The multidisciplinary team is important in applying correct conducts for the safe use of medicines, to reduce the burden on health spending and improving the quality of life of patients.


Pentraxin3 in chronic thromboembolic pulmonary hypertension: a new biomarker for screening from remitted pulmonary thromboembolism.
Pentraxin3 (PTX3) is a protein, which has multifaceted effects on innate immunity, angiogenesis, and vascular remodeling then could be a disease marker of acute myocardial infarction, heart failure, vasculitis. In addition, PTX3 has been recognized as a biomarker for pulmonary arterial hypertension, however whether it is the case in chronic thromboembolic pulmonary hypertension (CTEPH) remains unclear. Therefore, we investigated whether PTX3 would be a useful biomarker for detecting CTEPH with respect to differentiation from stable pulmonary thromboembolism (PTE), in comparison to other biomarkers. Plasma PTX3 and brain natriuretic peptide (BNP) levels were measured in 70 patients with CTEPH at their first diagnostic right heart catheterization (CTEPH group) and in 20 patients with clinically stable PTE more than three months after the acute episode (control group). The levels of plasma C-reactive protein (CRP) and heart-type fatty acid-binding protein (H-FABP) were also analyzed to compare the diagnostic ability of these biomarkers. The mean level of PTX3 (ng/mL) was significantly higher in the CTEPH group than in the control group (5.51±4.53 versus 2.01±0.96, respectively), and PTX3 levels had mild negative correlation with cardiac output. BNP levels were also higher in the CTEPH group and better correlated with pulmonary hemodynamics than PTX3. However, a receiver operating characteristic (ROC) curve showed PTX3 levels were better for detecting CTEPH, and could detect CTEPH patients with less severe pulmonary hemodynamics and low plasma BNP levels. There was no significant increase in CRP and H-FABP levels in the CTEPH patients. Plasma PTX3 level was the most sensitive biomarker of CTEPH. Although plasma PTX3 levels did not correlate with the severity of the pulmonary hemodynamics compared to BNP, high levels in clinically stable patients following PTE should prompt a further work-up for CTEPH, which may lead to an early diagnosis.


Coarse-grained representation of the quasi adiabatic propagator path integral for the treatment of non-Markovian long-time bath memory.
The description of non-Markovian effects imposed by low frequency bath modes poses a persistent challenge for path integral based approaches like the iterative quasi-adiabatic propagator path integral (iQUAPI) method. We present a novel approximate method, termed mask assisted coarse graining of influence coefficients (MACGIC)-iQUAPI, that offers appealing computational savings due to substantial reduction of considered path segments for propagation. The method relies on an efficient path segment merging procedure via an intermediate coarse grained representation of Feynman-Vernon influence coefficients that exploits physical properties of system decoherence. The MACGIC-iQUAPI method allows us to access the regime of biological significant long-time bath memory on the order of hundred propagation time steps while retaining convergence to iQUAPI results. Numerical performance is demonstrated for a set of benchmark problems that cover bath assisted long range electron transfer, the transition from coherent to incoherent dynamics in a prototypical molecular dimer and excitation energy transfer in a 24-state model of the Fenna-Matthews-Olson trimer complex where in all cases excellent agreement with numerically exact reference data is obtained.


Evaluation of a UDP-glucose-4-epimeraseless mutant of Salmonella typhi as a liver oral vaccine.
A mutant (Ty21a) of Salmonella typhi, which lacks the enzyme uridine 5'-diphosphate-glucose-4-epimerase, was evaluated in volunteers for use as a live attenuated oral typhoid vaccine. Five to eight doses of vaccine (containing 3-10(10) viable organisms per dose) were given to 155 men without significant side effects. The rate of excretion of the vaccine strain in stools was low, and the majority of isolations occurred on day 1 after vaccination. Revertants able to fement galactose were not found in any of 958 stool isolates tested. The mutant, strain Ty21a, grown in brain-heart infusion broth (BHIB) with 0.1% galactose, produces more O side chain than the same vaccine strain cultivated without galactose. Volunteers vaccinated with strain Ty21a grown in galactose and then challenged with 10(5) virulen S. typhi were significantly protected from disease and also had decreased stool carriage of S. typhi as compared with controls. Strain Ty21a grown without galactose did not provide vaccinees significant protection nor decrease fecal excretion of S. typhi as compared with controls. Strain Ty21a, when grown in BHIB with 0.1% galactose, results in a safe, stable and protective oral vaccine that warrants further study in field trials.


The phenomenological structure of drug-induced ego states. II. Barbiturates and sedative-hypnotics: phenomenology and implications.
Empirically derived descriptions of experiential states, induced by heavy, chronic consumption of drugs, provide valuable information for treatment personnel as well as for scientists studying drug abuse or pharmacology. A 7-year program of research has studied persons committed to heavy, long-term use of several prominent substances of abuse. This report results from that research and provides a phenomenological description of the psychological state induced by heavy, chronic use of barbiturates and sedative-hypnotics. Interview, Q-sort and semantic differential data indicate the barbiturate state is intensely unpleasant: a state in which users lose desired characteristics, take on undesired characteristics, engage in self-destructive acts, and emerge in worse condition than before entering it. Explaining why people choose to enter such a state is difficult. Several theoretical alternatives for doing so are considered. Psychotherapy with these individuals must deal with the theme of abandonment/rejection that permeates their lives and with the diffuse hostility, expectations of failure and defeat, self-destructive tendencies, and feelings of hopelessness that they display. Suggestions are presented for treatment of individual cases.


Contextual factors affect absent reference comprehension in 14-month-olds.
How do infants come to understand references to absent objects? 14-month-old infants first learned a name for a novel toy, which was then placed out of view. The infants who listened to a story mentioning the nonvisible object, looked, pointed, and searched for it more often than did infants who heard a story using a different name. Their behavior was affected by minor changes in context; they responded to the name of the out-of-view toy less often when it was not easily accessible or after a delay. These findings indicate that the development of absence reference comprehension depends on the interaction of representational and contextual factors.


Utility of global positioning system to measure active transport in urban areas.
The purpose of this study was to determine test-retest reliability of global positioning system (GPS) units for measuring distance traveled when walking and cycling (AT), and to determine whether GPS unit placement influences accuracy. Participants (N = 19) completed two walking and cycling trials at self-selected speeds on a measured 1489-m course wearing two Garmin GPS units, worn in lanyard and waistband placements. GPS estimates of travel distance were compared with actual distance, and test-retest reliability was examined. Data-cleaning protocols were developed to remove signal noise. Results are presented for both raw and cleaned data. For both raw and cleaned data, no significant differences were observed between trials (trial 1 vs trial 2), unit placement (lanyard vs waistband), or AT mode (walk vs cycle) (P >or= 0.05). Both lanyard and waistband units significantly overestimated distance traveled during walking trials (P <or= 0.05), but not cycling trials (P >or= 0.05). The relative technical error of measurement (TEM) of the raw data ranged from 3.74 to 15.51%, and average absolute errors ranged from 5.03 to 8.53% for all trials. A significant position by AT mode interaction was observed for clean data (P < 0.05). Relative TEM for the clean data ranged from 1.42 to 1.98%, and average absolute errors ranged from 0.32 to 1.97%. Intraclass correlations (ICC) were poor to fair for all trials using raw and cleaned data. Signal noise during unit initialization may adversely affect unit performance; however, application of data-cleaning procedures to remove data associated with signal noise improves unit ability to measure distance. Results suggest that the lanyard position is the optimal placement for units during data collection.


Successful closure of the arterial duct in the setting of rubella syndrome.
A 9-year-old boy, with significant left-to-right shunting across a large duct in the context of rubella syndrome, was tested during catheterization to establish the feasability of occluding the duct with a device. The testing, including temporary closure of the duct and monitoring of pulmonary vascular reactivity to vasodilative substances, lead to the decision to implant an Amplatzer occluder. Sixteen months later, there was no residual shunting across the duct, and pulmonary arterial pressures had normalised. It remains unclear why the patient had not developed irreversible pulmonary vascular disease.


Exploring dysregulated miRNAs in cryptorchidism: a systematic review.
To identify dysregulated miRNAs in testicular tissues from animal models and patients with cryptorchidism. Databases were systematically searched for studies published before 10 May 2020 that had investigated miRNAs in cryptorchidism. Predicted targets of the identified miRNA biomarkers were obtained by searching TargetScan and Starbase. Gene ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analyses were subsequently conducted. Five publications met the eligibility criteria for the review. 21 differentially expressed miRNAs were the most abundantly reported in 185 animal and human tissue samples. Three miRNAs (miR-210, miR-449a and miR-34c) were dysregulated in both animal and human testicular tissues. The top five relevant lncRNAs associated with the miRNAs were NEAT1, KCNQ1OT1, XIST, AC005154.1, and TUG1. Further research is warranted to explore the potential of these dysregulated miRNAs as biomarkers or therapeutic targets for male infertility associated with cryptorchidism.


Posttranslational processing of mouse and human BMP-15: potential implication in the determination of ovulation quota.
There has been significant attention to the growing recognition that oocytes have a critical capacity to organize and govern surrounding somatic cells. Bone morphogenetic protein 15 (BMP-15) is an oocyte-secreted factor that has raised particular interest due to its established role in determining ovulation quota and female fertility in mammals. As a first step in determining whether there are species-specific differences in the BMP-15 system that may play causal roles in the differences in ovulation quota observed in different mammalian species, we here compare the molecular characteristics of BMP-15 of polyovulatory mice with that of monoovulatory humans. We found that, although human BMP-15 mature protein is readily produced, there are defects in the production of mouse BMP-15 mature protein in an in vitro system of transfected cells. The generation of chimeric constructs consisting of different combinations of mouse and human BMP-15 proregions, cleavage sites, and mature regions indicates that the defects in the production of mouse BMP-15 mature protein depend on the presence of the mouse BMP-15 proregion. The mouse proregion also caused a significant reduction in the production of human BMP-15 mature protein. The coexpression with a convertase cleavage enzyme, furin, results in complete processing of all these chimeras; however, no mouse mature protein is detected in either secreted or cell-confined forms except when associated with the human proregion. Based on the biological role of BMP-15, defects in the production of mouse BMP-15 mature protein could correlate with the high ovulation quota and litter size observed in mice.


Dynamic charge acceptance and hydrogen evolution of a new MXene additive in advanced lead-acid batteries via a rapid screening three-electrode method.
A methodology to screen additives in lead-acid batteries is critical. We developed a three-electrode system that can rapidly check the dynamic charge acceptance (DCA) and hydrogen evolution of electrodes. The electrode with 2% MXene and 0.2% carbon black shows a better DCA, which indicates its great potential in the start-stop technology.


Therapeutic outcomes of early and delayed endoscopic retrograde cholangiopancreatography and percutaneous transhepatic cholangial drainage in patients with obstructive severe acute biliary pancreatitis.
Obstructive severe acute biliary pancreatitis (SABP) is a clinical emergency with a high rate of mortality that can be alleviated by endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangial drainage (PTCD) selectively. However, the optimal timing of ERCP and PTCD requires elucidation. The aim of this study was to evaluate outcome parameters in patients with SABP subjected to ERCP and PTCD compared to SABP patients who were not subjected to any form of invasive intervention. A total of 62 patients with obstructive SABP who had been treated from July 2013 to July 2019 were included in this retrospective case-control study and stratified into a PTCD group (N = 22), ERCP group (N = 24), and conservative treatment group (N = 16, control). Patients in the PTCD and ERCP groups were substratified into early (≤72 h) and delayed (>72 h) treatment groups based on the timing of the intervention after diagnosis. Clinical chemistry, hospitalization days, liver function, abdominal pain, and complications were determined to assess the treatment efficacy and safety of each modality and to establish the optimal timing for PTCD and ERCP. The average hospitalization time, time to abdominal pain relief, and time to normalization of hematological and clinical chemistry parameters (leukocyte count, amylase, alanine transaminase [ALT], and total bilirubin [TBiL]) were shorter in the PTCD and ERCP groups compared to the conservative treatment group (p < 0.05). The average hospitalization time in the ERCP group (16.7 ± 4.0 d) was shorter compared to the PTCD group (19.6 ± 4.3 d) (p < 0.05). Compared to the conservative treatment group (62.5%), there were more complications in patients treated with ERCP and PTCD (p < 0.05). In the early ERCP group, the average hospitalization time (13.9 ± 3.3 d) and the time to normalization of leukocyte count (6.3 ± 0.9 d) and TBiL (9.1 ± 2.0 d) were lower than in the delayed ERCP group (18.6 ± 4.1 d, 9.9 ± 2.4 d, 11.8 ± 2.9 d, respectively) and early PTCD group (16.4 ± 3.7 d, 8.5 ± 2.1 d, 10.9 ± 3.1 d, respectively) (p < 0.05). In the delayed ERCP group, the average hospitalization time (18.6 ± 4.1 d) and ALT recovery time (12.2 ± 2.6 d) were lower than in the delayed PTCD group (21.9 ± 4.3 d and 14.9 ± 3.9 d, respectively) (p < 0.05). ERCP and PTCD effectively relieve SABP-associated biliary obstruction with comparable overall incidence of complications. It is recommended that ERCP is performed within 72 h after diagnosis; and PTCD drainage may be considered an alternative approach in cases where patients are unable or unwilling to undergo ERCP, or when ERCP is unsuccessful. ERCP and PTCD in patients with obstructive SABP can resolve biliary obstruction and delay progression of the disease. Performing ERCP and PTCD within 72 h (i.e., optimal treatment time window) can be beneficial to patients, especially in terms of post-operative recovery. Visual biliary endoscopy (oral or percutaneous transhepatic) may be used for concomitant therapeutic interventions in the biliary system.


Interleukin-1-like activity in capsular material from Haemophilus actinomycetemcomitans.
This paper describes the activity of a bacterial surface component (capsular material, CM) in biological assays for interleukin-1 (IL-1). CM from the periodontal pathogen Haemophilus actinomycetemcomitans was tested in the following in vitro assays: mouse thymocyte proliferation (LAF assay), stimulation of collagenase and prostaglandin (PG) E2 synthesis by articular chondrocytes, and stimulation of PGE2 synthesis by fibroblasts. In all these assays, CM gave a response similar to an IL-1 preparation. This ability to mimic IL-1 suggests an important role for CM in both cell-mediated immunity and connective tissue destruction in localized juvenile periodontitis (LJP).


Second window ICG predicts postoperative MRI gadolinium enhancement in high grade gliomas and brain metastases.
A prospective trial evaluating the utility of second window indocyanine green (SWIG) in predicting postoperative MRI gadolinium enhancement was performed on high-grade gliomas (HGGs) and brain metastases. Compared to white light alone, SWIG demonstrated a higher sensitivity, negative predictive value, and accuracy in predicting residual neoplasm on MRI. The specificity of SWIG for predicting MRI enhancement was higher in HGGs than brain metastases. Clinically, near-infrared (NIR) imaging was better able to predict tumor recurrence than postoperative MRI. These results illustrate how SWIG is able to take advantage of gadolinium-like distribution properties to extravasate into the tumor microenvironment, enabling guidance in surgical resection. The video can be found here: https://stream.cadmore.media/r10.3171/2021.10.FOCVID21204.


Epidemiology and treatment of psoriasis: a Brazilian perspective.
Psoriasis is a chronic immune-mediated systemic disease that is influenced by genetic and environmental factors, is associated with comorbidities, and has a negative impact on the quality of life of affected individuals. The prevalence of psoriasis varies among different ethnic groups, but this topic has not been studied in Brazil to date. In this review, we evaluate the epidemiology and treatment of psoriasis from a Brazilian perspective. We focused on studies that involved Brazilian subjects. The prevalence of psoriasis in Brazil is estimated to be 2.5%, but no population study has been performed previously. Environmental factors, such as tropical climate, in association with genetic factors, such as miscegenation, may exert a beneficial impact on the course and frequency of psoriasis in Brazil. A number of studies have advanced our understanding of the cardiovascular, ophthalmic, and oral comorbidities that are associated with psoriasis. Concerns about biological therapy, such as endemic leprosy, human T-cell lymphotropic virus (HTLV), and tuberculosis infections, are discussed. The nonavailability of treatment options for psoriasis in the public health system contradicts the Brazilian Society of Dermatology guidelines, stimulating the judicialization of access to medicines in psoriasis care.


Adipose-immune interactions during obesity and caloric restriction: reciprocal mechanisms regulating immunity and health span.
Increasing evidence suggests a tight coupling of metabolic and immune systems. This cross-talk mediated by neuroendocrine peptides as well as numerous cytokines and chemokines is believed to be responsible for integrating energy balance to immune function. These neuroendocrine-immune interactions are heightened during the state of chronic positive energy balance, as seen during obesity, and negative energy balance caused by caloric restriction (CR). Emerging evidence suggests that obesity may be associated with an immunodeficient state and chronic inflammation, which contribute to an increased risk of premature death. The direct interactions between expanded leukocyte populations within the adipose tissue during obesity and an increased number of adipocytes within an aging lymphoid microenvironment may constitute an important adaptive or pathological response as a result of change in energy balance. In stark contrast to obesity, CR causes negative energy balance and robustly prolongs a healthy lifespan in all of the species studied to date. Therefore, the endogenous neuroendocrine-metabolic sensors elevated or suppressed as a result of changes in energy balance may offer an important mechanism in understanding the antiaging and potential immune-enhancing nature of CR. Ghrelin, one such sensor of negative energy balance, is reduced during obesity and increased by CR. Ghrelin also regulates immune function by reducing proinflammatory cytokines and promotes thymopoiesis during aging and thus, may be a new CR mimetic target. The identification of immune effects and molecular pathways used by such orexigenic metabolic factors could offer potentially novel approaches to enhance immunity and increase healthy lifespan.


The role of high-dose therapy and autologous bone marrow reinfusion in the treatment of malignant lymphomas.
In a significant fraction of patients with NHL or HD, disease develops that is resistant to conventional chemotherapy. Experience using high-dose chemotherapy, with or without TBI, and ABMR is expanding. In HD, remissions can be achieved in approximately half of the patients with relapsed advanced disease. This may also be true in patients with NHL who do not respond to conventional regimens. High-dose chemoradiotherapy regimens are toxic and require extensive supportive care. Relapse frequently occurs in areas of previous disease, suggesting failure of the conditioning regimen rather that an infusion of occult tumor cells in the autologous bone marrow had occurred. Thus, the role of marrow purging in this therapy needs to be further evaluated and compared with findings involving nonpurged marrow reinfusion. It is also important to evaluate the effects of more vigorous attempts at cytoreduction of bulky disease prior to high-dose therapy and ABMR. We recommend that high-dose therapy and ABMR in an investigational setting be used (1) in patients with HD who experience relapse after MOPP/ABVD or equivalent regimens and (2) in patients with intermediate or high-grade NHL whose disease recurs or is resistant to conventional regimens. Potential areas for development include the use of this modality as intensification therapy following conventional therapy in patients with intermediate or high-grade NHL with poor prognostic features. Toxicity can be decreased and efficacy increased only if therapy is administered to patients who have not been heavily pretreated and who have lower tumor burden and a good performance status. The role of high-dose chemotherapy of ABMR in the nodular lymphomas is not known at this point. Finally, high-dose ABMR therapy has a definite role in salvaging patients with malignant lymphomas. Many issues need to be resolved, including (i) the optimal timing of this approach, (ii) the optimal conditioning regimen, and (iii) the need for purging bone marrow prior to reinfusion. The past 10 years have led to significant gains. During the next 10 years, it may be possible to refine this therapy and find solutions to the above issues.


Extensive expression of craniofacial related homeobox genes in canine mammary sarcomas.
The global gene expression in three types of canine mammary tumors: carcinoma, fibrosarcoma and osteosarcoma were investigated by Affymetrix gene array technology. Unsupervised clustering analysis revealed a close clustering of the respective tumor types, with fibrosarcomas clustering close to the osteosarcomas and the carcinomas clustering closer to non-malignant mammary tissues (NMTs). A number of epithelial markers were expressed in both carcinomas and NMTs, whereas the sarcomas expressed genes related to mesenchymal differentiation. A comparison of the gene expression profile of the sarcomas versus carcinoma/NMTs revealed that the sarcomas, in particular the osteosarcomas, showed a striking upregulation of a panel of homeobox genes previously linked to craniofacial bone formation. In line with this finding, osteosarcomas showed an upregulation of bone morphogenetic proteins (BMPs) and of genes associated with retinoic acid signaling. Increased homeobox gene expression in sarcomas was also confirmed at the protein level by immunohistochemical analysis of tumor tissue, and in an osteosarcoma cell line after stimulation by BMP-2. These findings suggest that the development of mammary sarcomas specifically involves triggering of a set of homeobox genes related to neural crest and craniofacial bone development.