Cascaded Stokes and anti-Stokes laser based on an optical resonator with a self-assembled organic monolayer.
Due to their high circulating intensities, ultra-high quality factor dielectric whispering gallery mode resonators have enabled the development of low threshold Raman microlasers. Subsequently, other Raman-related phenomena, such as cascaded stimulated Raman scattering (CSRS) and stimulated anti-Stokes Raman scattering (SARS), were observed. While low threshold frequency conversion and generation have clear applications, CSRS and SARS have been limited by the low Raman gain. In this work, the surface of a silica resonator is modified with an organic monolayer, increasing the Raman gain. Up to four orders of CSRS are observed with sub-milliwatt (mW) input power, and the SARS efficiency is improved by three orders of magnitude compared to previous studies with hybrid resonators.


The effect of different nitrate preparations on plasma heparin concentrations and the activated partial thromboplastin time.
There is evidence that intravenous nitrates which are frequently used in acute coronary syndromes may interfere with the anticoagulant effect of heparin. We compared the effect of two different nitrate preparations on the activated partial thromboplastin time (APTT), anti-thrombin III activity (AT III) and plasma heparin levels in patients (n = 50) undergoing routine percutaneous transluminal coronary angioplasty (PTCA) for stable angina. Patients were randomized to either: (1) intravenous heparin and nitroglycerin (GTN); or (2) intravenous heparin and isosorbide dinitrate. The APTT, plasma heparin concentration and AT III activity were measured before PTCA and at 2 and 4 hours after commencement of infusions. Both groups received identical doses of heparin. Group 1 patients received a constant dose of 16.6 micrograms/minute of GTN, and group 2 patients received 33.3 micrograms/minute of isosorbide dinitrate. At 4 hours the median APTT ratio was significantly lower in group 1 compared with group 2 (2.6 versus 4.5) (P < 0.05) as was the plasma heparin concentration (0.18 U/ml versus 0.32 U/ml (P < 0.05). However, no significant difference in APTT ratios or plasma heparin concentrations were noted at any of the other sample times. AT III activity was not significantly different between the groups at any sample time. Within-group analysis showed significantly lower APTT ratio and heparin concentrations at 4 hours compared with the respective 2 hour values. These results would suggest that there is a potential impairment of anticoagulation with low-dose intravenous nitroglycerin and to a lesser extent with low-dose isosorbide dinitrate. Early and frequent monitoring may therefore be appropriate when intravenous nitrates and heparin are used in combination.


Repurposing ospemifene for potentiating an antigen-specific immune response.
Ospemifene, an estrogen receptor agonist/antagonist approved for the treatment of dyspareunia and vaginal dryness in postmenopausal women, has potential new indications as an immune modulator. The overall objective of the present series of preclinical studies was to evaluate the immunomodulatory activity of ospemifene in combination with a peptide cancer vaccine. Immune regulating effects, mechanism of action and structure activity relationships of ospemifene and related compounds were evaluated by examining expression of T-cell activating cytokines in vitro, and antigen-specific immune response and cytotoxic T-lymphocyte activity in vivo. The effects of ospemifene (OSP) on the immune response to a peptide cancer vaccine (PV) were evaluated after chronic [control (n = 22); OSP 50 mg/kg (n = 16); PV (n = 6); OSP+PV (n = 11)], intermittent [control (n = 10); OSP 10 and 50 mg/kg (n = 11); PV (n = 11); combination treatment (n = 11 each dose)] and pretreatment [control; OSP 100 mg/kg; PV 100 μg; combination treatment (n = 8 all groups)] ospemifene oral dosing schedules in a total of 317 mixed-sex tumor-bearing and nontumor-bearing mice. The results showed that ospemifene induced expression of the key TH1 cytokines interferon gamma and interleukin-2 in vitro, which may be mediated by stimulating T-cells through phosphoinositide 3-kinase and calmodulin signaling pathways. In combination with an antigen-specific peptide cancer vaccine, ospemifene increased antigen-specific immune response and increased cytotoxic T-lymphocyte activity in tumor-bearing and nontumor-bearing mice. The pretreatment, intermittent, and chronic dosing schedules of ospemifene activate naive T-cells, modulate antigen-induced tolerance and reduce tumor-associated, pro-inflammatory cytokines, respectively. Taken together, ospemifene's dose response and schedule-dependent immune modulating activity offers a method of tailoring and augmenting the efficacy of previously failed antigen-specific cancer vaccines for a wide range of malignancies.


A Molecular Dynamics Simulations Study of the Influence of Prestrain on the Pop-In Behavior and Indentation Size Effect in Cu Single Crystals.
The pop-in effect in nanoindentation of metals represents a major collective dislocation phenomenon that displays sensitivity in the local surface microstructure and residual stresses. To understand the deformation mechanisms behind pop-ins in metals, large scale molecular dynamics simulations are performed to investigate the pop-in behavior and indentation size effect in undeformed and deformed Cu single crystals. Tensile loading, unloading, and reloading simulations are performed to create a series of samples subjected to a broad range of tensile strains with/without pre-existing dislocations. The subsequent nanoindentation simulations are conducted to investigate the coupled effects of prestrain and the presence of resulting dislocations and surface morphology, as well as indenter size effects on the mechanical response in indentation processes. Our work provides detailed insights into the deformation mechanisms and microstructure-property relationships of nanoindentation in the presence of residual stresses and strains.


A Corynebacterium glutamicum gene conferring multidrug resistance in the heterologous host Escherichia coli.
A chromosomal DNA fragment from the erythromycin-sensitive bacterium Corynebacterium glutamicum ATCC 13032 was shown to mediate resistance against erythromycin, tetracycline, puromycin, and bleomycin in Escherichia coli. Multicopy cloning of the fragment did not cause a resistance phenotype in C. glutamicum. The corresponding gene encodes a hydrophobic protein with 12 potential transmembrane-spanning ex-helical segments showing similarity to drug-H+ antiporters.


Influences on neighborhood walking in older adults.
The purpose of this cross-sectional survey study was to examine the influence of self-efficacy, outcome expectations, and environment on neighborhood walking in older adults with (n = 163, mean age = 78.7, SD = 7.96 years) and without (n = 163, mean age = 73.6, SD = 7.93 years) mobility limitations, controlling for demographic characteristics. Multiple regression revealed that in mobility-limited older adults, demographic characteristics, self-efficacy, and outcome expectations explained 17.4% of variance in neighborhood walking, while environment (neighborhood destinations and design) explained 9.4%. Destinations, self-efficacy, sex, and outcome expectations influenced walking. In those without mobility limitations, demographic characteristics, self-efficacy, and outcome expectations explained 15.6% of the variance, while environment explained 5.6%. Self-efficacy, sex, and design influenced walking. Neighborhood walking interventions for older adults should include self-efficacy strategies tailored to mobility status and neighborhood characteristics.


Prevalence and treatment of heart failure in Swedish nursing homes.
Since the burden of care for elderly patients with heart failure (HF) can be decreased by therapeutic measures, it is important that such patients are identified correctly. This study explores the prevalence of HF in nursing homes in Sweden, with special consideration of the risk of failure to diagnose HF in the study population. A second aim is to explore medication and the adherence to guidelines for the treatment of HF. 429 patients from 11 nursing homes were included during 2008-2011. Information about diagnoses and medications from patient records, blood samples, questionnaire responses and blood pressure measurements were collected. The baseline characteristics of the patients, their medications and one-year mortality were identified and then compared regarding HF diagnosis and B-type natriuretic peptide (BNP) levels. A BNP level of >100 ng/L was used to identify potential cases of HF. The point prevalence of HF diagnosis in the medical records in the study population was 15.4%. With the recommended cut-off value for BNP, up to 196 subjects in the study population (45.7%) qualified for further screening of potential HF.The subjects in the HF and non-HF groups were similar with the exception of mean age, BNP levels and Mini Mental State Examination results which were higher in the HF group, and the eGFR and blood pressure, which were lower when HF. The subjects with higher BNP values were older and had lower eGFR, Hb, diastolic blood pressure and BMI. The subjects with HF diagnoses were in many cases not treated according to the guidelines. Loop diuretics were often used without concomitant ACE inhibitors or angiotensin receptor blockers. The subjects without HF diagnoses in the medical records at inclusion but with BNP values >100 ng/L had less appropriate HF medication. The one-year mortality was 52.9% in the population with HF. Our study suggests that the estimated prevalence of HF in nursing homes in Sweden would increase if BNP measurements were used to select patients for further examinations. The pharmacological treatment of HF varied substantially, as did adherence to guidelines.


Upregulation of HES1 Promotes Cell Proliferation and Invasion in Breast Cancer as a Prognosis Marker and Therapy Target via the AKT Pathway and EMT Process.
HES1 is a transcriptional repressor involved in cell differentiation and proliferation as well as in various cancer developments, but its expression pattern and biological roles in breast cancer have not been examined. In this study, we assessed HES1 expression in breast cancer tissues using immunohistochemistry and Western blot analyses and investigated HES1 function using MTT and Matrigel invasion assays. Significant relationships were observed between HES1 upregulation and advanced TNM stage (p=0.011), node metastasis (p=0.043), negative oestrogen receptor expression (p=0.001) and triple-negative status (p=0.001). HES1 overexpression was correlated with poor prognosis in breast cancer patients (p<0.05). The MTT and Matrigel invasion assays showed that silencing HES1 in MDA-MB-231 cells decreased cell proliferation and invasion, whereas overexpression of HES1 in MCF-7 cells enhanced its proliferation and invasion. Further analyses showed that silencing HES1 downregulated p-AKT and impeded epithelial-mesenchymal transition (EMT), whereas overexpression of HES1 upregulated AKT phosphorylation and induced EMT. Our study demonstrated that HES1 upregulation is a predictor of poor prognosis in human breast cancers and might be a critical contributor to the proliferation and invasion of breast cancer cells. Moreover, the proportion of cells with overexpression of HES1 in triple-negative breast cancer (TNBC) samples was significantly higher. Thus, HES1 might be a potential therapeutic target in the treatment of TNBC.


Microbiological and physicochemical properties of smoked ricotta cheese during refrigeration and temperature abuse storage.
In the last years changes occurred in the production process of ricotta mustia, a traditional smoked, salted and sometimes ripened ricotta cheese, produced in Sardinia. Fresher, slightly smoked and with reduced salt content products, were introduced into the market to meet changes in consumer's preferences for milder products. The present study of durability was conducted on an innovative fresh and smoked industrial product, also characterized by the small size and the packaging in modified atmosphere. A durability test to assess the evolution of microbiological and physicochemical profile of the product stored at refrigeration (4°C) and mild abuse (7°C) temperatures was carried out. A total of 126 ricotta samples smoked for either 1, 2, or 3 h were analyzed at intervals during shelflife for the determination of aerobic mesophilic counts, Enterobacteriaceae, yeast, moulds, L. monocytogenes, Pseudomonas spp. and B. cereus. Intrinsic properties, physic-chemical and headspace gas composition were also analyzed. Average and standard deviation were respectively 6,06±0,22 for pH, 0,982±0,05 for aW, 74,67%±1,81% for moisture, 10,25%±1,35% for fat, 10,92%±0,46% for protein and 1,70%±0,42% for salt content. Total bacterial count ranged between 3.88±0.48 log cfu/g at T0 and 3.25±1.02 at T45. L. monocytogenes, Pseudomonas spp. and E. coli were always below the detection limit. Enterobacteriaceae prevalence (percentage) was 3.17% (2.62±0.42 lg10 cfu/g) and was limited to samples stored longer than 30 days while B. cereus was recovered in 5.55% (2.36±0.35 lg10 cfu/g) of the samples and was never observed in samples after 45 days of refrigerated storage. The durability study is preliminary to challenge test to assess the shelf-life of this product in compliance with the requirements of Regulation (EC) 2073/2005.


[Physiotherapy in dogs. Initial practice results].
Physical therapy in thirty-eight dogs is documented and evaluated. To begin with, the methods of physical therapy adopted in various cases in which a veterinary diagnosis was established, are reviewed. Subsequently, the results are reported and classified by veterinary diagnosis. Finally, the limitations of the present evaluation are shown as well as the possibilities of improving indications as a result of investigations, which will require a co-ordinated approach.


Influence of Actor's Congruent and Incongruent Gaze on Language Processing.
In interpreting spoken sentences in event contexts, comprehenders both integrate their current interpretation of language with the recent past (e.g., events they have witnessed) and develop expectations about future event possibilities. Tense cues can disambiguate this linking but temporary ambiguity in their interpretation may lead comprehenders to also rely on further, situation-specific cues (e.g., an actor's gaze as a cue to his future actions). How comprehenders reconcile these different cues in real time is an open issue that we must address to accommodate comprehension. It has been suggested that relating a referential expression (e.g., a verb) to a referent (e.g., a recent event) is preferred over relying on other cues that refer to the future and are not yet referentially grounded ("recent-event preference"). Two visual-world eye-tracking experiments compared this recent-event preference with effects of an actor's gaze and of tense/temporal adverbs as cues to a future action event. The results revealed that people overall preferred to focus on the recent (vs. future) event target in their interpretation, suggesting that while a congruent and incongruent actor gaze can jointly with futuric linguistic cues neutralize the recent-event preference late in the sentence, the latter still plays a key role in shaping participants' initial verb-based event interpretation. Additional post-experimental memory tests provided insight into the longevity of the gaze effects.


Fear of crime is associated with loneliness among older adults in Singapore: Gender and ethnic differences.
Fear of crime is a complex perception and has underlying psychological, social and health repercussions. The influence of fear of crime on psychosocial outcomes, however, may be moderated by various social factors. This study examined how fear of crime influences loneliness among low-income older adults attending a Senior Activity Centre (SAC) in multiethnic Singapore. In addition, we tested whether these associations were moderated by gender and ethnicity. We analysed cross-sectional data (N = 1,266) from The SAC Study, a survey conducted with older adults who were attending a SAC between March 2015 and August 2015. Multilevel models were used to test whether fear of crime was associated with loneliness; and whether the association was moderated by gender and ethnicity. We found that fear of crime was positively associated with loneliness, and that this association was stronger among men than women, but ethnicity did not moderate this relationship. Findings from our study suggest that fear of crime may have a stronger negative effect on men's psychological well-being, even though they report lower fear of crime. This highlights the importance of sociocultural context when examining the psychosocial implications of fear of crime in the population.


A factor present in fetal calf serum enhances oncogene-induced transformation of rodent fibroblasts.
Our previous studies indicated that addition of the tumor promoters 12-O-tetradecanoylphorbol-13-acetate (TPA) or teleocidin to Dulbecco modified Eagle medium supplemented with calf serum enhanced T24-induced focus formation in both the murine C3H 10T1/2 and rat 6 embryo fibroblast cell lines. In the present studies we have found that fetal calf serum (FCS) is more potent than 12-O-tetradecanoylphorbol-13-acetate in enhancing T24-induced focus formation, in terms of the number and size of the foci, in both C3H 10T1/2 and rat 6 cells. Time course studies indicate that FCS can exert this enhancing effect when it is added several days after the transfection with T24 DNA. In rat 6 cells, an 11-fold increase in T24-induced focus formation occurred when the transfected cultures were maintained for only 1 day in 5% FCS, starting 4 days after the transfection. Several known growth factors, including epidermal growth factor, transforming growth factors alpha and beta, insulin, and platelet-derived growth factor, did not enhance T24-induced transformation in these cell systems. Fractionation studies indicate that the factor present in FCS has a molecular weight of about 1,300, is not lipid soluble, and is acid, base, and heat stable. These findings suggest that a factor(s) normally present in serum may enhance the emergence of tumor cells in vivo, by acting in concert with an activated oncogene, during the multistage carcinogenic process.


Man's underground best friend: domestic ferrets, unlike the wild forms, show evidence of dog-like social-cognitive skills.
Recent research has shown that dogs' possess surprisingly sophisticated human-like social communication skills compared to wolves or chimpanzees. The effects of domestication on the emergence of socio-cognitive skills, however, are still highly debated. One way to investigate this is to compare socialized individuals from closely related domestic and wild species. In the present study we tested domestic ferrets (Mustela furo) and compared their performance to a group of wild Mustela hybrids and to domestic dogs (Canis familiaris). We found that, in contrast to wild Mustela hybrids, both domestic ferrets and dogs tolerated eye-contact for a longer time when facing their owners versus the experimenter and they showed a preference in a two-way choice task towards their owners. Furthermore, domestic ferrets, unlike the wild hybrids, were able to follow human directional gestures (sustained touching; momentary pointing) and could reach the success rate of dogs. Our study provides the first evidence that domestic ferrets, in a certain sense, are more dog-like than their wild counterparts. These findings support the hypothesis that domestic species may share basic socio-cognitive skills that enable them to engage in effectively orchestrated social interactions with humans.


Binding of organic compounds to rat liver and lung.
The binding of various radioisotopically labeled organic compounds to rat liver and lung was investigated in vitro. Pieces of rat lung and slices of rat liver were incubated at 37 degrees C under a nitrogen atmosphere in a modified Krebs-Ringer phosphate solution (pH 7.4) CONTAININg the compound to be studied. Of the neutral compounds investigated, digitoxin, digoxin and dexamethasone were highly bound to both liver and lung tissue, whereas the degree of binding of amitrole, erythritol, and ouabain was 20% or less. The weak acids which were bound to the greatest extent in both liver and lung were phenobarbital, pentobarbital, and diphenylhydantoin. Barbital was poorly bound, and there was no evidence for the binding of 5,5-dimethyloxazolidine-2,4-dione or p-aminohippuric acid in either tissue. Binding of the cardiac glycosides and the barbiturates directly paralleled their lipid solubilities. The degree of binding of neutral compounds and weak acids to lung and liver tissue did not vary greatly with concentration, even though broad concentration ranges were studied. This was also true of the weak base morphine. On the other hand, the binding to liver and lung of the organic bases nicotine, pilocarpine, d-amphetamine, lidocaine, erythromycin, and chloroquine, did vary with concentration. The quaternary ammonium compound decamethonium was bound only to liver, and this binding also varied with concentration. Two additional quaternary ammonium compounds, tetraethylammonium and N1-methylnicotinamide, were not significantly bound to either tissue. Comparisons on the basis of equal content of solids revealed that the binding of diverse organic compounds in liver is greater than or equal to that in lung.


Strain-Stiffening in Dynamic Supramolecular Fiber Networks.
The cytoskeleton is a highly adaptive network of filamentous proteins capable of stiffening under stress even as it dynamically assembles and disassembles with time constants of minutes. Synthetic materials that combine reversibility and strain-stiffening properties remain elusive. Here, strain-stiffening hydrogels that have dynamic fibrous polymers as their main structural components are reported. The fibers form via self-assembly of bolaamphiphiles (BA) in water and have a well-defined cross-section of 9 to 10 molecules. Fiber length recovery after sonication, H/D exchange experiments, and rheology confirm the dynamic nature of the fibers. Cross-linking of the fibers yields strain-stiffening, self-healing hydrogels that closely mimic the mechanics of biological networks, with mechanical properties that can be modulated by chemical modification of the components. Comparison of the supramolecular networks with covalently fixated networks shows that the noncovalent nature of the fibers limits the maximum stress that fibers can bear and, hence, limits the range of stiffening.


Identification and characterization of wolframin, the product of the wolfram syndrome gene (WFS1), as a novel calmodulin-binding protein.
To search for calmodulin (CaM) targets, we performed affinity chromatography purification of a rat brain extract using CaM fused with GST as the affinity ligand. Proteomic analysis was then carried out to identify CaM-binding proteins. In addition to identifying 36 known CaM-binding proteins, including CaM kinases, calcineurin, nNOS, the IP(3) receptor, and Ca(2+)-ATPase, we identified an ER transmembrane protein, wolframin [the product of the Wolfram syndrome gene (WFS1)] as interacting. A CaM overlay and an immunoprecipitation assay revealed that wolframin is capable of binding the Ca(2+)/CaM complex in vitro and in transfected cells. Surface plasmon resonance analysis and zero-length cross-linking showed that the N-terminal cytoplasmic domain (residues 2-285) of wolframin binds to an equimolar unit of CaM in a Ca(2+)-dependent manner with a K(D) for CaM of 0.15 muM. Various truncation and deletion mutants showed that the Ca(2+)/CaM binding region in wolframin is located from Glu90 to Trp186. Furthermore, we demonstrated that three mutations (Ala127Thr, Ala134Thr, and Arg178Pro) associated with Wolfram syndrome completely abolished CaM binding of wolframin. This observation may indicate that CaM binding is important for wolframin function and that impairment of this interaction by mutation contributes to the pathology seen in Wolfram syndrome.


Detection of multiple human papillomavirus types in the lower genital tract correlates with cervical dysplasia.
Some human papillomavirus (HPV) types, such as HPV 16, are clearly associated with cervical dysplasia; however, the role played by other HPV types occasionally found in dysplasia is less certain. In addition, most methods used to detect HPV in clinical specimens cannot easily distinguish among more than two or three HPV types in a single specimen. Therefore, the significance of infection with multiple HPV types is not known. To address this question, we analyzed cervicovaginal lavage specimens from three cohorts of women for HPV DNA using a PCR/reverse blot assay system that permits the detection and partial quantitation of 26 genital HPV types. As expected, 94.1% of women who had dysplasia (n = 34) and 71.4% of women who had atypical squamous cells of uncertain significance (ASCUS) (n = 21) on cytology had HPV DNA detected compared to 54.5% of age matched women with normal cytology. HPV 16 DNA was detected in 35% of dysplasia patients compared to 9% of cytologic normals (P = 0.0044). Dysplasia patients had a mean of 3.29 (range 0-10) different HPV types detected compared to 1.04 (range 0-7) HPV types among those with normal cytology (P < 0.0001). These data support a possible role for multiple HPV types in the development or progression of cervical dysplasia.


Differential induction and regulation of c-jun, junB, junD and c-fos by human papillomavirus type 11 E5a oncoprotein.
The E5a gene of human papillomavirus type 11 (HPV-11) is a transforming oncogene. In this study, we investigated the mechanism of E5a induced transformation. Our results show that the expression of c-jun and junB, but not junD, was activated by HPV-11 E5a in NIH 3T3 cells and human epidermal keratinocytes. However, the expression of c-fos was activated by E5a in NIH 3T3 cells, but not in keratinocytes. We further investigated the mechanism of c-jun and junB induction by E5a. The amount of c-jun and junB RNAs correlated with the amount of E5a RNA in the heavy metal inducible system. E5a constitutively activated the expression of c-jun and junB at the initiation of transcription level. In addition, analyses of the effect of serum on c-jun expression in E5a transformed human epidermal keratinocytes show that EGF might have a stimulatory effect on c-jun gene expression in E5a expressing keratinocytes.


In vitro establishment, validation and characterisation of conjunctival epithelium outgrowth using tissue fragments and amniotic membrane.
To set up the in vitro conditions for renewal of the conjunctival epithelium using healthy fragments of conjunctival tissue glued over an amniotic membrane. We evaluated the capability of conjunctival tissue fragments to generate conjunctival cell outgrowth after seeding them onto amniotic membrane and culture plates; we then assessed conjunctival molecular marker expression by immunofluorescence. We also evaluated the efficiency of glueing the fragments over the amniotic membrane to determine the best setting and the feasibility of shipping preloaded amniotic membranes. Epithelial outgrowth was detected in 65%-80% of conjunctival fragments starting 48-72 hours after glueing, without major differences between type of membrane preparation and fragment size. Within 6-13 days, a full epithelium covered the surface of the amniotic membrane. Specific marker expression (conjunctival epithelium, Muc1, K19, K13; stemness, p63; tight junctions, ZO-1) was detected. Results of the shipping test showed that only 31% of the fragments were still glued over the epithelial side of the membrane within 24 hours compared to more than 90% of fragments stayed attached in the remaining conditions. The in vitro regeneration of conjunctival epithelium following outgrowth from conjunctival tissue fragments glued over an amniotic membrane may offer a viable strategy to renew the epithelium in vivo once applied over the ocular surface at the recipient site.


The prevalence of nutritional anemia in pregnancy in an east Anatolian province, Turkey.
Anemia is considered a severe public health problem by World Health Organization when anemia prevalence is equal to or greater than 40% in the population. The purpose of this study was to determine the anemia prevalence with the associated factors in pregnant women and to determine the serum iron, folate and B12 vitamin status in anaemic pregnants in Malatya province. This is a cross-sectional survey. A multi-sage stratified probability-proportional-to-size cluster sampling methodology was used. A total of 823 pregnant women from sixty clusters were studied. Women were administered a questionnaire related with the subject and blood samples were drawn. Total blood count was performed within four hours and serum iron, folate and B12 vitamin were studied after storing sera at -20 C for six months. Anemia prevalence was 27.1% (Hb < 11.0 gr/dl). Having four or more living children (OR = 2.2), being at the third trimester (OR = 2.3) and having a low family income (OR = 1.6) were determined as the independent predictors of anemia in pregnancy. Anemia was also associated with soil eating (PICA) in the univariate analysis (p < 0.05). Of anaemic women, 50.0% had a transferrin saturation less than 10% indicating iron deficiency, 34.5% were deficient in B12 vitamin and 71.7% were deficient in folate. Most of the anemias were normocytic-normochromic (56.5%) indicating mixed anemia. In Malatya, for pregnant women anemia was a moderate public health problem. Coexisting of iron, folate and B vitamin deficiencies was observed among anaemics. To continue anemia control strategies with reasonable care and diligence was recommended.


Genome Analysis of a Verrucomicrobial Endosymbiont With a Tiny Genome Discovered in an Antarctic Lake.
Organic Lake in Antarctica is a marine-derived, cold (-13∘C), stratified (oxic-anoxic), hypersaline (>200 gl-1) system with unusual chemistry (very high levels of dimethylsulfide) that supports the growth of phylogenetically and metabolically diverse microorganisms. Symbionts are not well characterized in Antarctica. However, unicellular eukaryotes are often present in Antarctic lakes and theoretically could harbor endosymbionts. Here, we describe Candidatus Organicella extenuata, a member of the Verrucomicrobia with a highly reduced genome, recovered as a metagenome-assembled genome with genetic code 4 (UGA-to-Trp recoding) from Organic Lake. It is closely related to Candidatus Pinguicocccus supinus (163,218 bp, 205 genes), a newly described cytoplasmic endosymbiont of the freshwater ciliate Euplotes vanleeuwenhoeki (Serra et al., 2020). At 158,228 bp (encoding 194 genes), the genome of Ca. Organicella extenuata is among the smallest known bacterial genomes and similar to the genome of Ca. Pinguicoccus supinus (163,218 bp, 205 genes). Ca. Organicella extenuata retains a capacity for replication, transcription, translation, and protein-folding while lacking any capacity for the biosynthesis of amino acids or vitamins. Notably, the endosymbiont retains a capacity for fatty acid synthesis (type II) and iron-sulfur (Fe-S) cluster assembly. Metagenomic analysis of 150 new metagenomes from Organic Lake and more than 70 other Antarctic aquatic locations revealed a strong correlation in abundance between Ca. Organicella extenuata and a novel ciliate of the genus Euplotes. Like Ca. Pinguicoccus supinus, we infer that Ca. Organicella extenuata is an endosymbiont of Euplotes and hypothesize that both Ca. Organicella extenuata and Ca. Pinguicocccus supinus provide fatty acids and Fe-S clusters to their Euplotes host as the foundation of a mutualistic symbiosis. The discovery of Ca. Organicella extenuata as possessing genetic code 4 illustrates that in addition to identifying endosymbionts by sequencing known symbiotic communities and searching metagenome data using reference endosymbiont genomes, the potential exists to identify novel endosymbionts by searching for unusual coding parameters.


Insights from dietitians providing individualised dietetic care to people living with disabilities: A single site exploration in the community.
The present study aims to share insights and lessons learnt by dietitians providing individualised care to people living with disabilities in the community. This is important to build the evidence to inform dietetic best practice standards. The study involved a cross-sectional data audit of dietitian reports for clients living with a disability seen at a metropolitan dietitian clinic in South Australia. Content analysis of the reports was conducted. Initial coding occurred deductively followed by inductive qualitative content analysis. Thirty-one participants consented to have their dietitian reports included in the study. Intellectual disabilities made up the majority (48%) of disabilities reported in the sample. Nutrition diagnoses predominantly related to energy imbalances (54%). Barriers to dietary change included a reliance on others and limitations in the disability support system. Kitchen skills and cooking were the most often employed nutrition strategy suggested by dietitians. Following dietetic intervention, improvements were seen in the types of foods people with a disability consumed along with changes to their body weight. Dietitians reported the importance of effective communication with the care team and providing engaging methods to instigate dietary behaviour change. The present study highlights that there are opportunities to build on individualised dietetic care provided to people living with disabilities. These opportunities include addressing excess energy consumption, fostering collaborations with other health providers and understanding how to better work with carers. Further research is required to understand how to progress these opportunities forward and to understand the generalisability of the findings.


Allosteric modulation of muscarinic acetylcholine receptors.
Muscarinic acetylcholine receptors (mAChRs) are prototypical Family A G protein coupled-receptors. The five mAChR subtypes are widespread throughout the periphery and the central nervous system and, accordingly, are widely involved in a variety of both physiological and pathophysiological processes. There currently remains an unmet need for better therapeutic agents that can selectively target a given mAChR subtype to the relative exclusion of others. The main reason for the lack of such selective mAChR ligands is the high sequence homology within the acetylcholine-binding site (orthosteric site) across all mAChRs. However, the mAChRs possess at least one, and likely two, extracellular allosteric binding sites that can recognize small molecule allosteric modulators to regulate the binding and function of orthosteric ligands. Extensive studies of prototypical mAChR modulators, such as gallamine and alcuronium, have provided strong pharmacological evidence, and associated structure-activity relationships (SAR), for a "common" allosteric site on all five mAChRs. These studies are also supported by mutagenesis experiments implicating the second extracellular loop and the interface between the third extracellular loop and the top of transmembrane domain 7 as contributing to the common allosteric site. Other studies are also delineating the pharmacology of a second allosteric site, recognized by compounds such as staurosporine. In addition, allosteric agonists, such as McN-A-343, AC-42 and N-desmethylclozapine, have also been identified. Current challenges to the field include the ability to effectively detect and validate allosteric mechanisms, and to quantify allosteric effects on binding affinity and signaling efficacy to inform allosteric modulator SAR.


Delayed Admissions to the Pediatric Intensive Care Unit: Progression of Disease or Errors in Emergency Department Management.
Few studies have evaluated impact of emergency department (ED) management on delayed transfers to the pediatric intensive care unit (PICU). Our study objectives were to describe patient characteristics of PICU transfers less than or equal to 12 hours of admission and determine the reason for transfer. We conducted a retrospective chart review of patients transferred to PICU less than or equal to 12 hours of admission. We extracted patient demographics, emergency severity index category, ED, floor and PICU length of stay (LOS), and PICU "significant" interventions. Charts were reviewed independently by the study principal investigator and a PICU attending who classified transfers as secondary to progression of disease or error in ED management. Furthermore, errors were classified as diagnostic, management, or disposition errors. A total of 164 patients met inclusion criteria. Most were male (86/164, 52.4%), with emergency severity index category 2 (116/164, 70.7%) and respiratory diagnosis (98/164, 59.8%). Most transfers (136/164, 82.9%) resulted from progression of illness. No significant interventions were performed in 48.8% (80/164) of patients. Of 164 transfers, 28 (17.1%) resulted from ED error, and half of these were management errors. Compared with disease progression, the ED error group had a significantly shorter median floor LOS {3.45 [interquartile range (IQR): 2.15, 7.56] vs 6.58 (IQR: 3.70, 9.20); P = 0.005}, more PICU interventions [1.5 (IQR: 0, 4) vs 0 (IQR: 0, 2); P = 0.006], and longer PICU LOS [2.50 (IQR: 1.09, 4.25) vs 1.36 (IQR: 0.80, 2.50); P = 0.013]. Most PICU transfers less than or equal to 12 hours after admission result from illness progression. Half of these do not require significant interventions. The PICU transfers after ED management error had significantly shorter floor LOS, longer PICU LOS, and more interventions.


Melanocortin 3 receptor activation with [D-Trp8]-γ-MSH suppresses inflammation in apolipoprotein E deficient mice.
The melanocortin MC1 and MC3 receptors elicit anti-inflammatory actions in leukocytes and activation of these receptors has been shown to alleviate arterial inflammation in experimental atherosclerosis. Thus, we aimed to investigate whether selective targeting of melanocortin MC3 receptor protects against atherosclerosis. Apolipoprotein E deficient (ApoE-/-) mice were fed high-fat diet for 12 weeks and randomly assigned to receive either vehicle (n = 11) or the selective melanocortin MC3 receptor agonist [D-Trp(8)]-gamma-melanocyte-stimulating hormone ([D-Trp8]-γ-MSH; 15 μg/day, n = 10) for the last 4 weeks. Lesion size as well as macrophage and collagen content in the aortic root plaques were determined. Furthermore, leukocyte counts in the blood and aorta and cytokine mRNA expression levels in the spleen, liver and aorta were quantified. No effect was observed in the body weight development or plasma cholesterol level between the two treatment groups. However, [D-Trp8]-γ-MSH treatment significantly reduced plasma levels of chemokine (C-C motif) ligands 2, 4 and 5. Likewise, cytokine and adhesion molecule expression levels were reduced in the spleen and liver of γ-MSH-treated mice, but not substantially in the aorta. In line with these findings, [D-Trp8]-γ-MSH treatment reduced leukocyte counts in the blood and aorta. Despite reduced inflammation, [D-Trp8]-γ-MSH did not change lesion size, macrophage content or collagen deposition of aortic root plaques. In conclusion, the findings indicate that selective activation of melanocortin MC3 receptor by [D-Trp8]-γ-MSH suppresses systemic and local inflammation and thereby also limits leukocyte accumulation in the aorta. However, the treatment was ineffective in reducing atherosclerotic plaque size.


Danazol for the Treatment of Myelodysplastic Syndromes: A Systematic Review.
Purpose To study the potential utility of danazol for treating patients with myelodysplastic syndromes, with a focus on efficacy and adverse effects (AEs). Methods MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus were searched for relevant publications from inception June 1, 1950, until June 28, 2022. The studies were screened by title and abstract, followed by full-text screening. The quality of the included studies was assessed via a prespecified set of questionnaires. Data on the efficacy measures and adverse outcomes were extracted and included in a descriptive summary. Results Nine studies consisting of 246 participants were included in our review. The overall quality of the included studies was fair. The age of the participants ranged from 61 to 78 years. In all 9 studies, more male patients had been enrolled than female patients. Overall, a proportion of patients in all the studies reported a desired major response to a danazol dose of 400 to 800 mg/day. Few studies did not observe any improvement in the platelet count. Elevated liver enzyme levels, weight gain, headache, dermatitis, and weakness were the most common AEs observed. One study reported a fatal intracerebral hemorrhage in 1 participant. Conclusions Danazol has been effective in increasing platelet count and hemoglobin level. Despite a few AEs, danazol is a safe drug for the treatment of patients with myelodysplastic syndromes.


Heritability of heart rate recovery and vagal rebound after exercise.
The prognostic power of heart rate recovery (HRR) after exercise has been well established but the exact origin of individual differences in HRR remains unclear. This study aims to estimate the heritability of HRR and vagal rebound after maximal exercise in adolescents. Furthermore, the role of voluntary regular exercise behavior (EB) in HRR and vagal rebound is tested. 491 healthy adolescent twins and their siblings were recruited for maximal exercise testing, followed by a standardized cooldown with measurement of the electrocardiogram and respiratory frequency. Immediate and long-term HRR (HRR60 and HRR180) and vagal rebound (heart rate variability in the respiratory frequency range) were assessed 1 and 3 min after exercise. Multivariate twin modeling was used to estimate heritability of all measured variables and to compute the genetic contribution to their covariance. Heritability of HRR60, HRR180 and immediate and long-term vagal rebound is 60 % (95 % CI: 48-67), 65 % (95 % CI: 54-73), 23 % (95 % CI: 11-35) and 3 % (95 % CI: 0-11), respectively. We find evidence for two separate genetic factors with one factor influencing overall cardiac vagal control, including resting heart rate and respiratory sinus arrhythmia, and a specific factor for cardiac vagal exercise recovery. EB was only modestly associated with resting heart rate (r = -0.27) and HRR (rHRR60 = 0.10; rHRR180 = 0.19) with very high genetic contribution to these associations (88-91 %). Individual differences in HRR and immediate vagal rebound can to a large extent be explained by genetic factors. These innate cardiac vagal exercise recovery factors partly reflect the effects of heritable differences in EB.


2-Dodecylcyclobutanone, a radiolytic product of palmitic acid, is genotoxic in primary human colon cells and in cells from preneoplastic lesions.
The irradiation of fat results in the formation of 2-alkylcyclobutanones, a new class of food contaminants. Results of previous in vitro studies with primary human colon cells and in vivo experiments with rats fed with 2-alkylcyclobutanones indicated that these radiolytic derivatives may be genotoxic and enhance the progression of colon tumors. The underlying mechanisms of these effects, however, are not clearly understood. Therefore we performed additional investigations to elucidate the genotoxic potential of 2-dodecylcyclobutanone (2dDCB) that is generated from palmitic acid. In particular, we explored the relative sensitivities of human colon cells, representing different stages of tumor development and healthy colon tissues, respectively. HT29clone19A cells, LT97 adenoma cells and primary human epithelial cells were exposed to 2dDCB (150-2097 microM). We determined cytotoxic effects using trypan blue exclusion. Genotoxicity, reflected as strand breaks, was assessed using the alkaline version of the comet assay and chromosomal abnormalities were investigated by 24-color fluorescence-in-situ-hybridization. 2dDCB was cytotoxic in a time- and dose-dependent manner in LT97 adenoma cells and in freshly isolated primary cells but not in the human colon tumor cell line. Associated with this was a marked induction of DNA damage by 2dDCB in LT97 adenoma cells and in freshly isolated colonocytes, whereas in the HT29clone19A cells no strand breaks were detectable. A long-term incubation of LT97 adenoma cells with lower concentrations of 2dDCB revealed cytogenetic effects. In summary, 2dDCB was clearly genotoxic in healthy human colon epithelial cells and in cells representing preneoplastic colon adenoma. These findings provide additional evidence that this compound may be regarded as a possible risk factor for processes in colon carcinogenesis related to initiation and progression.


The neurobiology of APOE in schizophrenia and mood disorders.
APOE is a major component of several lipoproteins. In addition to its role as a lipid transport protein APOE also serves a dual role as a glial derived, synaptic signalling molecule and thought to play an important role in synaptic plasticity and cognition. Polymorphisms within the APOE gene have been associated with the incidence of Alzheimer's disease. In light of the similarities in the cognitive deficits experienced in both Alzheimer's disease and schizophrenia as well as the comorbidity of depression in Alzheimer's disease, aberrant APOE signalling has been implicated in the pathologies of schizophrenia and mood disorders. The schizophrenia candidate gene, reelin, also shares common receptors with APOE, further supporting a role for APOE in the pathology of these disorders. This review will summarise the current understanding of the involvement of APOE and its receptors in the symptomatology and pathology of schizophrenia and mood disorders and the implications of this involvement for drug treatment.


Intergenerational effects of nutrition on immunity: a systematic review and meta-analysis.
Diet and immunity are both highly complex processes through which organisms interact with their environment and adapt to variable conditions. Parents that are able to transmit information to their offspring about prevailing environmental conditions have a selective advantage by 'priming' the physiology of their offspring. We used a meta-analytic approach to test the effect of parental diet on offspring immune responses. Using the geometric framework for nutrition (a method for analysing diet compositions wherein food nutrient components are expressed as axes in a Cartesian coordinate space) to define dietary manipulations in terms of their energy and macronutrient compositions, we compiled the results of 226 experiments from 38 published papers on the intergenerational effects of diet on immunity, across a range of study species and immunological responses. We observed intergenerational impacts of parental nutrition on a number of offspring immunological processes, including expression of pro-inflammatory biomarkers as well as decreases in anti-inflammatory markers in response to certain parental diets. For example, across our data set as a whole (encompassing several types of dietary manipulation), dietary stress in parents was seen to significantly increase pro-inflammatory cytokine levels measured in offspring (overall d = 0.575). All studies included in our analysis were from experiments in which the offspring were raised on a normal or control diet, so our findings suggest that a nutrition-dependent immune state can be inherited, and that this immune state is maintained in the short term, despite offspring returning to an 'optimal' diet. We demonstrate how the geometric framework for nutrition can be used to disentangle the role that different forms of dietary manipulation can have on intergenerational immunity. For example, offspring B-cell responses were significantly decreased when parents were raised on a range of different diets. Similarly, our approach allowed us to show that a parental diet elevated in protein (regardless of energy composition and relative to a control diet) can increase expression of inflammatory markers while decreasing B-cell-associated markers. By conducting a systematic review of the literature, we have identified important gaps that impair our understanding of the intergenerational effects of diet, such as a paucity of experimental studies involving increased protein and decreased energy, and a lack of studies directed at the whole-organism consequences of these processes, such as immune resilience to infection. The results of our analyses inform our understanding of the effects of diet on physiological state across diverse biological fields, including biomedical sciences, maintenance of agricultural breed stock and conservation breeding programs, among others.


The effects of blueberry anthocyanins on histone acetylation in rat liver fibrosis.
To determine the effects ofanthocyanins from blueberries on hepatic stellate cell (HSCs-T6) and on histone acetylation during liver fibrosis induced by CCl4 in rats. Fifty male SD rats weighing 180 ± 20g were randomly placed into a control group, a hepatic fibrosis group, a blueberry treatment group, a blueberry intervention group, and a natural recovery group. After the rats were sacrificed, the livers and the liver indexes were measured, and the pathological changes were observed by HE staining and Masson staining. The blood was analyzed for the four indexes of liver fibrosis and liver function; nucleoprotein from liver tissues and karyoplasm were isolated to determine the expression of acH3K9, acH3K14, and acH3K18 by Western blotting. Compared with the lethal rate of the control group, the median lethal rate of HSCs-T6 cells treated with a the 50μmol/L concentration was 66.94% (P < 0.05). The protein expression on α-SMA, type I collagen, TIMP1 significantly decreased (P < 0.05) following treatment with 50 ug/ml of anthocyanin for 36 h; moreover, the expression of acH3K9, acH3K14 and acH3K18 modification were up-regulated (P < 0.05). Furthermore, compared with the liver in the model group, the liver in the intervention group showed the most obvious improvement (P < 0.01), and its karyoplasm had increased expression of acH3K9, acH3K14 and acH3K18 (P<0.01). Regulating histone acetylation could improve liver function and liver fibrosis indexes in rats with hepatic fibrosis. The mechanism might be related to certain genes that promote apoptosis, so as to inhibit the effect of anti hepatic fibrosis.


[Uretero-vesicovaginal fistula].
The paper outlines the problems in the diagnosis and treatment of associated ++uretero-vesicovaginal fistulas on the basis of a follow-up of 72 patients. The most informative diagnostic methods and effective operative techniques are proposed.


Sex-related impairment and patient needs/benefits in anogenital psoriasis: Difficult-to-communicate topics and their impact on patient-centred care.
Genital psoriasis affects 2-5% of psoriasis patients; generalised plaque or intertriginous psoriasis also affects the genital area in 29-40% of cases. Anogenital psoriasis has been associated with significant quality of life impairments, but little is known about specific patient needs/treatment goals. This study aimed to examine the overall and sex-related disease burden, patient needs and treatment benefits in patients with anogenital psoriasis, compared to patients with psoriasis not affecting the anal/genital areas. Within the cross-sectional nationwide survey, 2,009 participants were consecutively recruited in 157 randomly assigned German dermatology practices and clinics, according to the following inclusion criteria aged 18 years or over; diagnosis of psoriasis vulgaris; ability to answer the questionnaires; and written informed consent. Based on a high-resolution grid on the topical distribution of psoriasis, two groups were formed: anogenital psoriasis (n = 622) and comparison group (n = 1,303). Clinical severity was assessed by the Psoriasis Area and Severity Index (PASI). Patients completed the EuroQoL visual analogue scale (EQ VAS), the Dermatology Life Quality Index (DLQI), and the Patient Benefit Index (PBI). Patients with anogenital psoriasis had higher PASI (13.0±10.6 vs. 8.9±7.6, P < 0.001) and more DLQI impairments (8.9±6.9 vs. 7.0±6.2, P = 0.002) than controls. At the item-level, they also reported more sex-related DLQI impairments (DLQI-i9: 0.5±0.8 vs. 0.3±0.7, P < 0.001) and treatment needs (PBI-i17: 2.2±1.8 vs. 1.9±1.8, P = 0.001). A great percentage of missing/not-relevant responses was found for sex-related items (23.3-41.9%). These results suggest that the assessment of sex-related impairments and treatment needs should be prioritised in patients with anogenital psoriasis. Questionnaires may be used as a less uncomfortable way for patients to discuss their genital lesions and sexual function during healthcare visits. However, the great percentage of missing/not-relevant responses to sex-related items calls for in-depth assessments and effective patient-physician communication regarding these sensitive topics.


Renoprotection of Kolaviron against benzo (A) pyrene-induced renal toxicity in rats.
Benzo(a)pyrene (B[a]P), a polycyclic aromatic hydrocarbon generally formed from incomplete combustion of organic matter, reportedly causes renal injury and elicits a nephropathic response. The present study investigated the modulatory effect of Kolaviron, an isolated bioflavonoid from the seed of Garcinia kola, on renal toxicity induced by B[a]P in Wistar rats. Benzo[a]pyrene was administered at a dose of 10 mg/kg alone or in combination with Kolaviron at 100 and 200 mg/kg for 15 d. Administration of B[a]P alone resulted in significant increase in plasma levels of urea and creatinine in the treated rats. Moreover, B[a]P exposure significantly decreased the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione-s-transferase (GST) as well as glutathione (GSH) level in the kidneys of treated rats. Conversely, myeloperoxidase (MPO) activity, hydrogen peroxide (H2O2) and malondialdehyde (MDA) levels were markedly elevated in kidneys of B[a]P-treated rats compared with control. Further, B[a]P exposure significantly decreased the circulatory concentrations of triiodothyronine (T3) and T3/T4 ratio without affecting thyroxine (T4) in the treated rats. Light microscopy revealed tubular lumen with numerous protein casts in kidneys of rats exposed to B[a]P alone. Kolaviron co-treatment significantly improved the renal antioxidant status, thyroid gland function and restored the renal histology, thus demonstrating the protective effect of Kolaviron in B[a]P-treated rats. Dietary inclusion of Kolaviron could exert protective effects against renal toxicity resulting from B[a]P exposure.


Ubiquitin-mediated protein degradation and methylation-induced gene silencing cooperate in the inactivation of the INK4/ARF locus in Burkitt lymphoma cell lines.
Burkitt lymphoma is one of the most aggressive tumors affecting humans. Together with the characteristic chromosomal translocation that constitutively activates the c-Myc oncogene, alterations in cellular tumor suppressor pathways are additionally required in order to allow the cells to overcome anti-oncogenic barriers and proliferate in an uncontrolled manner. The INK4a/ARF locus on chromosome 9p21 is considered a safeguard locus since it encodes the two important tumor suppressor proteins, p14(ARF) and p16(INK4a). By regulating the p53 and Rb pathways p14(ARF) and p16(INK4a) respectively act as pro-apoptotic and cell cycle inhibitor proteins. The importance of the INK4a/ARF locus has been well documented in several human tumors as well as in Burkitt lymphoma. Although the mechanisms responsible for the transcriptional regulation of the INK4a/ARF locus have been thoroughly characterized, less is known about its posttranscriptional control. In this study we found that p16(INK4a) and p14(Arf) are concurrently inactivated in a panel of BL cell lines. We demonstrate that along with the epigenetic silencing of the p16INK4a gene, the complete inactivation of the locus is achieved by the improper turnover of INK4/ARF proteins by the ubiquitin-proteasome system (UPS), as the proteasome inhibitor MG-132 blocks p14(ARF) degradation and induces a dramatic stabilization of the p16(INK4a) protein. We establish that the simultaneous deregulation of both DNA methylation patterns and the ubiquitin-dependent proteolysis system is required to completely inactive the INK4/ARF locus, opening new prospects for the understanding and treatment of Burkitt lymphoma.


DNMT3B-mediated FAM111B methylation promotes papillary thyroid tumor glycolysis, growth and metastasis.
Over the past decades, the incidence of thyroid cancer (TC) rapidly increased all over the world, with the papillary thyroid cancer (PTC) accounting for the vast majority of TC cases. It is crucial to investigate novel diagnostic and therapeutic targets for PTC and explore more detailed molecular mechanisms in the carcinogenesis and progression of PTC. Based on the TCGA and GEO databases, FAM111B is downregulated in PTC tissues and predicts better prognosis in PTC patients. FAM111B suppresses the growth, migration, invasion and glycolysis of PTC both in vitro and in vivo. Furthermore, estrogen inhibits FAM111B expression by DNMT3B methylation via enhancing the recruitment of DNMT3B to FAM111B promoter. DNMT3B-mediated FAM111B methylation accelerates the growth, migration, invasion and glycolysis of PTC cells. In clinical TC patient specimens, the expression of FAM111B is inversely correlated with the expressions of DNMT3B and the glycolytic gene PGK1. Besides, the expression of FAM111B is inversely correlated while DNMT3B is positively correlated with glucose uptake in PTC patients. Our work established E2/DNMT3B/FAM111B as a crucial axis in regulating the growth and progression of PTC. Suppression of DNMT3B or promotion of FAM111B will be potential promising strategies in the estrogen induced PTC.


Foodstate vitamin C complex may beneficially affect haemostasis and fibrin network structure in hyperlipidaemic patients.
This randomized, placebo-controlled, double-blind, crossover study on 25 free-living hyperlipidaemic volunteers aspired to prove the hypothesis that supplementation for 8 weeks with a FoodState Vitamin C complex (500 mg vitamin C, 160 mg bioflavonoids, 600 mg magnesium and 900 mg vitamin B complex) may improve haemostatic factors and fibrin network structures. Of the haemostatic factors measured, only median plasmin-antiplasmin complex (PAP) and thrombin-antithrombin complex (TAT) concentrations were both significantly decreased with FoodState Vitamin C complex compared with placebo [PAP, -4.05% (-23.39, -0.23) versus 1.81% (-8.95, 8.09); TAT, -5.81% (-18.47, 0.39) versus 0.12% (-8.03, 13.5)]. As for fibrin network structures, only compaction was significantly increased from baseline to end [49.95% (47.55, 53.70) to 51.85% (48.55, 56.65)] by FoodState Vitamin C complex supplementation. No significant changes were found in plasma fibrinogen, plasminogen activator inhibitor 1 activity, tissue plasminogen activator antigen, D-dimer, serum lipids or lipoprotein (a) concentrations. In conclusion, the decreases in TAT and PAP are possibly an indication that the FoodState Vitamin C complex decreased the initiation of haemostasis, which in turn led to a compensatory reduction in fibrinolysis. FoodState Vitamin C complex may therefore be protective of cardiovascular disease by causing a new reduced steady state of haemostatic balance and less rigid clots (increased compaction).


Effects of multiple stressors on cyanobacteria abundance vary with lake type.
Blooms of cyanobacteria are a current threat to global water security that is expected to increase in the future because of increasing nutrient enrichment, increasing temperature and extreme precipitation in combination with prolonged drought. However, the responses to multiple stressors, such as those above, are often complex and there is contradictory evidence as to how they may interact. Here we used broad scale data from 494 lakes in central and northern Europe, to assess how cyanobacteria respond to nutrients (phosphorus), temperature and water retention time in different types of lakes. Eight lake types were examined based on factorial combinations of major factors that determine phytoplankton composition and sensitivity to nutrients: alkalinity (low and medium-high), colour (clear and humic) and mixing intensity (polymictic and stratified). In line with expectations, cyanobacteria increased with temperature and retention time in five of the eight lake types. Temperature effects were greatest in lake types situated at higher latitudes, suggesting that lakes currently not at risk could be affected by warming in the future. However, the sensitivity of cyanobacteria to temperature, retention time and phosphorus varied among lake types highlighting the complex responses of lakes to multiple stressors. For example, in polymictic, medium-high alkalinity, humic lakes cyanobacteria biovolume was positively explained by retention time and a synergy between TP and temperature, while in polymictic, medium-high alkalinity, clear lakes only retention time was identified as an explanatory variable. These results show that, although climate change will need to be accounted for when managing the risk of cyanobacteria in lakes, a "one-size fits-all" approach is not appropriate. When forecasting the response of cyanobacteria to future environmental change, including changes caused by climate and local management, it will be important to take this differential sensitivity of lakes into account.


F2Cor: fast 2-stage correlation algorithm for FCS and DLS.
We present a new multiple-tau correlation algorithm which is the fastest to date. The resulting curve is identical to that obtained with the conventional multiple-tau algorithm, but the calculation time is much shorter. It combines two approaches. For short values of the lag-time a very simple correlation histogram is used, while for higher lag-time values the traditional multiple-tau bin-and-multiply approach is used. The lag-time limit between these two stages depends on the count rate. The computation time scales linearly with the count rate and is as fast as 0.1 µs/photon.


Bioenergetic considerations in cereal breeding for protein improvement.
The bioenergetic implications of changing cereal grain protein concentrations and amino acid compositions by plant breeding are examined. It is shown that increased inputs of carbon assimilates and nitrogen are necessary when increasing protein concentration in cereal grains while maintaining high yields. Also, energetic requirements for obtaining endosperm proteins with a high lysine content in genotypes of maize and barley are slightly higher than in normal lysine stocks. The implications for plant breeding are discussed.


Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia.
We assessed the efficacy and safety of tadalafil dosed once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia. Following a 4-week, single-blind, placebo run-in 281 men were randomly assigned (1:1) to 5 mg tadalafil for 6 weeks, followed by dose escalation to 20 mg for 6 weeks or 12 weeks of placebo. Tadalafil significantly improved the mean change from baseline in International Prostate Symptom Score at 6 weeks (5 mg tadalafil -2.8 vs placebo -1.2) and at 12 weeks (5/20 mg tadalafil -3.8 vs placebo -1.7). Larger changes were observed with inclusion of the placebo run-in at 12 weeks (5/20 mg tadalafil -7.1 vs placebo -4.5). Significant improvements were also seen in the International Prostate Symptom Score irritative and obstructive domains, the International Prostate Symptom Score quality of life index, a question about urinary symptom improvement and the Benign Prostatic Hyperplasia Impact Index (significant at 12 weeks) vs placebo. International Prostate Symptom Score and International Index of Erectile Function erectile function domain scores significantly improved in the 56% of men with lower urinary tract symptoms/benign prostatic hyperplasia who were sexually active and had erectile dysfunction. Changes in uroflowmetry parameters were similar in the placebo and tadalafil groups. Commonly reported (2% or greater) treatment emergent adverse events were "erection increased," dyspepsia, back pain, headache, nasopharyngitis and upper respiratory tract infection (each 5.1% or less). No change in post-void residual volume was seen with tadalafil treatment. Tadalafil once daily was well tolerated and demonstrated clinically meaningful and statistically significant symptomatic improvement for lower urinary tract symptoms/benign prostatic hyperplasia. Tadalafil also improved erectile function in men with lower urinary tract symptoms and erectile dysfunction.


Maternal deaths in NSW (2000-2006) from nonmedical causes (suicide and trauma) in the first year following birth.
Trauma, including suicide, accidental injury, motor traffic accidents, and homicides, accounts for 73% of all maternal deaths (early and late) in NSW annually. Late maternal deaths are underreported and are not as well documented or acknowledged as early deaths. Linked population datasets from births, hospital admissions, and death registrations were analysed for the period from 1 July 2000 to 31 December 2007. There were 552,901 births and a total of 129 maternal deaths. Of these deaths, 37 were early deaths (early MMR of 6.7/100,000) and 92 occurred late (late MMR of 16.6/100,000). Sixty-seven percent of deceased women had a mental health diagnosis and/or a mental health issue related to substance abuse noted. A notable peak in deaths appeared to occur from 9 to 12 months following birth with the odds ratio of a woman dying of nonmedical causes within 9-12 months of birth being 3.8 (95% CI 1.55-9.01) when compared to dying within the first 3 months following birth. Perinatal services are often constructed to provide short-term support. Long-term identification and support of women at particular risk of maternal death due to suicide and trauma in the first year following birth may help lower the incidence of late maternal deaths.


[In vitro sensitivity of epidermoid lung cancer to cytostatics depending upon the degree of tumor differentiation].
In vitro sensitivity of epidermoid lung carcinoma to chemotherapeutic agents in short-term cultures versus degree of tumor differentiation was evaluated for the following drugs: 5-fluorouracil, methotrexate, olivomycin, bleomycin, carminomycin, adriablastin, prospidium chloride, vincristine, thiophosphamide, novembichine and photrine. The results of the investigation using resected material from 77 cases of histologically confirmed epidermoid lung carcinoma failed to establish any relationship between the parameters under study for all above drugs except vincristine. However, tumors showing similar levels of differentiation demonstrated different sensitivity to certain drugs.


Wolfram Syndrome Type 2: A Systematic Review of a Not Easily Identifiable Clinical Spectrum.
Wolfram syndrome (WS) is a rare autosomal recessive disorder that is characterized by the presence of diabetes mellitus, optic atrophy and hearing loss, all of which are crucial elements for the diagnosis. WS is variably associated with diabetes insipidus, neurological disorders, urinary tract anomalies, endocrine dysfunctions and many other systemic manifestations. Since Wolfram and Wagener first described WS in 1938, new phenotypic/genotypic variants of the syndrome have been observed and the clinical picture has been significantly enriched. To date, two main subtypes of WS that associated with two different mutations are known: WS type 1 (WS1), caused by the mutation of the wolframine gene (WS1; 606201), and WS type 2 (WS2), caused by the mutation of the CISD2 gene (WS2; 604928). A systematic review of the literature was describe the phenotypic characteristics of WS2 in order to highlight the key elements that differentiate it from the classic form. WS2 is the rarest and most recently identified subtype of WS; its clinical picture is partially overlapping with that of WS1, from which it traditionally differs by the absence of diabetes insipidus and the presence of greater bleeding tendency and peptic ulcers.


Activation of adenosine A2a receptor pathway reduces leukocyte infiltration but enhances edema formation in rat caerulein pancreatitis.
Adenosine plays important roles in a variety of pathophysiologic conditions through receptor-mediated mechanisms. Recent studies have shown that adenosine exerts potent anti-inflammatory properties that are chiefly brought about through the occupancy of the A2a receptor. To examine the effect of A2a receptor stimulation or inhibition on the pathologic findings during acute pancreatitis. Rats were randomized into three groups and received a selective A2a receptor agonist CGS-21680 (CGS), a selective A2a antagonist 3,7-dimethyl-1-[2-propynyl]-xanthine (DMPX), or saline. Thirty minutes after the injection, acute pancreatitis was produced in the rats by seven intraperitoneal injections of caerulein. The severity of acute pancreatitis was evaluated by serum amylase activity, pancreas myeloperoxidase (MPO) activity, Evans blue extravasation, and pathologic changes of the pancreas. In addition, we investigated the effects of CGS on the pathologic findings of caerulein pancreatitis induced in neutrophil-depleted rats. Administration of caerulein produced hyperamylasemia and morphologic changes of the pancreas including interstitial edema, acinar cell vacuolization, and infiltration of inflammatory cells. In CGS-treated rats, the pancreatic edema and the Evans blue extravasation were aggravated significantly compared with those of saline-treated rats, whereas leukocyte infiltration and MPO activity of the pancreas were decreased. In contrast to CGS, administration of DMPX ameliorated the pancreatic edema and Evans blue extravasation. Treatment with CGS accelerated the pancreatic edema in pancreatitis even after the depletion of neutrophils. The activation of adenosine A2a receptors modulates the pathology of acute pancreatitis through at least two diverse properties. One is an anti-inflammatory effect involving neutrophils, and the other is a propagating effect for pancreatic edema formation. The actions of the A2a receptor pathways are unique, and they may have an important role in the progression of acute pancreatitis.


Lazarillo, a new GPI-linked surface lipocalin, is restricted to a subset of neurons in the grasshopper embryo.
Lazarillo, a protein recognized by the monoclonal antibody 10E6, is expressed by a subset of neurons in the developing nervous system of the grasshopper. It is a glycoprotein of 45x10(3) M(r) with internal disulfide bonds and linked to the extracellular side of the plasma membrane by a glycosylphosphatidylinositol moiety. Peptide sequences obtained from affinity purified adult protein were used to identify an embryonic cDNA clone, and in situ hybridizations confirmed that the distribution of the Lazarillo mRNA paralleled that of the monoclonal antibody labeling on embryos. Sequence analysis defines Lazarillo as a member of the lipocalin family, extracellular carriers of small hydrophobic ligands, and most related to the porphyrin- and retinol-binding lipocalins. Lazarillo is the first example of a lipocalin anchored to the plasma membrane, highly glycosylated, and restricted to a subset of developing neurons.


Anorexia Nervosa, Autism, and the ADOS: How Appropriate Is the New Algorithm in Identifying Cases?
Thirty years of scholarship has suggested that anorexia nervosa (AN) may be a "female presentation" of autism, supported by work which has found elevated rates of autism traits and diagnoses among women with clinical levels of AN. These traits are often assessed using the Autism Diagnostic Observation Schedule 2nd Edition (ADOS-2), considered the "gold-standard" tool. Recently, the authors of the ADOS-2 revised the diagnostic algorithm for the adult version of the assessment-the one most often used with AN patients. We therefore examined differences in the scores, rates of diagnosis, and correlations with other mental health issues between the two diagnostic algorithms among women with and without AN. One hundred seventy-five women with current AN, who had recovered from AN, and with no history of AN, between the ages of 12 and 53, took part in an ADOS-2 assessment. Their scores were then calculated according to both the original and the new algorithms. The new ADOS-2 algorithm identifies more women as potentially being on the autism spectrum than the old algorithm. Under both algorithms, more currently ill AN patients were identified as potentially being autistic than those with no history of AN. Recovered individuals represented a midpoint between the scores of those with and without AN on both algorithms. There were no correlations with mental health scores in any group, meaning that the new ADOS-2 algorithm is not falsely identifying anxious behaviors or depressive presentations as signs of autism in this group. Overall, we found that more AN patients and recovered individuals scored above cut-off on the new ADOS-2 algorithm, suggesting that women who experience AN may have more autistic traits, which in part persist following weight restoration and recovery. However, the ADOS-2 should not be used alone but in combination with broader clinical assessments to determine whether an autism diagnosis is appropriate for these women.


Decreased S100B expression in chronic liver diseases.
Hepatic innervation in liver diseases is not fully understood. We here evaluated S100B expression as a marker of hepatic nerves in patients with various chronic liver diseases, topographically and semi-quantitatively. Liver specimens were obtained from 70 subjects (three controls, and 32 chronic hepatitis B, 14 chronic hepatitis C, 14 liver cirrhosis, and seven hepatocellular carcinoma patients). The hepatic nerve density was calculated based on immunohistochemical staining of S100B protein in the portal tracts and hepatic lobules. S100B mRNA levels were semi-quantitatively assessed as the S100B/glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA ratio. The densities of the hepatic nerves in portal tracts of chronic liver diseases were not significantly different from those of normal controls but the hepatic nerve densities in lobular areas of liver cirrhosis were significantly decreased (p = 0.025). Compared to the control, the S100B/GAPDH mRNA ratio was significantly decreased in chronic liver diseases (p = 0.006) and most decreased in chronic hepatitis C patients (p = 0.023). In chronic liver diseases, The S100B/GAPDH mRNA ratio tended to decrease as the fibrosis score > 0 (p = 0.453) but the overall correlation between the S100B/GAPDH mRNA ratio and fibrosis score was not statistically significant (r = 0.061, p = 0.657). Hepatic innervation is decreased in cirrhotic regenerating nodules compared to the control group and seems to decrease in early stages of fibrosis progression. Further studies are needed to clarify the association between changes of hepatic innervation and chronic liver disease progression.


Characterization of multidrug resistance by fluorescent dyes.
Fluorimetric techniques were used to examine accumulation of fluorescent probes by the P388 murine leukemia and an anthracycline-resistant subline, P388/Adriamycin(ADR), which expresses the multidrug-resistant phenotype. P388 could be differentiated from P388/ADR on the basis of fluorescence intensity measurements using 3 classes of cationic dyes that are sensitive to membrane potential differences: rhodamine esters, cyanines, and styrylpyridinium dyes. But fluorescence intensity differences were also observed with potential-insensitive dyes: zwitterionic rhodamines and an acridine orange derivative. In all cases, fluorescence intensity differences were caused by impaired dye accumulation, and could be eliminated by treatment of P388/ADR cells with verapamil. Moreover, fluorescence signals from 2 anionic potential-sensitive dyes, merocyanine 540 and a bis-oxonol, were identical in P388 and P388/ADR. None of these dyes could be used to delineate CCRF-CEM, a lymphoblastic leukemia of human origin from the CEM/VM-1 subline that exhibits a markedly atypical drug resistance pattern not based on an enhanced outward transport. But accumulation of both neutral and cationic dyes was impaired in CEM/VLB100, a subline of CCRF-CEM expressing mdr. These studies show that many cationic and neutral fluorescent probes are substrates for the enhanced outward drug transport system associated with P388/ADR cells, and cannot be used to probe membrane-potential differences in cells expressing the mdr phenotype. With several dyes, differences in fluorescence intensity were sufficient so that flow cytometry could be used to delineate P388 from P388/ADR and CCRF-CEM from CEM-VLB100. The latter technique may be useful for identifying malignant cell populations expressing multidrug resistance in patients with neoplastic disease.


Measurement of cerebral blood flow by intravenous xenon-133 technique and a mobile system. Reproducibility using the Obrist model compared to total curve analysis.
The recent development of a mobile 10 detector unit, using i.v. Xenon-133 technique, has made it possible to perform repeated bedside measurements of cerebral blood flow (CBF). Test-retest studies were carried out in 38 atherosclerotic subjects, in order to evaluate the reproducibility of CBF level and side-to-side asymmetry. Data were analysed according to the Obrist model and the results compared with those obtained using a model correcting for the air passage artifact. Reproducibility was of the same order of magnitude as reported using stationary equipment. The side-to-side CBF asymmetry was considerably more reproducible than CBF level. Using a single detector instead of five regional values averaged as the hemispheric flow increased standard deviation of CBF level by 10-20%, while the variation in asymmetry was doubled. In optimal measuring conditions the two models revealed no significant differences, but in low flow situations the artifact model yielded significantly more stable results. The present apparatus, equipped with 3-5 detectors covering each hemisphere, offers the opportunity of performing serial CBF measurements in situations not otherwise feasible.


Incidental findings in chest computed tomography of patients with thoracic trauma: what we need to know.
This study emphasizes the importance of appropriately evaluating incidental findings (IF) detected in chest computed tomography (CCTs) of patients with trauma and provides related guidance and information. All patients aged ≥ 18 years who were admitted to the emergency department and underwent CCT for thoracic trauma were retrospectively screened, and 567 patients were included in the study. The findings were divided into five groups: those requiring immediate intervention, clinical evaluation, additional examination, and control examination after follow-up and those not requiring follow-up. Additionally, to evaluate the emergency reporting of these pathologies, the CCT reports were evaluated to reveal the IF rate. The mean age of the 567 patients was 47.96 ± 19.38 years (18-102 years); of which, 372 (65.6%) were male and 195 (34.4%) were female. At least one IF was observed in 261 (46%) patients. The lungs of 81 (13.6%) patients exhibited the highest rate of IFs. No difference was observed between males and females in terms of the presence of at least one IF (p = 0.144). The mean age of the patients with IF was significantly higher than that of those without IF (p < 0.001). Of the 294 patients whose CCT was presented in an emergency report by a radiologist, 142 (48.6%) had at least one IF; however, no IF was mentioned in the reports of 77 patients (54.5%). IFs should be properly reported according to their severity and included in patient records, consequently facilitating early treatment or additional examinations and eliminating the need for performing repeated examinations for those not requiring follow-up.


Aortic false lumen thrombosis induction by embolotherapy (AFTER) following endovascular repair of aortic dissection.
To report the use of a technique (AFTER: aortic false lumen thrombosis induction by embolotherapy) to achieve false lumen (FL) thrombosis and aortic remodeling in patients with residual FL patency after initial endovascular repair of aortic dissection. Between January 2003 and January 2010, 31 patients underwent staged total aortic and branch vessel endovascular reconstruction (STABLE) of type A (n = 13) and type B (n = 18) dissection. Of these, 10 patients (5 men; mean age 61 years) who had undergone repair of 4 acute type A, 3 acute type B, and 3 chronic type B dissections demonstrated re-entry tear(s) and FL patency associated with aortic expansion ≥5 mm or flow into a persistently dilated aortic segment. Catheter-directed embolization using coils, glue, or occlusion balloons was performed via a transfemoral approach to the true lumen at a mean of 7 months (range <1 to 26) after initial repair. Technical success was achieved in all patients, with no intraoperative complications. Thirty-day morbidity and mortality was nil. Mean follow-up was 63 months (range 13-96). Reversal or stabilization (<5-mm increase) of thoracoabdominal aortic growth occurred in 9 patients. Complete thrombosis of the thoracic and abdominal FL occurred in 2 patients. In 4, FL occlusion and subsequent thrombosis of the upstream thoracic segment was achieved. Four demonstrated partial FL thrombosis in the thoracic and abdominal aorta. One patient with chronic aneurysmal type B dissection died 4 months post-embolization from aortic rupture. The AFTER strategy appears to be a safe and promising adjunctive endovascular approach to treat residual FL patency or aortic enlargement post endovascular repair of aortic dissection. Elimination of FL flow and stabilization of aortic expansion may reduce the risk of late distal aortic complications.


The effect of TERC haploinsufficiency on the inheritance of telomere length.
Telomeres protect chromosome ends from end-to-end fusion and degradation. Loss of telomere function causes cell-cycle arrest or cell death. Autosomal dominant dyskeratosis congenita (AD DC), a rare inherited bone marrow failure syndrome, is caused by mutations in TERC, the RNA component of telomerase. Here, we studied the telomere dynamics over three generations in a 32-member extended family with AD DC due to a TERC gene deletion. Our analysis shows that peripheral blood cells from family members haploinsufficient for TERC have very short telomeres. Telomeres are equally short in all individuals carrying the TERC gene deletion irrespective of their age. Chromosome-specific telomere analysis distinguishing the parental origin of telomeres showed that in gene deletion carriers, paternal and maternal telomeres are similarly short and similar in length to those of the affected parent. In children of affected parents who have normal TERC genes, parental telomeres are again similar in length, but two generations appear to be necessary to fully restore normal telomere length. These results are consistent with a model in which telomerase preferentially acts on the shortest telomeres. When TERC is limiting, this preference leads to the accelerated shortening of longer telomeres. The limited amount of active telomerase in TERC RNA haploinsufficiency may not be able to maintain the minimal length of the increasing number of short telomeres. Thus, the number of cells with excessively short telomeres and the degree of residual telomerase activity may determine the onset of disease in patients with AD DC.


An evaluation of the DS-175, DS-145, and DS-115, digital blood pressure/pulse meter devices.
The performances of three electronic digital blood pressure/pulse meter models, Nissei DS-175, DS-145, and DS-115, were compared with measurements obtained using the mercury sphygmomanometer and auscultatory technique. Significant correlations (p less than 0.01) were found between the accepted medical criterion and the three models evaluated for both systolic (r = 0.64 to 0.74) and diastolic (r = 0.58 to 0.61) pressure measurements; however, the accuracies of the devices were deemed inadequate. The DS-175 was found to significantly overestimate both systolic (p less than 0.025) and diastolic (p less than 0.05) pressures. Furthermore, all models tended to overestimate low blood pressures, whereas high blood pressures were underestimated. Variables associated with home use by the lay person are also discussed.


Impaired social attention detected through eye movements in children with early-onset epilepsy.
Children with early-onset epilepsy (CWEOE; epilepsy onset before 5 years) exhibit impaired social functioning, but social attention has not yet been examined. In this study we sought to explore visual attention via eye tracking as a component of social attention and examine its relationship with social functioning and Autism Spectrum Disorder (ASD) risk scores. Forty-seven CWEOE (3-63 months) and 41 controls (3-61 months) completed two eye-tracking tasks: (1) preference for social versus nonsocial naturalistic scenes, and (2) face region preference task. ASD risk was measured via the Modified Checklist for Autism in Toddlers or Conners Early Childhood Total Score. Social functioning was assessed via the Greenspan Social-Emotional Growth Chart, or Infant-Toddler Social & Emotional Assessment Competence Scale, or Conners Early Childhood Social Functioning Scale, depending on age. Fixation preferences for social scenes and eyes were compared between groups and evaluated by age and social functioning scores. Regression analysis revealed that CWEOE viewed the social scene to a significantly less degree than controls. The greatest difference was found between the youngest CWEOE and controls. Fixation duration was independently and significantly related to social functioning scores. There were no significant differences between CWEOE and controls in the face scanning task, and there was no significant relationship between either task and ASD risk scores. CWEOE exhibit task-specific atypical social attention early in the course of the disease. This may be an early marker of impaired social development, and it suggests abnormal social brain development.


Nucleolin Acts as a Scavenger Receptor for Acetylated Low-Density Lipoprotein on Macrophages.
Although macrophage phagocytoses modified low-density lipoprotein (LDL), excessive accumulation of modified LDL induces macrophage foam cell formation, which is a feature of atherosclerotic plaque. Thus, the identification of scavenger receptor for modified LDL will provide better understanding of an atherosclerotic event. We recently showed that nucleolin expressed on macrophages acts as a scavenger receptor for various endogenous discarded products. Here, we investigated whether or not nucleolin is involved in the uptake of acetylated LDL (AcLDL). In contrast to normal LDL, AcLDL directly bound to immobilized nucleolin. AcLDL exhibited a higher affinity for macrophages than normal LDL. This binding of AcLDL was inhibited by anti-nucleolin antibody and antineoplastic guanine-rich oligonucleotide (AGRO), a nucleolin-specific oligonucleotide aptamer. In addition, AcLDL exhibited a higher affinity for HEK cells transfected with nucleolin than those without. Further, intracellular accumulation of AcLDL was also inhibited by anti-nucleolin antibody. The results of this study suggest that nucleolin expressed on macrophages is a receptor for AcLDL.


Characteristics and service needs of women and babies admitted to residential parenting units in New South Wales: A mixed-methods study.
To examine the characteristics and service needs of women and babies admitted to residential parenting services (RPS) in the first year following birth in New South Wales, Australia. In Australia, there is a tiered system to support maternal, child and family health, which includes RPS. Sequential explanatory mixed-methods design. Individual patient data were obtained from a random review of 10% of all medical records (n = 300 of 3,011 admissions) of women with an infant of <12 months of age who were admitted to RPS in 2013. Following review of the medical records, qualitative data were collected via interviews with eight women who accessed RPS. Chi-square analysis and Student's t test were used to analyse quantitative data. Qualitative data were analysed using a descriptive interpretive approach. An integrative approach was taken in reporting the findings. Women admitted to the RPS were on average 32 years of age, were Australian born (72%) and had a university qualification (40%), and most were employed. The majority of women were primiparous (60%) and had a vaginal birth (61%). Women with male infants were much more likely to be admitted to the RPS (58%) compared to the NSW male-to-female ratio (51.3% vs. 48.7%). Over 50% of women reported mental health issues with 27% having an Edinburgh Postnatal Depression Scale score ≥13 on admission. The primary reason women sought parenting support was for sleep and settling (83%). During their stay, services used by women included social workers (44%), psychologists (52%) and psychiatrists (4.5%). Women who access RPS report psychosocial and mental health issues. Services provided by RPS support women during this challenging early parenting period by providing multidisciplinary, holistic and peer support. A high prevalence of mental health issues identified in this study indicated a need for ongoing training and support for RPS staff. Ensuring clinicians have the appropriate skill sets to best support their clientele will maximise the outcomes for women and families who access RPS during the early parenting period.


Nephrolithiasis among male patients with newly diagnosed gout.
An elevated serum urate level is recognised as a cause of gouty arthritis and uric acid stone. The level of serum uric acid that accelerates kidney stone formation, however, has not yet been clarified. This study aimed to find out if a high serum urate level is associated with nephrolithiasis. Patients were recruited from the rheumatology clinic of Taipei City Hospital (Renai and Zhongxing branches) in Taiwan from March 2015 to February 2016. A total of 120 Chinese male patients with newly diagnosed gout and serum urate concentration of >7 mg/dL and no history of kidney stones were divided into two groups according to their serum urate level: <10 mg/dL (group 1, n=80) and ≥10 mg/dL (group 2, n=40). The mean body mass index, blood urea nitrogen level, creatinine level, urinary pH, and kidney ultrasonography were compared between the two groups. There were no significant differences in blood urea nitrogen or creatinine level between the two groups. The urine pH in both groups was similar and not statistically significant. Kidney stone formation was detected via ultrasonography in 6.3% (5/80) and 82.5% (33/40) of patients in groups 1 and 2, respectively (P<0.05). A serum urate level of ≥10 mg/dL may precipitate nephrolithiasis. Further studies are warranted to substantiate the relationship between serum urate level and kidney stone formation.


The Basic Biology of BACE1: A Key Therapeutic Target for Alzheimer's Disease.
Alzheimer's disease (AD) is an intractable, neurodegenerative disease that appears to be brought about by both genetic and non-genetic factors. The neuropathology associated with AD is complex, although amyloid plaques composed of the beta-amyloid peptide (Abeta) are hallmark neuropathological lesions of AD brain. Indeed, Abeta plays an early and central role in this disease. beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is the initiating enzyme in Abeta genesis and BACE1 levels are elevated under a variety of conditions. Given the strong correlation between Abeta and AD, and the elevation of BACE1 in this disease, this enzyme is a prime drug target for inhibiting Abeta production in AD. However, nine years on from the initial identification of BACE1, and despite intense research, a number of key questions regarding BACE1 remain unanswered. Indeed, drug discovery and development for AD continues to be challenging. While current AD therapies temporarily slow cognitive decline, treatments that address the underlying pathologic mechanisms of AD are completely lacking. Here we review the basic biology of BACE1. We pay special attention to recent research that has provided some answers to questions such as those involving the identification of novel BACE1 substrates, the potential causes of BACE1 elevation and the putative function of BACE1 in health and disease. Our increasing understanding of BACE1 biology should aid the development of compounds that interfere with BACE1 expression and activity and may lead to the generation of novel therapeutics for AD.


The Bipolar Depression Rating Scale (BDRS): its development, validation and utility.
Unipolar and bipolar depression differ neurobiologically and in clinical presentation. Existing depression rating instruments, used in bipolar depression, fail to capture the necessary phenomenological nuances, as they are based on and skewed towards the characteristics of unipolar depression. Both clinically and in research there is a growing need for a new observer-rated scale that is specifically designed to assess bipolar depression. An instrument reflecting the characteristics of bipolar depression was drafted by the authors, and administered to 122 participants aged 18-65 (44 males and 78 females) with a diagnosis of DSM-IV bipolar disorder, who were currently experiencing symptoms of depression. The Bipolar Depression Rating Scale (BDRS) was administered together with the Hamilton Depression Rating Scale (HAM-D), Montgomery Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS). The BDRS has strong internal consistency (Cronbach's alpha = 0.917), and robust correlation coefficients with the MADRS (r = 0.906) and HAM-D (r = 0.744), and the mixed subscale correlated with the YMRS (r = 0.757). Exploratory factor analysis showed a three-factor solution gave the best account of the data. These factors corresponded to depression (somatic), depression (psychological) and mixed symptom clusters. This study provides evidence for the validity of the BDRS for the measurement of depression in bipolar disorder. These results suggest good internal validity, provisional evidence of inter-rater reliability and strong correlations with other depression rating scales.


The interfacial behaviour of single poly(N,N-dimethylacrylamide) chains as a function of pH.
We have studied the pH-dependent conformational behaviour of poly(N,N-dimethylacrylamide) (PDMAc) at silicon and gold surfaces using single-molecule force spectroscopy and a quartz crystal microbalance (QCM). Despite the pH dependence, nuclear magnetic resonance and titration experiments demonstrate that PDMAc is not a weak polybase. The interaction between single chains and a silicon surface (with native oxide layer intact) in aqueous solution was investigated using force spectroscopy. Single-molecule force measurements were performed using thiol-functionalized PDMAc and gold-coated AFM cantilevers. The forces of interaction between PDMAc and the native oxide-coated silicon surface vary with the pH. The shape of the retraction curve for low pH solution includes a greater number of 'train' conformations, which suggests a stronger interaction with the surface relative to the surrounding media at low pH. The adsorption behaviour of PDMAc, from liquid onto silicon surfaces, was monitored using a QCM, which shows greater PDMAc adsorption onto silicon at low pH. The force spectroscopy and QCM investigations confirm that the PDMAc chain is more extended and stiffer in low pH solution. We attribute the pH-dependent behaviour to an increased number of hydrogen bonding sites on the silicon surface at low pH.


Changes in acute biochemical markers of inflammatory and structural stress in rugby union.
Rugby union is a sport governed by the impacts of high force and high frequency. Analysis of physiological markers following a game can provide an understanding of the physiological response of an individual and the time course changes in response to recovery. Urine and saliva were collected from 11 elite amateur rugby players 24 h before, immediately after, and at 17, 25, 38, 62 and 86 h post-game. Myoglobin, salivary immunoglobulin A and cortisol were analysed by ELISA, whereas neopterin and total neopterin were analysed by high-performance liquid chromatography. There was a significant post-game increase of all four markers. The increases were cortisol 4-fold, myoglobin 2.85-fold, neopterin 1.75-fold and total neopterin 2.3-fold when corrected with specific gravity. All significant changes occurred post-game only, with markers returning to and remaining at baseline within 17 h. The intensity of the game caused significant changes in key physiological markers of stress. They provide an understanding of the stress experienced during a single game of rugby and the time course changes associated with player recovery. Neopterin provides a new marker of detecting an acute inflammatory response in physical exercise, while specific gravity should be considered for urine volume correction post-exercise.


In vitro transcriptase deficiency of temperature-dependent host range mutants of Chandipura virus.
Ten of 12 Chandipura virus tdCE mutants, which exhibit temperature-dependent restriction of growth in chick embryo (CE) cells but not in BS-C-1 cells, showed deficient transcriptase activity in vitro at 39 degrees C relative to wild-type virus. A gradation in transcriptional activity at 39 degrees C in vitro was observed. Reversion of the tdCE phenotype to unrestricted growth in CE cells at 39 degrees C was accompanied by partial restoration of normal transcriptase activity at 39 degrees C, suggesting that reversion was mediated by either extragenic or intragenic suppression. Viral protein synthesis was reduced or absent in CE cells at 39 degrees C indicating that transcription was also defective in vivo under these conditions. Induction of heat-shock proteins in CE cells at 39 degrees C occurred normally in tdCE mutant-infected cells and RNA methylation in vitro was unaffected.