[The prevalence of atrophic gastritis and intestinal metaplasia according to gender, age and Helicobacter pylori infection in a rural population].
The objective of this study was to evaluate the prevalence of atrophic gastritis and intestinal metaplasia according to gender, age and Helicobacter pylori infection in a rural population in Korea. Between April 2003 and January 2007, 713 subjects (298 men and 415 women, age range: 18-85) among the 2,161 adults who participated in a population-based survey received gastrointestinal endoscopy. All the subjects provided informed consent. Multiple biopsy specimens were evaluated for the presence of atrophic gastritis and intestinal metaplasia. The presence of Helicobacter pylori was determined using CLO and histology testing. The age-adjusted prevalence of atrophic gastritis was 42.7% for men and 38.1% for women and the prevalence of intestinal metaplasia was 42.5% for men and 32.7% for women. The prevalence of atrophic gastritis and intestinal metaplasia increased significantly with age for both men and women (p for trend<0.001). The age-adjusted prevalence of Helicobacter pylori was similar for men (59.0%) and women (56.7%). The subjects with Helicobacter pylori infection showed a significantly higher prevalence of intestinal metaplasia (44.3%) compared with that (26.8%) of the noninfected subjects (p<0.001). However, the prevalence of atrophic gastritis was not statistically different between the Helicobacter pylori-infected subjects and the noninfected individuals. Our findings suggest that the prevalence of atrophic gastritis and intestinal metaplasia is higher for a Korean rural population than that for a Western population; this may be related to the high incidence of gastric cancer in Koreans. Especially, the prevalence of intestinal metaplasia was high for the subjects with Helicobacter pylori infection. The multistep process of gastric carcinogenesis and the various factors contributing to each step of this process need to be determined by conducting future follow-up studies.


RNA-sequencing and microarray data mining revealing: the aberrantly expressed mRNAs were related with a poor outcome in the triple negative breast cancer patients.
Triple negative breast cancer (TNBC) account for about 20% of breast carcinomas and the American society of clinical oncology guidelines does not specify approaches for TNBC patients since lack of specific driver molecules and targeted drugs. We filtered out the aberrantly expressed mRNAs on the basis of RNA-seq data deposited in the Gene Expression Omnibus database, and verified and deeply analyzed screened differentially expressed genes (DEGs) using a combined bioinformatics approach. Of 21,755 genes with 472 TNBC cases from 3 independent laboratories, 159 mRNAs were identified as DEGs. To verify our results, we assessed the expression levels of top 8 DEGs in Oncomine database. The hierarchical clustering analysis, functional and pathway enrichment analysis were carried out for all DEGs. The results reveal that N-acetyltransferase 1 (NAT1) is most obvious of expression change's gene. Protein-protein interaction (PPI) network construction of 159 DEGs selected 3 hub genes: desmoglein 3 (DSG3), family with sequence similarity 83 member D (FAM83D) and GATA binding protein 3 (GATA3). For further analysis of the potential role of NAT1 in TNBC, the co-expression profiles of NAT1 in BC were made out, and we found that there are 5 genes [GATA3, trefoil factor 3 (TFF3), forkhead box A1 (FOXA1), signal peptide, CUB domain and EGF like domain containing 2 (SCUBE2), G protein-coupled receptor 160 (GPR160)] which co-expressed with NAT1 also were DEGs that we screened out before. Co-occurrence analysis confirmed that same as DEGs, GATA3 and SCUBE2 co-expressed with NAT1, and had a tendency towards a co-occurrence with NAT1 in TNBC. The survival curves showed that NAT1, GATA3 and SCUBE2 expression are significantly related with prognosis. From all above results, we speculate that NAT1, GATA3 and SCUBE2 play a vital role in TNBC.


Acquired von Willebrand syndrome: experience from 2 years in a single laboratory compared with data from the literature and an international registry.
Acquired von Willebrand syndrome (avWS) has gained more attention during the last years. An International Registry has been compared with the literature. It could be shown that the data collected from 123 publications compared well with the data from the registry, albeit with differences in the number of patients suffering from lymphoproliferative diseases and cardiovascular disorders, that were more prominent in the registry and the group of miscellaneous conditions underrepresented in the registry. Our data are clearly different for the lymphoproliferative diseases with only four patients in 2 years. These patients usually suffer from severe bleeding complications together with low to very low factor VIII/von Willebrand factor (FVIII/vWF) concentrations and thus will not go undiagnosed. In contrast to this, patients with cardiovascular disorders usually bleed only during surgical procedures or catheter procedures. At that time they have increased vWF parameters. Because of this and because the acute bleeding is of limited duration and usually not life threatening, many of them are discharged without a proper diagnosis and are only rarely referred to a specialized diagnostic work-up thereafter. In conclusion, avWS, although not a frequent disease, is nevertheless clearly underdiagnosed. This should be addressed in future prospective studies.


Association between functional psychosis and expanded CAG/CTG repeats is not explained by health stratification.
A number of studies have reported an association between large CAG/CTG repeats and both schizophrenia and bipolar disorder. Recently, we reported an inverse correlation between CAG/CTG repeat size and age in a health-selected population, raising the possibility that selection of control groups for physical health was a confounding factor in our previous association studies. We investigated this by health-selection of patients with schizophrenia and bipolar disorder. The maximum CAG/CTG repeat size remained significantly larger in probands with functional psychosis compared with control individuals, and in probands with a diagnosis of schizophrenia compared with control individuals. The number of probands in the healthy bipolar group was small, and although on average this group also had longer CAG/CTG repeats than control individuals, this failed to reach statistical significance. Our findings do not support the notion that the original results with psychosis as a whole, and schizophrenia specifically, are attributable to a stratification effect consequent on health selection. Nevertheless, we are unable formally to reject the hypothesis that the previously observed difference between bipolar probands and control individuals is the result of this phenomenon.


Combinations of Photodynamic Therapy with Other Minimally Invasive Therapeutic Technologies against Cancer and Microbial Infections.
The rapid rise in research and development following the discovery of photodynamic therapy to establish novel photosensitizers and overcome the limitations of the technology soon after its clinical translation has given rise to a few significant milestones. These include several novel generations of photosensitizers, the widening of the scope of applications, leveraging of the offerings of nanotechnology for greater efficacy, selectivity for the disease over host tissue and cells, the advent of combination therapies with other similarly minimally invasive therapeutic technologies, the use of stimulus-responsive delivery and disease targeting, and greater penetration depth of the activation energy. Brought together, all these milestones have contributed to the significant enhancement of what is still arguably a novel technology. Yet the major applications of photodynamic therapy still remain firmly located in neoplasms, from where most of the new innovations appear to launch to other areas, such as microbial, fungal, viral, acne, wet age-related macular degeneration, atherosclerosis, psoriasis, environmental sanitization, pest control, and dermatology. Three main value propositions of combinations of photodynamic therapy include the synergistic and additive enhancement of efficacy, the relatively low emergence of resistance and its rapid development as a targeted and high-precision therapy. Combinations with established methods such as chemotherapy and radiotherapy and demonstrated applications in mop-up surgery promise to enhance these top three clinical tools. From published in vitro and preclinical studies, clinical trials and applications, and postclinical case studies, seven combinations with photodynamic therapy have become prominent research interests because they are potentially easily applied, showing enhanced efficacy, and are rapidly translating to the clinic. These include combinations with chemotherapy, photothermal therapy, magnetic hyperthermia, cold plasma therapy, sonodynamic therapy, immunotherapy, and radiotherapy. Photochemical internalization is a critical mechanism for some combinations.


Measurement of testicular volume in Wistar rats using a caliper and ultrasonography in experimental surgery.
To compare the measurement of the testicular volume of Wistar rats using a caliper and ultrasonography. Forty Wistar rats were randomly assigned into four groups. A tensile force of 1.6 Newton (N) and 1.0 N was applied to the right spermatic cord in group I and group II, respectively. Group III was the sham group, and group IV served as a control. The initial and final testicular volumes were measured using a caliper and ultrasonography and compared. A significance level of 5% was used. The Kappa coefficient was equal to 0.292 (p = 0.006). The Pearson correlation coefficient obtained for the percent reduction in the right testicular volume using ultrasonography and a caliper was equal to 0.696 (p < 0.001). There was reasonable agreement and a significant positive correlation between the percent reduction in the right testicular volume using ultrasonography and a caliper.


Colon cancer-induced interleukin-35 inhibits beta-catenin-mediated pro-oncogenic activity.
The occurrence and development of colon cancer is closely related to inflammation. Therefore, this study was conducted a current retrospective research to study the effect of IL-35 (interleukin 35), a newly identified anti-infective factor, on colon cancer development. The expression of IL-35 in colon cancer samples and their adjacent normal mucosa by real-time PCR, ELISA (enzyme-linked immunosorbent assay). The effect of IL-35 on patient survival, colon cancer progression, and its effect on Wnt/β-catenine signaling pathway was also assessed. IL-35 is minimally expressed in colon cancer tissues but is highly expressed in adjacent normal tissues. The down-regulation of IL-35 was significantly associated with the American Cancer Joint Committee stage and overall survival of colon cancer patients. The overexpression of IL-35 in colon cancer cells inhibits cell migration, invasion, proliferation, colony formation and cancer stem cells by inhibiting beta-catenin. IL-35 inhibits colon neoplasms in mouse. Our results suggest that IL-35 has an inhibitory effect on the development of colon cancer as a novel prognostic indicator and potential therapeutic target.


Total fumonisins are reduced in tortillas using the traditional nixtamalization method of mayan communities.
Fumonisin B1 (FB1) is a maize mycotoxin. In tortilla preparation, maize is treated with lime (nixtamalization), producing hydrolyzed FB1 (HFB1) due to loss of the tricarballylic acid side chains. This study determined the following: 1) whether nixtamalization by Mayan communities reduces total fumonisins, and 2) the steps in the process at which reduction occurs. Tortillas prepared by the traditional process contained FB1, FB2 and FB3 and their hydrolyzed counterparts. There were equimolar amounts of FB1 and HFB1 in the tortillas, but the total fumonisins were reduced 50%. The total FB1 plus HFB1 in the residual lime water and water washes of the nixtamal accounted for 50% of the total FB1 in the uncooked maize. HFB1 and FB1 were present in a 1:1 mol/L ratio in the water washes of the nixtamal, the masa dough and the cooked tortillas, whereas the ratio of HFB1:FB1 in lime water after steeping was 21. Water washes contained 11% of the FB1 that was in the uncooked maize. The results show that the traditional method reduced the total fumonisins in tortillas and reduced the sphinganine elevation (a biomarker closely correlated with fumonisin toxicity) in cells treated with extracts of tortillas compared with cells treated with extracts of contaminated maize.


Application of a conceptual framework for distance learning in dental hygiene education and allied health disciplines.
Distance education (DE) and distance learning (DL) technologies use continues to experience exponential, global growth. Various DE delivery platforms are being used for dental hygiene and allied health programs offered in post-secondary education. However, a need exists to analyze factors of program and student success using DL modalities. Administrators and educators should consider building educational programs on sound pedagogical principles when using DL for their delivery mechanism. This paper offers an applied conceptual framework as a model when developing DE/DL programs for preparing professionals in dental hygiene and allied health careers.


Prophylactic antiepileptic treatment in Sturge-Weber disease.
In Sturge-Weber disease, motor and cognitive defects are supposed to result mostly from severe epilepsy. They might, therefore be partly prevented by prophylactic antiepileptic drug treatment. This condition constitutes a possible model for the study of prophylactic drug treatment in severe epilepsy. In the present study, we compared the outcome of patients treated prospectively with phenobarbitone before the first seizure, with those referred following the first seizure, in order to identify the issues related to the evaluation of prophylactic treatment of severe epilepsy. Motor and cognitive outcome were compared in patients treated prophylactically with phenobarbitone (16 cases) and in those treated following the first seizures (21 cases). Whereas the incidence of motor deficit was similar in both groups (44 vs. 52%), that of mental retardation was lower in the group treated prophylactically (76.2 vs. 43.7%, P< 0.05). The major methodological issues encountered included the small number of patients identified at birth that could be included in the study, the need for randomization taking into account the size of the angioma, and the choice of the prophylactic medication, including the occurrence of epilepsy together with the course of motor and cognitive functions among the endpoints. Prophylactic anti-epileptic drug treatment is worth considering for Sturge-Weber disease, but a randomized prospective study is necessary to determine this. It should be multicentric, take in account the size of the angioma, and decide what the most appropriate medication should be.


Certainties and Uncertainties of Cardiac Magnetic Resonance Imaging in Athletes.
Prolonged and intensive exercise induces remodeling of all four cardiac chambers, a physiological process which is coined as the "athlete's heart". This cardiac adaptation, however, shows overlapping features with non-ischemic cardiomyopathies, such as dilated, arrhythmogenic and hypertrophic cardiomyopathy, also associated with athlete's sudden cardiac death. Cardiac magnetic resonance (CMR) is a well-suited, highly reproducible imaging modality that can help differentiate athlete's heart from cardiomyopathy. CMR allows accurate characterization of the morphology and function of cardiac chambers, providing full coverage of the ventricles. Moreover, it permits an in-depth understanding of the myocardial changes through specific techniques such as mapping or late gadolinium enhancement. In this narrative review, we will focus on the certainties and uncertainties of the role of CMR in sports cardiology. The main aspects of physiological adaptation due to regular and intensive sports activity and the application of CMR in highly trained athletes will be summarized.


Mammary epithelial morphogenesis and early breast cancer. Evidence of involvement of basal components of the RNA Polymerase I transcription machinery.
Upregulation of RNA Polymerase (Pol I)-mediated transcription of rRNA and increased ribogenesis are hallmarks of breast cancer. According to several datasets, including The Cancer Genome Atlas (TCGA), amplification/upregulation of genes encoding for basal components of the Pol I transcriptional machinery is frequent at different breast cancer stages. Here we show that knock down of the RNA polymerase I-specific transcription initiation factor RRN3 (TIF-IA) in breast cancer cells is sufficient to reduce rRNA synthesis and inhibit cell proliferation, and second that stable ectopic expression of RRN3 in human mammary epithelial (HME1) cells, by increasing rRNA transcription, confers increased sensitivity to the anti-proliferative effects of a selective Pol I inhibitor. Further, RRN3-overexpressing HME1 cells, when grown in in vitro 3-dimensional (3D) culture, develop into morphologically aberrant acinar structures lacking a lumen and filled with proliferative cells, thus acquiring a morphology resembling in situ ductal breast cancer lesions (DCIS). Consequently, interference with RRN3 control of Pol I transcription seems capable of both compromising mammary epithelial morphogenetic processes at early breast cancer stages, and driving breast cancer progression by fostering proliferation.


Tumour-associated macrophages-derived CXCL8 determines immune evasion through autonomous PD-L1 expression in gastric cancer.
Our previous studies have identified CXCL8 as the crucial chemokine responsible for gastric cancer metastasis mediated by loss of RACK1. However, the regulatory effect of CXCL8 on immune surveillance in gastric cancer remains obscure. Flow cytometry analyses were performed to examine major source of CXCL8 and phenotypes of immune cells in fresh tumour tissues from 76 patients with gastric cancer. Real-time PCR was performed to analyse CXCL8 mRNA level in gastric cancer tissues. For immunohistochemical analyses, a total of 420 patients with gastric cancer undergoing curative resection were enrolled. In vitro culture of fresh tumour tissue was performed to evaluate the potential therapeutic effect of blocking CXCL8 pathway in gastric cancer. Increased level of CXCL8 indicates poor clinical outcome and tumour progression in patients with gastric cancer. In gastric cancer tissues, CXCL8 is predominantly secreted by macrophages and colony stimulating factor 2 (CSF-2) facilitates macrophage-derived CXCL8 secretion. High level of CXCL8 is associated with decreased CD8+ T cells infiltration and Ki67+ CD8+ T cells proportion. Moreover, CXCL8 also inhibits CD8+ T cells function by inducing the expression of PD-L1 on macrophages. Finally, we show that a small-molecule CXCR2 inhibitor, reparixin, drives the decreased programmed death-ligand 1 (PD-L1+) macrophages and promotes antitumour immunity. Accordingly, high levels of CXCL8+ macrophages are positively correlated with poor prognosis in patients with gastric cancer. CXCL8 is predominantly secreted by macrophages and contributes to the immunosuppressive microenvironment by inducing PD-L1+ macrophages in gastric cancer. CXCL8 inhibitors may drive antitumour response, providing potential therapeutic effects for patients with gastric cancer.


Development of a Novel Restrictive Medium for Monascus Enrichment From Hongqu Based on the Synergistic Stress of Lactic Acid and Ethanol.
Hongqu is a famous fermented food produced by Monascus and has been used as food coloring, wine starters and food additives for thousands of years in China. Excellent Monascus strain is an important prerequisite for producing high-quality Hongqu. However, the isolation of Monascus pure culture from Hongqu samples is time-consuming and laborious because it is easily interfered by other microorganisms (especially filamentous fungi). Therefore, the development of restrictive medium for Monascus enrichment from Hongqu is of great significance for the preparation and screening of excellent Monascus strains. Results of this study showed that Monascus has good tolerance to lactic acid and ethanol. Under the conditions of tolerance limits [7.5% lactic acid (v/v) and 12.0% ethanol (v/v)], Monascus could not grow but it still retained the vitality of spore germination, and the spore activity gradually decreased with the increasing concentrations of lactic acid and ethanol. More interestingly, the addition of lactic acid and ethanol significantly changed the microbial community structure in rice milk inoculated with Hongqu. After response surface optimization, Monascus could be successfully enriched without the interference of other microorganisms when 3.98% (v/v) lactic acid and 6.24% (v/v) ethanol were added to rice milk simultaneously. The optimal enrichment duration of Monascus by the restrictive medium based on the synergistic stress of lactic acid and ethanol is 8∼24 h. The synergistic stress of lactic acid and ethanol had no obvious effects on the accumulation of major metabolites in the progeny of Monascus, and was suitable for the enrichment of Monascus from different types of Hongqu. Finally, the possible mechanisms on the tolerance of Monascus to the synergistic stress of lactic acid and ethanol were preliminarily studied. Under the synergistic stress of lactic acid and ethanol, the cell membrane of Monascus defends against lactic acid and ethanol into cells to some extent, and the superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities of Monascus were higher than those of other fungi, which significantly reduced the degree of lipid peroxidation of cell membrane, while secreting more amylase to make reducing sugars to provide the cells with enough energy to resist environmental stress. This work has great application value for the construction of Monascus strain library and the better development of its germplasm resources.


A 17-Year-Old Boy With Right Face Palsy, Left Leg Weakness, and Lytic Skull-Bone Lesions.
Human T-cell lymphotropic virus (HTLV), an infection that is endemic in certain parts of Asia, Africa, and South America, has been associated with malignancy and neurological deficits. Here, we describe a pediatric patient with chronic HTLV-I infection who developed complications associated with HTLV-I (ie, adult T-cell leukemia/lymphoma and HTLV-I-associated myelopathy/tropical spastic paraparesis). To our knowledge, this presentation in a child has never been described. The patient underwent a bone marrow transplant and, at the time of this writing, was in remission. This case report highlights the fact that HTLV-related complications, previously expected to occur after decades of infection, also can occur in pediatric patients, particularly those who acquired HTLV-I perinatally.


High-density lipoprotein administration attenuates liver proinflammatory response, restores liver endothelial nitric oxide synthase activity, and lowers portal pressure in cirrhotic rats.
In patients with cirrhosis, endotoxic shock is a major complication of portal hypertension, which is related partly to intrahepatic endothelial nitric oxide synthase (eNOS) down-regulation. High-density lipoproteins (HDLs), whose plasma levels are reduced in cirrhosis, have an anti-inflammatory effect by neutralizing circulating lipopolysaccharide (LPS), and they increase eNOS activity in endothelial cells. Therefore, the aim of this study was to assess the effects of reconstituted high-density lipoprotein (rHDL) administration on the LPS-induced proinflammatory response, intrahepatic eNOS regulation, and portal hypertension in cirrhotic rats. Cirrhotic and control rats were pretreated with rHDL or saline and challenged with LPS or saline. The neutralization of LPS in HDL was assessed by the measurement of HDL-bound fluorescent LPS levels. Plasma tumor necrosis factor alpha (TNFalpha) and lipopolysaccharide binding protein (LBP) levels were measured. The expression of hepatic TNFalpha, LBP, inducible nitric oxide synthase (iNOS), and caveolin-1 (a major eNOS inhibitor) and the activity of protein kinase B (Akt; a major eNOS activator) and eNOS were determined. The portal pressure was measured. The plasma HDL levels were significantly lower in cirrhotic rats than in control rats. In cirrhotic rats, the plasma levels of HDL-bound fluorescent LPS were 50% lower than those in controls, and they were restored after rHDL administration. The plasma TNFalpha levels were significantly higher in LPS-challenged cirrhotic rats than in controls and significantly decreased after rHDL administration. rHDL administration decreased hepatic TNFalpha, LBP, iNOS, and caveolin-1 expression, restored hepatic eNOS and Akt activity, and significantly lowered the portal pressure and intrahepatic vascular resistance. In cirrhotic rats, rHDL administration decreases the hepatic proinflammatory signals induced by LPS, restores the hepatic eNOS activity, and lowers the portal pressure. This suggests that the decrease in circulating HDL in cirrhosis plays a role in the excessive proinflammatory response and intrahepatic eNOS down-regulation.


Impact of water-dispersible beadlets as a vehicle for the delivery of carotenoids to cultured cells.
Water-dispersible beadlets of carotenoids were used as supplements for human umbilical vein endothelial cells (HUVECs), human peripheral blood mononuclear cells (PBMCs) and human monocytes. Stability, cellular association and cytotoxicity of the carotenoid beadlets were compared with carotenoids delivered with tetrahydrofuran (THF). Incubations with lycopene, beta-carotene, lutein and astaxanthin dissolved in THF resulted in a lower stability in the medium, lower cellular association, and a higher standard deviation. Beadlets provided 60, 4, 6, and 2 times greater accumulation of lycopene, beta-carotene, lutein and astaxanthin, respectively, by PBMCs than THF. The cellular association of carotenoids delivered by THF seems to be more carotenoid-specific than when carotenoids are delivered by beadlets. After 48 h of incubation under cell culture conditions all of the four carotenoids (1 microM) delivered by beadlets to the medium showed a reduction less than 30%. In addition, no cytotoxic effect of the carotenoid beadlets or the vehicle alone was detected in a concentration range of 0.5-5 microM. The results show that beadlets are a non-toxic vehicle for supplementing and stabilizing carotenoids in culture media offering a reasonable compromise in term of cell accumulation efficiency.


Fusarium proliferatum strains change fumonisin biosynthesis and accumulation when exposed to host plant extracts.
Fumonisin concentrations in mycelia and media were studied in liquid Fusarium proliferatum cultures supplemented with host plant extracts. Furthermore, the kinetics of fumonisin accumulation in media and mycelia collected before and after extract addition was analysed as well as the changes in the expression of the FUM1 gene. Fumonisin content in culture media increased in almost all F. proliferatum strains shortly after plant extracts were added. The asparagus extract induced the highest FB level increase and the garlic extract was the second most effective inducer. Fumonisin level decreased constantly until 14th day of culturing, though for some strains also at day 8th an elevated FB level was observed. Pineapple extract induced the highest increase of fum1 transcript levels as well as fumonisin synthesis in many strains, and the peas extract inhibited fungal growth and fumonisin biosynthesis. Moreover, fumonisins were accumulated in mycelia of studied strains and in the respective media.


The predominant circular form of avocado sunblotch viroid accumulates in planta as a free RNA adopting a rod-shaped secondary structure unprotected by tightly bound host proteins.
Avocado sunblotch viroid (ASBVd), the type member of the family Avsunviroidae, replicates and accumulates in chloroplasts. Whether this minimal non-protein-coding circular RNA of 246-250 nt exists in vivo as a free nucleic acid or closely associated with host proteins remains unknown. To tackle this issue, the secondary structures of the monomeric circular (mc) (+) and (-) strands of ASBVd have been examined in silico by searching those of minimal free energy, and in vitro at single-nucleotide resolution by selective 2'-hydroxyl acylation analysed by primer extension (SHAPE). Both approaches resulted in predominant rod-like secondary structures without tertiary interactions, with the mc (+) RNA being more compact than its (-) counterpart as revealed by non-denaturing polyacryamide gel electrophoresis. Moreover, in vivo SHAPE showed that the mc ASBVd (+) form accumulates in avocado leaves as a free RNA adopting a similar rod-shaped conformation unprotected by tightly bound host proteins. Hence, the mc ASBVd (+) RNA behaves in planta like the previously studied mc (+) RNA of potato spindle tuber viroid, the type member of nuclear viroids (family Pospiviroidae), indicating that two different viroids replicating and accumulating in distinct subcellular compartments, have converged into a common structural solution. Circularity and compact secondary structures confer to these RNAs, and probably to all viroids, the intrinsic stability needed to survive in their natural habitats. However, in vivo SHAPE has not revealed the (possibly transient or loose) interactions of the mc ASBVd (+) RNA with two host proteins observed previously by UV irradiation of infected avocado leaves.


Gender differences in steady-state levels of oxidative damage to DNA in healthy individuals.
Oxidative damage to DNA has often been used as a biomarker for oxidative stress and more specifically for cancer risk. Indeed, the measurement of oxidative damage to DNA, particularly of 8-hydroxyguanine (8OHG) and 8-hydroxy-2'-deoxyguanosine (8OHdG), has been adopted as a method for establishing the effects of antioxidant supplementation towards protection from certain cancers, cardiovascular and neuro-degenerative diseases, both in patients and healthy individuals. However, reported levels of 8OHdG or 8OHG vary considerably, possibly due to the different methodologies used, and only few data are available for the non-smoking and the female population. In this paper, steady-state levels of oxidative damage to DNA measured in a group of 20 males and 19 females are reported. Significant gender differences in levels of modified DNA bases such as 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FAPy guanine), 8-hydroxyadenine (8OHA) and 5-hydroxycytosine (5OHC), measured by gas chromatography-mass spectrometry (GC/MS), were observed. The results are discussed in relation to the Vitamin C and iron status of the subjects and to the existing, yet limited, literature data. The role of gender in predisposition to oxidative damage to DNA needs to be addressed in future studies.


Distribution of pro-opiomelanocortin and its peptide end products in the brain and hypophysis of the aquatic toad, Xenopus laevis.
Using in situ hybridization with a pro-opiomelanocortin (POMC)-mRNA probe and immunocytochemistry with antisera to POMC and to various POMC-derived peptides, it is shown that melanotrope cells in the pars intermedia of the hypophysis of the South African aquatic toad Xenopus laevis contain POMC, alpha-melanophore-stimulating hormone (alpha-MSH), gamma-MSH, acetylated and non-acetylated endorphins and adrenocorticotropic hormone (ACTH). With the exception of gamma-MSH, these peptides are also found in the corticotrope cells in the rostral pars distalis. In the Xenopus brain, neuronal cell bodies in the ventral hypothalamic nucleus express POMC, alpha-MSH, gamma-MSH, non-acetylated endorphins and ACTH, neurones in the anterior preoptic area reveal POMC, alpha-MSH, gamma-MSH and non-acetylated endorphin, neurones in the suprachiasmatic nucleus contain alpha-MSH, non-acetylated endorphin and ACTH and neurones in the posterior tubercle show alpha-MSH, non-acetylated endorphin and ACTH immunoreactivities. In the locus coeruleus POMC and ACTH coexist, whereas alpha-MSH and non-acetylated endorphin occur together in the nucleus accumbens, the striatum and the nucleus of the paraventricular organ. Finally, alpha-MSH alone is present in the olfactory bulb, the medial septum, the medial and lateral parts of the amygdala, the ventromedial and posterior thalamic nuclei, the optic tectum and the anteroventral tegmental nucleus, and non-acetylated endorphin alone appears in the epiphysis. It is suggested that neurones that form POMC-derived peptides may play a direct or indirect role in the control of POMC-producing hypophyseal cells and/or in the physiological processes these endocrine cells regulate. This idea is supported by the fact that the suprachiasmatic nucleus and the locus coeruleus, both involved in melanotrope cell control, show POMC and POMC-peptide expression. A possible involvement in melanotrope and/or corticotrope control of the anterior preoptic and ventral hypothalamic nuclei, which both express POMC and various POMC-derived peptides, deserves future attention.


THE DEVELOPMENTAL APPEARANCE OF PATERNAL FORMS OF LACTATE DEHYDROGENASE AND MALATE DEHYDROGENASE IN HYBRID HORSESHOE CRABS.
Differences in electrophoretic mobilities of lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) existed between three Asian horseshoe crabs, Tachypleus tridentatus, Tachypleus gigas, and Carcinoscorpius rotundicauda, used for interspecific hybridization. After electrophoresis of extracts of hybrid horseshoe crab embryos on starch gels, the paternal, maternal, and hybrid forms of the LDH and MDH were detected with specific enzyme staining. In viable hybrids the paternal form of the LDH was detected at stage 17 (immediately before the 1st embryonic molt). Similarly, evidence of gene expression for mitochondrial MDH was seen at stage 14 (stage of appearance of rudimental appendages). Gene expression for supernatant MDH was seen at stage 17 (immediately before the 1st embryonic molt). Regarding the onset of genome control in embryogenesis, it was suggested that prior to the activation of the maternal gene of the LDH, the paternal gene of the LDH was activated in horseshoe crab hybrids. Furthermore, there was evidence that the maternal effects on early embryogenesis were due to enzymes present in the egg prior to fertilization, not to continued synthesis directed by stable messenger RNA.


Semantic fluency in deaf children who use spoken and signed language in comparison with hearing peers.
Deafness has an adverse impact on children's ability to acquire spoken languages. Signed languages offer a more accessible input for deaf children, but because the vast majority are born to hearing parents who do not sign, their early exposure to sign language is limited. Deaf children as a whole are therefore at high risk of language delays. We compared deaf and hearing children's performance on a semantic fluency task. Optimal performance on this task requires a systematic search of the mental lexicon, the retrieval of words within a subcategory and, when that subcategory is exhausted, switching to a new subcategory. We compared retrieval patterns between groups, and also compared the responses of deaf children who used British Sign Language (BSL) with those who used spoken English. We investigated how semantic fluency performance related to children's expressive vocabulary and executive function skills, and also retested semantic fluency in the majority of the children nearly 2 years later, in order to investigate how much progress they had made in that time. Participants were deaf children aged 6-11 years (N = 106, comprising 69 users of spoken English, 29 users of BSL and eight users of Sign Supported English-SSE) compared with hearing children (N = 120) of the same age who used spoken English. Semantic fluency was tested for the category 'animals'. We coded for errors, clusters (e.g., 'pets', 'farm animals') and switches. Participants also completed the Expressive One-Word Picture Vocabulary Test and a battery of six non-verbal executive function tasks. In addition, we collected follow-up semantic fluency data for 70 deaf and 74 hearing children, nearly 2 years after they were first tested. Deaf children, whether using spoken or signed language, produced fewer items in the semantic fluency task than hearing children, but they showed similar patterns of responses for items most commonly produced, clustering of items into subcategories and switching between subcategories. Both vocabulary and executive function scores predicted the number of correct items produced. Follow-up data from deaf participants showed continuing delays relative to hearing children 2 years later. We conclude that semantic fluency can be used experimentally to investigate lexical organization in deaf children, and that it potentially has clinical utility across the heterogeneous deaf population. We present normative data to aid clinicians who wish to use this task with deaf children.


Pyrrolidine dithiocarbamate exerts anti-proliferative and pro-apoptotic effects in renal cell carcinoma cell lines.
The activation of nuclear factor-kappaB (NF-kappaB) has been implicated in the development, progression and metastasis of renal cell carcinoma (RCC). This study investigates the effect of pyrrolidine dithiocarbamate (PDTC), a NF-kappaB inhibitor, on two metastatic human RCC cell lines, ACHN and SN12K1. RCC cell lines and normal cells were exposed to 25 or 50 microM of PDTC. Apoptosis was measured by flow cytometry and TdT-mediated nick end labelling methods. Cell viability and proliferation were measured by MTT and BrdU assays, respectively. Expression of NF-kappaB subunits, IkappaBs, IkappaB Kinase (IKK) complex and apoptotic regulatory proteins were analysed by western blotting and/or immunofluorescence. DNA-binding activity of NF-kappaB subunits were measured by ELISA. RCC cell lines had a higher basal level expression of all the five subunits of NF-kappaB than normal primary cultures of human proximal tubular epithelial cells or HK-2 cells. PDTC decreased the viability and proliferation of RCC, but not normal cells. Of the two RCC cell lines, ACHN had a higher basal level expression of all the five NF-kappaB subunits than SN12K1 and was more resistant to PDTC. While PDTC induced an overall decrease in expression of all the five NF-kappaB subunits in both RCC cell lines, unexpectedly, it increased the nuclear expression of NF-kappaB in ACHN, but not in SN12K1. PDTC reduced the DNA-binding activity of all the NF-kappaB subunits and the expression of the IKK complex (IKK-alpha, IKK-beta and IKK-gamma) and the inhibitory units IkappaB-alpha and IkappaB-beta. PDTC induced a significant increase in apoptosis in both RCC cell lines. This was associated with a decrease in expression of the anti-apoptotic proteins, Bcl-2 and Bcl-(XL), without marked changes in the pro-apoptotic protein Bax. These data suggest that PDTC has the potential to be an anticancer agent in some forms of RCC.


Disseminated Cutaneous Trichosporonosis in an Adult Bone Marrow Transplant Patient.
The Trichosporon species are yeast-like opportunistic pathogens in immunocompromised patients. Trichosporon asahii infections have been reported in pediatric bone marrow transplant (BMT) patients. However, its incidence is low in the adult literature. A 52-year-old Chinese woman who was diagnosed with acute myeloid leukemia received induction chemotherapy and underwent allogenic bone marrow transplant, which was complicated by a relapse and required salvage chemotherapy. She developed persistent non-neutropenic fever secondary to presumed hepatosplenic candidiasis. Antifungal therapy with fluconazole and anidulafungin was administered. She remained febrile and tender dusky nodules appeared over all the four limbs. Histopathological examination and fungal culture identified T. asahii. Oral voriconazole was initiated with complete resolution of her lesions. The Trichosporon species is a frequently isolated yeast species from cancer patients. Voriconazole has become the first choice agent against Trichosporon. We highlight the increased awareness and clinical suspicion required for diagnosis and subsequent management in similar adult patients.


CD46: a complement regulator and pathogen receptor that mediates links between innate and acquired immune function.
In the last 10 years, the human cell-surface molecule, CD46, has evolved from 'just another complement regulator' to a receptor for a striking array of pathogens. CD46 not only protects cells from complement-mediated attack and facilitates infection by a large number of pathogens, but also exerts complex effects on cellular immune function. It has been proposed that CD46 links innate and adaptive immunity by affecting cellular immune function in response to complement binding, and the role of CD46 in the pathogenesis of many infectious pathogens is now the subject of intense investigation. So far, the flood of information that implicates CD46 in modifying a host response to measles, Neisseria, human herpes virus 6, and pathogens that activate complement has not yet been matched with a comprehensive understanding of the molecular mechanisms by which CD46 affects immune function. This review summarizes the evidence that points to a significant role for CD46 in a range of pathological processes and describes how CD46 might exert its effects by altering signal transduction and antigen presentation pathways.


Association of adult glioma with medical conditions, family and reproductive history.
A population-based case-control study of 416 histologically diagnosed, incident gliomas in adults was carried out in Melbourne, Australia, to determine whether past medical, family or reproductive histories are risk factors for developing glioma. A total of 422 controls were selected from the Australian electoral roll and matched to cases for age, sex and post code of residence. An increased risk of developing glioma was observed among first-born individuals OR (95% CI) 2.0 (1.4-2.9). It is possible that this effect is due to residual confounding by socio-economic status or that it is a chance finding. Alternatively, it may be that this is due to some other effect linked to the first pregnancy, such as maternal age, birth weight or circumstances of delivery. There was no apparent association between the development of glioma and other neuropsychiatric or general medical conditions or with family history or reproductive history. Allergies (asthma and eczema) were not associated with a decreased risk of glioma, as has previously been suggested.


Geometry, Allometry and Biomechanics of Fern Leaf Petioles: Their Significance for the Evolution of Functional and Ecological Diversity Within the Pteridaceae.
Herbaceous plants rely on a combination of turgor, ground tissues and geometry for mechanical support of leaves and stems. Unlike most angiosperms however, ferns employ a sub-dermal layer of fibers, known as a hypodermal sterome, for support of their leaves. The sterome is nearly ubiquitous in ferns, but nothing is known about its role in leaf biomechanics. The goal of this research was to characterize sterome attributes in ferns that experience a broad range of mechanical stresses, as imposed by their aquatic, xeric, epiphytic, and terrestrial niches. Members of the Pteridaceae meet this criteria well. The anatomical and functional morphometrics along with published values of tissue moduli were used to model petiole flexural rigidity and susceptibility to buckling in 20 species of the Pteridaceae. Strong allometric relationships were observed between sterome thickness and leaf size, with the sterome contributing over 97% to petiole flexural rigidity. Surprisingly, the small-statured cheilanthoid ferns allocated the highest fraction of their petiole to the sterome, while large leaves exploited aspects of geometry (second moment of area) to achieve bending resistance. This pattern also revealed an economy of function in which increasing sterome thickness was associated with decreasing fiber cell reinforcement, and fiber wall fraction. Lastly, strong petioles were associated with durable leaves, as approximated by specific leaf area. This study reveals meaningful patterns in fern leaf biomechanics that align with species leaf size, sterome attributes and life-history strategy.


A comparison of 5-fluorouridine and 5-fluorouracil in an experimental model for the treatment of vitreoretinal scarring.
5-Fluorouridine (5-FUR), a ribonucleotide metabolite of 5-Fluorouracil (5-FU), is a more potent inhibitor of cellular proliferation and cell-mediated contraction in vitro than 5-FU. We compared the efficacy of these two drugs in a cell injection model of proliferative vitreoretinopathy using New Zealand albino rabbits. Forty-five eyes were divided into three groups and injected intravitreally with homologous fibroblasts. Eyes were examined at the time of injection and 7, 14, 21 and 28 days thereafter. By day 28, 70.5% (12 of 17) of 5-FUR treated eyes demonstrated no appreciable proliferative or tractional activity compared with 41.7% (5 of 12) of 5-FU treated eyes and 10% (1 of 10) of control eyes (p < 0.006). Medullary ray puckers developed in 29.4% (5 of 17) and 25% (3 of 12) of 5-FUR and 5-FU treated eyes respectively. No 5-FUR treated eye developed extensive tractional or combined tractional and rhegmatogenous retinal detachment compared with 33.3% (4 of 12) of 5-FU treated eyes and 80% (8 of 10) of control eyes (p < 0.001). These results suggest that 5-Fluorouridine may be more effective than 5-FU for the treatment of vitreoretinal scarring.


[Effects of ganoderma lucidum spores on cytochrome C and mitochondrial calcium in the testis of NIDDM rats].
To observe the effects of Ganoderma lucidum spores on Cytochrome C (Cyt-C) and mitochondrial calcium in the testis of NIDDM rats. Fifty male Wistar rats were divided randomly into three groups: model, ganoderma and normal control, the first two groups injected with 2% STZ through vena caudalis, and the last one with half-and-half sodium citrate/citrate buffer solution. Two weeks after normal diet, glucose tolerance tests were performed and the rats with abnormal glucose tolerance from the model and ganoderma groups received high-fat and high-carbohydrate food, the ganoderma group given Ganoderma lucidum spores (250mg/[ kg x d] ) in addition, both for 10 weeks. Glucose tolerance tests were repeated 1 day before the end of the experiment and the rats were castrated and relevant indexes measured. The NIDDM model was successfully constructed. In the model group, the levels of mitochondrial Cyt-C and mitochondrial calcium were significantly lower (P <0. 05) while that of the plasma Cyt-C was significantly higher than in the ganoderma and the control groups. Cyt-C and calcium ion are involved in the damage of the testis. Ganoderma lucidum spores can protect the testis of NIDDM rats.


Two Overlapping Clusters of Group B Streptococcus Late-onset Disease in a Neonatal Intensive Care Unit.
Current predominant routes of group B Streptococcus (GBS) transmission in preterm neonates admitted to neonatal intensive care unit (NICU) are poorly defined. We report 2 overlapping clusters of GBS late-onset disease (LOD) from June to September 2015 in an Italian NICU. During the outbreak, possible sources of transmission (equipment, feeding bottles and breast pumps) were swabbed. Specimens from throat and rectum were collected on a weekly basis from all neonates admitted to NICU. Colonized or infected neonates had cohorting. Bacterial isolates were characterized by serologic and molecular typing methods. GBS was isolated in 2 full-term and 7 preterm neonates. Strains belonged to serotype III, with 3 different sequence types (ST17, ST182 and ST19). Full-term neonates were colonized with GBS strains unrelated to the clusters (ST182 and ST19). Two distinct ST17 strains caused 2 clusters in preterm neonates: a first cluster with 1 case of LOD and a second, larger cluster with 6 LOD in 5 neonates (one of them had recurrence). ST17 strains were isolated from vaginorectal and milk samples of 2 mothers. Two preterm neonates had no evidence of colonization for weeks, until they presented with LOD. Molecular analyses identified the presence of multiclonal GBS strains and 2 clusters of 7 cases of GBS-LOD. The dynamics of transmission of GBS within the NICU were complex. Breast milk was suspected to be one of the possible sources. In a research setting, the screening of GBS carrier mothers who deliver very preterm could contribute to the tracking of GBS transmission.


DNA lesions and DNA damage response: even long lasting relationships need a "break".
The elucidation of the spatiotemporal map of the DNA damage response (DDR) has been critical to our understanding of how cells are protected against insults to genomic integrity. Recruitment and transient immobilization at DNA breaks is a typical characteristic of many DDR proteins. Here, I discuss evidence that stable association of DDR proteins with chromatin is sufficient to activate the DDR even in the absence of damage. These observations critically support the notion that nuclear repair compartments play a primary role in triggering and amplifying DDR.


[Recommendations for management of acute chest pain. Report of the Belgium Interdisciplinary Working Group on Acute Cardiology].
The Belgium Interdisciplinary Working group on Acute Cardiology, including cardiologists, intensivists and urgentists was formed to provide consensus regarding the management of acute chest pain in the prehospital and the early hospital phase. General recommendations and critical pathways are proposed to improve the treatment of the patients with acute coronary syndromes.


Selective inhibition of Fe- versus Cu/Zn-superoxide dismutases by 2,3-dihydroxybenzoic acid derivatives.
A series of catechol derivatives were synthesised and tested for their ability to inactivate the iron-containing superoxide dismutase (Fe-SOD) from Escherichia coli and the bovine erythrocytes Cu/Zn-SOD. Incubation of catechols with Fe- or Cu/Zn SODs resulted in a time-dependent loss of enzyme activity with highly selective inhibition for the iron-dependent enzyme. Catechol-induced inactivation of SODs was correlated with the auto-oxidation of the catechol compounds to their corresponding ortho-quinone derivatives, which was found to be non-dependent on the presence of enzymes. Mass electrospray experiments on catechol-incubated Fe-SOD provided evidence for the irreversible nature of the inhibition process, yielding to a complex mixture of modified proteins.


Human immunodeficiency virus and hepatitis testing and prevalence among surgical patients in an urban university hospital.
Human immunodeficiency virus (HIV), hepatitis B, and hepatitis C represent significant public health problems in an urban community. Early diagnosis and treatment of these infections can improve survival and allow for preventive strategies to reduce further transmission within a community. The aim of this study was to evaluate the surgical setting as a potential opportunity for early diagnosis of HIV, hepatitis B, and hepatitis C among trauma and non-trauma patients. We performed a retrospective review of patients presenting for surgery over a 10-year period (July 1994 to July 2004) in an urban, university-based general surgical practice that includes all trauma services, as well as emergency department, inpatient, and outpatient surgical consultations. Data collected included diagnosis, operation, age, race, history of intravenous drug abuse, and HIV, hepatitis B, and hepatitis C test results. Among 2876 patients presenting for surgery, testing for blood-borne pathogens was less likely among trauma patients (21%, 79/380) compared to non-trauma patients (47%, 1183/2496) (P < .001). Among patients tested, the incidence of blood-borne pathogens was similar in the two groups: HIV (26% trauma vs 24% non-trauma, not significant [NS]), hepatitis B (4% trauma vs 3% non-trauma, NS), hepatitis C (33% trauma vs 41% non-trauma, NS), and co-infection with HIV and hepatitis C (18% trauma vs 12% non-trauma, NS). In both groups, blood-borne pathogens were associated with intravenous drug abuse (P < .01). HIV, hepatitis B, and hepatitis C are common in an urban community among both trauma and non-trauma surgical patients, although testing is less common among trauma patients. Testing of patients during a surgical admission may represent an excellent opportunity for early disease-specific services and preventive interventions.


Advances in the surgical treatment of colon and rectal cancer.
A family history of colorectal cancer is the basis for risk stratification and allows reliable screening recommendations for individual patients. It is also the starting point for diagnosing hereditary forms of colorectal cancer. The surgical implications of treating hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis are briefly described. Laparoscopic colectomy and sentinel node biopsies are new techniques with potential application in the treatment of colon cancer. For rectal cancer, advances have resulted in better preoperative staging and improved oncologic and functional outcomes. Surgical intervention for recurrent colorectal cancer requires careful patient selection and a multidisciplinary approach. The evaluation and treatment of patients with different patterns of recurrent colorectal cancer is described.


Overexpression of the human glucocorticoid receptor alpha and beta isoforms inhibits AP-1 and NF-kappaB activities hormone independently.
The human glucocorticoid receptor isoforms GRalpha and GRbeta are generated by alternative splicing. Upon hormone binding, GRalpha regulates positively or negatively transcription. In particular, it represses numerous genes encoding pro-inflammatory mediators by inhibiting the transcription factors activator protein (AP)-1 and nuclear factor (NF)-kappaB. The observation that GRbeta, which does not bind the hormone, may act as a dominant negative receptor is subject to controversy. Because GRbeta must be more abundant than GRalpha to act as such, we evaluated the relative amounts of GRalpha and GRbeta in COS-1, A549 and HeLa cells using a monoclonal antibody that recognises the two isoforms equally well on western blots. Messenger RNA levels of GRalpha and GRbeta were compared by reverse transcriptase polymerase chain reaction analysis. To gain insight into the possible function of GRbeta, we examined the ability of overexpressed GRbeta to alter transcription of glucocorticoid, AP-1 and NF-kappaB inducible reporter genes using transient transfection in COS-1 and A549 cells. Subcellular localisation of GRbeta was determined in A549 cells by immunofluoresence microscopy. Data indicate that GRalpha is the predominant endogenous isoform in A549 and HeLa cells. GRbeta became the major form after transfection with the corresponding expression vector and translocated into cell nuclei even in the absence of hormone. Overexpression of GRbeta inhibited glucocorticoid-induced transcription markedly in COS-1 cells but weakly in A549 cells. We found that GRbeta did not act as a dominant negative modulator of GRalpha for repression of AP-1 and NF-kappaB activities. In fact, both GRbeta and GRalpha inhibited hormone-independently these activities by 25-60%. This property was not shared by the closely related mineralocorticoid receptor. Our results suggest that overexpression of either GRalpha or GRbeta may have an anti-inflammatory effect.


The importance of equity in payments to encourage coexistence with large mammals.
Large mammals often impose significant costs such as livestock depredation or crop foraging on rural communities, and this can lead to the retaliatory killing of threatened wildlife populations. One conservation approach - payments to encourage coexistence (PEC) - aims to reduce these costs through financial mechanisms such as compensation, insurance, revenue-sharing, and conservation performance payments. Little is known about the equitability of PEC, however, despite its moral and instrumental importance, prevalence as a conservation approach, and the fact that other financial tools for conservation are often inequitable. Here, using examples from the literature, we first demonstrate the capability of PEC - as currently perceived and implemented - to be inequitable. We then provide three recommendations to improve the equitability of current and future schemes. These include the co-operative design of schemes that promote compensatory equity, the greater consideration of conservation performance payments, and changing the international model for funding PEC in order to reduce global coexistence inequalities. New and existing programmes must address issues of equitability across scales, to ensure that conservation efforts are not undermined by diminished social legitimacy. This article is protected by copyright. All rights reserved.


Regulation of the frequency-dependent facilitation of L-type Ca2+ currents in rat ventricular myocytes.
1. An increase in the rate of stimulation induces an augmentation of L-type Ca2+ currents (ICa) and concomitant slowing of current decay in rat ventricular cells. This facilitation is quasi immediate (1-3 s), graded with the rate of stimulation, and occurs only from negative holding potentials. We investigated this effect using trains of stimulation at 1 Hz and the whole-cell patch-clamp technique (18-22 degrees C). 2. The decay of ICa is normally bi-exponential and comprises fast and slow current components (ICa,fc and ICa,sc, respectively). Facilitation of ICa was observed only when ICa,fc was predominant. 3. Facilitation developed during the run-up of ICa with the interconversion of ICa,sc into ICa,fc, and vanished during the run-down of ICa with the loss of ICa,fc.Ni2+ (300 microM) and nifedipine (1 microM) suppressed facilitation owing to the preferential inhibition of ICa,fc. 4. Facilitation of ICa was not altered (when present) or favoured (when absent) by the cAMP-dependent phosphorylation of Ca2+ channels promoted by isoprenaline or by intracellular application of cAMP or of the catalytic subunit of protein kinase A (C-sub). A similar effect was observed when the dihydropyridine agonist Bay K 8644 was applied. In both cases, facilitation was linked to a preferential increase of ICa,fc. 5. Following intracellular application of inhibitors of protein kinase A in combination with a non-hydrolysable ATP analogue, ICa consisted predominantly of ICa,sc and no facilitation was observed. The calmodulin antagonist naphthalenesulphonamide had no effect on facilitation. 6. When Bay K 8644 was applied in combination with isoprenaline, cAMP or C-sub, the decay of ICa was slowed with the predominant development of ICa,sc, and facilitation of ICa was nearly abolished. Facilitation also depended on extracellular Ca2+, and was suppressed when Ba2+ replaced Ca2+ as the permeating ion. 7. When no EGTA was included in the patch pipette, facilitation was not further enhanced but a use-dependent decrease of ICa frequently occurred. When BAPTA was used in place of EGTA, the rate of inactivation of ICa was reduced and facilitation was abolished. 8. In conclusion, the facilitation of ICa that reflects a voltage-driven interconversion of ICa,fc into ICa,sc is also regulated by Ca2+ and by cAMP-dependent phosphorylation. The presence of the gating pattern typified by ICa,fc is required. Ca2+ may exert its effect near the inner pore of the Ca2+ channel protein and control the distribution between the closed states of the two gating pathways.


Surface adsorption of poisonous Pb(II) ions from water using chitosan functionalised magnetic nanoparticles.
In this study, chitosan functionalised magnetic nano-particles (CMNP) was synthesised and utilised as an effective adsorbent for the removal of Pb(II) ions from aqueous solution. The experimental studies reveal that adsorbent material has finer adsorption capacity for the removal of heavy metal ions. Parameters affecting the adsorption of Pb(II) ions on CMNP, such as initial Pb(II) ion concentration, contact time, solution pH, adsorbent dosage and temperature were studied. The adsorption equilibrium study showed that present adsorption system followed a Freundlich isotherm model. The experimental kinetic studies on the adsorption of Pb(II) ions exhibited that present adsorption process best obeyed with pseudo-first order kinetics. The maximum monolayer adsorption capacity of CMNP for the removal of Pb(II) ions was found to be 498.6 mg g-1. The characterisation of present adsorbent material was done by FTIR, energy disperse X-ray analysis and vibrating sample magnetometer studies. Thermodynamic parameters such as Gibbs free energy (ΔG°), enthalpy (ΔH°) and entropy (ΔS°) have declared that the adsorption process was feasible, exothermic and spontaneous in nature. Sticking probability reported that adsorption of Pb(II) ions on CMNP was favourable at lower temperature and sticking capacity of Pb(II) ions was very high.


5-fluorouracil-Induced cardiotoxicity.
Cardiotoxicity due to antineoplastic agents such as doxorubicin, daunorubicin, cyclophosphamide, vincristin, vinblastin, cisplatin and busulfan is well known. However, 5-fluorouracil-induced cardiotoxicity is yet to be widely recognized by cardiologists. We report a patient who developed 5-fluorouracil-induced cardiotoxicity syndrome.


Analysis of in planta Expressed Orphan Genes in the Rice Blast Fungus Magnaporthe oryzae.
Genomes contain a large number of unique genes which have not been found in other species. Although the origin of such "orphan" genes remains unclear, they are thought to be involved in species-specific adaptive processes. Here, we analyzed seven orphan genes (MoSPC1 to MoSPC7) prioritized based on in planta expressed sequence tag data in the rice blast fungus, Magnaporthe oryzae. Expression analysis using qRT-PCR confirmed the expression of four genes (MoSPC1, MoSPC2, MoSPC3 and MoSPC7) during plant infection. However, individual deletion mutants of these four genes did not differ from the wild-type strain for all phenotypes examined, including pathogenicity. The length, GC contents, codon adaptation index and expression during mycelial growth of the four genes suggest that these genes formed during the evolutionary history of M. oryzae. Synteny analyses using closely related fungal species corroborated the notion that these genes evolved de novo in the M. oryzae genome. In this report, we discuss our inability to detect phenotypic changes in the four deletion mutants. Based on these results, the four orphan genes may be products of de novo gene birth processes, and their adaptive potential is in the course of being tested for retention or extinction through natural selection.


R.T.R® promotes bone marrow mesenchymal stem cells osteogenic differentiation by upregulating BMPs/SMAD induced cbfa1 expression.
Bone marrow mesenchymal stem cells (BMSCs) of rats were isolated and Bio-Oss® and R.T.R® materials were used in this study.Alkaline phosphatase (ALP) activity in each group was calculated. The ability of adhesion and proliferation of BMSCs on Bio-Oss® and R.T.R® increased with time, but they were significantly higher on R.T.R® than that of Bio-Oss® at all time points (p<0.05). Compared with Bio-Oss®, R.T.R® could promote the expression and activity of ALP in BMSCs, and the expression of bone formation related transcription factors bone morphogenetic protein-1 (BMP-1), Cbfa1 and osteoblast marker genes ALP, collagen I, osteopontin, osseomucin and osteocalcin. The expression levels of cbfa1, ALP, collagen I, osteopontin, osseomucin and osteocalcin were inhibited after downregulated expression of BMP-1 in BMSCs and inoculation with R.T.R®. R.T.R® could up-regulate BMP-1 expression and cbfa1 expression through BMPs/SMAD signaling pathway, thereby promoting the expression of ALP, collagen I, osteopontin, osseomucin and osteocalcin and promoting osteoblast differentiation.


A SYNDROME OF ISCHEMIC LEG NECROSIS IN NORTHERN GANNETS (MORUS BASSANUS).
The Northern Gannet (Morus bassanus) is a large marine bird whose whole North American population breeds in waters of eastern Canada. Opportunities to identify causes of morbidity and mortality in recently hatched birds of this species are therefore limited to this region of North America. During the three decades since 1990 of wildlife health surveillance at the Atlantic regional center of the Canadian Wildlife Health Cooperative, what appears to be a previously undescribed syndrome of ischemic leg necrosis affecting mainly hatch-year Northern Gannets has emerged, which may relate to some unique aspects of the life history of these birds. This syndrome, observed in 14 birds, is characterized by severe necrosis and fibrinopurulent inflammation of soft tissues of the feet extending along the whole tarsometatarsus. An infectious cause is proposed to explain the pattern of lesions observed in these birds, possibly favored by a specialized and rich vascular system in their legs and feet. An acute or subacute cardiomyopathy, thought to be secondary to the severe leg lesions, was also observed microscopically in six of these birds.


Methodological issues in studies of the treatment, diagnosis, and etiology of prostate cancer.
Clinical and epidemiological research on prostate cancer is faced with some unusual methodological challenges. The very high prevalence of latent cancer, much of which never becomes clinically manifest, complicates the approach to screening and the conduct of epidemiological studies. Cost-effectiveness issues are especially relevant regarding screening policies, and these trade-offs are complicated by the absence of definitive results on the effectiveness of the various treatment options. The presentation of advanced disease is also unusual, in that the vast majority of patients do not have measurable disease suitable for traditional studies of new chemotherapy agents. These problems necessitate creative approaches to the design and analysis of research studies in this disease: cost-effectiveness analysis is crucial to the evaluation of screening policies; opportunistic designs will be essential to the valid study of cancer etiology, eg, the use of cystoprostatectomy series for studies of epidemiologic risk factors; and posttreatment changes in PSA levels may be valuable as a criterion for screening new agents in advanced disease. Regardless of these new methods, traditional methodological approaches are essential to the valid study of prostate cancer. Randomization is required for valid comparison of treatments and screening strategies. Statistical analysis should observe the intent-to-treat principle whereby patient groups are analyzed with respect to the planned, rather than the delivered therapy, and studies should have sufficiently large sample sizes to reliably distinguish the true effects of the interventions from random statistical fluctuation. Recently, meta-analysis has become popular as a tool for synthesizing the information from available studies on a specific clinical problem. Its most conspicuous success has been in showing the efficacy of adjuvant therapy in breast cancer, for which many individual studies appeared to give conflicting results.64 In this setting there was a large number of published randomized trials, many of which had large sample sizes and long follow-up, and so the meta-analysis was able to show convincingly a small but clinically meaningful treatment effect on long-term disease recurrence and survival. This is similar to the situation in localized prostate cancer in all respects except for the availability of randomized trials. Unfortunately there is no free lunch. This technique can only be applied if the high quality data are available. One must be similarly cautious in applying decision analytic techniques (and also cost-effectiveness analysis) to try to resolve clinical dilemmas.(ABSTRACT TRUNCATED AT 400 WORDS)


Automatic activation of adolescents' peer-relational schemas: evidence from priming with facial identity.
This study provides experimental evidence for automatic, relationship-specific social information processing in 13-year-old adolescents. Photographs of participants' liked, disliked, and unknown peers were used as primes in an affective priming task with happy and angry facial expression probes and in a hypothetical vignette task. For the affective priming, reaction times were faster for congruent than for incongruent prime-probe pairs when the prime visibility was high and the prime-probe stimulus onset asynchrony was long. In the vignette task, participants attributed more hostility toward the protagonist, experienced more anger, and were more likely to retaliate when the disliked peer served as a prime. It is concluded that peer-relational schemas and related affect are activated automatically upon perception of a peer.


Virus-mimicking optical nanomaterials: near infrared absorption and fluorescence characteristics and physical stability in biological environments.
The use of viruses as platforms for the development of optical imaging materials has received increasing attention in recent years. We have engineered a hybrid nanomaterial composed of the capsid proteins of genome-depleted plant-infecting Brome mosaic virus that encapsulates the near-infrared (NIR) dye indocyanine green. Herein, we investigate the NIR absorption and fluorescence characteristics of these nanomaterials in biological environments consisting of cell culture media with and without serum proteins. Our results demonstrate that the NIR absorption and fluorescence emission of the constructs are enhanced in the presence of serum proteins. The constructs remain physically stable and maintain their NIR absorption and fluorescence properties for at least 79 days. The presence of serum proteins also reduces the aggregation of the constructs. These findings have relevance for the further development of optical imaging and phototherapeutic methods on the basis of such virus-mimicking nanomaterials as well as the expected optical and physical characteristics of these nanomaterials in vivo.


Race/ethnicity, socioeconomic status, and lifetime morbidity burden in the women's health initiative: a cross-sectional analysis.
We sought to assess the extent to which race/ethnicity and socioeconomic status (SES) are independently and jointly related to lifetime morbidity burden by comparing the impact of SES on lifetime morbidity among women of different racial/ethnic groups: white, black, Hispanic, American Indian/Alaska Native (AIAN), and Asian/Pacific Islander (API). Using baseline data from the Women's Health Initiative (WHI), a national study of 162,000 postmenopausal women, we measured lifetime morbidity burden using a modified version of the Charlson Index, and measured SES with educational attainment and household income. In multivariable simple polytomous logistic regression models, we first assessed the effect of SES on lifetime morbidity burden among women of each racial/ethnic group, then assessed the combined effect of race/ethnicity and SES. Five percent of all women in the study population had high lifetime morbidity burden. Women with high lifetime morbidity were more likely to be AIAN or black; poor; less educated; divorced, separated, or widowed; past or current smokers; obese; uninsured or publicly insured. Lower SES was associated with higher morbidity among most women. The extent to which morbidity was higher among lower SES compared to higher SES women was about the same among Hispanic women and white women, but was substantially greater among black and AIAN women compared with white women. This study demonstrates the importance of considering race/ethnicity and class together in relation to health outcomes.


Xenografting restores spermatogenesis to cryptorchid testicular tissue but does not rescue the phenotype of idiopathic testicular degeneration in the horse (Equus caballus).
Spermatogenesis from many mammalian species occurs in fragments of normal testis tissue xenografted to mice. Here we apply xenografting to the study of testicular pathology. Using the horse model, we investigated whether exposure to a permissive extratesticular environment in the mouse host would rescue spermatogenesis in cryptorchid testicular tissue or in tissue affected by idiopathic testicular degeneration (ITD). In cryptorchid tissue, where the extratesticular environment is abnormal, xenografting induced spermatogenesis up to meiosis in a subpopulation of seminiferous tubules. Thus, spermatogonia survive and partially retain their potential to differentiate in cryptorchid horse testes. In contrast, the primary defect in equine ITD is hypothesised to be tissue autologous. In support of this, xenografting did not restore spermatogenesis to tissue affected by ITD, thus confirming that the testis itself is primarily diseased. This outcome was not affected by supplementation of exogenous gonadotropins to the mouse host or by reconstitution of a normal reproductive regulatory axis supplied by functional porcine testicular xenografts. These studies demonstrate the usefulness of xenografting for the study of testicular pathology.


FOXO3 is inhibited by oncogenic PI3K/Akt signaling but can be reactivated by the NSAID sulindac sulfide.
Overactivation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway has emerged as a pivotal trigger of thyroid carcinogenesis. Recent findings from other tumor entities revealed that PI3K/Akt-driven carcinogenesis critically involves the inactivation of the tumor-suppressive transcription factor Forkhead box O (FOXO)-3. However, little is known about FOXO3 in the thyroid context. We sought to investigate the influence of the thyroid oncogenes BRAFV600E, H-RASV12, and p110α (H1074R) on the regulation of the PI3K downstream target FOXO3 in vitro. Furthermore, the impact of the expression of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) on the transcriptional activity of FOXO3 was assessed in a panel of 44 human thyroid tumors. Finally, we tried to modulate FOXO3 activity pharmacologically with help of the nonsteroidal antiinflammatory drug sulindac sulfide (SS). We found that the overexpression of p110α H1074R results in the inactivation of FOXO3 via its nuclear exclusion. In vivo, we observed a direct correlation between PTEN expression and the transcriptional activation of FOXO3. In vitro, we found that stimulation with SS reversed PI3K/Akt-driven inactivation of FOXO3, resulting in its nuclear relocation and a combined induction of the antiproliferative FOXO target genes Gadd45α and p27(kip1) and the proapoptotic FOXO target gene Bim in benign (FRTL-5) and malignant human thyrocytes (FTC-133). In agreement with this, SS promoted the cell cycle arrest and apoptosis in thyroid cells, which could be amplified by the transfection of exogenous FOXO3. Our data suggest that deregulation of proapoptotic FOXO3 represents a central step in PI3K/Akt-mediated thyroid carcinogenesis. Thus, SS might represent an attractive pharmacological tool for targeting thyroid neoplasia with aberrant PI3K/Akt/FOXO3 signaling.


Localized orbital corrections for the calculation of ionization potentials and electron affinities in density functional theory.
This paper describes the extension of a previously reported empirical localized orbital correction model to the correction of ionization potential energies (IP) and electron affinities (EA) for atoms and molecules of first and second row elements. The B3LYP localized orbital correction version of the model (B3LYP-LOC) uses 22 heuristically determined parameters that improve B3LYP DFT IP and EA energy calculations on the G2 data set of 134 molecules from a mean absolute deviation (MAD) from experiment of 0.137 to 0.039 eV. The method significantly reduces the number of outliers and overall MAD to error levels below that achieved with G2 wave function based theory; furthermore, the new model has zero additional computational cost beyond standard DFT calculations. Although the model is heuristic and is based on a multiple linear regression to experimental errors, each of the parameters is justified on physical grounds, and each provides insight into the fundamental limitations of DFT, most importantly the failure of current DFT methods to accurately account for nondynamical electron correlation.


Differentiating laryngeal carcinomas from precursor lesions by diffusion-weighted magnetic resonance imaging at 3.0 T: a preliminary study.
Diffusion-weighted magnetic resonance imaging (DWI) has been introduced in head and neck cancers. Due to limitations in the performance of laryngeal DWI, including the complex anatomical structure of the larynx leading to susceptibility effects, the value of DWI in differentiating benign from malignant laryngeal lesions has largely been ignored. We assessed whether a threshold for the apparent diffusion coefficient (ADC) was useful in differentiating preoperative laryngeal carcinomas from precursor lesions by turbo spin-echo (TSE) DWI and 3.0-T magnetic resonance. We evaluated DWI and the ADC value in 33 pathologically proven laryngeal carcinomas and 17 precancerous lesions. The sensitivity, specificity, and accuracy were 81.8%, 64.7%, 76.0% by laryngostroboscopy, respectively. The sensitivity, specificity, and accuracy of conventional magnetic resonance imaging were 90.9%, 76.5%, 86.0%, respectively. Qualitative DWI analysis produced sensitivity, specificity, and accuracy values of 100.0, 88.2, and 96.0%, respectively. The ADC values were lower for patients with laryngeal carcinoma (mean 1.195±0.32×10(-3) mm(2)/s) versus those with laryngeal precancerous lesions (mean 1.780±0.32×10(-3) mm(2)/s; P<0.001). ROC analysis showed that the area under the curve was 0.956 and the optimum threshold for the ADC was 1.455×10(-3) mm(2)/s, resulting in a sensitivity of 94.1%, a specificity of 90.9%, and an accuracy of 92.9%. Despite some limitations, including the small number of laryngeal carcinomas included, DWI may detect changes in tumor size and shape before they are visible by laryngostroboscopy. The ADC values were lower for patients with laryngeal carcinoma than for those with laryngeal precancerous lesions. The proposed cutoff for the ADC may help distinguish laryngeal carcinomas from laryngeal precancerous lesions.


A few years later. Update of the cost-effectiveness of infant pneumococcal vaccination in Dutch children.
This study aimed to calculate the cost-effectiveness of infant pneumococcal vaccination in the Netherlands, using the 13-valent PCV13 vs. the currently used 10-valent PCV10. We adapted a previously published model, using recent estimates of epidemiological and efficacy data. In 12 scenarios, we explored the impact of different assumptions on the incremental cost-effectiveness ratio (ICER) of PCV13 over PCV10.Taking only direct effects on invasive pneumococcal disease into account, PCV13 was not found to be cost-effective at a price difference of €11 per dose. If herd protection, replacement and non-invasive disease were also taken into account, the ICER of PCV13 compared with PCV10 was below €30 000/QALY gained in 11 of 12 scenarios. PCV13 was considered dominant in the primary scenario with a price difference below €2.63 per dose.


HLA and complement C4 antigens in polyarticular onset seronegative juvenile chronic arthritis: association of early onset with HLA-DRw8.
HLA-A,B,C,DR and DQ antigens were tested in 53 British Caucasian patients with polyarticular onset seronegative juvenile chronic arthritis (JCA); C4 allotypes were also tested in 46. A strong association with HLA-DRw8 was found (RR = 6.1, Fp = 7.6 x 10(-5)), with increased -B5(51) and C4A QO, and decreased -DR7 frequencies. DRw8 incidence correlated with an onset under 5 years, 9 of 12 DRw8+ cases being in this subgroup (Fp = less than 0.06), whereas B5 and C4A QO were prevalent in late onset (greater than or equal to 5 years). Erosions after 5 years associated with HLA-DRw6, and their absence with -Cw1 and -DR5. Genetic susceptibility factors and a further subdivision by onset age are thus demonstrated in this disease. Comparative data suggest that the genetic basis of susceptibility to early onset disease is similar to that of pauciarticular JCA.


The antibiotic peptaibol alamethicin from Trichoderma permeabilises Arabidopsis root apical meristem and epidermis but is antagonised by cellulase-induced resistance to alamethicin.
Trichoderma fungi live in the soil rhizosphere and are beneficial for plant growth and pathogen resistance. Several species and strains are currently used worldwide in co-cultivation with crops as a biocontrol alternative to chemical pesticides even though little is known about the exact mechanisms of the beneficial interaction. We earlier found alamethicin, a peptide antibiotic secreted by Trichoderma, to efficiently permeabilise cultured tobacco cells. However, pre-treatment with Trichoderma cellulase made the cells resistant to subsequent alamethicin, suggesting a potential mechanism for plant tolerance to Trichoderma, needed for mutualistic symbiosis. We here investigated intact sterile-grown Arabidopsis thaliana seedlings germinated in water or growth medium. These could be permeabilised by alamethicin but not if pretreated with cellulase. By following the fluorescence from the membrane-impermeable DNA-binding probe propidium iodide, we found alamethicin to mainly permeabilise root tips, especially the apical meristem and epidermis cells, but not the root cap and basal meristem cells nor cortex cells. Alamethicin permeabilisation and cellulase-induced resistance were confirmed by developing a quantitative in situ assay based on NADP-isocitrate dehydrogenase accessibility. The combined assays also showed that hyperosmotic treatment after the cellulase pretreatment abolished the induced cellulase resistance. We here conclude the presence of cell-specific alamethicin permeabilisation, and cellulase-induced resistance to it, in root tip apical meristem and epidermis of the model organism A. thaliana. We suggest that contact between the plasma membrane and the cell wall is needed for the resistance to remain. Our results indicate a potential mode for the plant to avoid negative effects of alamethicin on plant growth and localises the point of potential damage and response. The results also open up for identification of plant genetic components essential for beneficial effects from Trichoderma on plants.


The DNA-binding Polycomb-group protein Pleiohomeotic maintains both active and repressed transcriptional states through a single site.
Although epigenetic maintenance of either the active or repressed transcriptional state often involves overlapping regulatory elements, the underlying basis of this is not known. Epigenetic and pairing-sensitive silencing are related properties of Polycomb-group proteins, whereas their activities are generally opposed by the trithorax group. Both groups modify chromatin structure, but how their opposing activities are targeted to allow differential maintenance remains a mystery. Here, we identify a strong pairing-sensitive silencing (PSS) element at the 3' border of the Drosophila even skipped (eve) locus. This element can maintain repression during embryonic as well as adult eye development. Transgenic dissection revealed that silencing activity depends on a binding site for the Polycomb-group protein Pleiohomeotic (Pho) and on pho gene function. Binding sites for the trithorax-group protein GAGA factor also contribute, whereas sites for the known Polycomb response element binding factors Zeste and Dsp1 are dispensible. Normally, eve expression in the nervous system is maintained throughout larval stages. An enhancer that functions fully in embryos does not maintain expression, but the adjacent PSS element confers maintenance. This positive activity also depends on pho gene activity and on Pho binding. Thus, a DNA-binding complex requiring Pho is differentially regulated to facilitate epigenetic transcriptional memory of both the active and the repressed state.


GATA transcription factors in hematologic disease.
GATA family transcription factors play essential roles in broad developmental settings. GATA-1, one of the hematopoietically expressed members, is required for normal erythroid and megakaryocytic differentiation. Over the past few years, mutations in the gene encoding GATA-1 have been linked to several human hematologic disorders, including X-linked dyserythropoietic anemia and thrombocytopenia, X-linked thrombocytopenia and beta-thalassemia, and Down syndrome acute megakaryoblastic leukemia. This review summarizes the role of GATA-1 during normal hematopoiesis and discusses how disease-associated mutations may affect its function.


Transformation of the peripheral intravenous catheter placement experience in pediatrics.
"Needle pokes" are the most frequent cause of pain encountered by pediatric patients in the hospital setting. Poor control of pain during needle pokes leads to short- and long-term adverse outcomes for both patients and hospitals. J-Tips are a needle-free injection system that use pressurized gas to inject lidocaine in a fine stream of fluid that penetrates the skin. This study undertook an evaluation of their effectiveness at decreasing the pain of the needle poke that takes place with IV insertion. Participation was limited to patients between the ages of 3 and 16 who received an IV during a 3-week period at an academic pediatric hospital. Furthermore, patients requiring more than one attempt to place the IV were not included. Participants were recruited within 24 hours after having received their IV. The 10-point, Wong-Baker Faces Pain Rating Scale was the tool used to collect pain scores. Patients were recruited to the study by convenience sampling. Pain scores were collected from 85 patients. There were 41 patients who received needle-free injected lidocaine prior to IV insertion. There were 44 patients who received an IV without previous lidocaine injection. Mean pain scores for the two groups were 2.45 for the patients who received the needle-free injected lidocaine and 5.8 for the patients who did not (p value <0.001). Results were consistent with the hypothesis that needle-free injection of lidocaine is an effective therapy for the management of pain in children between the ages of 3-16 years who receive an IV.


Inhibitor-GCPII Interaction: Selective and Robust System for Targeting Cancer Cells with Structurally Diverse Nanoparticles.
Glutamate carboxypeptidase II (GCPII) is a membrane protease overexpressed by prostate cancer cells and detected in the neovasculature of most solid tumors. Targeting GCPII with inhibitor-bearing nanoparticles can enable recognition, imaging, and delivery of treatments to cancer cells. Compared to methods based on antibodies and other large biomolecules, inhibitor-mediated targeting benefits from the low molecular weight of the inhibitor molecules, which are typically stable, easy-to-handle, and able to bind the enzyme with very high affinity. Although GCPII is established as a molecular target, comparing previously reported results is difficult due to the different methodological approaches used. In this work, we investigate the robustness and limitations of GCPII targeting with a diverse range of inhibitor-bearing nanoparticles (various structures, sizes, bionanointerfaces, conjugation chemistry, and surface densities of attached inhibitors). Polymer-coated nanodiamonds, virus-like particles based on bacteriophage Qβ and mouse polyomavirus, and polymeric poly(HPMA) nanoparticles with inhibitors attached by different means were synthesized and characterized. We evaluated their ability to bind GCPII and interact with cancer cells using surface plasmon resonance, inhibition assay, flow cytometry, and confocal microscopy. Regardless of the diversity of the investigated nanosystems, they all strongly interact with GCPII (most with low picomolar Ki values) and effectively target GCPII-expressing cells. The robustness of this approach was limited only by the quality of the nanoparticle bionanointerface, which must be properly designed by adding a sufficient density of hydrophilic protective polymers. We conclude that the targeting of cancer cells overexpressing GCPII is a viable approach transferable to a broad diversity of nanosystems.


Assessment of mitral valve geometry in nonvalvular atrial fibrillation patients with or without ventricular dysfunction: insights from high volume rate three-dimensional transesophageal echocardiography.
Meticulous understanding of the mechanisms underpinning mitral regurgitation in atrial fibrillation (AF) patients is crucial to optimize therapeutic strategies. The morphologic characteristics of mitral valves in atrial functional mitral regurgitation (FMR) patients with and without left ventricular (LV) dysfunction were evaluated by high volume rate (HVR) three-dimensional transesophageal echocardiography (3D-TEE). In our study, 68 of 265 AF patients who underwent 3D-TEE were selected, including 36 patients with AF, FMR, and preserved LV function (AFMR group) and 32 patients with AF, FMR, and LV dysfunction (VFMR group). In addition, 36 fever patients without heart disease were included in the control group. Group comparisons were performed by one-way analysis of variance for continuous variables. The left atrium (LA) was enlarged in the AFMR and VFMR groups compared with the control group. The mitral annulus (MA) in the AFMR group was enlarged and flattened compared with the control group and was smaller than in the VFMR group. The annulus area fraction was significantly diminished in the AFMR and VFMR groups, indicative of reduced MA contractility. The posterior mitral leaflet (PML) angle was smallest in the AFMR group and largest in the control group, whereas the distal anterior mitral leaflet angle did not significantly differ among the three groups. LA remodeling causes expansion of the MA and reduced MA contractility, disruption of the annular saddle shape, and atriogenic PML tethering. Comparison of atrial FMR patients with and without LV dysfunction indicates that atriogenic PML tethering is an important factor that aggravates FMR. HVR 3D-TEE improves the 3D temporal resolution greatly.


Imipramine receptors in human platelets: effect of age.
Imipramine receptors were studied in platelets from six healthy young subjects (age between 24 and 38 years), five newborns, and six healthy elderly persons (age between 70 and 81 years). Binding parameters, the maximum binding capacity (Bmax) and the apparent dissociation constant (Kd), were determined by Scatchard's analysis. Level of differences between young subjects and the other groups was determined by Student's t-test. Bmax (mean +/- SD) was 1162 +/- 138 (young persons), 564 +/- 65 (newborn), and 508 +/- 98 (elderly persons) fmol/mg protein. The figure for the young was different from that of the newborn (p less than 0.001) and the elderly (p less than 0.01). Kd (means +/- SD) was 1.78 +/- .69 (young persons), 0.68 +/- 0.13 (newborn), and 0.80 +/- 0.27 nM in the elderly. Kd in the volunteers was different from that in the newborn or the elderly subjects (p less than 0.01). Imipramine receptors in platelets appear to be influenced by development and aging.


[Critical analysis of requirements for scientific assessment as a basis for good governance: case of the chikungunya epidemic on Reunion Island and Mayotte in 2005 and 2006].
The constitutional precautionary principle as applied in laws governing health care at the community level requires rigorous scientific assessment. The goal of this assessment is to provide authorities with sound evidence as a basis for implementing precautionary measures in function of degree of risk and other parameters such as the level of public health protection that is high in the EU. As the political authority, the government can act independently of conclusions issued by scientific commissions provided that the commission's level of expertise meets national and European standards and that research methodology and findings are consistent with scientific data published in the international literature. These requirements were not meet for the chikungunya pandemic that struck France on Reunion Island and Mayotte from 2004 to 2006. This epidemic that was preceded by many outbreaks in Indonesia between 2001 and 2003 began in Africa and then swept across the Indian Ocean to India and Asia. After an overview of the scientific assessment, this article raises arguments supporting possible allegations of gross misgovernance by the state and experts.


Caring in patient-focused care: the relationship of patients' perceptions of holistic nurse caring to their levels of anxiety.
Holistic nurse caring, also called patient-focused care, is a helping relationship between nurse and patient with the potential to enhance health and healing. Few studies, however, have examined the relationship of the process of nurse caring to patient outcomes. Hospitalized patients face many stressors that cause anxiety. It is known that abnormally high levels of anxiety can interfere with patients' recovery. The article reports a study of patients' perceptions of holistic nurse caring and the relationship of perceptions of caring to levels of anxiety. Patients perceived caring to be evident, and there was a significant relationship between these perceptions and patients' levels of anxiety.


[Study of lymphocyte subpopulations in chronic autoimmune inflammatory rheumatic diseases. II. Polymyalgia rheumatica: behaviour of lymphocyte subpopulations during treatment with two different corticosteroids].
The aim of this paper was to study the distribution of CD8+ subsets, of soluble receptors of CD8 and IL-2 during a steroid treatment with prednisone and deflazacort. Forty-eight patients (9 males and 39 females, mean age 69.4(6.5 years) with active polymyalgia rheumatica (ESR 74 (18 mm, 1(st) h) were studied. In order to determine the distribution of lymphocyte subpopulations a panel of monoclonal antibodies was utilised. Flow cytometry with a FACSCAN machine and ELISA method were utilized. At base-time in comparison with normal subjects: reduction (P<0.05) of CD4(-)/CD8(+) (356+/-112/mL vs 564(132/mL), due to reduction (P<0.001) of CD8(+)bright (224(86/mL vs 426+/-124/mL) and CD8(+)bright/CD57(-) (123+/-44/mL vs 256(58/mL); increasing (P<0.001) of sCD8 (514+/-123 U/mL vs 312+/-102 U/mL) and (P<0.005) sIL-2r (984(346 U/mL vs 244+/-58 U/mL). Group-PDN: significant (P<0.001) reduction of CD4(-)/CD8(+) (466+/-102), CD89(+))bright (302(74), CD8+bright/CD57- (186+/-51), sCD8 (418+/-96) and of sIL-2r (450+/-163) at 1(st) week, and toward the normal range at 1(st) month. Group-DFZ: normal values at 6th month: CD4(-)/CD8(+) (497+/-133), CD8(+)bright (401+/-98), CD8(+)bright/CD57(-) (240+/-64), sCD8 (317+/-82), while sIL-2r è (P<0.0005) higher vs group-PDN. Group-PDN: VES <50 at 1st week, normal value (14+/-7) at 3(rd) month; PCR, 2.2+/-1.2 at 3(rd) month and 1(0.8 at 6th month. Group-DFZ: VES >20 (24+/-5) at 6th month e PCR increased. PDN shows a faster action vs DFZ. DFZ does not seem to be able in reducing sIL-2r probably showing a persistent inflammation and immune activation status.


Costimulation Blockade in Kidney Transplantation: An Update.
In the setting of solid-organ transplantation, calcineurin inhibitor (CNI)-based therapy remains the cornerstone of immunosuppression. However, long-term use of CNIs is associated with some degree of nephrotoxicity. This has led to exploring the blockade of some costimulation pathways as an efficient immunosuppressive tool instead of using CNIs. The only agent already in clinical use and approved by the health authorities for kidney transplant patients is belatacept (Nulojix), a fusion protein that interferes with cytotoxic T lymphocyte-associated protein 4. Belatacept has been demonstrated to be as efficient as cyclosporine-based immunosuppression and is associated with significantly better renal function, that is, no nephrotoxicity. However, in the immediate posttransplant period, significantly more mild/moderate episodes of acute rejection have been reported, favored by the fact that cytotoxic T lymphocyte-associated protein pathway has an inhibitory effect on the alloimmune response; thereby its inhibition is detrimental in this regard. This has led to the development of antibodies that target CD28. The most advanced is FR104, it has shown promise in nonhuman primate models of autoimmune diseases and allotransplantation. In addition, research into blocking the CD40-CD154 pathway is underway. A phase II study testing ASK1240, that is, anti-CD40 antibody has been completed, and the results are pending.