The SMYD family proteins in immunology: An update of their obvious and non-obvious relations with the immune system.
Epigenetics is an emerging field, due to its relevance in the regulation of a wide range of biological processes. The Su(Var)3-9, Enhancer-of-zeste and Trithorax (SET) and Myeloid, Nervy, and DEAF-1 (MYND) domain-containing (SMYD) proteins, named SMYD1, SMYD2, SMYD3, SMYD4 and SMYD5, are enzymes that catalyse methylation of histone and non-histone substrates, thereby playing a key role in gene expression regulation in many biological contexts, such as muscle development and physiology, haematopoiesis and many types of cancer. This review focuses on a relatively unexplored aspect of SMYD family members - their relation with immunology. Here, immunology is defined in the broadest sense of the word, including basic research on macrophage function or host immunity against pathogen infection, as well as clinical studies, most of which are centred on blood cancers.


Synthesis and biological evaluation of a new class of geldanamycin derivatives as potent inhibitors of Hsp90.
The heat shock protein Hsp90 has increasingly become an important therapeutic target especially for treatment of cancers. Inhibition of the ATPase activity of Hsp90 by natural products (e.g., 17-allylaminogeldanamycin or radicicol) leads to the ubiquitination of oncogenic client proteins such as Her-2, Raf-1, and p-Akt followed by their proteasomal degradation. Hsp90 inhibitors simultaneously target multiple oncogenic proteins and provide an advantage for cancer therapy due to the potential for increased efficacy and overcoming drug resistance. In an effort to convert geldanamycin into a druglike compound with better pharmacokinetic properties and efficacy in human tumor xenograft models, geldanamycin was derivatized on the 17-position to prepare new analogues such as 17-geldanamycin amides, carbamates, and ureas and 17-arylgeldanamycins. All the compounds were first evaluated ex vivo using a cell-based Her-2 degradation assay and in vitro using biochemical assays that measure recombinant Hsp90 (rHsp90) competitive binding and changes in rHsp90 conformation. In addition, we confirmed the selectivity of geldanamycin analogues for Hsp90 derived from tumor cells using a novel cell lysate binding assay.


Intralesional injection versus mouth rinse of triamcinolone acetonide in oral lichen planus: a randomized controlled study.
To compare the efficacy, relapse, and adverse effects between intralesional injection and mouth rinse of triamcinolone acetonide (TA) in patients with oral lichen planus (OLP). A randomized controlled study. College medical center. Forty consecutive patients, who had been diagnosed with OLP, were recruited. Participants were randomly divided into 2 groups using intralesional injection or mouth rinse of TA. The severity of pain and burning sensation on a 10-cm visual analog scale (VAS) and the Oral Health Impact Profile-14 (OHIP-14) were assessed at weeks 0, 1, 2, 3, 4, and 6. The signs of OLP were quantified using a special scoring system for OLP. The rate of relapse and the adverse effects were compared between both groups. The VAS scores for pain and burning mouth sensation and objective scoring for OLP were significantly improved at 1, 2, 3, 4, and 6 weeks in both groups. The changes in the VAS for burning mouth sensation, OHIP-14, and objective scoring for OLP were similar between both groups. The change in the VAS for pain from baseline to week 1 in the intralesional injection group was significantly higher than in the mouth rinse group. The rate of adverse effects was significantly higher in the mouth rinse group than in the intralesional injection group (44.4% vs 5.0%). The efficacies of both treatments were similar. The rate of adverse effects was significantly lower for intralesional injection of TA than mouth rinse of TA.


Facilitated Visual Interpretation of Scores in Principal Component Analysis by Bioactivity-Labeling of 1H-NMR Spectra-Metabolomics Investigation and Identification of a New α-Glucosidase Inhibitor in Radix Astragali.
Radix Astragali is a component of several traditional medicines used for the treatment of type 2 diabetes in China. Radix Astragali is known to contain isoflavones, which inhibit α-glucosidase in the small intestines, and thus lowers the blood glucose levels. In this study, 21 samples obtained from different regions of China were extracted with ethyl acetate, then the IC50-values were determined, and the crude extracts were analyzed by 1H-NMR spectroscopy. A principal component analysis of the 1H-NMR spectra labeled with their IC50-values, that is, bioactivity-labeled 1H-NMR spectra, showed a clear correlation between spectral profiles and the α-glucosidase inhibitory activity. The loading plot and LC-HRMS/NMR of microfractions indicated that previously unknown long chain ferulates could be partly responsible for the observed antidiabetic activity of Radix Astragali. Subsequent preparative scale isolation revealed a compound not previously reported, linoleyl ferulate (1), showing α-glucosidase inhibitory activity (IC50 0.5 mM) at a level comparable to the previously studied isoflavones. A closely related analogue, hexadecyl ferulate (2), did not show significant inhibitory activity, and the double bonds in the alcohol part of 1 seem to be important structural features for the α-glucosidase inhibitory activity. This proof of concept study demonstrates that bioactivity-labeling of the 1H-NMR spectral data of crude extracts allows global and nonselective identification of individual constituents contributing to the crude extract's bioactivity.


Evidence for a common mechanism for spontaneous rhythmic contraction and myogenic contraction induced by quick stretch in detrusor smooth muscle.
Detrusor smooth muscle exhibits myogenic contraction in response to a quick stretch (QS) as well as spontaneous rhythmic contraction (SRC); however, whether the same population of actomyosin crossbridges with a common regulatory mechanism is responsible for these two types of contraction has not been determined. Detrusor strips from New Zealand white rabbit bladders were allowed to develop SRC at a reference muscle length (L ref), or rhythmic contraction (RC) was induced with tetraethylammonium (TEA). Multiple 10-msec stretches of 15% L ref were then imposed at L ref randomly during the rhythm cycle, and the nadir-to-peak (NTP) tension amplitude of the resulting myogenic contraction was measured. The amplitude and period of the rhythm cycle were measured prior to each QS. NTP was larger when a QS was imposed during a portion the cycle when tension was smaller (n = 3 each SRC and TEA-induced RC). These data suggest that when the rhythmic mechanism was mostly inactive and tension was near a minimum, a larger portion of a shared population of crossbridges was available to produce a myogenic response to a QS. Rho kinase, cyclooxygenase-1, and cyclooxygenase-2 inhibitors (H-1152, SC-560, and NS-398) affected SRC amplitude and NTP amplitude following a QS to the same degree (n = 3 each drug), providing additional evidence to support the hypothesis that a common mechanism is responsible for SRC and myogenic contraction due to QS. If a common mechanism exists, then QS is a potential mechanical probe to study SRC regulation and its alteration in overactive bladder.


The nationwide systematic prevention of cardiovascular disease: the UK's health check programme.
High-income countries have witnessed marked reductions in cardiovascular disease (CVD) in recent years. Aging populations, however, maintain CVD as a major threat to public health and health system's financial stability. England has commenced on a population-wide screening and prevention program for CVD, the NHS Health Check program, the first national program of its type. We outline the program, its implications for public health and primary care, potential threats to the program, and its implications for the US health system. We conclude that the universal approach adopted contains a number of risks and uncertainties. The program's ongoing evaluation is vital and will provide internationally valuable data.


Adherence to Injury Prevention Exercise Programmes in Amateur Adolescent and Adult Football: A Detailed Description of Programme Use from a Randomised Study.
Injury prevention exercise programmes (IPEPs) efficaciously reduce injuries. However, it is challenging to achieve sufficient adherence across a season. The main aim was to describe adherence to IPEPs in three groups of coaches and players partaking in a cluster randomised trial. Secondary aims were to describe perceptions of IPEPs, use of programme material, and overall preventive strategies. This is a sub-study analysing data from a three-armed randomised trial with teams randomised to use either a comprehensive IPEP (extended Knee Control) or an adductor strength programme, and non-randomised teams that already used a self-chosen IPEP regularly at study start (comparison group). Teams were instructed to use their respective intervention across the 2020 football season. Male and female, adolescent (≥ 14 years of age), and adult amateur players took part. Coaches and players responded to weekly and end-of-season questionnaires. Data were presented descriptively. Weekly player data were reported by 502 players (weekly response rate 65%), 289 (58%) responded to end-of-season questionnaires. Teams in the extended Knee Control and comparison group used their respective IPEP in 483/529 (91%) and 585/641 (91%) of training sessions, and teams in the adductor group in in 199/315 (63%) sessions. Regarding utilisation fidelity, 42-52% of players in each group used 1-10 repetitions per exercise. Seven out of 17 teams in the adductor group had progressed as recommended in terms of number of repetitions. Two teams (10%) in the extended Knee Control group, and 7/24 of comparison teams used the same exercises across the season. Coaches accessed the IPEPs by different means (printed material, films, workshops, etc.), but half did not use the provided digital material. The players appreciated that the IPEPs could reduce injury risk and that they improved their exercise performance, but disliked that they had less time for football and that the exercises were boring. Forty-nine players had experienced pain during IPEP performance. Adherence with the IPEPs was generally high. To meet different coach needs, programme material should be available via different digital and printed resources. The number of players reporting pain during IPEP performance is a noteworthy finding. Clinical Trials gov identifier: NCT04272047. Registered February 17, 2020. https://clinicaltrials.gov/ct2/show/NCT04272047 .


Upper Limb Neuromuscular Activities and Synergies Comparison between Elite and Nonelite Athletics in Badminton Overhead Forehand Smash.
This study is aimed at comparing muscle activations and synergies in badminton forehand overhead smash (BFOS) between elite and nonelite players to clarify how the central nervous system (CNS) controls neuromuscular synergy and activation to generate complex overhead movements. EMG of five upper limb muscles was recorded through surface electromyography (EMG) electrodes from twenty players. Athletics is divided into two groups: elite and nonelite. Eventually, nonnegative matrix factorization (NNMF) was utilized to the calculated electromyography signals for muscle synergy comparison. Similarities between elite and nonelite groups were calculated by scalar product method. Results presented that three muscles synergies could sufficiently delineate the found electromyography signals for elite and nonelite players. Individual muscle patterns were moderately to highly similar between elite and nonelite groups (between-group similarity range: 0.52 to 0.90). In addition, high similarities between groups were found for the shape of synergy activation coefficients (range: 0.85 to 0.89). These results indicate that the synergistic organization of muscle coordination during badminton forehand overhead smash is not profoundly affected by expertise.


Dietary factors associated with plasma high molecular weight and total adiponectin levels in apparently healthy women.
Our aim was to investigate associations between dietary factors and high molecular weight (HMW) as well as total adiponectin in a sample of apparently healthy adult Mediterranean women. Two hundred and twenty women were enrolled in this study. Anthropometric and body composition measurements were performed in all subjects. Fasting blood samples were taken; HMW and total adiponectin concentrations were measured. Food intake was evaluated using 3-day food records. The frequency of consumption of several food groups was approximately quantified in terms of number of servings per day. Furthermore, dietary intakes of betaine, choline, and free choline were estimated. Women in the highest HMW adiponectin tertile had higher fruit intake compared with those with lower levels, after adjusting for potential confounders (P=0.04). On the contrary, dietary betaine and choline intakes were not different among HMW adiponectin tertiles. In linear models, fruit consumption, controlling for biological and lifestyle variables, was significantly related to HMW adiponectin (partial r=0.15, P=0.04), but the association with total adiponectin did not reach statistical significance (partial r=0.11, P=0.12). A significant negative correlation between total adiponectin and refined cereals was also observed (partial r=-0.16, P=0.03). This is the first study that evaluates associations between dietary factors and HMW adiponectin levels. The associations found are moderate and indicate that, after multivariate adjustment, fruit consumption is related to HMW adiponectin in both linear and nonlinear models.


Manganese superoxide dismutase (MnSOD) gene (Ala-9Val, Ile58Thr) polymorphism in patients with age-related macular degeneration (AMD).
Oxidative stress is involved in the pathogenesis of many chronic disorders including cancer, inflammation, and neurologic diseases. Reactive oxygen species (ROS) may play a major role in age-related macular degeneration (AMD). This study investigated the mRNA and protein profiles of manganese superoxide dismutase MnSOD in patients with AMD and healthy controls, while examining its genetic sequence polymorphism (Ala-9Val, Ile58Thr). Our intent was to find a correlation between the expression of MnSOD genes and nucleotide sequence polymorphisms encoded in the gene of the dry and wet form of AMD. We examined 300 unrelated AMD patients and 300 unrelated healthy controls who gave free consent to participate in the study. The MnSOD gene polymorphisms were determined by PCR/RFLP method. We also used real-time RT-PCR and ELISA methods to estimate expression of MnSOD mRNA and protein. There were statistically significant differences in the genotype distribution between patients with AMD and controls. Our results showed positive correlations between gene sequence polymorphism and the level of MnSOD mRNA and protein expression. The Ala-9Ala genotype and alanine allele (Ala-9Val sequence polymorphism) is much more frequent in AMD patients than in healthy subjects. Healthy controls who are homozygotes Val/Val and heterozygotes Ala/Val showed lower expression of the MnSOD gene as compared to homozygote Ala/Ala. The lowest expression of MnSOD (homozygotes Val/Val and heterozygotes Ala/Val for wet and dry form of AMD) was noted in patients with AMD. These data suggest a genetic role of MnSOD polymorphism in the development of age-related degeneration.


[Peculiarities of inflammatory intoxication syndrome in elderly patients with extrahospital pneumonia].
The aim of the study was to evaluate the clinical and diagnostical features of extrahospital pneumonia (EHP) in elderly patients to optimize their complex medical providence under the conditions of a pulmonological department. In particular, the authors studied the manifestations of endogenous inflammatory intoxication syndrome (EIIS). The subjects, 142 elderly patients (more than 60 years of age) with EHP, and the controls, 125 patients under 40, were treated in the Pulmonology Department, Burdenko Military Hospital, in 2002-2004. The results of the study show that EIIS does not play the leading part in the clinical picture in elderly EHP patients; its manifestations are often not as prominent as those in the young and thus they can only serve as an approximate indicator for complex clinicoradiological examination, undertaken in order to reveal and determine the severity of this dangerous disease.


The utility of the MMPI-2 malingering discriminant function index in the detection of malingering: a study of criminal defendants.
This study examined the utility of the Minnesota Multiphasic Personality Inventory-2's (MMPI-2) malingering discriminant function index (M-DFI), recently developed by Bacchiochi and Bagby, in the detection of malingering in a forensic sample. Criminal defendants were divided into "malingering" and "not malingering" groups using the structured interview of reported symptoms (SIRS) criteria proposed by Rogers. Logistic regression analysis (LRA) revealed that the MMPI-2 infrequency (F) scale had the best predictive utility of the traditional infrequency scales. Although the M-DFI did significantly differentiate the malingering from the not malingering groups, it did not add significantly to the predictive utility of the MMPI-2 F scale. Receiver operating characteristics analyses demonstrated acceptable sensitivity and specificity for the MMPI-2 F scale, but poor sensitivity for the M-DFI scale. The results are discussed in terms of the utility of the M-DFI in detecting malingering and problems of extending the findings of simulation studies to the forensic context.


The sex-specific association between maternal paraben exposure and size at birth.
Parabens are a group of esters of parahydroxybenzoic acid and are utilized as antimicrobial preservatives in the majority of personal care products (PCPs). Epidemiological studies regarding the adverse effects of parabens on fetuses are still limited. The aim of this study was to determine the association between maternal paraben exposure and birth outcomes. One hundred and ninety-nine pregnant women were enrolled, and maternal urine was collected in the third trimester. The urine concentrations of four parabens (methyl (MP), ethyl (EP), propyl (PP), and butyl (BP)) were determined by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Generalized additive model-penalized regression splines and a multivariable regression model were employed to determine the association between paraben exposure levels and birth outcomes. A causal mediation analysis was conducted to determine the mediation effect of oxidative stress on birth outcomes. The geometric means of urinary MP, EP, PP, and BP were 51.79, 1.26, 4.21, and 1.25 μg/g cre., respectively. In the penalized regression splines, sex-specific associations between maternal MP levels and birth outcomes were observed; a downward curvature was observed between the MP level and birth weight, length, head circumference, and thoracic circumference among female newborns. Pregnant women in the group with MP levels above the third quartile had neonates with significantly lower body weight (β = -215.98 g, p value = 0.02) compared to those in the group with MP levels lower than the third quartile. No significant mediation of oxidative stress was observed between maternal MP exposure and female birth weight. The estimated proportion mediated ranged from -6% to 15%. The negative association between maternal paraben exposure and female birth outcomes in relation to child development should be carefully considered.


Autophagy Regulates Proteasome Inhibitor-Induced Pigmentation in Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells.
The impairment of autophagic and proteasomal cleansing together with changes in pigmentation has been documented in retinal pigment epithelial (RPE) cell degeneration. However, the function and co-operation of these mechanisms in melanosome-containing RPE cells is still unclear. We show that inhibition of proteasomal degradation with MG-132 or autophagy with bafilomycin A1 increased the accumulation of premelanosomes and autophagic structures in human embryonic stem cell (hESC)-derived RPE cells. Consequently, upregulation of the autophagy marker p62 (also known as sequestosome-1, SQSTM1) was confirmed in Western blot and perinuclear staining. Interestingly, cells treated with the adenosine monophosphatedependent protein kinase activator, AICAR (5-Aminoimidazole-4-carboxamide ribonucleotide), decreased the proteasome inhibitor-induced accumulation of premelanosomes, increased the amount of autophagosomes and eradicated the protein expression of p62 and LC3 (microtubule-associated protein 1A/1B-light chain 3). These results revealed that autophagic machinery is functional in hESC-RPE cells and may regulate cellular pigmentation with proteasomes.


Targeted Association and Intracellular Delivery of Nanocargoes into Primary T Lymphocytes via Interleukin-2 Receptor-Mediated Endocytosis.
Despite the tremendous progress in immunotherapy regimens using T cells, efforts to modulate the functions of T cells are still significantly hampered by the lack of reliable methods to deliver various cargoes into the T cells. This ongoing challenge originates from the intrinsic resistance of T cells in taking up exogenous materials. Here, we strategically aimed to hijack the natural endocytosis of Interleukin-2 (IL2) by the activated T cells for the targeted association and intracellular delivery of cargoes in varying sizes. First, we carefully characterized the fluctuations in the expression levels of IL2 receptor (IL2R) subunits (CD25, CD122, and CD132) during the murine primary T cell cultures over 12 days. We identified the highest fraction of T cells that would express the high-affinity trimeric IL2R on Day 3. By examining the association and uptake efficiencies of IL2 molecules that are biotinylated via either random lysine-targeting chemical reaction (using NHS-PEG4-Biotin) or site-specific enzymatic modification (using Avitag sequence), we demonstrated that the most efficient delivery of cargo can be achieved by C-terminal conjugation. Upon confirmation of successful delivery of a small model cargo, streptavidin, we employed superparamagnetic iron oxide nanoparticles (SPIONs) as bigger model cargoes having core diameters of 50, 100, and 200 nm. We examined the association and intracellular delivery of the IL2-conjugated nanocargoes using flow cytometry, confocal laser scanning microscopy, and transmission electron microscopy. While cargoes of all tested sizes were successfully associated with the IL2R-expressing T cells in comparable efficiencies, the uptake efficiencies were inversely proportional to the sizes of the cargoes. Nevertheless, our current definitive report confirms that nanocargoes with a practical maximum size limit around 100-200 nm can be intracellularly delivered into activated primary T cells using IL2R-mediated endocytosis, which opens a new horizon for engineering and manufacturing of various T cell immunotherapeutics.


In vitro mimicry of essential fatty acid deficiency in human endothelial cells by TNFalpha impact of omega-3 versus omega-6 fatty acids.
Severe endothelial abnormalities are a prominent feature in sepsis with cytokines such as tumor necrosis factor (TNF)alpha being implicated in the pathogenesis. As mimic to inflammation, human umbilical vascular endothelial cells (HUVEC) were incubated with TNFalpha for 22 h, in the absence or presence of the omega-6 fatty acid (FA), arachidonic acid (AA), or the alternative omega-3 FA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). TNFalpha caused marked alterations in the PUFA profile and long chain PUFA content of total phospholipids (PL) decreased. In contrast, there was a compensatory increase in mead acid [MA, 20:3(omega-9)], the hallmark acid of the essential fatty acid deficiency (EFAD) syndrome. Corresponding changes were noted in phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol, but not in the sphingomyelin fraction. Supplementation with AA, EPA, or DHA markedly increased the respective FA contents in the PL pools, suppressed the increase in MA, and resulted in a shift either toward further predominance of omega-6 or predominance of omega-3 FA. We conclude that short-term TNFalpha incubation of HUVEC causes an EFAD state hitherto only described for long-term malnutrition, and that endothelial cells are susceptible to differential influence by omega-3 versus omega-6 FA supplementation under these conditions.


MdMYB52 regulates lignin biosynthesis upon the suberization process in apple.
Our previous studies, comparing russeted vs. waxy apple skin, highlighted a MYeloBlastosys (Myb) transcription factor (MdMYB52), which displayed a correlation with genes associated to the suberization process. The present article aims to assess its role and function in the suberization process. Phylogenetic analyses and research against Arabidopsis thaliana MYBs database were first performed and the tissue specific expression of MdMYB52 was investigated using RT-qPCR. The function of MdMYB52 was further investigated using Agrobacterium-mediated transient overexpression in Nicotiana benthamiana leaves. An RNA-Seq analysis was performed to highlight differentially regulated genes in response MdMYB52. Transcriptomic data were supported by analytical chemistry and microscopy. A massive decreased expression of photosynthetic and primary metabolism pathways was observed with a concomitant increased expression of genes associated with phenylpropanoid and lignin biosynthesis, cell wall modification and senescence. Interestingly key genes involved in the synthesis of suberin phenolic components were observed. The analytical chemistry displayed a strong increase in the lignin content in the cell walls during MdMYB52 expression. More specifically, an enrichment in G-Unit lignin residues was observed, supporting transcriptomic data as well as previous work describing the suberin phenolic domain as a G-unit enriched lignin-like polymer. The time-course qPCR analysis revealed that the observed stress response, might be explain by this lignin biosynthesis and by a possible programmed senescence triggered by MdMYB52. The present work supports a crucial regulatory role for MdMYB52 in the biosynthesis of the suberin phenolic domain and possibly in the fate of suberized cells in russeted apple skins.


[The prognostic analysis of hepatocellular carcinoma based on the tumor neo-vessels, macrophages and α-SMA in tumor microenvironment].
Objective: To analyze the quantitative expression and prognostic significance of tumor neo-vessels, macrophages and fibroblasts in tumor microenvironment of hepatocellular carcinoma (HCC). Methods: The clinic-pathological features and tissue samples for 101 HCC cases were collected. Immunohistochemistry was used to stain the tumor neo-vessels, macrophages and fibroblasts on tumor tissue. The distribution results and quantitative data of above key components were acquired by inverted microscopy equipped with CRi Nuance multispectral analysis system. The number of tumor neo-vessels and macrophages on HCC tissue were counted and the thickness of cancer stroma based on the expression of fibroblasts was measured. The clinic-pathological characteristics and overall survival were analyzed. Results: The median disease free survival (DFS) of 101 HCC cases was 5 month. The quantitative analysis of tumor neo-vessels, macrophages and fibroblasts showed that the expression range was 51-429 with median 218, 110-555 with median 259, 35.61-555.35 with median 246.98, respectively. To take the median as cutoff, all the cases could be classified into high and low expression group. The survival analysis demonstrated that the high density group of macrophages (P=0.022) and fibroblasts (P<0.001) has shorter DFS than low density group, with statistical significance. The high tumor neo-vessels group has shorter DFS with median 5 month than low density group with median 7 month. However, there was no statistical significance between these two group (P=0.197). Combined with above the three stromal components, all the cases could be classified into low, middle and high group. The survival analysis demonstrated that the high density group of stromal components has shorter DFS than the other two groups with median 3 month (P=0.001). Multivariate analysis by Cox regression indicated that cirrhosis, metastasis status, macrophages and fibroblasts density were the independent prognostic factors. Conclusion: The key elements in tumor microenvironment including tumor neo-vessels, macrophages and fibroblasts were heterogenic in HCC tissues and played significant roles in HCC invasion and metastasis.


Role of HLA-B27 in the pathogenesis of ankylosing spondylitis (Review).
The study of ankylosing spondylitis (AS) has made significant progress over the last decade. Genome-wide association studies have identified and further substantiated the role of susceptibility genes outside the major histocompatibility complex locus. However, human leukocyte antigen (HLA)‑B27 has been suggested to be important in the pathogenesis of AS, contributing to ~20.1% of AS heritability. The current review will present the classical and non‑classical forms of HLA-B27, as well as their pathogenic roles, and further discuss the hypotheses regarding the potential pathogenesis of AS. In addition, the association between the pathogenic role of HLA‑B27 and inflammatory indexes, including the interleukin-23/‑17 axis will be investigated to provide novel insights into the pathogenesis of AS. The aim of the present review is to provide an update of the current research into the pathogenesis of AS, and provide a comprehensive description of the pathogenic role of HLA-B27 in AS.


Neurobiology of Recovery of Motor Function after Stroke: The Central Nervous System Biomarker Effects of Constraint-Induced Movement Therapy.
Recovery of motor function after stroke involves many biomarkers. This review attempts to identify the biomarker effects responsible for recovery of motor function following the use of Constraint-Induced Movement Therapy (CIMT) and discuss their implications for research and practice. From the studies reviewed, the biomarker effects identified include improved perfusion of motor areas and brain glucose metabolism; increased expression of proteins, namely, Brain-Derived Neurotrophic Factor (BDNF), Vascular Endothelial Growth Factor (VEGF), and Growth-Associated Protein 43 (GAP-43); and decreased level of Gamma-Aminobutyric Acid (GABA). Others include increased cortical activation, increased motor map size, and decreased interhemispheric inhibition of the ipsilesional hemisphere by the contralesional hemisphere. Interestingly, the biomarker effects correlated well with improved motor function. However, some of the biomarker effects have not yet been investigated in humans, and they require that CIMT starts early on poststroke. In addition, one study seems to suggest the combined use of CIMT with other rehabilitation techniques such as Transcortical Direct Stimulation (tDCs) in patients with chronic stroke to achieve the biomarker effects. Unfortunately, there are few studies in humans that implemented CIMT during early poststroke. Thus, it is important that more studies in humans are carried out to determine the biomarker effects of CIMT especially early on poststroke, when there is a greater opportunity for recovery. Furthermore, it should be noted that these effects are mainly in ischaemic stroke.


TNF and type I IFN induction of the IRG1-itaconate pathway restricts Coxiella burnetii replication within mouse macrophages.
The intracellular Gram-negative bacterium Coxiella burnetii replicates within macrophages and causes a zoonotic disease known as Q fever. In murine macrophages, the cytokine tumor necrosis factor (TNF) is critical for restriction of intracellular C. burnetii replication. Here, we show that TNF collaborates with type I interferon (IFN) signaling for maximal control of C. burnetii. We found that TNF and type I IFN upregulate the expression of the metabolic enzyme immune responsive gene 1 (IRG1), also known as cis-aconitate decarboxylase 1 (ACOD1), and that IRG1 is required to restrict C. burnetii T4SS translocation and replication within macrophages. Further, we show that itaconic acid, the metabolic product of IRG1, restricts C. burnetii replication both intracellularly and in axenic culture. These data reveal that TNF and type I IFN upregulate the IRG1-itaconate pathway to restrict intracellular C. burnetii replication within murine macrophages.


Influence of imipramine treatment on the group I of metabotropic glutamate receptors in CA1 region of hippocampus.
Effects of repeated imipramine treatment on inositol phosphates accumulation and on the reactivity of neurons to metabotropic glutamate receptor (mGlu) agonist (1S,3R)-1-carboxycyclopentane-3acetic acid (1S,3R-ACPD) were investigated in the rat hippocampal slices. The concentration-dependent increase in inositol phosphate accumulation in the slices from CA1 region of hippocampus induced by 1S,3R-ACPD was not modified by imipramine treatment. 1S,3R-ACPD produced a concentration-dependent increase in population spike amplitude recorded in the CA1 cell layer. This effect of 1S,3R-ACPD was markedly attenuated by repeated imipramine administration. Our results indicate that antidepressant treatment may induce a subsensitivity of mGlu receptors in the CA1 region of hippocampus when estimated by electrophysiological, but not biochemical measures.


Magnetic Fe3O4@chitosan nanoparticle: synthesis, characterization and application as catalyst carrier.
A novel method was developed to prepare Fe3O4@CS beads with core-shell structure using a double-crosslinking process. Before the coating process, an unique crosslinking agent, glutaraldehyde (GA), was adsorbed onto the surface of Fe3O4 in advance, so the subsequent CS can uniformly coat around the magnetic core processed from the strong interaction between GA and CS, forming a perfect core-shell structure. The obtained Fe3O4@CS beads were followed by the Pd deposition through in-situ reduction method, and the prepared composite catalyst was applied exemplarily in synthesizing nabumetone to check its reusing property. The nanoparticles were characterized by transmission electron microscopy (TEM), X-ray powder diffraction (XRD), Fourier transformation infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), and the magnetic hysteresis loop determination method. This novel composite catalyst showed admirable potential in reusable catalysis.


Thailand's national universal developmental screening programme for young children: action research for improved follow-up.
In low-income and middle-income countries, it is estimated that one in every three preschool-age children are failing to meet cognitive or socioemotional developmental milestones. Thailand has implemented a universal national developmental screening programme (DSPM) for young children to enable detection of developmental disorders and early intervention that can improve child health outcomes. DSPM implementation is being hampered by low attendance at follow-up appointments when children fail the initial screening. Action research, using qualitative methods was conducted with 19 caregivers, 5 health workers and 1 chief at two Health Promotion Hospitals to explore the factors affecting attendance at follow-up appointments. Transcripts and notes were analysed using descriptive content analysis. Findings were then discussed with 48 health workers, managers, researchers and policymakers. The high workload of health workers during busy vaccination clinics, and inadequate materials prevented clear communication with caregivers about the screening, how to stimulate child development and the screening result. Caregivers, particularly grandparents, had a lack of understanding about how to stimulate child development, and did not fully understand failed screening results. Caregivers felt blamed for not stimulating their child's development, and were either worried that their child was severely disabled, or they did not believe the screening result and therefore questioned its usefulness. This led to a lack of attendance at follow-up appointments. Task-sharing, mobile health (mhealth), community outreach and targeted interventions for grandparent caregivers might increase awareness about child development and screening, and allow health workers more time to communicate effectively. Sharing best practices, communication training and mentoring of DSPM workers coupled with mhealth job aids could also improve caregiver attendance at follow-up. Engagement of caregivers in understanding the barriers to attendance at follow-up and engagement of stakeholders in the design and implementation of interventions is important to ensure their effectiveness.


Successful Use of Extracorporeal Membrane Oxygenation for the Treatment of Cardiogenic Shock due to Scorpion Envenomation.
Introduction. The occurrence of a cardiogenic shock is a rare presentation after scorpion envenomation. The treatment includes classically the use of inotropes and specific vasodilators. Case Presentation. We report a case of an 11-year-old boy presenting with cardiogenic shock and pulmonary edema after a scorpion sting. Despite adequate management at the emergency department and intensive care unit, the patient's hemodynamic status worsened rapidly, justifying his transfer to our department for ventricular mechanical assistance by venoarterial extracorporeal membrane oxygenation. The following outcomes were favorable and the boy was discharged home on day 29 without aftereffects. Conclusion. This is the first report of successful use of extracorporeal membrane oxygenation for the treatment of cardiogenic shock after scorpion envenomation.


Bone sarcomas in 239Pu-treated mice.
Female ICR mice were injected with a monomeric form of 239Pu (180.1 kBq/kg) at the age of 10 weeks and during the long-term contamination the incidence of bone sarcomas was studied. Average survival of 100 control mice was 545 +/- 14 days, the 100 plutonium-given mice survived 420 +/- 10 d and 50 sarcoma-bearing animals 456 +/- 11 days. Most of the 61 induced sarcomas were located in the spine (70%) and in trabecular parts of the other bones. Among these 61 tumors there were 55 osteoblastic osteosarcomas, 4 immature undifferentiated sarcomas and 2 angiosarcomas. In 6 tumor-bearing mice metastases were observed in lungs, liver, intracranial cavity and in mediastinal lymph nodes. Among control mice only one osteogenic mandibular sarcoma was verified. The osteosarcoma incidence was evaluated with respect to the retained activity and cumulative average skeletal dose. The results were discussed and compared with data published by others.


Childhood origins of arterial disease.
The present article reviews the importance of classical and novel risk factors that present in childhood, track into adult life and contribute to arterial disease. The value of noninvasive techniques that can assist in characterization of preclinical atherosclerotic changes as intermediate phenotypes is also discussed. Noninvasive functional and structural techniques are now available and provide the opportunity to characterize early arterial disease long before cardiovascular complications present. By using these techniques, it has been possible to quantify the impact of conventional and novel cardiovascular risk factors seen in childhood on the development of preclinical atherosclerotic changes. Scientific interest has recently widened to include not only study of mechanisms and biomarkers of injury but also mechanisms that promote vascular repair. In this new field, characterization of endothelial progenitor cells has presented new opportunities for cardiovascular research. Atherosclerosis begins in early life. Primary prevention strategies for adult cardiovascular disease beginning in childhood have great potential as the disease process is most reversible at this stage. Several guidelines have recently been published for screening and implementation of appropriate therapeutic choices in early life.


Genetic characterization and founder effect analysis of recently introduced Salers cattle breed population.
Salers are a native French breed used for beef and dairy production that has expanded to all the continents. The Salers breed was introduced to the north of Spain in 1985 with only 15 individuals from France and has successfully increased to over 20 000 animals. Although over time new animals have been imported from France for breeding, it is possible that the limiting number of founder animals could have resulted in a reduction of the genetic diversity found in Spanish Salers. Thus, the purpose of the present study has been to characterize the genetic diversity of Salers breed in Spain and evaluate a possible founder effect due to reduced number of the first reproducers. A total of 403 individuals from 12 Salers herds were analyzed using 12 microsatellite markers and compared with phylogenetically and geographically close related Blonde d'Aquitaine, Limousin and Charolais French breeds but also other 16 European breeds. Microsatellites in Salers were polymorphic, with a mean allelic richness of 5.129 and an expected heterozygosity of 0.621 across loci (0.576 to 0.736 among all breeds). Average observed heterozygosity was 0.618. All the loci fit the Hardy-Weinberg (HW) equilibrium except TGLA227 locus due to a significant deficit of heterozygotes in only one of the herds, probably attributable to a sampling effect. When all loci were combined, Salers inbreeding coefficient did not differ statistically from 0 (F IS=0.005), indicating not significant excess or deficit of heterozygotes (P=0.309). Based in allelic distribution, Salers revealed a frequency of 0.488 in BM2113-131 and 0.064 in BM2113-143 diagnostic alleles, which are specific to the African zebu. These zebu alleles are also found in some French breeds, supported by STR data previously postulated hypothesis of a migration route through Mediterranean route by which North African cattle may have left a genetic signature in southern Europe. Phylogenetic tree and population structure analyses could unambiguously differentiate Salers cattle from the other populations and 10% of the total genetic variability could be attributed to differences among breeds (mean R ST=0.105; P<0.01). Mutation-drift equilibrium tests (sign test and Wilcoxon's sign rank test) were in correspondence to the absence of founder effect when Bonferroni was applied. Gene diversity previously reported in French Salers was comparable with the observed in our population. Thus, high genetic diversity in Spanish Salers highlights the resources of this population, which looks toward future breeding and selection programs.


Disturbance and management effects on forest soil organic carbon stocks in the Pacific Northwest.
Carbon (C)-informed forest management requires understanding how disturbance and management influence soil organic carbon (SOC) stocks at scales relevant to landowners and forest policy and management professionals. The continued growth of data sets and publications allows powerful synthesis approaches to be applied to such questions at increasingly fine scales. Here, we report results from a synthesis that used meta-analysis of published studies and two large observational databases to quantify disturbance and management impacts on SOC stocks. We conducted this, the third in a series of ecoregional SOC assessments, for the Pacific Northwest, which comprises ~8% of the land area but ~12% of the U.S. forest sector C sink. At the ecoregional level, our analysis indicated that fundamental patterns of vegetation, climate, and topography are far more important controls on SOC stocks than land use history, disturbance, or management. However, the same patterns suggested that increased warming, drying, wildland fire, and forest regeneration failure pose significant risks to SOC stocks across the region. Detailed meta-analysis results indicated that wildfires diminished SOC stocks throughout the soil profile, while prescribed fire only influenced surface organic materials and harvesting had no significant overall impact on SOC. Independent observational data corroborated the negative influence of fire on SOC derived from meta-analysis, suggested that harvest impacts may vary subregionally with climate or vegetation, and revealed that forests with agricultural uses (e.g., grazing) or legacies (e.g., cultivation) had smaller SOC stocks. We also quantified effects of a range of common forest management practices having either positive (organic amendments, nitrogen [N]-fixing vegetation establishment, inorganic N fertilization) or no overall effects on SOC (other inorganic fertilizers, urea fertilization, competition suppression through herbicides). In order to maximize the management applications of our results, we qualified them with ratings of confidence based on degree of support across approaches. Last, similar to earlier published assessments from other ecoregions, we supplemented our quantitative synthesis results with a literature review to arrive at a concise set of tactics for adapting management operations to site-specific criteria.


Contact-independent exposure to Rhodococcus rhodochrous DAP96253 volatiles does not improve the survival rate of Myotis lucifugus (little brown bats) affected by White-nose Syndrome.
Since the emergence of White-nose Syndrome, a fungal disease in bats, caused by Pseudogymnoascus destructans, hibernating populations of little brown bats (Myotis lucifugus) have declined by 70-90% within P. destructans positive hibernacula. To reduce the impact of White-nose Syndrome to North American little brown bat populations we evaluated if exposure to volatile organic compounds produced by induced cells from Rhodococcus rhodochrous strain DAP96253 could improve the overwinter survival of bats infected by P. destructans. Two simultaneous field treatment trials were conducted at natural hibernacula located in Rockcastle and Breckinridge counties, Kentucky, USA. A combined total of 120 little brown bats were randomly divided into control groups (n = 60) which were not exposed to volatile organic compounds and treatment groups (n = 60) which were exposed to volatile organic compounds produced by non-growth, fermented cell paste composed of R. rhodochrous strain DAP96253 cells. Cox proportional hazard models revealed a significant decreased survival at the Rockcastle field trial site but not the Breckinridge field site. At the Breckinridge hibernacula, overwinter survival for both treatment and control groups were 60%. At the Rockcastle hibernacula, Kaplan-Meier survival curves indicated significantly increased overwinter survival of bats in the control group (43% survived) compared to the treatment group (20% survived). Although complete inhibition of P. destructans by volatile organic compounds produced by induced R. rhodochrous strain DAP96253 cells was observed in vitro studies, our results suggest that these volatile organic compounds do not inhibit P. destructans in situ and may promote P. destructans growth.


Highly sensitive inference of time-delayed gene regulation by network deconvolution.
Gene regulatory network (GRN) is a fundamental topic in systems biology. The dynamics of GRN can shed light on the cellular processes, which facilitates the understanding of the mechanisms of diseases when the processes are dysregulated. Accurate reconstruction of GRN could also provide guidelines for experimental biologists. Therefore, inferring gene regulatory networks from high-throughput gene expression data is a central problem in systems biology. However, due to the inherent complexity of gene regulation, noise in measuring the data and the short length of time-series data, it is very challenging to reconstruct accurate GRNs. On the other hand, a better understanding into gene regulation could help to improve the performance of GRN inference. Time delay is one of the most important characteristics of gene regulation. By incorporating the information of time delays, we can achieve more accurate inference of GRN. In this paper, we propose a method to infer time-delayed gene regulation based on cross-correlation and network deconvolution (ND). First, we employ cross-correlation to obtain the probable time delays for the interactions between each target gene and its potential regulators. Then based on the inferred delays, the technique of ND is applied to identify direct interactions between the target gene and its regulators. Experiments on real-life gene expression datasets show that our method achieves overall better performance than existing methods for inferring time-delayed GRNs. By taking into account the time delays among gene interactions, our method is able to infer GRN more accurately. The effectiveness of our method has been shown by the experiments on three real-life gene expression datasets of yeast. Compared with other existing methods which were designed for learning time-delayed GRN, our method has significantly higher sensitivity without much reduction of specificity.


Gelling properties of black soldier fly (Hermetia illucens) larvae protein after ultrasound treatment.
H. illucens, black soldier fly larvae (BSFL) is one of the sustainable sources of protein. However, the research on the functionality of BSFL proteins is limited and need to be explored to increase consumer acceptance. The aim of this study is to create a gel system from BSFL protein and evaluate the impact of ultrasound treatment at different exposure time (5, 15, 30 min) on the physicochemical properties of BSFL protein. The highest values for surface hydrophobicity, size, ζ-potential were obtained after 15 min of ultrasound treatment and the same was found for the elastic modulus. Finally, confocal laser scanning microscopy (CLSM) along with image analysis revealed the lowest pore size after 15 min of treatment. The high protein content of BSFL protein extract and its promising gel system herein created, are important features to be considered for further development of insect-based food.


Repair of postinfarction ventricular septal defect.
Recently I successfully repaired a necrotic, acute septal defect by modifying the standard intracavitary repair of postinfarction aneurysm. The technique was modified after a patient who had undergone standard intracavitary repair developed a systolic murmur and had to be returned to surgery, where I found that the continuous suture had become detached at the posterior extent of the repair. The pericardial baffle was reattached using interrupted sutures with felt pledgets. As a result of this experience, we have modified our standard intracavitary repair for postinfarction aneurysm to account for the area of necrotic myocardium often associated with acute septal defects.


Is use of the hydrophobic moment a sound basis for predicting the structure-function relationships of membrane interactive alpha-helices?
Amphiphilic alpha-helices play a fundamental role in protein membrane association and show a segregation of polar and apolar amino acid residues. Based on correlations between amphiphilic properties and biological function, a number of theoretical approaches have been developed, which quantify alpha-helix amphiphilicity and then attempt to assign function. The most commonly used measure of amphiphilicity is the hydrophobic moment, < microH >, which, when used in conjunction with an alpha-helix's mean hydrophobicity, < H >, has been used to classify membrane interactive amphiphilic alpha-helices as either surface active or transmembrane. Here, the predictive efficacy of plot methodology is reviewed by examining published data, which compare the function of known membrane interactive amphiphilic alpha-helices to that assigned by this methodology. The results of this review are discussed in relation to the reliability of < microH > as a quantifier of alpha-helical amphiphilicity, and the ability of < microH > and < H > to describe alpha-helical structure / function relationships. It is concluded that hydrophobic moment plot methodology is not a generally reliable predictor of alpha-helical structure / function relationships. It appears that the inefficacy of plot methodology is primarily due to the inability of the plot diagram to accommodate the heterogeneity of the alpha-helical classes it attempts to define. However, the predictive efficacy of the methodology appears to be improved if other alpha-helical parameters are also considered when assigning alpha-helical function. It is suggested that the conventional methodology should be seen only as an indicator for the assignation of structure / function relationships, providing a guide to future experimental investigations.


Pressure support compared with controlled mechanical ventilation in experimental lung injury.
It has been suggested that, in acute lung injury (ALI), spontaneous breathing activity may increase oxygenation because of an improvement of ventilation-perfusion distribution. Pressure support ventilation (PSV) is one of the assisted spontaneous breathing modes often used in critical care medicine. We sought to determine the prolonged effects of PSV on gas exchange in experimental ALI. We hypothesized that PSV may increase oxygenation because of an improvement in ventilation-perfusion distribution. Thus, ALI was induced in 20 pigs by using repetitive lung lavage. Thereafter, the animals were randomized to receive either PSV with a pressure level set to achieve a tidal volume >4 mL/kg and a respiratory rate <40 min(-1) (n = 10) or controlled mechanical ventilation (CMV) with a tidal volume of 10 mL/kg and a respiratory rate of 20 min(-1) (n = 10). Positive end-expiratory pressure was set at 10 cm H(2)O in both groups. Blood gas analyses and determination of ventilation-perfusion (.V(A)/.Q) distribution were performed at the onset of ALI and after 2, 4, 8, and 12 h. The main result was an improvement of oxygenation because of a decrease of pulmonary shunt and an increase of areas with normal .V(A)/.Q ratios during PSV (P < 0.005). However, during CMV, a more pronounced reduction of shunt was observed compared with PSV (P < 0.005). We conclude that, in this model of ALI, PSV improves gas exchange because of a reduction of .V(A)/.Q inequality. However, improvements in .V(A)/.Q distribution may be more effective with CMV than with PSV. Assisted spontaneous breathing may have beneficial effects on gas exchange in acute lung injury. We tested this hypothesis for pressure support ventilation in an animal model of acute lung injury. Our results demonstrate that pressure support does not necessarily provide better gas exchange than controlled mechanical ventilation.


The Impact of Nonalcoholic Fatty Liver Disease on Renal Function in Children with Overweight/Obesity.
The association between nonalcoholic fatty liver disease (NAFLD) and chronic kidney disease has attracted interest and attention over recent years. However, no data are available in children. We determined whether children with NAFLD show signs of renal functional alterations, as determined by estimated glomerular filtration rate (eGFR) and urinary albumin excretion. We studied 596 children with overweight/obesity, 268 with NAFLD (hepatic fat fraction ≥5% on magnetic resonance imaging) and 328 without NAFLD, and 130 healthy normal-weight controls. Decreased GFR was defined as eGFR < 90 mL/min/1.73 m². Abnormal albuminuria was defined as urinary excretion of ≥30 mg/24 h of albumin. A greater prevalence of eGFR < 90 mL/min/1.73 m² was observed in patients with NAFLD compared to those without liver involvement and healthy subjects (17.5% vs. 6.7% vs. 0.77%; p < 0.0001). The proportion of children with abnormal albuminuria was also higher in the NAFLD group compared to those without NAFLD, and controls (9.3% vs. 4.0% vs. 0; p < 0.0001). Multivariate logistic regression analysis revealed that NAFLD was associated with decreased eGFR and/or microalbuminuria (odds ratio, 2.54 (confidence interval, 1.16-5.57); p < 0.05) independently of anthropometric and clinical variables. Children with NAFLD are at risk for early renal dysfunction. Recognition of this abnormality in the young may help to prevent the ongoing development of the disease.


The Effect of Acetylation on the Physicochemical Properties of Chickpea Starch.
The effect of acetylation on the physicochemical properties of chickpea starch was studied. After the chickpea starch was acetylated, the basic properties were measured. When the degree of substitution (DS) was 0.1004 and the temperature was 95 °C, the solubility and swelling power of starch were 19.6% and 21.4 g/g, respectively. The freeze-thaw stability of acetylated starch paste increased with the increase in the degree of substitution. The surface morphology of starch granules changed, but the crystalline morphology did not change, and the C-type crystalline structure was still maintained. There are three new absorption peaks in the infrared spectroscopy of starch, and the -COCH3 group was introduced. With the increase in DS, the viscosity of esterified chickpea starch decreased gradually. Compared with unmodified chickpea starch, the ability to form gel was poor.


Adoptively transferred ex vivo activated memory T cells with cyclophosphamide: effective tumor-specific chemoimmunotherapy of advanced metastatic murine melanoma and carcinoma.
Autolymphocyte therapy (ALT) is adoptive cellular therapy of neoplastic disease based upon ex vivo activation of autologous peripheral blood mononuclear cells by either the supernatant derived from a previously prepared one-way mixed lymphocyte culture (MLC) or using low doses of the mitogenic monoclonal antibody anti-CD3 and a mixture of previously prepared autologous cytokines (T3CS). We have previously demonstrated that nonspecific ex vivo activation of splenocytes from murine tumor-bearing hosts (TBH) using an MLC supernatant or T3CS without the use of tumor antigen results in the expansion of the CD44+ (memory) T-cell subset. These memory T cells or autolymphocytes (ALT cells) mediate in vivo specificity when infused into murine TBH. To determine if cyclophosphamide (CY) could enhance the effectiveness of these ALT cells, C57BL/6J TBH with B16 melanoma or Lewis lung (3LL) carcinoma were treated with adoptive chemoimmunotherapy (ACIT) consisting of ALT cells and varying doses of CY. ALT cells were derived from the splenocytes of C57BL/6J TBH with B16 melanoma or 3LL carcinoma and activated ex vivo with T3CS. 3LL or B16 TBH received ALT cells derived from 3LL TBH splenocytes, B16 TBH splenocytes, CY alone, or ACIT with ALT cells and CY. Significantly greater antitumor activity as demonstrated by a decreased number of lung metastases (Day 21) and cure of primary and metastatic disease (Day 100) was seen in B16 or 3LL TBH that received ACIT using CY with B16-derived and 3LL-derived ALT cells, respectively, rather than ALT cells alone, CY alone, or ACIT with CY and reciprocal tumor-derived ALT cells. TBH cured by ACIT using CY and ALT cells derived from syngeneic TBH with the identical tumor displayed tumor-specific immunity as they were able to reject a lethal challenge of their previous B16 or 3LL tumor but not reciprocal tumors. TBH cured by ACIT using CY and ALT cells derived from splenocytes of syngeneic TBH with reciprocal tumors were able to reject lethal challenges of both tumors. These data demonstrate that effective ACIT using CY combined with ex vivo T3CS-activated CD44+ memory T cells from TBH conveys long-term tumor-specific immunity.


Dance and sexuality: many moves.
This literature review of dance and sexual expression considers dance and religion, dance and sexuality as a source of power, manifestations of sexuality in Western theater art and social dance, plus ritual and non-Western social dance. Expressions of gender, sexual orientation, asexuality, ambiguity, and adult entertainment exotic dance are presented. Prominent concerns in the literature are the awareness, closeting, and denial of sexuality in dance; conflation of sexual expression and promiscuity of gender and sexuality, of nudity and sexuality, and of dancer intention and observer interpretation; and inspiration for infusing sexuality into dance. Numerous disciplines (American studies, anthropology, art history, comparative literature, criminology, cultural studies, communication, dance, drama, English, history, history of consciousness, journalism, law, performance studies, philosophy, planning, retail geography, psychology, social work, sociology, and theater arts) have explored dance and sexual expression, drawing upon the following concepts, which are not mutually exclusive: critical cultural theory, feminism, colonialism, Orientalism, postmodernism, poststructuralism, queer theory, and semiotics. Methods of inquiry include movement analysis, historical investigation, anthropological fieldwork, autoethnography, focus groups, surveys, and self-reflection or autobiographical narrative. Directions for future exploration are addressed.


Amphotericin B lipid complex in the management of invasive aspergillosis in immunocompromised patients.
The efficacy and renal safety of amphotericin B lipid complex (ABLC) were assessed in 398 patients with invasive aspergillosis. The most common underlying conditions were hematopoietic stem-cell transplantation (101/398 [25%]), hematologic malignancy (101/398 [25%]), and solid-organ transplantation (109/398 [27%]). The most common reason for administration of ABLC was lack of response to prior antifungal therapy. Overall, 65% of patients had a favorable clinical response: 44% were cured or improved, and 21% were stabilized. Clinical responses were similar for patients who received ABLC as either first-line or second-line therapy. One hundred forty-four patients whose results could be evaluated received ABLC concurrently with or after therapy with itraconazole. No antagonism was observed when therapy with ABLC followed therapy with itraconazole. Patients infected with Aspergillus terreus, an innately polyene-resistant species, experienced a 37% response rate. Changes in serum creatinine levels were not clinically significant in most patients; however, dialysis was initiated in 7 patients, of whom 6 had prior antifungal therapy or preexisting renal disease. Analysis of this large database demonstrated the efficacy and safety of ABLC in the treatment of invasive aspergillosis.


Conversion of 7-alpha,12-alpha-dihydroxycholest-4-en-3-one to 5-alpha-cholestane-3-alpha, 7-alpha,12-alpha-triol by iguana liver microsomes.
The role of 7alpha,12alpha-dihydroxycholest-4-en-3-one as an intermediate in the formation of 5alpha-bile acids from cholesterol was investigated with liver preparations of Iguana iguana in vitro. The microsomal fraction of iguana liver catalyzed the transformation of 7alpha,12alpha-dihydroxycholest-4-en-3-one to 5alpha-cholestane-3alpha,7alpha,12alpha-triol in good yield. 7alpha,12alpha-dihydroxy-5alpha-cholestan-3-one served as an intermediate. Under the conditions employed, formation of the corresponding 5beta-isomers could not be detected. High speed supernatant solution and mitochondrial fraction of iguana liver did not reduce 7alpha,12alpha-dihydroxycholest-4-en-3-one to a measurable extent. The microsomal enzyme system required NADPH as hydrogen donor and was inactive in the presence of NADH. It is suggested that 7alpha,12alpha-dihydroxycholest-4-en-3-one may serve as a common intermediate in the formation of 5alpha- and 5beta-bile acids from cholesterol.


Functional neuroimaging studies of bipolar disorder: examining the wide clinical spectrum in the search for disease endophenotypes.
Bipolar disorder (BP) is among the top ten most disabling illnesses worldwide. This review includes findings from recent studies employing functional neuroimaging to examine functional abnormalities in neural systems underlying core domains of the psychopathology in BP: emotion processing, emotion regulation and executive control, and common comorbid features of BP, that are relevant to the wide spectrum of BP rather than focused on the more traditional BPI subtype, and that may facilitate future identification of diagnostically-relevant biomarkers of the disorder. In addition, an emerging number of studies are reviewed that demonstrate the use of neuroimaging to elucidate biomarkers whose identification may help to (1) identify at-risk individuals who will subsequently develop the illness to facilitate early intervention, (2) identify targets for treatment and markers of treatment response. The use of newer neuroimaging techniques and potential confounds of psychotropic medication upon neuroimaging findings in BP are also examined. These approaches will help to improve diagnosis and the mental well-being of all individuals with BP.


The binding of polyamines and of ethidium bromide to tRNA.
The binding of spermidine and ethidium bromide to mixed tRNA and phenylalanine tRNA has been studied under equilibrium conditions. The numbers and classes of binding sites obtained have been compared to those found in complexes isolated by gel filtration a low ionic strength. The latter complexes contain 10-11 moles of either spermidine or ethidium per mole of tRNA; either cation is completely displaceable by the other. In ethidium complexes, the first 2-3 moles are bound in fluorescent binding sites; the remaining 7-8 molecules bind in non-fluorescent form. At least one of the binding sites for spermidine appears similar to a binding site for fluorescent ethidium. Similar results are found with E. coli formylmethionine tRNA. Spermine, in excess of 18-20 moles per mole tRNA, causes precipitation of the complex. Putrescine does not form isolable complexes with yeast tRNA and displaces ethidium less readily from preformed ethidium-tRNA complexes. Under equilibrium conditions, in the absence of Mg++, there are 16-17 moles of spermidine bound per mole of tRNA as determined by equilibrium dialysis. Of these, 2-3 bind with a Ksence of 9 mM Mg++, the total number of binding sites is decreased slightly and there appears to be only one class of sites with a Ka = 600 M(-1). Quantitatively similar results are obtained for the binding of spermidine to yeast phenylalanine tRNA. When the interaction between ethidium bromide and mixed tRNA is studied by equilibrium dialysis or spectrophotometric titration, two classes of binding sites are obtained: 2-3 molecules bind with an average Ka = 6.6 x 10(5) M(-1) and 14-15 molecules bind with an average Ka = 4.1 x 10(4) M(-1). Spermidine, spermine, and Mg++ compete effectively for both classes of ethidium sites and have the effect of reducing the apparent binding constants for ethidium. When the binding of ethidium is studied by fluorometry, there are 3-4 highly fluorescent sites per tRNA. These sites are also affected by spermidine, spermine and Mg++. Putrescine has little effect on any of the classes of binding sites. These data are consistent with those found under non-equilibrium conditions. They suggest that polyamines bind to fairly specific regions of tRNA and may be involved in the maintenance of certain structural features of tRNA.


[Active immunization against tick-borne encephalitis virus infection in residents of North-Eastern Poland].
Group consisted of 78 persons was selected among 1587 persons vaccinated against tick-borne encephalitis. Efficiency of vaccination, controlled by measurement of specific IgM and IgG antibodies presence, was evaluated as 70.2% (47.4%-90%). The highest efficiency was observed in urban residents occasionally stayed in forest areas, that showed trace, of antibody level at the begining of study.


Primary osteoarthritis of hip, knee, and hand in relation to occupational exposure.
To identify occupations with excess prevalence of osteoarthritis of the knee, hip, and hand in a nationwide survey and to compare occupations with and without excess prevalence with regard to biomechanical stresses and severity of osteoarthritis. Patients presenting with osteoarthritis of the knee, hip, or hand were recruited throughout France by their treating physician who collected information on history, including age at onset, occupation, and occupational stresses to joints. Severity was assessed using joint specific functional status questionnaires: Lequesne for the hip and knee and Dreiser for the hand. The distribution of osteoarthritis patients by occupation was compared with the distribution of occupations in all workers in France to obtain prevalence rate ratios. Occupations with the greatest prevalence rate ratio were female cleaners (6.2; 95% CI 4.6 to 8.0), women in the clothing industry (5.0; 95% CI 3.9 to 6.3), male masons and other construction workers (2.9; 95% CI 2.6 to 3.3), and agriculture male and female workers (2.8; 95% CI 2.5 to 3.2). A twofold greater prevalence rate was observed within certain occupations between self-employed and salaried workers. Early onset of osteoarthritis was seen in the more heavy labour jobs with almost 40% of patients reporting their first symptoms before the age of 50. The early onset and severity of osteoarthritis in certain occupations warrants an urgent need for occupation specific studies for the development and evaluation of preventive strategies in this leading cause of disability in Western countries.


Sample-independent approach to normalize two-dimensional data for orthogonality evaluation using whole separation space scaling.
Orthogonality is a key parameter that is used to evaluate the separation power of chromatography-based two-dimensional systems. It is necessary to scale the separation data before the assessment of the orthogonality. Current scaling approaches are sample-dependent, and the extent of the retention space that is converted into a normalized retention space is set according to the retention times of the first and last analytes contained in a unique sample to elute. The presence or absence of a highly retained analyte in a sample can thus significantly influence the amount of information (in terms of the total amount of separation space) contained in the normalized retention space considered for the calculation of the orthogonality. We propose a Whole Separation Space Scaling (WOSEL) approach that accounts for the whole separation space delineated by the analytical method, and not the sample. This approach enables an orthogonality-based evaluation of the efficiency of the analytical system that is independent of the sample selected. The WOSEL method was compared to two currently used orthogonality approaches through the evaluation of in silico-generated chromatograms and real separations of human biofluids and petroleum samples. WOSEL exhibits sample-to-sample stability values of 3.8% on real samples, compared to 7.0% and 10.1% for the two other methods, respectively. Using real analyses, we also demonstrate that some previously developed approaches can provide misleading conclusions on the overall orthogonality of a two-dimensional chromatographic system.


Living Kidney Donation Is Recipient Age Sensitive and Has a High Rate of Donor Organ Disqualifications.
Living donor kidney transplantation (LDKT) is the best therapy for patients with chronic renal failure. Its advantages, compared with cadaveric transplantation, include the possibility of avoiding dialysis, the likelihood of best outcome, and donor pool expansion. Careful assessment of potential donors is important to minimize the risks and ensure success. However, the proportion of donors disqualified has been poorly investigated. The aim of this work is to describe our experience and present the main reasons for missed donation. This was a single-center, retrospective study of all potential donors and recipients evaluated for LDKT between January 2008 and December 2017. During the period of study, 81 donor-recipient pairs were evaluated. Of these, 45.7% were disqualified and 37 LDKTs were carried out. LDKT was the first choice in 68% of cases and preemptive in 20%; 60% of transplants were among family members. Sex distribution revealed a prevalence of females in the donor group (69%) and males in the recipient group (70%). The mean living donor age was 53 ± 9.5 years; the mean recipient age was lower in recipients listed in the living transplant program than those listed for cadaver transplantation (45.8 ± 13.4 vs 54.2 ± 11.08; P < .0001). Reasons for denial included hypertension (18.9%), deceased donor transplant performed during the study period (16.2%), urologic pathology (13.5%), incompatibility (13.5%), withdrawal of consent by donor or recipient (13.5%), psychological unsuitability (8.1%), donor cancer (5.4%), and reduced renal clearance (2.7%). LDKT is considered an option especially for younger recipients. Of the potential kidney living donors, 45.7% were disqualified during the evaluation, with medical reasons being the primary cause.


Recombination-mediated remodelling of host-pathogen interactions during Staphylococcus aureus niche adaptation.
Large-scale recombination events have led to the emergence of epidemic clones of several major bacterial pathogens. However, the functional impact of the recombination on clonal success is not understood. Here, we identified a novel widespread hybrid clone (ST71) of livestock-associated Staphylococcus aureus that evolved from an ancestor belonging to the major bovine lineage CC97, through multiple large-scale recombination events with other S. aureus lineages occupying the same ruminant niche. The recombination events, affecting a 329 kb region of the chromosome spanning the origin of replication, resulted in allele replacement and loss or gain of an array of genes influencing host-pathogen interactions. Of note, molecular functional analyses revealed that the ST71 hybrid clone has acquired multiple novel pathogenic traits associated with acquired and innate immune evasion and bovine extracellular matrix adherence. These findings provide a paradigm for the impact of large-scale recombination events on the rapid evolution of bacterial pathogens within defined ecological niches.


BodyPressure - Inferring Body Pose and Contact Pressure From a Depth Image.
Contact pressure between the human body and its surroundings has important implications. For example, it plays a role in comfort, safety, posture, and health. We present a method that infers contact pressure between a human body and a mattress from a depth image. Specifically, we focus on using a depth image from a downward facing camera to infer pressure on a body at rest in bed occluded by bedding, which is directly applicable to the prevention of pressure injuries in healthcare. Our approach involves augmenting a real dataset with synthetic data generated via a soft-body physics simulation of a human body, a mattress, a pressure sensing mat, and a blanket. We introduce a novel deep network that we trained on an augmented dataset and evaluated with real data. The network contains an embedded human body mesh model and uses a white-box model of depth and pressure image generation. Our network successfully infers body pose, outperforming prior work. It also infers contact pressure across a 3D mesh model of the human body, which is a novel capability, and does so in the presence of occlusion from blankets.


Rare variant testing of imputed data: an analysis pipeline typified.
Important methodological advancements in rare variant association testing have been made recently, among them collapsing tests, kernel methods and the variable threshold (VT) technique. Typically, rare variants from a region of interest are tested for association as a group ('bin'). Rare variant studies are already routinely performed as whole-exome sequencing studies. As an alternative approach, we propose a pipeline for rare variant analysis of imputed data and develop respective quality control criteria. We provide suggestions for the choice and construction of analysis bins in whole-genome application and support the analysis with implementations of standard burden tests (COLL, CMAT) in our INTERSNP-RARE software. In addition, three rare variant regression tests (REG, FRACREG and COLLREG) are implemented. All tests are accompanied with the VT approach which optimizes the definition of 'rareness'. We integrate kernel tests as implemented in SKAT/SKAT-O into the suggested strategies. Then, we apply our analysis scheme to a genome-wide association study of Alzheimer's disease. Further, we show that our pipeline leads to valid significance testing procedures with controlled type I error rates. Strong association signals surrounding the known APOE locus demonstrate statistical power. In addition, we highlight several suggestive rare variant association findings for follow-up studies, including genomic regions overlapping MCPH1, MED18 and NOTCH3. In summary, we describe and support a straightforward and cost-efficient rare variant analysis pipeline for imputed data and demonstrate its feasibility and validity. The strategy can complement rare variant studies with next generation sequencing data.


Light diffusion through composite restorations added with spherical glass mega fillers.
Evaluate how the spherical glass mega fillers (SGMFs) can positively interfere with light diffusion when incorporated in a composite restoration. 30 samples (Ss) were performed, applying 2 composite layers of 3 mm each: 6 were made with composite only; 6 with a layer of SGMFs of O1.5mm within the first layer of composite; 6 with 2 overlapping layers of SGMFs of O1.5mm; 6 with a layer of SGMFs of O2mm; 6 with 2 overlapping layers of SGMFs of O2mm. The curing time was set at 40s for the first layer, and 120s for the second layer, transilluminated through the first layer. Digital pictures were taken, in standardized settings, during the transillumination, and the light intensity was measured with a digital image analysis software. From a lateral view the Ss with a single layer of SGMFs of O1.5mm and O2mm, the relative increments of light intensity, were of 24.37% and 33.33% respectively. Concerning the Ss made with 2 layers of SGMFs, the relative increments were of 67.99% and 66.4% respectively. In front view has emerged a relative increase rate of light intensity of 53.66% and 79.58%, in the Ss with a single layer of SGMFs of O1.5mm and of O2mm respectively. Furthermore, in the Ss with two layers of SGMFs of O1.5mm and O2mm the relative increments were of 267.53 and 319.63% respectively. The SGMFs are reliable in facilitating light diffusion within the light-curing composite resins.


[Physiology of food intake and regulation of body weight].
Feeding is often influenced by competitive needs or by environmental factors. Nevertheless, in physiological conditions hunger is elicited by depletion of macronutrients. The first question is what specific signals cause food intake? Recent data suggest that the signal comes not from exclusive depletion of carbohydrates or of anyone type of the major macronutrients but from overall decreased cellular power production (hypoischymetric signal). Locomotion free metabolic rate has been shown to decrease preceding hunger and to increase in order to determine satiety. Satiation, which occurs largely before ingested nutrients can cross the intestinal barrier and replete the inner milieu, obeys a specific mechanism. Following the stimulation by ingestion of the oro-gastro-intestinal receptors metabolic hormones such as glucagon and insulin are released and enhance metabolism of endogenous reserves. The so-induced endogenous "meal" brings about an anticipatory hypermetabolism which inhibits further ingestion. Post-absorptive satiety subsequently will replace the pre-absorptive state of satiation. The long term regulation of body weight is more subtle. When the actual body weight exceeds its defended value, responsiveness towards signals of hunger diminishes. This hyporesponsiveness seems to be a consequent of an enlargement of the microscopic fat depot at the level of hypothalamic receptive structures which parallels the peripheral increase of the macroscopic fat depot. Thus, hunger promoting signals become less effective and feeding decreases. A symmetrical process takes place in case of body weight loss which results in central hyperresponsiveness to hunger related stimuli and thus facilitates feeding and body weight recovery.


Reproductive coercion in college health clinic patients: Risk factors, care seeking and perpetration.
Reproductive coercion is associated with poor health outcomes in women. This study examined exposure to and use of reproductive coercion and care seeking among college students. A cross-sectional survey was administered to 2291 college students of all genders seeking care in college health and counselling centres as baseline data for a cluster-randomized controlled trial. Online surveys were collected (9/2015-3/2017). Descriptive statistics, chi-square, Fisher's exact and t-tests were analysed. Among female participants, 3.1% experienced reproductive coercion in the prior 4 months. Experience was associated with older age (p = .041), younger age at first intercourse (p = .004), Black/African American race (p < .001), behaviourally bisexual (p = .005), more lifetime sexual partners (p < .001) and ever pregnant (p = .010). Sexually transmitted infection (p < .001), recent drug use or smoking (p = .018; p = .001), requiring special health equipment (p = .049), poor school performance (p < .001) and all categories of violence (p = <.001-.015) were associated with women's reproductive coercion experience. Participants who experienced reproductive coercion were more likely to seek care for both counselling and healthcare, (p = .022) and sexually transmitted infection (p = .004). Among males, 2.3% reported recent use of reproductive coercion; these participants reported sexual violence perpetration (p = .005), less condom use (p = .003) and more sexual partners than non-perpetrators (p < .001). Although reproductive coercion was reported infrequently among college students, those students experiencing it appear to be at risk for poor health and academic outcomes. Health and counselling centres are promising settings to address RC and related health behaviours.


DNA damage checkpoint adaptation genes are required for division of cells harbouring eroded telomeres.
In budding yeast, telomerase and the Cdc13p protein are two key players acting to ensure telomere stability. In the absence of telomerase, cells eventually enter a growth arrest which only few can overcome via a conserved process; such cells are called survivors. Survivors rely on homologous recombination-dependent mechanisms for telomeric repeat addition. Previously, we showed that such survivor cells also manage to bypass the loss of the essential Cdc13p protein to give rise to Cdc13-independent (or cap-independent) strains. Here we show that Cdc13-independent cells grow with persistently recognized DNA damage, which does not however result in a checkpoint activation; thus no defect in cell cycle progression is detectable. The absence of checkpoint signalling rather is due to the accumulation of mutations in checkpoint genes such as RAD24 or MEC1. Importantly, our results also show that cells that have lost the ability to adapt to persistent DNA damage, also are very much impaired in generating cap-independent cells. Altogether, these results show that while the capping process can be flexible, it takes a very specific genetic setup to allow a change from canonical capping to alternative capping. We hypothesize that in the alternative capping mode, genome integrity mechanisms are abrogated, which could cause increased mutation frequencies. These results from yeast have clear parallels in transformed human cancer cells and offer deeper insights into processes operating in pre-cancerous human cells that harbour eroded telomeres.


Infecting epidemiology with genetics: a new frontier in disease ecology.
Disease ecologists strive to understand the causes and consequences of parasite infection, including the emergence, spread, persistence and evolution of infectious disease. These processes can be illuminated by parasite genetic markers, which can be used to track parasite spread and infer population history. Recently, a growing number of studies have used molecular tools to examine questions on the ecology of infectious diseases. We review this burgeoning area of research by focusing on three topics where genetic tools will increasingly make major contributions: inferring parasite transmission, reconstructing epidemiological history and identifying physical and environmental drivers of disease spread. We also discuss areas for future research and highlight the promise of multidisciplinary collaborations among geneticists, ecologists and epidemiologists.


Preliminary study of highly cross-linked hyaluronic acid-based combination therapy for management of knee osteoarthritis-related pain.
Hyaluronic acid has been extensively used for treatment of knee osteoarthritis due to its anti-inflammatory properties and its ability to act as a synovial lubricant. Furthermore, it has found application in combination with other drugs in the dermatological field and in pre-clinical studies in animal models of osteoarthritis. Experimental evidence suggests that a combination of this macromolecule with other drugs may act as a slow-release depot. However, to date, to the best of our knowledge, no one has tested local intra-articular delivery of highly cross-linked hyaluronic acid combined with bisphosphonate or nonsteroidal anti-inflammatory drugs for management of knee osteoarthritis pain in the clinical setting. The aim of the present randomized double-blind study was to investigate, for the first time, the effect of a highly cross-linked hyaluronic acid, Variofill(®), alone or in combination with diclofenac sodium or sodium clodronate, for management of bilateral knee osteoarthritis-related pain. Sixty-two patients with symptomatic bilateral medial tibiofemoral knee osteoarthritis (Kellgren-Lawrence grade II and III) and pain in both knees corresponding to a daily visual analog scale (VAS) score ≥ 30 in the month before the beginning of the study were included in this investigation. Patients were divided into three groups: group 1, treated with an injection of hyaluronic acid alone (66 mg) into each knee; group 2, treated with an injection of hyaluronic acid (49.5 mg) plus diclofenac sodium (5 mg) into each knee; group 3, treated with an injection of hyaluronic acid (49.5 mg) plus sodium clodronate (5 mg) into each knee. Patients also underwent blood tests for measurement of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) immediately before and at 6-month follow-up. Hyaluronic acid alone and in combination with sodium clodronate or diclofenac sodium produced a significant improvement in mean VAS pain score at 3 and 6-month follow-up. At 6-month follow-up, therapy with hyaluronic acid plus sodium clodronate was the most beneficial in terms of percentage improvement in VAS pain score. A significant improvement in ESR and CRP was observed at 6-month follow-up in each treatment group. No significant difference was observed when the percentage change from baseline related to these parameters was compared among the groups. No dropout was observed in any group. No serious adverse events were observed. Further studies are necessary to determine the effect of a therapy based on hyaluronic acid combined with diclofenac sodium or sodium clodronate in larger cohorts of patients affected by knee osteoarthritis and in longer-term follow-up.


Beware Dichotomies.
This essay combines our thoughts concerning the generally destructive practice of dichotomization with a selective review of the literature supporting our critique. The apparent simplicity of dichotomous thinking encourages its use even when a dyadic representation is totally inadequate to understanding complex situations, and this "simpler is better" mantra continues to stymie our understanding of many of the world's complexities. The identification and naming of two distinct, opposing categories often results in their being seen as in opposition to one another, and that it is somehow incumbent upon us to choose one or the other. This either/or orientation reinforces the original split, confusing explanans and explanandum. We begin by considering dichotomization in general terms, and then turn to brief descriptions of several particular dichotomies. Some of these persist despite what might well be considered sufficient evidence to deny their usefulness, and this often deflects attention away from the more fertile, interesting, and important questions that may be directed to the points at which they intermingle.


HIV-1 Tat binds to SH3 domains: cellular and viral outcome of Tat/Grb2 interaction.
The Src-homology 3 (SH3) domain is one of the most frequent protein recognition modules (PRMs), being represented in signal transduction pathways and in several pathologies such as cancer and AIDS. Grb2 (growth factor receptor-bound protein 2) is an adaptor protein that contains two SH3 domains and is involved in receptor tyrosine kinase (RTK) signal transduction pathways. The HIV-1 transactivator factor Tat is required for viral replication and it has been shown to bind directly or indirectly to several host proteins, deregulating their functions. In this study, we show interaction between the cellular factor Grb2 and the HIV-1 trans-activating protein Tat. The binding is mediated by the proline-rich sequence of Tat and the SH3 domain of Grb2. As the adaptor protein Grb2 participates in a wide variety of signaling pathways, we characterized at least one of the possible downstream effects of the Tat/Grb2 interaction on the well-known IGF-1R/Raf/MAPK cascade. We show that the binding of Tat to Grb2 impairs activation of the Raf/MAPK pathway, while potentiating the PKA/Raf inhibitory pathway. The Tat/Grb2 interaction affects also viral function by inhibiting the Tat-mediated transactivation of HIV-1 LTR and viral replication in infected primary microglia.


Factors regulating the response of cells cultured from human giant cell tumors of bone to parathyroid hormone.
Exposure of cells cultured from human giant cell tumors of bone to parathyroid hormone (PTH) results in an increase in the intracellular cAMP content. When cells are preincubated with PTH for periods as short as 10 min and then reexposed to this hormone, there is a decrease in the subsequent PTH-induced cAMP response. This decrease is inversely related to the concentration of PTH present during the preincubation. To investigate the factors responsible for this decrease in hormone response, we used a synthetic substituted analog of bovine PTH, [Nle8, Nle18, Tyr34]bPTH-(3-34) amide (PTH-Inh), which had previously been shown to be a competitive inhibitor of PTH-induced cAMP response in renal and bone-derived tissues. Incubation of these cultured cells with this analog failed to increase intracellular cAMP levels. In contrast to the results obtained with native hormone, when cells were preincubated with PTH-Inh, the acute cAMP response to native PTH after the removal of PTH-Inh was not diminished. In addition, simultaneous preincubation with native PTH and PTH-Inh partially overcame desensitization to PTH. These results suggest that occupancy of the PTH receptor alone is not sufficient to cause desensitization. Rather, steps subsequent to hormone binding, including activation of adenylate cyclase, may be required for the induction of a state of desensitization to PTH.


Vagal nerve stimulator pocket infections.
Vagal nerve stimulator pocket infections are uncommon but can cause considerable morbidity. We describe 3 children from our institution and 8 others previously reported with infection after vagal nerve stimulator implantation for seizure control. Infection was suppressed but recurred despite appropriate antimicrobial therapy when the device remained in situ. Device removal was required in all patients to achieve cure.


Evaluation of prognostic differences in elderly patients with pneumonia treated by between pulmonologists and non-pulmonologists: a propensity score analysis.
The incidence of pneumonia among elderly people is increasing in aged countries, and both pulmonologists and non-pulmonologists treat such patients. The aim of this study was to assess prognostic differences between elderly patients treated by pulmonologists and those treated by non-pulmonologists. This study was a retrospective cohort using a propensity score analysis. Patients 65 years of age or over with pneumonia were consecutively included. The propensity score was estimated based on the patient's background and severity of pneumonia. The difference in 30-day and 90-day mortality depending on the attending physician's specialty was analyzed after adjusting for other variables, including the propensity score. We assessed 68 and 182 patients treated by pulmonologists and non-pulmonologists, respectively. The pulmonologists tended to be in charge of patients with hypoxemia, chronic obstructive pulmonary disease or dementia without aspiration pneumonia or renal dysfunction (area under receiver operating characteristic curve to predict treatment by a pulmonologist according to the propensity score = 0.737, P < 0.001). In the multivariate analysis, white blood count cell (adjusted hazard ratio, 1.000, P = 0.030) and the serum albumin level (0.382, P = 0.001) were associated with 30-day mortality, and a bedridden status (3.000, P = 0.013) and the serum albumin level (0.382, P < 0.001) were associated with 90-day mortality; however, the attending physician's specialty was not associated with these prognoses. The overall prognosis of pneumonia in elderly patients may not necessarily improve, irrespective of treatment by pulmonologists, and host factors seemed to be associated with mortality.


Relationship between Ki-67 positive cells, growth rate and histological type of human intracranial tumors.
The proliferation rate of 40 intracranial neoplasms (30 gliomas, 1 hemangioblastoma, 3 meningiomas, 1 neurinoma and 5 brain metastases) was investigated using the monoclonal antibody Ki-67. In eleven of the gliomas recurrences could be observed, and two of them recurred for second time. In total the Ki-67 labelling indices of 53 specimens were investigated. The Ki-67 nuclear antigen was demonstrated in frozen sections by application of the appropriate monoclonal antibodies according to a modified alkaline phosphatase-antialkaline phosphatase (APAAP) technique. The proliferation rate was evaluated by cell count calculation of the staining index. Ki-67-labelled glioma cells varied from 0.2 percent in one meningioma (WHO-grade I) to 9.1 percent in one glioblastoma. In ten glioma recurrences, higher Ki-67 staining indices could be observed than in their primaries, even when the histological grading did not change substantially. In a cerebellar hemangioblastoma, a trigeminal neurinoma and two endotheliomatous meningiomas the fraction of stained nuclei was less than one percent; however, one recurrent transitional meningioma without any histological sign of malignancy showed a staining index of 2.4 percent. The staining indices of five brain metastases of different malignancies ranged from 1.5 percent in a malignant melanoma to 6.1 percent in bronchial carcinoma. In the majority of the cases examined, the percentage of Ki-67 labelled cells was in accordance with the histologic grade of the neoplasm. In general, there was a direct relationship between the number of stained nuclei and the frequency of mitoses (mitotic index) evaluated in hematoxylin-eosin stained frozen sections. Interestingly, the frequency of mitosis and stained nuclei were higher in tumor recurrences than in the primaries. The results of this study imply that immunohistological labelling of the proliferating cell fraction should become an important additional criterion to predict the biological behaviour of human nervous system neoplasms.


Camouflage through colour change: mechanisms, adaptive value and ecological significance.
Animals from a wide range of taxonomic groups are capable of colour change, of which camouflage is one of the main functions. A considerable amount of past work on this subject has investigated species capable of extremely rapid colour change (in seconds). However, relatively slow colour change (over hours, days, weeks and months), as well as changes arising via developmental plasticity are probably more common than rapid changes, yet less studied. We discuss three key areas of colour change and camouflage. First, we review the mechanisms underpinning colour change and developmental plasticity for camouflage, including cellular processes, visual feedback, hormonal control and dietary factors. Second, we discuss the adaptive value of colour change for camouflage, including the use of different camouflage types. Third, we discuss the evolutionary-ecological implications of colour change for concealment, including what it can tell us about intraspecific colour diversity, morph-specific strategies, and matching to different environments and microhabitats. Throughout, we discuss key unresolved questions and present directions for future work, and highlight how colour change facilitates camouflage among habitats and arises when animals are faced with environmental changes occurring over a range of spatial and temporal scales.This article is part of the themed issue 'Animal coloration: production, perception, function and application'.


An overview of atopic dermatitis.
Atopic dermatitis (AD) is an inflammatory disease, characterized by marked pruritus, which typically assumes a chronically relapsing course. Although AD is primarily a childhood disease, 60% to 70% of adults with AD suffer from hand eczema. Caring for patients with AD is time consuming and difficult. Patients and parents need proper education and detailed instructions from nurses and physicians to avoid flares and complications. Recognizing signs of infection and beginning appropriate treatment for them are important. Instruction on corticosteroid therapy as well as use of topical immunomodulators is crucial to effective acute and long-term management of AD.