Clinical Features of Neuroendocrine Carcinoma of the Uterine Cervix: A Single-Institution Retrospective Review.
Neuroendocrine carcinoma of the cervix is a rare and aggressive subtype of cervical cancer and includes small cell neuroendocrine carcinoma (SCNEC) and large cell neuroendocrine carcinoma (LCNEC). We conducted a single-institution retrospective review to explore the pattern of treatments and outcomes with the aim of defining an optimum treatment strategy for these carcinomas. Twenty-three consecutive patients with SCNEC or LCNEC of the cervix diagnosed at the Hyogo Cancer Center between 1996 and 2013 were included in this study. Pertinent information, including clinical and pathological characteristics, and survival data were collected from clinical records and/or telephone surveys. The pathological review was conducted by a pathologist specializing in gynecologic cancer. Eleven patients had SCNEC and 12 had LCNEC. Eighteen patients with International Federation of Gynecology and Obstetrics (FIGO) stage I/II underwent type III radical hysterectomy with pelvic lymphadenectomy. After surgery, 9 received adjuvant chemotherapy (8, irinotecan plus cisplatin; 1, paclitaxel plus carboplatin), 7 received concurrent chemoradiation therapy (CCRT; 6, nedaplatin; 1, cisplatin), and 2 received radiation therapy (RT). Patients who received adjuvant chemotherapy had a better overall survival than did patients who received CCRT or RT (hazard ratio, 0.21; 95% confidence interval, 0.030-1.51; P = 0.12). Although the overall survival rates are not statistically significant, the 9 patients who underwent radical hysterectomy followed by adjuvant chemotherapy are all alive. Among the remaining 5 patients who did not undergo radical hysterectomy, 2 with FIGO stage III and 1 with stage IVa received CCRT, and 2 with stage IVb received palliative RT or chemotherapy. These 5 patients with FIGO stage III/IV died of disease within 36 months. Radical hysterectomy followed by platinum-based chemotherapy, especially the irinotecan plus cisplatin combination, is beneficial for long-term survival in patients with early-stage neuroendocrine carcinoma of the cervix.


Refractory autoimmune thrombocytopenic purpura: responses to treatment with a recombinant antibody to lymphocyte membrane antigen CD20 (rituximab).
"Refractory" autoimmune thrombocytopenia represents a life-threatening condition, having failed to respond to a variety of therapeutic measures. We report a series of cases, all failing splenectomy and multiple therapeutic programs, including, in two patients, marrow transplant. Five of the six cases reported responded to a recombinant antibody to the lymphocyte membrane antigen CD20 (rituximab), an agent commonly employed in the treatment of non-Hodgkin's lymphoma. Our experiences over a period of 4 years are documented. The results support the use of this product, rituximab, in the treatment of patients with autoimmune thrombocytopenia who have not attained a hemostatically effective platelet count following splenectomy and require a continuing therapeutic management program.


Sustainable food systems-a health perspective.
Malnutrition in all forms, ranging from undernourishment to obesity and associated diet-related diseases, is one of the leading causes of death worldwide, while food systems often have major environmental impacts. Rapid global population growth and increases in demands for food and changes in dietary habits create challenges to provide universal access to healthy food without creating negative environmental, economic, and social impacts. This article discusses opportunities for and challenges to sustainable food systems from a human health perspective by making the case for avoiding the transition to unhealthy less sustainable diets (using India as an exemplar), reducing food waste by changing consumer behaviour (with examples from Japan), and using innovations and new technologies to reduce the environmental impact of healthy food production. The article touches upon two of the challenges to achieving healthy sustainable diets for a global population, i.e., reduction on the yield and nutritional quality of crops (in particular vegetables and fruits) due to climate change; and trade-offs between food production and industrial crops. There is an urgent need to develop and implement policies and practices that provide universal access to healthy food choices for a growing world population, whilst reducing the environmental footprint of the global food system.


Evolution of autonomy in idiopathic non-toxic goiter, evaluated by regional suppressibility of 99mTc-uptake and TSH response to TRH.
Seventeen euthyroid patients with non-toxic goiter were studied, 7 had diffuse goiters and 10 had nodular goiters. The TSH response to TRH and the 99mTc-uptake were measured before and after T3 suppression. The uptake, measured with a gamma camera, was calculated for the whole gland and for a maximum of 6 regions within the thyroid gland. The suppressibility of 99mTc-uptake (percent change of uptake) ranged from 0 to 95%, it was significantly greater in patients with diffuse than in those with nodular goiters, and was alike in nodular and internodular tissue. The patients with diffuse goiter were significantly younger than those with nodular goiter. Abolished TSH response to TRH was seen in 2 patients with negative T3 suppression tests. In another 2 patients impaired TSH response was associated with impaired suppressibility. In 13 patients with normal TRH tests, the suppression of uptake was normal in 8 and subnormal in 5. The results suggest that nodularity and functional autonomy may develop in non-toxic goiters. In some of these goiters the mass of autonomous tissue may be large enough to cause negative TRH tests, probably indicating hypersecretion of thyroid hormones, although not necessarily above the normal range.


Spatiotemporal signal detection using continuous shrinkage priors.
Periodontal disease (PD) is a chronic inflammatory disease that affects the gum tissue and bone supporting the teeth. Although tooth-site level PD progression is believed to be spatio-temporally referenced, the whole-mouth average periodontal pocket depth (PPD) has been commonly used as an indicator of the current/active status of PD. This leads to imminent loss of information, and imprecise parameter estimates. Despite availability of statistical methods that accommodates spatiotemporal information for responses collected at the tooth-site level, the enormity of longitudinal databases derived from oral health practice-based settings render them unscalable for application. To mitigate this, we introduce a Bayesian spatiotemporal model to detect problematic/diseased tooth-sites dynamically inside the mouth for any subject obtained from large databases. This is achieved via a spatial continuous sparsity-inducing shrinkage prior on spatially varying linear-trend regression coefficients. A low-rank representation captures the nonstationary covariance structure of the PPD outcomes, and facilitates the relevant Markov chain Monte Carlo computing steps applicable to thousands of study subjects. Application of our method to both simulated data and to a rich database of electronic dental records from the HealthPartners ® Institute reveal improved prediction performances, compared with alternative models with usual Gaussian priors for regression parameters and conditionally autoregressive specification of the covariance structure.


The template update problem.
Template tracking dates back to the 1981 Lucas-Kanade algorithm. One question that has received very little attention, however, is how to update the template so that it remains a good model of the tracked object. We propose a template update algorithm that avoids the "drifting" inherent in the naive algorithm.


The body mass index (BMI) is significantly correlated with levels of cytokines and chemokines in cerebrospinal fluid.
Cytokines and chemokines regulate many functions in the body including the brain. The interactions between adipose tissue and the central nervous system (CNS) are important for the regulation of energy balance. CNS function is also influenced by age. The aim of the present study was to investigate the effects of body mass index (BMI) and age on cytokine and chemokine levels in cerebrospinal fluid. Cerebrospinal fluid samples (n=89) were collected from patients undergoing routine surgical procedures. The samples were analyzed using the multiplex proximity extension assay (PEA) in which 92 different cytokines are measured simultaneously using minute sample volume. We found no significant correlations between age and cytokine levels for any of the studied markers. In contrast, at a false discovery rate of 10%, 19 markers were significantly associated with BMI (in decreasing significance: FGF-5, ADA, Beta-NGF, CD40, IL-10RB, CCL19, TGF-alpha, SIRT2, TWEAK, SCF, CSF-1, 4E-BP1, DNER, LIF-R, STAMPB, CXCL10, CXCL6, VEGF-A and CX3CL1). This study reveals a clear effect of BMI on cytokine and chemokine levels in cerebrospinal fluid.


Regulation of the Jak2 tyrosine kinase by its pseudokinase domain.
Activation of Jak tyrosine kinases through hematopoietic cytokine receptors occurs as a consequence of ligand-induced aggregation of receptor-associated Jaks and their subsequent autophosphorylation. Jak kinases consist of a C-terminal tyrosine kinase domain, a pseudokinase domain of unknown function, and Jak homology (JH) domains 3 to 7, implicated in receptor-Jak interaction. We analyzed the functional roles of the different protein domains in activation of Jak2. Deletion analysis of Jak2 showed that the pseudokinase domain but not JH domains 3 to 7 negatively regulated the catalytic activity of Jak2 as well as Jak2-mediated activation of Stat5. Phosphorylation of Stat5 by wild-type Jak2 was dependent on the SH2 domain of Stat5; however, this requirement was lost upon deletion of the pseudokinase domain of Jak2. Investigation of the mechanisms of the pseudokinase domain-mediated inhibition of Jak2 suggested that this regulation did not involve protein tyrosine phosphatases. Instead, analysis of interactions between the tyrosine kinase domain and Jak2 suggested that the pseudokinase domain interacted with the kinase domain. Furthermore, coexpression of the pseudokinase domain inhibited the activity of the single tyrosine kinase domain. Finally, deletion of the pseudokinase domain of Jak2 deregulated signal transduction through the gamma interferon receptor by significantly increasing ligand-independent activation of Stat transcription factors. These results indicate that the pseudokinase domain negatively regulates the activity of Jak2, probably through an interaction with the kinase domain, and this regulation is required to keep Jak2 inactive in the absence of ligand stimulation. Furthermore, the pseudokinase domain may have a role in regulation of Jak2-substrate interactions.


Novalis intensity-modulated radiosurgery: methods for pretreatment planning.
The Novalis stereotactic radiotherapy system (BrainLAB, Heimstetten, Germany) allows for precise treatment of cranial base tumors with single-fraction radiosurgery. In some cases, however, proximity of the optic nerve and chiasm is a concern. In these cases, intensity-modulated stereotactic radiosurgery (IMRS) can be used to limit the dose to these structures. IMRS planning can be labor intensive, which poses a problem when it is performed on the day of treatment. We describe our methods and results of preprocedure planning for IMRS for patients with lesions in the cavernous sinus or parasellar regions in whom the dose to the optic nerve or chiasm might exceed our acceptable tolerance dose (8 Gy). Patients whose lesions were more than 4 mm from the optic nerve and chiasm on standard magnetic resonance imaging scans but who were questionable candidates for radiosurgery because of concerns of dose to the optic nerve or chiasm were considered for IMRS. Preprocedure imaging (computed tomography and magnetic resonance imaging) was fused and analyzed using the BrainLAB BrainScan 5.3 treatment planning system. Dynamic conformal arc plans for stereotactic radiosurgery and IMRS were evaluated. Doses to the planning target volume and optic apparatus were assessed by dose-volume histograms and conformality index calculated to characterize the quality of the different plans. When IMRS was used, the preplan allowed for a rapid recalculation on the treatment day, minimizing the time patients were in the head frame before treatment. We describe three patients with recurrent pituitary tumors and three with meningiomas. Doses were 1500 to 2000 cGy prescribed to the 80 to 96% isodose line delivered by eight to 22 fields. Tumor volumes ranged from 2.70 to 8.82 cm (mean, 5.7 cm). In five of the six patients, the dynamic conformal arc plan precluded delivery of therapeutic dose without exceeding optic nerve tolerance. On the basis of 95% coverage of target volume, maximum prescription doses of 7.7 to 20.64 Gy were possible with the dynamic conformal arc plans without exceeding 8 Gy to the optic apparatus. IMRS allowed maximum doses of 20 to 31 Gy using the same optic apparatus dose restriction. No complications have occurred, and all tumors have remained stable since treatment (mean follow-up period, 30 mo). We believe this pretreatment technique streamlines the process for IMRS, allowing for better patient comfort and efficient physician time use.


Calcium sensitivity of the contractile system and phosphorylation of troponin in hyperpermeable cardiac cells.
Bundles of cells from rat right ventricular myocardium were made "hyperpermeable" by an overnight soak in 10 mM EGTA (McClellan and Winegrad. 1978. J. Gen. Physiol. 72:737-764). In this preparation the cytoplasmic concentration of Ca++ and ATP could be controlled while sarcolemmal receptors and enzymes were retained. The Ca sensitivity of the tissues (as indicated by the pCa for 50% maximum activation) was altered to different extents in the presence of [32Pgamma]ATP by treatment with cyclic nucleotides, catecholamines, or a low concentration of nonionic detergent. The proteins of the tissue were then isolated by SDS-polyacrylamide gel electrophoresis, and the identity of 32P-labeled proteins was determined. The Ca sensitivity is inversely related to the relative amount of 32P incorporated into the inhibitory subunit of troponin (TNI). Extrapolation of the relation to the lowest Ca sensitivity observed gives a stoichiometry of about 0.8 mol PO4 per mol TNI. These results support the hypothesis that Ca sensitivity of cardiac myofibrils is regulated by a phosphrylation of TNI that is stimulated by cyclic AMP (cAMP) and inhibited by cGMP.


TFAM-Dependent Mitochondrial Metabolism Is Required for Alveolar Macrophage Maintenance and Homeostasis.
Alveolar macrophages (AMs) are major lung tissue-resident macrophages capable of proliferating and self-renewal in situ. AMs are vital in pulmonary antimicrobial immunity and surfactant clearance. The mechanisms regulating AM compartment formation and maintenance remain to be fully elucidated currently. In this study, we have explored the roles of mitochondrial transcription factor A (TFAM)-mediated mitochondrial fitness and metabolism in regulating AM formation and function. We found that TFAM deficiency in mice resulted in significantly reduced AM numbers and impaired AM maturation in vivo. TFAM deficiency was not required for the generation of AM precursors nor the differentiation of AM precursors into AMs, but was critical for the maintenance of AM compartment. Mechanistically, TFAM deficiency diminished gene programs associated with AM proliferation and self-renewal and promoted the expression of inflammatory genes in AMs. We further showed that TFAM-mediated AM compartment impairment resulted in defective clearance of cellular debris and surfactant in the lung and increased the host susceptibility to severe influenza virus infection. Finally, we found that influenza virus infection in AMs led to impaired TFAM expression and diminished mitochondrial fitness and metabolism. Thus, our data have established the critical function of TFAM-mediated mitochondrial metabolism in AM maintenance and function.


Staged treatment of mega aortic syndrome using the frozen elephant trunk and hybrid thoracoabdominal repair.
We report our experience with a staged hybrid approach for the treatment of extended aortic disease, also known as "mega aortic syndrome." A total of 15 patients (10 male, 5 female) underwent staged repair of the thoracoabdominal aorta, consisting of 3 separate stages (repair of ascending aorta and aortic arch using the frozen elephant trunk technique and hybrid thoracoabdominal repair with debranching of the renovisceral branches and stent graft implantation). The procedure was completed in 14 patients. After the first stage (repair of ascending aorta and aortic arch), no mortality or spinal cord ischemia occurred. One patient required temporary dialysis. After the thoracoabdominal repair, permanent paraplegia developed in 1 patient. One patient died intraoperatively after aneurysm rupture. The in-hospital mortality for the complete repair reached 6.7%. None of the surviving patients required permanent dialysis. Interval aortic events consisted of 1 contained rupture. The concept of a staged hybrid repair of the mega aortic syndrome is technically feasible. The frozen elephant trunk technique represents an attractive treatment option, offering an adequate landing zone for later thoracoabdominal repair in patients with extended aortic disease. For completion of the repair, a staged hybrid approach with renovisceral debranching and aneurysm exclusion using off-the-shelf stent grafts shows promising results with low surgical morbidity and mortality.


Ontogenic development of B-lymphocyte function and tolerance susceptibility in vivo and in an in vitro organ culture system.
The maturation of B-lymphocyte function during fetal development was studied in vivo and in an in vitro organ culture system. The results indicated that the progenitors for 2,4-dinitrophenol (DNP)-specific B cells are present as early as 14 d of gestation in liver and possibly as early as 15 d in spleen. In addition, it was found that the organ culture system supports the development of B lymphocytes as measured by an increase in both the percentage of surface immunoglobulin-positive cells and the frequency of clonable DNP-specific B cells after culturing. The majority of anti-DNP-secreting clones resulting from the antigenic stimulation of fetal B cells produced only the IgM isotype, and the ability to secrete the IgG isotypes increased as a function of gestational age. Because fetal DNP precursors from spleens and livers that had been incubated in organ culture resulted in a greater proportion of clones secreting IgG compared with age-matched uncultured controls, it was concluded that the maturation with regard to the ability to secrete IgG can occur in vitro. In studies relating to the ontogenetic development of tolerance susceptibility, it was found that up to one-half of the DNP-specific B-cell precursors from livers and spleens less than 18 or 19 d of gestation were resistant to tolerogen treatment for 24 h as if in a pretolerant phase. However, if tolerogen were present for 3--5 d during organ culture there was near total elimination of potential DNP clones. This finding suggested that the 24-h induction period was insufficient for affecting the DNP-specific precursors in livers and spleens from the earlier gestational ages, and that a proportion of precursors could subsequently form DNP clones in the splenic focus assay after the removal of tolerogen.


[Isolation of enzymes from mixed reversed micelles of surface-active agents].
The catalytic activities of lysozyme, horseradish peroxidase (HP), catalase, glucose-6-phosphate dehydrogenase (G6PDH) and lactate dehydrogenase (LDH) were studied in aqueous solutions and after isolation of the enzymes from mixed reversed micelles of Aerosol OT and Triton X-45 by organic solvents (acetone, ethanol, isopropanol), by acetone-water mixtures, as well as by aqueous solutions containing urea, glycerol, polyethylene glycol 6000 and ammonium sulphate. The isolation conditions were found for catalase with retaining all the activity and for HP and lysozyme with retaining 72 and 84% of the catalytic activity, respectively. The G6PDH isolation from micelles by aqueous solutions of urea (6%) and glycerol (10%) resulted in retaining only 43% of the enzyme activity and led to almost complete inactivation of LDH. Stability of the enzymes after their entrapment in micelles and isolation from those is compared with thermostability of the same enzymes in aqueous solutions.


Aujeszky's disease/pseudorabies in cats: ABCD guidelines on prevention and management.
Although pseudorabies in swine - Aujeszky's disease - has been eradicated from many pork-producing countries, the virus may still lurk in other vertebrate species and cause feline cases. Infection occurs through the ingestion of uncooked meat and organ material and presents as an acute encephalitis with a short incubation period and a rapidly fatal outcome. The ABCD considers this reason enough to include a review of this, now very rare, condition in this Special Issue.


Adaptive introgression in animals: examples and comparison to new mutation and standing variation as sources of adaptive variation.
Adaptive genetic variation has been thought to originate primarily from either new mutation or standing variation. Another potential source of adaptive variation is adaptive variants from other (donor) species that are introgressed into the (recipient) species, termed adaptive introgression. Here, the various attributes of these three potential sources of adaptive variation are compared. For example, the rate of adaptive change is generally thought to be faster from standing variation, slower from mutation and potentially intermediate from adaptive introgression. Additionally, the higher initial frequency of adaptive variation from standing variation and lower initial frequency from mutation might result in a higher probability of fixation of the adaptive variants for standing variation. Adaptive variation from introgression might have higher initial frequency than new adaptive mutations but lower than that from standing variation, again making the impact of adaptive introgression variation potentially intermediate. Adaptive introgressive variants might have multiple changes within a gene and affect multiple loci, an advantage also potentially found for adaptive standing variation but not for new adaptive mutants. The processes that might produce a common variant in two taxa, convergence, trans-species polymorphism from incomplete lineage sorting or from balancing selection and adaptive introgression, are also compared. Finally, potential examples of adaptive introgression in animals, including balancing selection for multiple alleles for major histocompatibility complex (MHC), S and csd genes, pesticide resistance in mice, black colour in wolves and white colour in coyotes, Neanderthal or Denisovan ancestry in humans, mimicry genes in Heliconius butterflies, beak traits in Darwin's finches, yellow skin in chickens and non-native ancestry in an endangered native salamander, are examined.


Regulation of the ovine MT1 melatonin receptor promoter: interaction between multiple pituitary transcription factors at different phases of development.
Pineal secretion of melatonin provides a neuroendocrine representation of the light-dark cycle, which is used to synchronise daily and annual rhythms of physiology and behaviour. In mammals, melatonin primarily acts through MT(1) melatonin receptors that exhibit a highly restricted tissue distribution. Expression of MT(1) receptors is subject to developmental and circadian control, which likely modulates the physiological actions of melatonin. To investigate the mechanisms controlling MT(1) expression we cloned the proximal 1.5kb region of the ovine MT(1) promoter. Sequence analysis revealed putative cis-elements for transcription factors involved in pituitary development, namely Pitx-1 and Egr-1, and multiple putative E-boxes, which are involved in both circadian and developmental gene regulation. Nuclear protein from ovine pars tuberalis (PT) cells, a site of high endogenous MT(1) expression, stimulated gene expression from a MT(1) expression construct, indicating the presence of a functional promoter. Pitx-1 was strongly expressed in the ovine PT and stimulated MT(1) promoter activity in transfection assays. Co-transfection with Egr-1 induced promoter-specific effects: Pitx-1-stimulated MT(1) activity was inhibited, whereas betaLH promoter activity was enhanced. In addition to Pitx-1 the circadian clock genes Clock and Bmal1 were also expressed in the PT. However, despite multiple putative E-boxes in the MT(1) promoter, transfected Clock and Bmal1 were unable to regulate either basal or Pitx-1-stimulated MT(1) promoter activity. The current data, in conjunction with our previous study of the rat MT(1) promoter, suggests a general model in which melatonin receptor expression in the mammalian pituitary is determined by the developmentally changing balance between stimulatory and inhibitory transcription factors. Furthermore, our data suggest that circadian variation in MT(1) gene expression does not depend upon the direct action of circadian clock genes on E-box cis-elements.


Sonic Hedgehog regulates brain-derived neurotrophic factor in normal and regenerating cavernous nerves.
The cavernous nerve (CN) is commonly injured during prostatectomy. Manipulation of the nerve microenvironment is critical to improve regeneration and develop novel erectile dysfunction therapies. Sonic hedgehog (SHH) treatment promotes CN regeneration. The mechanism of how this occurs is unknown. Brain-derived neurotrophic factor (BDNF) facilitates return of erectile function after CN injury and it has been suggested in cortical neurons and the sciatic nerve that BDNF may be a target of SHH. To determine if SHH promotes CN regeneration through a BDNF-dependent mechanism. Sprague Dawley rats underwent (i) bilateral CN crush (N = 15); (ii) SHH treatment of pelvic ganglia (PG)/CN (N = 10); (iii) SHH inhibition in PG/CN (N = 14 rats); (iv) CN crush with SHH treatment of PG/CN (N = 10 rats); (v) CN crush with SHH treatment and BDNF inhibition (N = 14 rats); and (vi) CN injury and SHH treatment of the penis (N = 23). BDNF and glial fibrillary acidic protein were quantified in PG/CN by Western, and a t-test was used to determine differences. In normal rats SHH inhibition in the PG/CN decreased BDNF 34% and SHH treatment increased BDNF 36%. BDNF was increased 44% in response to SHH treatment of crushed CNs, and inhibition of BDNF in crushed CNs treated with SHH protein hampers regeneration. SHH regulates BDNF in the normal and regenerating PG/CN. BDNF is part of the mechanism of how SHH promotes regeneration, thus providing an opportunity to further manipulate the nerve microenvironment with combination therapy to enhance regeneration.


Serum cotinine concentration and wound complications in head and neck reconstruction.
The authors examined whether the preoperative serum concentrations of cotinine accurately predict the risk of complications in patients undergoing flap reconstruction of head and neck cancer defects. Patients with incident stage III or IV squamous cell carcinoma of the head and neck undergoing resection with pedicled or free flap reconstruction were selected from an existing database of 500 patients with squamous cell carcinoma of the head and neck who participated in a prospective epidemiologic study and were reviewed retrospectively. Preoperative serum cotinine concentrations were determined using a competitive microplate immunoassay. Complications were defined as any adverse postoperative wound outcome at either the donor or recipient site. Eighty-nine patients underwent 101 flap reconstructions. Thirty-seven wound complications occurred in 33 patients. Forty of the 89 patients had a serum cotinine concentration greater than 10 ng/ml; twenty (50 percent) developed postoperative complications, whereas only 13 of 49 patients (27 percent) with a serum cotinine concentration of 10 ng/ml or less developed complications (p = 0.028). The relative risk of wound complications for those with a cotinine concentration greater than 10 ng/ml was approximately double that of patients with a lower cotinine concentration (relative risk, 1.9; 95 percent CI, 1.1 to 3.3). Patients with a cotinine concentration greater than 50 ng/ml had a particularly high risk (relative risk, 2.3; 95 percent CI, 1.1 to 16.7; p = 0.024). The relative risk of wound complications was not significantly associated with self-reported smoking status or history. A serum cotinine concentration greater than 10 ng/ml may predict an increased risk of wound complication in head and neck flap reconstruction and may serve as an objective, easily measured variable with which to identify patients who may benefit from an aggressive smoking cessation program before surgery.


Role of RBP2-Induced ER and IGF1R-ErbB Signaling in Tamoxifen Resistance in Breast Cancer.
Despite the benefit of endocrine therapy, acquired resistance during or after treatment still remains a major challenge in estrogen receptor (ER)-positive breast cancer. We investigated the potential role of histone demethylase retinoblastoma-binding protein 2 (RBP2) in endocrine therapy resistance of breast cancer. Survival of breast cancer patients according to RBP2 expression was analyzed in three different breast cancer cohorts including METABRIC (n = 1980) and KM plotter (n = 1764). RBP2-mediated tamoxifen resistance was confirmed by invitro sulforhodamine B (SRB) colorimetric, colony-forming assays, and invivo xenograft models (n = 8 per group). RNA-seq analysis and receptor tyrosine kinase assay were performed to identify the tamoxifen resistance mechanism by RBP2. All statistical tests were two-sided. RBP2 was associated with poor prognosis to tamoxifen therapy in ER-positive breast cancer (P = .04 in HYU cohort, P = .02 in KM plotter, P = .007 in METABRIC, log-rank test). Furthermore, RBP2 expression was elevated in patients with tamoxifen-resistant breast cancer (P = .04, chi-square test). Knockdown of RBP2 conferred tamoxifen sensitivity, whereas overexpression of RBP2 induced tamoxifen resistance invitro and invivo (MCF7 xenograft: tamoxifen-treated control, mean [SD] tumor volume = 70.8 [27.9] mm3, vs tamoxifen-treated RBP2, mean [SD] tumor volume = 387.9 [85.1] mm3, P < .001). Mechanistically, RBP2 cooperated with ER co-activators and corepressors and regulated several tamoxifen resistance-associated genes, including NRIP1, CCND1, and IGFBP4 and IGFBP5. Furthermore, epigenetic silencing of IGFBP4/5 by RBP2-ER-NRIP1-HDAC1 complex led to insulin-like growth factor-1 receptor (IGF1R) activation. RBP2 also increased IGF1R-ErbB crosstalk and subsequent PI3K-AKT activation via demethylase activity-independent ErbB protein stabilization. Combinational treatment with tamoxifen and PI3K inhibitor could overcome RBP2-mediated tamoxifen resistance (RBP2-overexpressing cells: % cell viability [SD], tamoxifen = 89.0 [3.8]%, vs tamoxifen with BKM120 = 41.3 [5.6]%, P < .001). RBP2 activates ER-IGF1R-ErbB signaling cascade in multiple ways to induce tamoxifen resistance, suggesting that RBP2 is a potential therapeutic target for ER-driven cancer.


Proteolytic inactivation of human factor VIII procoagulant protein by activated human protein C and its analogy with factor V.
Purified human factor VIII procoagulant protein (VIII:C) was treated with purified human activated protein C (APC) and the loss of VIII:C activity correlated with proteolysis of the VIII:C polypeptides. APC proteolyzed all VIII:C polypeptides with mol wt = 92,000 or greater, but not the doublet at mol wt = 79-80,000. These results and our previous thrombin activation studies of purified VIII:C, are analogous with similar studies of factor V and form the basis for the following hypothesis: activated VIII:C consists of heavy and light chain polypeptides [mol wt = 92,000 and mol wt = 79-80,000 (or 71-72,000), respectively] which are similar in Mr to the heavy and light chains of activated factor V. Thrombin activates VIII:C and V by generating these polypeptide chains from larger precursors and APC inactivates both molecules by cleavage at a site located in the heavy chain region of activated VIII:C and V.


Advances in the diagnosis of fungal pneumonias.
Fungal infections are increasingly encountered in clinical practice due to more favorable environmental conditions and increasing prevalence of immunocompromised individuals. The diagnostic approach for many fungal pathogens continues to evolve. Herein, we outline available diagnostic tests for the most common fungal infections with a focus on recent advances and future directions. We discuss the diagnostic testing methods for angioinvasive molds (Aspergillus spp. and Mucor spp.), invasive yeast (Candida spp. and Cryptococcus ssp.), Pneumocystis, and endemic fungi (Blastomyces sp., Coccidioides ssp., and Histoplasma sp.). The PubMed-NCBI database was searched within the past 5 years to identify the most recent available literature with dates extended in cases where literature was sparse. Diagnostic guidelines were utilized when available with references reviewed. Historically, culture and/or direct visualization of fungal organisms were required for diagnosis of infection. Significant limitations included ability to collect specimens and delayed diagnosis associated with waiting for culture results. Antigen and antibody testing have made great strides in allowing quicker diagnosis of fungal infections but can be limited by low sensitivity/specificity, cross-reactivity with other fungi, and test availability. Molecular methods have a rich history in some fungal diseases, while others continue to be developed.


Retinal arteriolar narrowing and left ventricular hypertrophy in African Americans. the Atherosclerosis Risk in Communities (ARIC) study.
Whether microvascular disease contributes to the development of left ventricular hypertrophy (LVH) is unclear. We examined the relationship of retinal microvascular signs with LVH in an African-American population. A population-based, cross-sectional study of 1,439 middle-aged African-American participants in Jackson, Mississippi. A retinal photograph of one randomly selected eye was obtained and graded for presence of retinal microvascular signs (focal arteriolar narrowing, arterio-venous (AV) nicking, and retinopathy) according to standardized protocols. Retinal vessel diameter was measured from a computer-assisted technique to define generalized arteriolar narrowing. LVH was defined from standardized echocardiography. In age and gender-adjusted models, retinal microvascular signs (except non-diabetic retinopathy) were significantly associated with LVH, with an odds ratio (OR) of 1.64 (95% confidence interval (CI) 1.29-2.09) for generalized arteriolar narrowing, OR 1.82 (95% CI 1.33-2.50) for focal arteriolar narrowing, and OR 1.35 (95% CI 1.02-1.79) for AV nicking. With further adjustment for cardiovascular (serum total cholesterol, fasting glucose, diabetes, diabetes duration, smoking, body mass index (BMI), waist-to-hip ratio, and exercise level) and hypertension-related factors (mean arterial blood pressure (MABP) at the time of retinal photography and antihypertensive medication use), associations were attenuated but remained significant for generalized and focal arteriolar narrowing, with OR 1.35 (95% CI 1.02-1.78) and OR 1.66 (95% CI 1.16-2.38), respectively. Middle-aged African Americans with generalized and focal retinal arteriolar narrowing were more likely to have LVH. This association was explained only partly by cardiovascular risk factors and hypertension.


Haemophilus influenzae Rd KW20 has virulence properties.
Haemophilus influenzae is a human-adapted commensal and pathogen that can cause mucosal infections such as sinusitis, otitis media and bronchitis. Certain strains also cause bacteraemia and meningitis. Clinical isolates are genetically heterogeneous and are often recalcitrant to standard genetic manipulation. H. influenzae strain Rd KW20 has traditionally been considered avirulent, since it does not survive in the bloodstream of animals, is readily killed by normal adult human sera and cannot colonize the nasopharynx of infant rats. The purpose of this study was to determine whether Rd KW20 could be used in certain infection models. It is shown here that strain Rd KW20 can invade certain human epithelial cell lines grown either as monolayers or as differentiated epithelium at the air-liquid interface. In addition, Rd KW20 can invade a monolayer of immortalized human brain microvascular endothelial cells. Finally, this strain can replicate and survive in human bronchial xenografts for up to 3 weeks. The complete genomic sequence of Rd KW20 is available and it is readily amenable to genetic manipulation. These properties and the results reported here indicate that this strain is a viable alternative to the use of clinical isolates for the investigation of H. influenzae virulence.


Enhanced live cell imaging via photonic crystal enhanced fluorescence microscopy.
We demonstrate photonic crystal enhanced fluorescence (PCEF) microscopy as a surface-specific fluorescence imaging technique to study the adhesion of live cells by visualizing variations in cell-substrate gap distance. This approach utilizes a photonic crystal surface incorporated into a standard microscope slide as the substrate for cell adhesion, and a microscope integrated with a custom illumination source as the detection instrument. When illuminated with a monochromatic light source, angle-specific optical resonances supported by the photonic crystal enable efficient excitation of surface-confined and amplified electromagnetic fields when excited at an on-resonance condition, while no field enhancement occurs when the same photonic crystal is illuminated in an off-resonance state. By mapping the fluorescence enhancement factor for fluorophore-tagged cellular components between on- and off-resonance states and comparing the results to numerical calculations, the vertical distance of labelled cellular components from the photonic crystal substrate can be estimated, providing critical and quantitative information regarding the spatial distribution of the specific components of cells attaching to a surface. As an initial demonstration of the concept, 3T3 fibroblast cells were grown on fibronectin-coated photonic crystals with fluorophore-labelled plasma membrane or nucleus. We demonstrate that PCEF microscopy is capable of providing information about the spatial distribution of cell-surface interactions at the single-cell level that is not available from other existing forms of microscopy, and that the approach is amenable to large fields of view, without the need for coupling prisms, coupling fluids, or special microscope objectives.


Effect of gentian violet on the growth of the N and T RFLP types of the Aspergillus niger aggregate.
Taxa included in the Aspergillus niger aggregate are difficult to distinguish by phenotypic characterization. In this work, the effect of gentian violet on the growth of the N and T RFLP types of A. niger aggregate strains has been investigated. In total, 105 strains from different sources and origins, including reference cultures and field isolates were studied. Type N and T RFLP patterns, ochratoxin A production and the effect of different concentrations of gentian violet on the growth were determined in these strains. Forty nine strains belonged to the N type and 56 strains to the T type. Sixteen out of the 105 strains assayed were OTA producers. All the OTA-producing species belonged to the RFLP type N and none of the T type strains was able to produce OTA. Approximately 90% of the N type strains grew in the presence of 25 ppm of gentian violet. Only five N type strains did not grow on this medium. One of these strains was A. niger ATCC 22343, a well documented induced mutant strain and the remaining four strains belonged to the new species A. brasiliensis. On the contrary, all the T type strains failed to grow on this medium after 3 days of incubation (sensitivity 89.79%; specificity 100%). The use of growth in gentian violet as an additional character for classification and identification purposes in this taxonomic group may be useful because no phenotypic methods have yet been found that can distinguish between these species.


Ecological distribution and potential roles of Woesearchaeota in anaerobic biogeochemical cycling unveiled by genomic analysis.
Woesearchaeota as a newly established member of the superphylum DPANN (Diapherotrites, Parvarchaeota, Aenigmarchaeota, Nanoarchaeota and Nanohaloarchaea) are surprisingly abundant and diverse in a wide variety of environments, including deep oil reservoir, sulfuric springs and anoxic aquifers, indicating a high diversity of their roles in global biogeochemical cycles. However, ecological functions of them remain elusive. To fill up this gap, we analyzed and compared the global distribution patterns of Woesearchaeota using the genomes available publicly. As a result, both ecological distribution patterns and metabolic predictions support a key role of woesearchaeotal lineages in cycling of carbon, nitrogen, and sulfur. Multivariate regression analysis reveals that Woesearchaeota might function in consortium with methanogens in the cycling of carbon in anaerobic environments, particularly in soils or sediments. Moreover, comparative genomic analysis and ecological distribution suggest the potential roles of Woesearchaeota in the processes of denitrification, nitrogen fixation, and dissimilatory nitrite reduction, especially in the wastewater treatment systems; and also uncovered the potential capability of sulfate reduction, sulfide oxidation and thiosulfate oxidation in sulfuric or sulfidic-rich environments. Our findings add more information into the ecological roles of archaea in the anoxic environment.


Columbus' environmental impact in the New World: Land use change in the Yaque River valley, Dominican Republic.
Columbus' arrival in the New World in AD 1492 on the northern coast of Hispaniola was followed by a suite of changes in land-use. We reconstruct environmental change from a 225-cm-long sediment core from site Los Indios from an abandoned and sediment-filled meander of the Yaque River, Cibao Valley, northeastern Dominican Republic. The sediment record starts ca. AD 195 (ca. 1755 cal. yr BP) and the history of the meander infill was monitored by changing grain size distributions, organic matter concentration and pollen from wetland plants. From ca. AD 200 to ca. AD 1525, the pollen record indicates a diverse forest assemblage; however, the presence of pollen from potential crop plants suggest nearby small-scale subsistence crop cultivation. More abundant charcoal after ca. AD 1410 shows Amerindians increasingly used fire. The record of grain size distributions shows that the meander was temporarily part of a low energetic drainage system in which bedload and suspended sediments accumulated. After European colonization of Hispaniola increasing spores of coprophilous fungi evidence that Europeans had introduced during the first decades of colonization cattle in the Cibao Valley which gradually resulted in more open forest. The charcoal record around ca. AD 1650 reflects intensive forest clearing, suggesting that small-scale Pre-Colonial practice of crop cultivation became replaced by large-scale agriculture on the moist and nutrient rich soils along the Yaque River. Further deforestation and signals of erosion suggest that the population of colonists and introduced enslaved labour force must have increased rapidly. After ca. AD 1740 charcoal influx decreased suggesting that last deforestation activities used selective cutting to produce fire wood and timber for construction, rather than burning forest in situ. Two centuries after European colonization, by the 18th century, land-use within the Cibao Valley had become a balance between substantial livestock and crop cultivation (pollen grains have evidenced cereals, maize, and potentially also sugar cane, amaranthaceous crops and tobacco). After ca. AD 1950, swamp vegetation of Typha and Cyperaceae decreased, pointing to an almost fully terrestrialized meander with only few bodies of standing water, reflecting the present-day setting. This multiproxy reconstruction of anthropogenic environmental change shows a clear differentiation between an immediate introduction of livestock and after some 150 years the development of a European style agriculture, providing a context for archaeological investigations.


Global patterns in ecological indicators of marine food webs: a modelling approach.
Ecological attributes estimated from food web models have the potential to be indicators of good environmental status given their capabilities to describe redundancy, food web changes, and sensitivity to fishing. They can be used as a baseline to show how they might be modified in the future with human impacts such as climate change, acidification, eutrophication, or overfishing. In this study ecological network analysis indicators of 105 marine food web models were tested for variation with traits such as ecosystem type, latitude, ocean basin, depth, size, time period, and exploitation state, whilst also considering structural properties of the models such as number of linkages, number of living functional groups or total number of functional groups as covariate factors. Eight indicators were robust to model construction: relative ascendency; relative overhead; redundancy; total systems throughput (TST); primary production/TST; consumption/TST; export/TST; and total biomass of the community. Large-scale differences were seen in the ecosystems of the Atlantic and Pacific Oceans, with the Western Atlantic being more complex with an increased ability to mitigate impacts, while the Eastern Atlantic showed lower internal complexity. In addition, the Eastern Pacific was less organised than the Eastern Atlantic although both of these systems had increased primary production as eastern boundary current systems. Differences by ecosystem type highlighted coral reefs as having the largest energy flow and total biomass per unit of surface, while lagoons, estuaries, and bays had lower transfer efficiencies and higher recycling. These differences prevailed over time, although some traits changed with fishing intensity. Keystone groups were mainly higher trophic level species with mostly top-down effects, while structural/dominant groups were mainly lower trophic level groups (benthic primary producers such as seagrass and macroalgae, and invertebrates). Keystone groups were prevalent in estuarine or small/shallow systems, and in systems with reduced fishing pressure. Changes to the abundance of key functional groups might have significant implications for the functioning of ecosystems and should be avoided through management. Our results provide additional understanding of patterns of structural and functional indicators in different ecosystems. Ecosystem traits such as type, size, depth, and location need to be accounted for when setting reference levels as these affect absolute values of ecological indicators. Therefore, establishing absolute reference values for ecosystem indicators may not be suitable to the ecosystem-based, precautionary approach. Reference levels for ecosystem indicators should be developed for individual ecosystems or ecosystems with the same typologies (similar location, ecosystem type, etc.) and not benchmarked against all other ecosystems.


Learning from work-from-home issues during the COVID-19 pandemic: Balance speaks louder than words.
During the 2019 novel coronavirus disease (COVID-19) pandemic, many employees have switched to working from home. Despite the findings of previous research that working from home can improve productivity, the scale, nature, and purpose of those studies are not the same as in the current situation with the COVID-19 pandemic. We studied the effects that three stress relievers of the work-from-home environment-company support, supervisor's trust in the subordinate, and work-life balance-had on employees' psychological well-being (stress and happiness), which in turn influenced productivity and engagement in non-work-related activities during working hours. In order to collect honest responses on sensitive questions or negative forms of behavior including stress and non-work-related activities, we adopted the randomized response technique in the survey design to minimize response bias. We collected a total of 500 valid responses and analyzed the results with structural equation modelling. We found that among the three stress relievers, work-life balance was the only significant construct that affected psychological well-being. Stress when working from home promoted non-work-related activities during working hours, whereas happiness improved productivity. Interestingly, non-work-related activities had no significant effect on productivity. The research findings provide evidence that management's maintenance of a healthy work-life balance for colleagues when they are working from home is important for supporting their psychosocial well-being and in turn upholding their work productivity.


The relationship between estimated sodium and potassium excretion and subsequent renal outcomes.
Patients are often advised to reduce sodium and potassium intake, but supporting evidence is limited. To help provide such evidence we estimated 24 h urinary sodium and potassium excretion in 28,879 participants at high cardiovascular risk who were followed for a mean of 4.5 years in the ONTARGET and TRANSCEND trials. The primary outcome was eGFR decline of 30% or more or chronic dialysis. Secondary outcomes were eGFR decline of 40% or more or chronic dialysis, doubling of serum creatinine or chronic dialysis, an over 5%/year loss of eGFR, progression of albuminuria, and hyperkalemia. Multinomial logit regression with multivariable fractional polynomials, adjusted for confounders, determined the association between urinary sodium and potassium excretion and renal outcomes, with death as a competing risk. The primary outcome occurred in 2,052 (7.6%) patients. There was no significant association between sodium and any renal outcome (primary outcome odds ratio 0.99; 95% CI 0.89-1.09 for highest [median 6.2 g/day] vs. lowest third [median 3.3 g/day]). Higher potassium was associated with lower odds of all renal outcomes (primary outcome odds ratio 0.74; 95% CI 0.67-0.82 for highest [median 2.7 g/day] vs. lowest third [median 1.7 g/day], except hyperkalemia nonsignificant. Thus, urinary potassium, but not sodium, excretion predicted clinically important renal outcomes. Our findings do not support routine low sodium and potassium diets for prevention of renal outcomes in people with vascular disease with or without chronic kidney disease.


Plexiform neurofibroma of the tongue: a case report of a child.
A three-year-old girl with a lingual plexiform neurofibroma treated by total excision is presented. Despite their occurrence in the head and neck region, neural sheath tumors are rarely encountered in the oral cavity. It is reported that 4-7% of patients affected by neurofibromatosis display oral manifestations. Neurofibromatosis is characterized by café-au-lait spots and cutaneous neurofibromas. Plexiform neurofibroma is said to be indicative of von Recklinghausen's disease (VRD) even though it may be the only manifestation of the disease. Generally, surgical resection represents the treatment of choice and the diagnosis can only be confirmed after histological examination. Affected patients need regular follow-up to detect malignant degeneration, an early recurrence or appearance of other manifestations of VRD.


Mandatory Reporting of Intimate Partner Violence: A Mixed Methods Systematic Review.
As one of the efforts to prevent intimate partner violence (IPV) and intimate partner homicide, countries have adopted legislation requiring professionals to report cases of IPV, or suspected IPV injuries, to the police or the criminal justice system. The term for this is mandatory reporting. In spite of its good intention, mandatory reporting of IPV is a controversial issue. The objective of this review was to systematically search for, appraise the quality of, and synthetize the evidence from quantitative and qualitative studies on mandatory reporting of IPV. A systematic review of the scientific literature was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. A comprehensive search was conducted through Ovid MEDLINE, PsycINFO, Scopus, Criminal Justice Abstracts, and SveMed+. Articles were included if they (a) were peer-reviewed empirical studies rather than theories or discussions, (b) described mandatory reporting of IPV, and (c) were written in English or Scandinavian languages. No time limit was applied. Twenty-five research studies met the criteria for review. Victims were generally supportive of a law requiring professionals to report IPV, although subsamples' attitudes opposing mandatory reporting were presented as main findings in a substantial number of studies. Group differences between abused or nonabused women and knowledge about mandatory reporting of IPV among professionals was mixed and inconclusive. Few professionals had actually reported IPV under mandatory reporting. Empirical research appears to be scarce, with moderate to high degree of bias and with only limited recent development.


Proteomic analysis of conditioned media from the PC3, LNCaP, and 22Rv1 prostate cancer cell lines: discovery and validation of candidate prostate cancer biomarkers.
Early detection of prostate cancer is problematic due to the lack of a marker that has high diagnostic sensitivity and specificity. The prostate specific antigen (PSA) test, in combination with digital rectal examination, is the gold standard for prostate cancer diagnosis. However, this modality suffers from low specificity. Therefore, specific markers for clinically relevant prostate cancer are needed. Our objective was to proteomically characterize the conditioned media from three human prostate cancer cell lines of differing origin [PC3 (bone metastasis), LNCaP (lymph node metastasis), and 22Rv1 (localized to prostate)] to identify secreted proteins that could serve as novel prostate cancer biomarkers. Each cell line was cultured in triplicate, followed by a bottom-up analysis of the peptides by two-dimensional chromatography and tandem mass spectrometry. Approximately, 12% (329) of the proteins identified were classified as extracellular and 18% (504) as membrane-bound among which were known prostate cancer biomarkers such as PSA and KLK2. To select the most promising candidates for further investigation, tissue specificity, biological function, disease association based on literature searches, and comparison of protein overlap with the proteome of seminal plasma and serum were examined. On the basis of this, four novel candidates, follistatin, chemokine (C-X-C motif) ligand 16, pentraxin 3 and spondin 2, were validated in the serum of patients with and without prostate cancer. The proteins presented in this study represent a comprehensive sampling of the secreted and shed proteins expressed by prostate cancer cells, which may be useful as diagnostic, prognostic or predictive serological markers for prostate cancer.


Severe Fatal Systemic Embolism Due to Non-Bacterial Thrombotic Endocarditis as the Initial Manifestation of Gastric Adenocarcinoma: Case Report.
Nonbacterial thrombotic endocarditis (NBTE), also known as marantic endocarditis, is a rare, underdiagnosed complication of cancer, in the context of a hypercoagulable state. NBTE represents a serious complication due to the high risk of embolisation from the sterile cardiac vegetations. If these are not properly diagnosed and treated, infarctions in multiple arterial territories may occur. The case of a 47-year-old male is described. The patient was diagnosed with a gastric adenocarcinoma, in which the first clinical manifestation was NBTE. Subsequently, a hypercoagulability syndrome was associated with multi-organ infarctions, including stroke and eventually resulted in a fatal outcome. NBTE must be considered in patients with multiple arterial infarcts with no cardiovascular risk factors, in the absence of an infectious syndrome and negative blood cultures. Cancer screening must be performed to detect the cause of the prothrombotic state.


Lower extremity abnormalities in children.
Rotational and angular problems are two types of lower extremity abnormalities common in children. Rotational problems include intoeing and out-toeing. Intoeing is caused by one of three types of deformity: metatarsus adductus, internal tibial torsion, and increased femoral anteversion. Out-toeing is less common than intoeing, and its causes are similar but opposite to those of intoeing. These include femoral retroversion and external tibial torsion. Angular problems include bowlegs and knock-knees. An accurate diagnosis can be made with careful history and physical examination, which includes torsional profile (a four-component composite of measurements of the lower extremities). Charts of normal values and values with two standard deviations for each component of the torsional profile are available. In most cases, the abnormality improves with time. A careful physical examination, explanation of the natural history, and serial measurements are usually reassuring to the parents. Treatment is usually conservative. Special shoes, cast, or braces are rarely beneficial and have no proven efficacy. Surgery is reserved for older children with deformity from three to four standard deviations from the normal.


The impairing effect of acute ethanol on spreading depression is antagonized by astaxanthin in rats of 2 young-adult ages.
Ethanol (EtOH) abuse and insufficient ingestion of antioxidants are external factors that can alter brain electrophysiology. Our previous studies have demonstrated that the excitability-related brain electrophysiological phenomenon known as cortical spreading depression (CSD) was facilitated by chronic EtOH intake, and chronic treatment with carotenoids attenuated this effect. Here, we investigated the acute effect of a single EtOH administration on CSD in young and adult rats previously (1 hour) treated with 10 μg/kg of astaxanthin. Male Wistar rats (5 young- and 5 adult groups, 60 to 80 and 150 to 180 days of age, respectively) were treated by 2 gavage procedures at 1-hour interval as follows: groups 1 and 2 received astaxanthin in gavage I combined with EtOH (group 1) or water (group 2) in gavage II; groups 3 and 4 received olive oil (the vehicle in which astaxanthin was dissolved) in gavage I combined with EtOH (group 3) or water (group 4) in gavage II; group 5 received water in gavage I combined with EtOH in gavage II. CSD was recorded on the cortical surface for 4 hours. Compared to the respective water and oil controls (groups 2 and 4; CSD velocities: 3.73 ± 0.09 and 3.78 ± 0.07 mm/min in the young groups; 2.99 ± 0.10 and 3.05 ± 0.19 mm/min in the adult groups), a single dose of EtOH (groups 3 and 5) decreased CSD propagation velocities (3.29 ± 0.23 and 3.16 ± 0.10 mm/min in the young groups; 2.71 ± 0.27 and 2.75 ± 0.31 mm/min in the adult groups). Astaxanthin antagonized the impairing effect of acute EtOH on CSD (group 1; mean velocity: 3.70 ± 0.19 and 3.13 ± 0.16 mm/min for the young and adult groups, respectively). The results showed an antagonistic effect of acute EtOH treatment on CSD propagation that was reverted by astaxanthin. The EtOH-astaxanthin interaction was not influenced by the age, as it was found in both young and adult animals.


Childhood history of abuse and child abuse potential: the role of parent's gender and timing of childhood abuse.
It has been suggested that being physically abused leads to someone becoming a perpetrator of abuse which could be associated to parents' gender, timing of the physical abuse and specific socio-demographic variables. This study aims to investigate the role the parents' gender, timing of childhood abuse and socio-demographic variables on the relationship between parents' history of childhood physical abuse and current risk for children. The sample consisted of 920 parents (414 fathers, 506 mothers) from the Portuguese National Representative Study of Psychosocial Context of Child Abuse and Neglect who completed the Childhood History Questionnaire and the Child Abuse Potential Inventory. The results showed that fathers had lower current potential risk of becoming physical abuse perpetrators with their children than mothers although they did not differed in their physical victimization history. Moreover, the risk was higher in parents (both genders) with continuous history of victimization than in parents without victimization. Prediction models showed that for fathers and mothers separately similar socio-demographic variables (family income, number of children at home, employment status and marital status) predicted the potential risk of becoming physical abuses perpetrators. Nevertheless, the timing of victimization was different for fathers (before 13 years old) and mothers (after 13 years old). Then our study targets specific variables (timing of physical abuse, parents' gender and specific socio-demographic variables), which may enable professionals to select groups of parents at greater need of participating in abuse prevention programs.


Pancreatic acinar atrophy in German shepherd dogs and rough-coated collies. Etiopathogenesis, diagnosis and treatment. A review.
In pancreatic acinar atrophy (PAA) a selective destruction of digestive enzyme-producing acinar cells leads to maldigestion signs typical of exocrine pancreatic insufficiency (EPI). Although the clinical disease is well-known, the etiopathogenesis of PAA has been long remained obscure. German shepherd dogs and rough-coated Collies with PAA show similar genetic, clinical and pathological findings indicating a similar etiopathogenesis of the disease in these two breeds. In this review article the etiopathogenesis of PAA is discussed, including the current suggestion of autoimmune nature of the disease. The diagnostic methods for detection both early and end-stage exocrine pancreatic dysfunction are described, as well as the treatment options and prognosis.


Plant breeding and drought in C3 cereals: what should we breed for?
Drought is the main abiotic constraint on cereal yield. Analysing physiological determinants of yield responses to water may help in breeding for higher yield and stability under drought conditions. The traits to select (either for stress escape, avoidance or tolerance) and the framework where breeding for drought stress is addressed will depend on the level and timing of stress in the targeted area. If the stress is severe, breeding under stress-free conditions may be unsuccessful and traits that confer survival may become a priority. However, selecting for yield itself under stress-alleviated conditions appears to produce superior cultivars, not only for optimum environments, but also for those characterized by frequent mild and moderate stress conditions. This implies that broad avoidance/tolerance to mild-moderate stresses is given by constitutive traits also expressed under stress-free conditions. In this paper, we focus on physiological traits that contribute to improved productivity under mild-moderate drought. Increased crop performance may be achieved through improvements in water use, water-use efficiency and harvest index. The first factor is relevant when soil water remains available at maturity or when deep-rooted genotypes access water in the soil profile that is not normally available; the two latter conditions become more important when all available water is exhausted by the end of the crop cycle. Independent of the mechanism operating, a canopy able to use more water than another would have more open stomata and therefore higher canopy temperature depression, and 13C discrimination (delta13C) in plant matter. The same traits would also seem to be relevant when breeding for hot, irrigated environments. Where additional water is not available to the crop, higher water-use efficiency (WUE) appears to be an alternative strategy to improve crop performance. In this context delta13C constitutes a simple but reliable measure of WUE. However, in contrast to lines performing better because of increased access to water, lines producing greater biomass due to superior WUE will have lower delta13C values. WUE may be modified not only through a decrease in stomatal conductance, but also through an increase in photosynthetic capacity. Harvest index is strongly reduced by terminal drought (i.e. drought during grain filling). Thus, phenological traits increasing the relative amount of water used during grain filling, or adjusting the crop cycle to the seasonal pattern of rainfall may be useful. Augmenting the contribution of carbohydrate reserves accumulated during vegetative growth to grain filling may also be worthwhile in harsh environmcnts. Alternatively, extending the duration of stem elongation without changing the timing of anthesis would increase the number of grains per spike and the harvest index without changing the amount of water utilized by the crop.


Ureidobenzenesulfonamides as Selective Carbonic Anhydrase I, IX, and XII Inhibitors.
Sulfonamides remain an important class of drugs, especially because of their inhibitory effects on carbonic anhydrases. Herein, we have synthesized several sulfonamides and tested them for their inhibitory activity against carbonic anhydrases hCA I, hCA II, hCA IX, and hCA XII, respectively. Thereby, biphenyl- and benzylphenyl-substituted sulfonamides showed high selectivity against hCA IX and hCA XII; these enzymes are common targets in the treatment of hypoxic cancers, and noteworthy inhibitory activity was observed for several compounds toward hCA I that might be of interest for future applications to treat cerebral edema. Compound 3 (4-[3-(2-benzylphenyl)ureido]benzenesulfonamide) held an exceptionally low Ki value of 1.0 nM for hCA XII.


Gene expression profiling identifies two regulatory genes controlling dormancy and ABA sensitivity in Arabidopsis seeds.
Seed dormancy is a very important trait that maximizes the survival of seed in nature, the control of which can have important repercussions on the yield of many crop species. We have used gene expression profiling to identify genes that are involved in dormancy regulation in Arabidopsis thaliana. RNA was isolated from imbibed dormant (D) and after-ripened (AR) ecotype C24 seeds, and then screened by quantitative RT-PCR (qRT-PCR) for differentially expressed transcription factors (TFs) and other regulatory genes. Out of 2207 genes screened, we have identified 39 that were differentially expressed during the first few hours of imbibition. After analyzing T-DNA insertion mutants for 22 of these genes, two displayed altered dormancy compared with the wild type. These mutants are affected in genes that encode a RING finger and an HDZip protein. The first, named DESPIERTO, is involved in ABA sensitivity during seed development, regulates the expression of ABI3, and produces a complete loss of dormancy when mutated. The second, the HDZip (ATHB20), is expressed during seed germination in the micropylar endosperm and in the root cap, and increases ABA sensitivity and seed dormancy when mutated.


Adverse reactions of artificial bone graft substitutes: lessons learned from using tricalcium phosphate geneX®.
Artificial bone graft substitutes are widely used to fill bony defects after curettage of benign tumors. We sought to evaluate the efficacy of one such bone graft substitute, geneX®, which contains tricalcium phosphate and calcium sulphate; however, during the course of this study we observed a high number of complications. The primary aim of this prospective series was assessment of the effectiveness of geneX® concerning resorption profile and bone healing and remodeling after surgery. We present the types and frequencies of complications observed in patients treated for bone tumors by curettage and filling the defect using geneX®. We planned to study 40 patients; however, after enrollment of the first 31 patients, the study was stopped as a result of serious complications. There were 20 female and 11 male patients with a mean age at surgery of 40 years (range, 6–71 years). Plain radiographs were obtained at different intervals during followup and CT scans were obtained 6 and 12 months postoperatively. Complications were assessed using a 5-point scale according to Goslings and Gouma. Five of the 31 patients (16%) had complications develop after surgery. In three cases, a sterile inflammation adjacent to the geneX® occurred, with delayed wound healing in two patients and local pain. In the third patient, geneX® produced moderate to severe skin damage in the area of the scar, needing revision surgery. In two other patients, inflammatory cystic formations developed in the soft tissues with sizes up to 15 cm, which gradually reduced in size with time. Overall, there were four Grade 1 complications and one Grade 2 according to Goslings and Gouma. We concluded from this series of patients that geneX® causes soft tissue inflammation and pain with its use. Based on this experience we believe that this type of bone substitute should not be used in the treatment of bony defects. Level IV, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence.


Species-specific PCR for the parasitic nematodes Haemonchus contortus and Trichostrongylus colubriformis.
Reliable species determination of gastrointestinal nematode parasites from sheep is usually carried out on third-stage larvae (L3) by visual differentiation. The culturing of L3 takes about 1 week so a reliable method that could use eggs for the determination would accelerate the procedure. We developed a polymerase chain reaction (PCR), using very small amounts of parasite DNA and an oligonucleotide set according to parts of the DNA sequence of a beta-tubulin gene from Haemonchus contortus, that can discriminate H. contortus DNA and Trichostrongylus colubriformis DNA from each other and from several other sheep nematode parasites. This method can be used for every stage of the parasite, including eggs. For the first time a PCR method is reported to discriminate between sheep nematode parasites.


Fear of cancer recurrence and associations with mental health status and individual characteristics among cancer survivors: Findings from a nationally representative sample.
Purpose: To describe the prevalence of fear of cancer recurrence (FCR) and test its associations with validated mental health status measures.Design: Cross-sectional survey using the Medical Expenditure Panel Survey Experiences with Cancer Survivorship Supplement.Sample: Post-treatment cancer survivors (n = 1032).Methods: Survey-weighted U.S. population-based estimates describe the prevalence of sociodemographic, health and mental health characteristics of cancer survivors by their level of FCR. Multinomial logistic regression was used to test associations of validated measures of mental health status and individual characteristics on levels of FCR in unadjusted models and those controlling for sociodemographic and health characteristics.Findings: Overall, 34.3% of cancer survivors reported no FCR, 54.4% reported low FCR, and 11.3% reported high FCR. Cancer survivors were at increased risk of reporting high FCR relative to no FCR if they had a low 12-item Short Form Health Survey Mental Component Summary score (≤48) compared to high scores (odds ratio = 2.88; 95% confidence interval = 1.57, 5.29). Reporting depressive symptoms or psychological distress did not significantly increase the risk of reporting high or low FCR relative to no FCR.Conclusions: To our knowledge, this study is the first to provide U.S. population-based estimates of associations between FCR and individual and health characteristics.Implications for Psychosocial Providers or Policy: Our results provide valuable information about which survivors are most at-risk for FCR. Future research is needed to more clearly differentiate FCR from other constructs.


Preoperative study of the surface ECG for the prognosis of atrial fibrillation maze surgery outcome at discharge.
The Cox-maze surgery is an effective procedure for terminating atrial fibrillation (AF) in patients requiring open-heart surgery associated with another heart disease. After the intervention, regardless of the patient's rhythm, all are treated with oral anticoagulants and antiarrhythmic drugs prior to discharge. Furthermore, patients maintaining AF before discharge could also be treated with electrical cardioversion (ECV). In view of this, a preoperative prognosis of the patient's rhythm at discharge would be helpful for optimizing drug therapy planning as well as for advancing ECV therapy. This work analyzes 30 preoperative electrocardiograms (ECGs) from patients suffering from AF in order to predict the Cox-maze surgery outcome at discharge. Two different characteristics of the AF pattern have been studied. On the one hand, the atrial activity (AA) organization, which provides information about the number of propagating wavelets in the atria, was investigated. AA organization has been successfully used in previous studies related to spontaneous reversion of paroxysmal AF and to the outcome of ECV. To assess organization, the dominant atrial frequency (DAF) and sample entropy (SampEn) have been computed. On the other hand, the second characteristic studied was the fibrillatory wave (f-wave) amplitude, which has been demonstrated to be a valuable indicator of the Cox-maze surgery outcome in previous studies. Moreover, this parameter has been obtained through a new methodology, based on computing the f-wave average power (fWP). Finally, all the computed indices were combined in a decision tree in order to improve prediction capability. Results for the DAF yielded a sensitivity (Se), a specificity (Sp) and an accuracy (Acc) of 61.54%, 82.35% and 73.33%, respectively. For SampEn the values were 69.23%, 76.00% and 73.33%, respectively, and for fWP they were 92.31%, 82.35% and 86.67%, respectively. Finally, the decision tree combining the three parameters analyzed improved the preoperative prognosis of the Cox-maze outcome with values of Se, Sp and Acc of 100%, 82.35% and 90%, respectively. As a consequence, the analysis of parameters related to the f-wave pattern, extracted from the preoperative ECG, has provided a considerable ability to predict the outcome of AF Cox-maze surgery at discharge.


Arylazide photoaffinity probe for alpha 2-adrenoceptors.
An arylazide photoaffinity probe for alpha 2-adrenoceptors has been developed and characterized. The compound, 3-methyl-6-chloro-9-azido-1H-2,3,4,5-tetrahydro-3-benzazepine (SKF 102229), had a Ki for the human platelet alpha 2-adrenoceptor of approximately 40 nM. Upon exposure to ultraviolet light, SKF 102229 irreversibly blocked the binding of [3H]yohimbine to both membrane bound and solubilized, partially purified, receptors. The extent of alpha 2-adrenoceptor blockade was dependent upon both the length of exposure to ultraviolet light and the concentration of SKF 102229. Typically, a 60% decrease in alpha 2-adrenoceptor number is obtained following 8 min of photolysis in the presence of 100 nM SKF 102229. The pharmacologic characteristics of the irreversible blockade produced by SKF 102229 were those of an alpha 2-adrenoceptor. Thus, photodependent, irreversible blockade of alpha 2-adrenoceptors by SKF 102229 was prevented by the concomitant presence of phentolamine or p-aminoclonidine but not by prazosin. Given its specificity and efficient blockade of the ligand binding site, SKF 102229 should prove useful for studies of the structure and function of alpha 2-adrenoceptors.


Design, synthesis, and study of main chain poly(n-heterocyclic carbene) complexes: applications in electrochromic devices.
A series of poly(N-heterocyclic carbene) complexes in which the carbene functionalities are orthogonally connected to the main chains of the respective polymers have been synthesized via oxidative electropolymerization of various bis(bithiophene)-substituted monomers with appended transition metal or main group entities (M = Ir, Au, Ag, or S). The polymers were characterized using a range of electrochemical, X-ray photoelectron spectroscopy, UV-vis spectroscopy, profilometry, and four-point probe conductivity measurements. Most of the polymers exhibited an intense absorbance wave at 700 nm under oxidative conditions which was attributable to the formation of polarons along the main chains. The iridium-containing thin film poly(8) was found to possess a significant NIR absorbance at 1100 nm in which the metal moiety effectively functioned as an electron sink. Electrochemical analyses of the polymer thin films revealed that they exhibited highly reversible electrochromic phenomena.


A fuzzy operator for the enhancement of blurred and noisy images.
Rule-based fuzzy operators are a novel class of operators specifically designed in order to apply the principles of approximate reasoning to digital image processing. This paper shows how a fuzzy operator that is able to perform detail sharpening but is insensitive to noise can be designed. The results obtainable by the proposed technique in the enhancement of a real image are presented.


Development and application of monoclonal antibody-based dot-ELISA and colloidal gold immunochromatographic strip for rapid, specific, and sensitive detection of tomato brown rugose fruit virus.
Tomato brown rugose fruit virus (ToBRFV) is an emerging tobamovirus that has become a great concern to tomato production industry. Due to the lack of resistant cultivars, precise detection of ToBRFV is essential to prevent the spread of ToBRFV. In this study, we produced highly sensitive and specific monoclonal antibodies against ToBRFV and established dot-enzyme-linked immunosorbent assay (dot-ELISA) and colloidal gold immunochromatographic strip (CGICS)-based methods for ToBRFV detection. These two methods could specifically detect ToBRFV without cross-reaction with seven tested tobamoviruses and three frequently occurring tomato-infecting viruses. Sensitivity analysis showed that the limit of detection of the established dot-ELISA and CGICS methods reached up to 1:6400 and 1:10,000 (w/v, g/mL) dilution of ToBRFV-infected tomato tissue, respectively. Further analyses using field-collected tomato foliar and fruit samples showed that the results obtained by dot-ELISA and CGICS were consistent with those obtained by reverse transcription polymerase chain reaction. The established methods here allow for specific, sensitive, and robust detection of ToBRFV, and will be helpful for precise monitoring and early warning of ToBRFV.


Defect-free network formation and swelling behavior in ionic liquid-based electrolytes of tetra-arm polymers synthesized using a Michael addition reaction.
The gelation mechanism of tetra-arm poly(ethylene glycol) (TetraPEG) prepolymers via a Michael addition reaction was investigated from the viewpoint of chemical reaction kinetics. The polymer network was formed by mixing two different TetraPEGs functionalized with maleimide and thiol terminal groups (TetraPEG-MA and TetraPEG-SH) in aqueous solutions, and the gelation rate was strongly dependent on the solution pH. We found that the gelation reaction can be a second-order reaction when the acid-base equilibrium of the terminal SH groups (-SH ⇆ -S- + H+) was taken into account, resulting in a quantitative estimation of the rate constant (kgel) in the current polymer solution system. Based on the kgel value, the network connectivity (p), which corresponds to efficiency at the linking point, was evaluated to be p > 95% at the end of the reaction; thus, the resulting TetraPEG hydrogels have a homogeneous polymer network without network defects. We used the TetraPEG network as a polymer matrix in a lithium-ion battery gel electrolyte: dried TetraPEG gels were swollen with ionic liquid-based electrolytes containing Li salts to prepare TetraPEG ion gel electrolytes. Swelling behaviors of the TetraPEG network were characterized from the swelling rate and the equilibrium swelling ratio, and we found that these swelling behaviors were significantly affected by the Li-ion component. We concluded that an intermolecular interaction between Li-ions and the polymer (Li-ion coordination with the O atoms within the PEG chains) plays a key role in the fundamental physical properties of the gel electrolyte.


Cytological effects of honokiol treatment and its potential mechanism of action in non-small cell lung cancer.
In this study, we aimed to explore key micro(mi)RNAs and their potential regulatory mechanisms induced by honokiol treatment in non-small cell lung cancer (NSCLC) cells. NSCLC A549 cells were treated with 0 (control) or 45 μM honokiol. Cell proliferation and migration were determined using CCK-8 and transwell assay, respectively, and apoptosis was determined using flow cytometry. RNA-sequencing was performed to detect the transcript expression levels. The differentially expressed miRNAs (DE-miRNAs) between the honokiol group and the control group were screened and analyzed for their functions and pathways. Then, protein-protein interaction (PPI) networks and miRNA-mRNA regulatory networks were constructed. In addition, survival analysis based on the key miRNAs was performed. Finally, the expression of the key miRNAs and their target genes were determined, and their effects on drug sensitivity were validated using their inhibitors. Cell proliferation and migration were inhibited (P < 0.01), and the apoptosis rate was increased (P < 0.01) after honokiol treatment compared to that in the control group. A total of 26 upregulated and 20 downregulated DE-miRNAs were screened. DE-miRNAs were enriched in 10 pathways and 48 biological processes, such as the PI3K/AKT signaling pathway (involving miR-148a-3p). The miRNA-mRNA regulatory networks involved eight upregulated (including miR-148a-3p and let-7c-5p) and seven downregulated miRNAs (including miR-7-5p) and 190 target mRNAs. Survival analysis revealed that let-7c-5p, miR-148a-3p, and miR-148a-5p levels correlated with NSCLC prognosis. The expression of let-7c-5p, miR-148a-3p, and miR-148a-5p was significantly increased and negatively correlated with the expression of their target genes. The cytological effects of honokiol on A549 cells was partly reversed by treatment with the inhibitors of Let-7c-5p and miR-148a-3p. Let-7c-5p, miR-148a-3p, miR-148a-5p, and miR-7-5p are favorable indicators of NSCLC patients treated with honokiol.


Effect of homologous and heterologous seminal plasma on the fertilizing ability of ejaculated bull spermatozoa assessed by penetration of zona-free bovine oocytes.
The ability of seminal plasma to influence the fertility of ejaculated bull spermatozoa was examined using a sperm penetration assay for zona-free bovine oocytes. Washed, ejaculated spermatozoa from bulls of below (low) or above average (high) fertility were mixed with seminal plasma from the same bull, or with seminal plasma from a bull of contrasting fertility. Treated spermatozoa were stained with different fluorochromes and competed to penetrate oocytes after heterospermic insemination in vitro. Washed spermatozoa exposed to seminal plasma from bulls of high fertility penetrated more oocytes than those spermatozoa mixed with seminal plasma from bulls of low fertility (P < 0.01). Mixing low fertility spermatozoa with high fertility seminal plasma generally improved penetrating ability compared with low fertility spermatozoa mixed with low fertility seminal plasma (P = 0.05). Washed spermatozoa from a bull of low fertility mixed with his own seminal plasma had greater ability to penetrate oocytes than did washed spermatozoa from a bull of high fertility mixed with seminal plasma from a bull of low fertility (P < 0.01). The bias associated with using low fertility seminal plasma from the bull providing the spermatozoa was removed by repeating this experiment using pooled seminal plasma from different subfertile bulls. After combination with pooled seminal plasma from bulls of low fertility spermatozoa from bulls of high or low fertility penetrated oocytes in a similar way, but high fertility spermatozoa had a slightly higher penetration rate (P = 0.12). In conclusion, the penetration of zona-free oocytes by ejaculated spermatozoa from bulls of low fertility was marginally improved by seminal plasma from bulls of high fertility, but penetration by high fertility spermaotoza was decreased by exposure to low fertility seminal plasma. Seminal plasma from bulls of low fertility similarly affected the penetrating ability of high and low fertility spermatozoa if the seminal plasma used was foreign to the spermatozoa being tested.


Arthroscopic psoas release for iliopsoas impingement after total hip replacement.
Psoas impingement is a rare cause of persisting pain after hip arthroplasty. Diagnosis is based on clinical examination and exclusion of other complications after arthroplasty by radiographs, ultrasound, CT and blood analysis. The diagnosis is strongly supported by temporary pain relief after infiltration. When conservative measures fail, treatment can consist of a psoas tenotomy or a revision arthroplasty. When there is no obvious cause such as malpositioning for component impingement, psoas release reliably improves pain and function. This procedure is mostly performed through an open approach, which can give significant complications. An arthroscopic technique for psoas tenotomy after hip arthroplasty is described. This report shows that this minimal invasive technique is safe and effective and allows for inspection of the implant in the same session. However, the score used did not improve in a significant way.


Association of active and passive smoking with risk of breast cancer among postmenopausal women: a prospective cohort study.
To examine the association between smoking and risk of invasive breast cancer using quantitative measures of lifetime passive and active smoking exposure among postmenopausal women. Prospective cohort study. 40 clinical centres in the United States. 79,990 women aged 50-79 enrolled in the Women's Health Initiative Observational Study during 1993-8. Self reported active and passive smoking, pathologically confirmed invasive breast cancer. In total, 3520 incident cases of invasive breast cancer were identified during an average of 10.3 years of follow-up. Compared with women who had never smoked, breast cancer risk was elevated by 9% among former smokers (hazard ratio 1.09 (95% CI 1.02 to 1.17)) and by 16% among current smokers (hazard ratio 1.16 (1.00 to 1.34)). Significantly higher breast cancer risk was observed in active smokers with high intensity and duration of smoking, as well as with initiation of smoking in the teenage years. The highest breast cancer risk was found among women who had smoked for ≥ 50 years or more (hazard ratio 1.35 (1.03 to 1.77) compared with all lifetime non-smokers, hazard ratio 1.45 (1.06 to 1.98) compared with lifetime non-smokers with no exposure to passive smoking). An increased risk of breast cancer persisted for up to 20 years after smoking cessation. Among women who had never smoked, after adjustment for potential confounders, those with the most extensive exposure to passive smoking (≥ 10 years' exposure in childhood, ≥ 20 years' exposure as an adult at home, and ≥ 10 years' exposure as an adult at work) had a 32% excess risk of breast cancer compared with those who had never been exposed to passive smoking (hazard ratio 1.32 (1.04 to 1.67)). However, there was no significant association in the other groups with lower exposure and no clear dose response to cumulative passive smoking exposure. Active smoking was associated with an increase in breast cancer risk among postmenopausal women. There was also a suggestion of an association between passive smoking and increased risk of breast cancer.


[Assessment of antibodies anti-saccharomyces cerevisiae (ASCA) and autoantibodies in patients with inflammatory bowel disease].
The incidence of inflammatory bowel disease (IBD) has been increasing worldwide, and despite the advances regarding their pathogenesis and therapeutics, the differential diagnosis between Crohn's Disease (CD) and Ulcerative Colitis (UC) is mainly based on clinically invasive tests. Recent studies have identified new serological markers with a potential value for the diagnosis of these pathologies, in particular the anti-Saccharomyces cerevisiae antibodies (ASCA) and anti-neutrophil cytoplasmic antibodies (ANCA). Also of note are the anti-goblet cells antibodies (anti-CCI) and the anti-pancreatic exocrine autoantibodies that react with the pancreatic acinus (anti-AP). We assessed these new serological markers and compared the efficiency between immune enzymatic (ELISA) and indirect immunofluorescence tests in the identification of ASCA of IgG or IgA class. We studied a set of 81 serum samples (with an initial diagnosis of IBD) and 33 control samples from healthy blood donors. The laboratory tests were correlated with the diagnosis of each patient, established in the Gastroenterology outpatient unit based on conventional methods. The agreement between the two laboratory methods employed in the identification of the ASCA was excellent (k = 0.63) for the IgG antibodies and good (k = 0.56) for the IgA antibodies. We found a weak agreement (k = 0.137) between ELISA (MPO and PR3 purified antigens) and the IFA test for ANCA. Regarding the serologic markers ANCA, anti-AP and anti-CCI, only the later showed no differences in the distribution of positive results between the studied groups. Positive ASCA IgG and IgA were significantly associated with diagnosis of DC, with both laboratorial methods tested. The identification of ANCA with the available solidphase tests does not seem appropriate for the screening of the autoantibodies with the atypical p-ANCA pattern of IBD. The combination between anti-AP and ASCA antibodies seems a good option for the laboratorial diagnosis of CD. This study shows that these serologic markers in spite of being non invasive laboratory tests, also have a considerable overlapping in the different IBD. Nevertheless, further prospective studies based on larger populations are required to clarify the relationship between these antibodies, the diagnosis and clinical evolution of inflammatory bowel disease.


Genes differentially expressed in Theobroma cacao associated with resistance to witches' broom disease caused by Crinipellis perniciosa.
SUMMARY The basidiomycete Crinipellis perniciosa is the causal agent of witches' broom disease of Theobroma cacao (cocoa). Hypertrophic growth of infected buds ('brooms') is the most dramatic symptom, but the main economic losses derive from pod infection. To identify cocoa genes differentially expressed during the early stages of infection, two cDNA libraries were constructed using the suppression subtractive hybridization (SSH) approach. Subtraction hybridization was conducted between cDNAs from infected shoot-tips of the susceptible genotype 'ICS 39' and the resistant 'CAB 214', in both directions. A total of 187 unique sequences were obtained, with 83 from the library enriched for the susceptible 'ICS 39' sequences, and 104 for the resistant 'CAB 214'. By homology search and ontology analyses, the identified sequences were mainly putatively categorized as belonging to 'signal transduction', 'response to biotic and abiotic stress', 'metabolism', 'RNA and DNA metabolism', 'protein metabolism' and 'cellular maintenance' classes. Quantitative reverse transcription amplification (RT-qPCR) of 23 transcripts identified as differentially expressed between genotypes revealed distinct kinetics of gene up-regulation at the asymptomatic stage of the disease. Expression induction in the susceptible 'ICS 39' in response to C. perniciosa was delayed and limited, while in 'CAB 214' there was a quicker and more intense reaction, with two peaks of gene induction at 48 and 120 h after inoculation, corresponding to morphological and biochemical changes previously described during colonization. Similar differences in gene induction were validated for another resistant genotype ('CAB 208') in an independent experiment. Validation of these genes corroborated similar hypothetical mechanisms of resistance described in other pathosystems.


A pilot trial of the anti-angiogenic copper lowering agent tetrathiomolybdate in combination with irinotecan, 5-flurouracil, and leucovorin for metastatic colorectal cancer.
Tetrathiomolybdate (TM) is an oral copper chelator under development as an anti-angiogenic agent. We evaluated TM in combination with irinotecan, 5-fluorouracil, and leucovorin (IFL). Serum vascular endothelial growth factor (VEGF), basic fibroblast growth factor, interleukin 6 (IL-6), and IL-8 were measured to evaluate the anti-angiogenic effect. Twenty-four patients with metastatic colorectal cancer were treated. The combination with IFL was well tolerated and dose intensity of IFL was maintained during combination therapy with TM. By intention to treat analysis, the overall response rate (RR) was 25% (95% CI 9.8-46.7) and the median time to progression (TTP) was 5.6 months (95% CI 2.7-7.7). VEGF levels were correlated with TTP, as were changes in VEGF, IL-8, and IL-6. TM can be safely added to IFL without compromising dose intensity or diminishing the expected RR. Changes in serum VEGF, IL-8, and IL-6 after treatment may directly reflect changes in CRC tissue angiogenesis.


A controlled social skills training for children with fetal alcohol spectrum disorders.
Children with fetal alcohol spectrum disorders (FASD) have significant social skills deficits. The efficacy of a child friendship training (CFT) versus a delayed treatment control (DTC) was assessed for 100 children ages 6 to 12 years with FASD. Children in the CFT showed clear evidence of improvement in their knowledge of appropriate social behavior, and according to parent report, CFT resulted in improved social skills and fewer problem behaviors compared with DTC. Gains were maintained at 3-month follow-up. After receiving treatment, the DTC group exhibited similar improvement. Teachers did not report improvement as a function of social skills treatment. The findings suggest that children with FASD benefit from CFT but that these social skills gains may not be observed in the classroom.


[Impact of weight-related discrimination on eating disorder and general psychopathology in children and adolescents with and without migration background].
Children and adolescents, especially those of higher weight, often suffer from perceived weight-related discrimination. Goal of the present study is to examine the association between weight-related teasing and eating disorder as well as general psychopathology in a sample of 367 normal- and overweight students with and without migration background. Results show that youth with and without migration background did not differ in frequency of weight-related teasing-experiences. Frequently teased youth reported increased psychopathology, independent of migration background. Additionally, weight-related teasing could be identified as a mediator between weight status and disorderd eating as well as a predictor for depressiveness. Findings emphasize the need to take weight-related teasing into consideration in prevention and therapy.


WS2 nanosheets functionalized by biomimetic lipids with enhanced dispersibility for photothermal and chemo combination therapy.
Multi-component combination therapy of cancer is currently a hot spot in the field of cancer treatment research. In this study, a WS2 nanosheet was selected as the substrate material and modified with a cell-like membrane biomimetic liposome (WS2-lipid). The lipid-modified WS2 nanomaterials were successfully prepared with good stability and biocompatibility. Its good photothermal characteristics and high drug loading amount were utilized to achieve a comprehensive chemo and photothermal therapeutic effect. The results showed that the lipid coating strongly enhanced the stability of the WS2 nanosheets before and after DOX loading and the WS2-lipid had a good photothermal performance and drug loading amount. According to the cellular results, WS2-lipid was able to be taken up by MCF-7 cells. Both photothermo-therapy and chemotherapy had a concentration dependent cytotoxicity on MCF-7 cells, and the combined application of both methods had an improved cytotoxicity. In addition, in vivo photothermal experiments indicated that lipid modification could promote intratumoral accumulation of the material. Thus, WS2-lipid can be used as a good nano-platform for phototherapy and chemotherapy combination therapy and has good application prospects in cancer therapy.


Kinetic behavior of three preparations of alpha-tocopherol after oral administration to postpubertal heifers.
To assess the kinetic behavior of 3 preparations of alpha-tocopherol (vitamin E) after oral administration to heifers. 8 postpubertal Friesian heifers. A single oral bolus of 5,000 U of alpha-tocopherol in oil or encapsulated in liposomes or cyclodextrin was administered to each cow, using a 4 X 4 design with 8 days between treatments. Blood samples for kinetic analyses were obtained at various times for 168 hours after treatment. Mean (+/- SEM) maximal plasma concentrations of alpha-tocopherol were 4.86 +/- 0.49 microg/ml, 5.03 +/- 0.39 microg/ml, and 5.08 +/- 0.56 microg/ml after administration of oil, liposomal, and cyclodextrin preparations, respectively. Plasma concentrations peaked 21 to 34 hours after administration. The disappearance rate constant (Kd) was less after administration of alpha-tocopherol encapsulated in liposomes, compared with the other 2 preparations. Area under the concentration versus time curve was greater after administration of either encapsulated form of alpha-tocopherol, compared with alpha-tocopherol in oil, but these differences were not significant. The lower Kd determined for alpha-tocopherol encapsulated in liposomes suggests that this formulation may result in longer persistance of the vitamin in plasma than the other 2 preparations. Dietary supplementation with alpha-tocopherol encapsulated in liposomes may enhance plasma availability of this vitamin in cattle and could be useful during periods of increased vitamin E requirements, such as parturition and early stages of life.