Neural Activation During Mental Rotation in Complete Androgen Insensitivity Syndrome: The Influence of Sex Hormones and Sex Chromosomes.
Sex hormones, androgens in particular, are hypothesized to play a key role in the sexual differentiation of the human brain. However, possible direct effects of the sex chromosomes, that is, XX or XY, have not been well studied in humans. Individuals with complete androgen insensitivity syndrome (CAIS), who have a 46,XY karyotype but a female phenotype due to a complete androgen resistance, enable us to study the separate effects of gonadal hormones versus sex chromosomes on neural sex differences. Therefore, in the present study, we compared 46,XY men (n = 30) and 46,XX women (n = 29) to 46,XY individuals with CAIS (n = 21) on a mental rotation task using functional magnetic resonance imaging. Previously reported sex differences in neural activation during mental rotation were replicated in the control groups, with control men showing more activation in the inferior parietal lobe than control women. Individuals with CAIS showed a female-like neural activation pattern in the parietal lobe, indicating feminization of the brain in CAIS. Furthermore, this first neuroimaging study in individuals with CAIS provides evidence that sex differences in regional brain function during mental rotation are most likely not directly driven by genetic sex, but rather reflect gonadal hormone exposure.


A scanning tunnelling study of immobilised cytochrome P450cam.
A site-specifically engineered surface cysteine residue, located in a region where the haem moiety is closest to the surface, is used to anchor cytochrome P450cam enzyme molecules covalently to a gold electrode. More reproducibly ordered adsorption, at high coverage, occurs with this K344C mutant than with the wild-type enzyme. The subsequently formed close-packed monolayer arrays have been probed by scanning tunnelling microscopy under ambient conditions and under aqueous (buffered) solution at high resolution. Initial indications suggest that the immobilised enzyme is both electrochemically addressable and catalytically active.


Bacterial iron reduction and biogenic mineral formation for the stabilisation of corroded iron objects.
Exploiting bacterial metabolism for the stabilisation of corroded iron artefacts is a promising alternative to conventional conservation-restoration methods. Bacterial iron reduction coupled to biogenic mineral formation has been shown to promote the conversion of reactive into stable corrosion products that are integrated into the natural corrosion layer of the object. However, in order to stabilise iron corrosion, the formation of specific biogenic minerals is essential. In this study, we used the facultative anaerobe Shewanella loihica for the production of stable biogenic iron minerals under controlled chemical conditions. The biogenic formation of crystalline iron phosphates was observed after iron reduction in a solution containing Fe(III) citrate. When the same biological treatment was applied on corroded iron plates, a layer composed of iron phosphates and iron carbonates was formed. Surface and cross-section analyses demonstrated that these two stable corrosion products replaced 81% of the reactive corrosion layer after two weeks of treatment. Such results demonstrate the potential of a biological treatment in the development of a stabilisation method to preserve corroded iron objects.


Genetic Variation in the TAS2R38 Bitter Taste Receptor and Smoking Behaviors.
Common TAS2R38 taste receptor gene variants specify the ability to taste phenylthiocarbamide (PTC), 6-n-propylthiouracil (PROP) and structurally related compounds. Tobacco smoke contains a complex mixture of chemical substances of varying structure and functionality, some of which activate different taste receptors. Accordingly, it has been suggested that non-taster individuals may be more likely to smoke because of their inability to taste bitter compounds present in tobacco smoke, but results to date have been conflicting. We studied three cohorts: 237 European-Americans from the state of Georgia, 1,353 European-Americans and 2,363 African-Americans from the Dallas Heart Study (DHS), and 4,973 African-Americans from the Dallas Biobank. Tobacco use data was collected and TAS2R38 polymorphisms were genotyped for all participants, and PTC taste sensitivity was assessed in the Georgia population. In the Georgia group, PTC tasters were less common among those who smoke: 71.5% of smokers were PTC tasters while 82.5% of non-smokers were PTC tasters (P = 0.03). The frequency of the TAS2R38 PAV taster haplotype showed a trend toward being lower in smokers (38.4%) than in non-smokers (43.1%), although this was not statistically significant (P = 0.31). In the DHS European-Americans, the taster haplotype was less common in smokers (37.0% vs. 44.0% in non-smokers, P = 0.003), and conversely the frequency of the non-taster haplotype was more common in smokers (58.7% vs. 51.5% in non-smokers, P = 0.002). No difference in the frequency of these haplotypes was observed in African Americans in either the Dallas Heart Study or the Dallas Biobank. We conclude that TAS2R38 haplotypes are associated with smoking status in European-Americans but not in African-American populations. PTC taster status may play a role in protecting individuals from cigarette smoking in specific populations.


Papulonecrotic tuberculid in children. A report of eight patients.
Papulonecrotic tuberculid (PNT), a form of cutaneous tuberculosis (TB), is uncommon in children. We identified eight children (six girls and two boys) with PNT. Their ages ranged from 19 to 139 months (median 47.5 months, mean:64.75 months). Skin lesions had been present for 2-24 weeks (median: 4 weeks) before diagnosis. All patients displayed scattered papulo- and/or pustulonecrotic lesions on the limbs, and the ears were involved in six patients. Lesions healed with varioliform scars. Associated pulmonary TB was present in seven patients. Additional clinical findings included fever (n = 4), hepatomegaly (n = 4), lymphadenopathy (n = 3), phlyctenular conjunctivitis (n = 3), and splenomegaly (n = 2). Histology of eight biopsies showed ulceration (n = 6), dermal necrosis (n = 6) (follicle-centered in two), granulomatous inflammation (n = 6) (palisading granuloma-like in three), superficial and deep infiltrate of lymphocytes (n = 7), erythrocyte extravasation (n = 7), and subepidermal edema (n = 3). Vasculitis was not a feature. A Ziehl-Neelsen stain was negative in all. Glycosaminoglycans were not increased. Immunohistochemistry found a predominance of T lymphocytes, macrophages, a few antigen-presenting cells, and no B lymphocytes, consistent with a type IV hypersensitivity reaction. Polymerase chain reaction (PCR) performed on deparaffinized tissue identified M. tuberculosis DNA in one biopsy. All patients received combination anti-TB treatment for 6 months. Six patients were compliant and were followed up for 6-30 months. Skin lesions and pulmonary TB healed in all. PNT in children resembles the adult form, but phlyctenular conjunctivitis and associated TB are more common, scrofuloderma and concomitant erythema induratum of Bazin are unusual, and vasculitis is not found. In cases where M. tuberculosis DNA can be confirmed with PCR, papulonecrotic TB is perhaps the more appropriate nomenclature.


Discontinuation of infliximab after attaining low disease activity in patients with rheumatoid arthritis: RRR (remission induction by Remicade in RA) study.
Tumour necrosis factor (TNF) inhibitors enable tight control of disease activity in patients with rheumatoid arthritis (RA). Discontinuation of TNF inhibitors after acquisition of low disease activity (LDA) is important for safety and economic reasons. To determine whether infliximab might be discontinued after achievement of LDA in patients with RA and to evaluate progression of articular destruction during the discontinuation. 114 patients with RA who had received infliximab treatment, and whose Disease Activity Score, including a 28-joint count (DAS28) was <3.2 (LDA) for 24 weeks, were studied. The mean disease duration of the 114 patients was 5.9 years, mean DAS28 5.5 and mean modified total Sharp score (mTSS) 63.3. After maintaining LDA for >24 weeks by infliximab treatment, the drug was discontinued and DAS28 in 102 patients was evaluated at year 1. Fifty-six patients (55%) continued to have DAS28<3.2 and 43% reached DAS<2.6 at 1 year after discontinuing infliximab. For 46 patients remission induction by Remicade in RA (RRR) failed: disease in 29 patients flared within 1 year and DAS28 was >3.2 at year 1 in 17 patients. Yearly progression of mTSS (DeltaTSS) remained <0.5 in 67% and 44% of the RRR-achieved and RRR-failed groups, respectively. The estimated DeltamTSS was 0.3 and 1.6 and Health Assessment Questionnaire-Disability Index was 0.174 and 0.614 in the RRR-achieved and RRR-failed groups, respectively, 1 year after the discontinuation. After attaining LDA by infliximab, 56 (55%) of the 102 patients with RA were able to discontinue infliximab for >1 year without progression of radiological articular destruction.


A human case of Hymenolepis diminuta in a child from eastern Sicily.
We report a case of Hymenolepis diminuta infection in a 2-year-old child living in a suburban area of Catania, Italy. This case was initially referred to us as Dipylidium caninum infection, which was not cured after being treated twice with mebendazole. However, by analyzing the clinical presentation and stool samples we arrived to the diagnosis of H. diminuta infection. The case presented with atypical allergic manifestations which had never been reported as clinical features of symptomatic H. diminuta infection; remittent fever with abdominal pain, diffuse cutaneous itching, transient thoracic rash, and arthromyalgias. The patient was treated with a 7-day cycle of oral niclosamide, which proved to be safe and effective. This case report emphasizes that a correct parasitological diagnosis requires adequate district laboratories and trained personnel. In addition, we recommend the importance of reporting all H. diminuta infection cases, in order to improve knowledge on epidemiology, clinical presentation, and treatment protocols.


Differential effects of word length and visual contrast in the fusiform and lingual gyri during reading.
Previous studies have shown differential responses in the fusiform and lingual gyri during reading and suggested that the former is engaged in processing local features of visual stimuli and the latter is engaged in global shape processing. We used positron emission tomography in order to investigate how these regions are modulated by two common variables in reading: word length (three, six and nine letters) and perceptive similarity to the background (high and low contrast). Increasing both word length and visual contrast had a positive monotonic effect on activation in the bilateral fusiform. However, in the lingual gyrus, activation increased with increasing word length but decreased with increasing contrast. On the basis of previous studies, we suggest that (i) increasing word length increases the demands on both local feature and global shape processing, but (ii) increasing visual contrast increases the demands on local feature processing while decreasing the demands on global shape processing.


The toxicity of staphylococcal enterotoxin B in mice is mediated by T cells.
Staphylococcal enterotoxin B (SEB) has been shown in the past to be a potent T cell stimulant in mouse or man. The toxin acts as a superantigen that is, it binds to class II MHC proteins and, as such a complex, stimulates T cells bearing particular V beta s as part of their receptors. The toxin also has several pathological effects, causing, in mice, rapid weight loss, thymus atrophy, immunosuppression, and, at high doses, death. The data in this paper show that at least one of these effects, weight loss, is T cell mediated. Staphylococcal enterotoxin-mediated weight loss is MHC dependent, and is almost absent in animals expressing MHC class II molecules, which, complexed with SEB, are poor T cell stimulants. Also, mice that lack T cell function, genetically or because of cyclosporin A treatment, lose no or less weight than controls in response to SEB. Finally, animals bred such that they express few T cells bearing V beta s with which SEB can interact lose much less weight in response to the toxin than littermate controls that have higher numbers of reactive T cells. It is therefore suggested that the pathological effects of the staphylococcal, T cell-stimulating toxins in mouse and man may be partially or wholly the consequence of massive T cell stimulation.


Genomic signatures associated with the development, progression, and outcome of prostate cancer.
Prostate cancer remains a common cause of cancer death in men. Applications of new genomic technologies to the recent development of high-quality prostate cancer models in multiple contexts have added great molecular insight into the development of and progression to metastasis. Genomic analysis of DNA, RNA, and protein alterations allows for the global assessment of this disease and provides the molecular framework to improve risk classification, outcome prediction, and development of targeted therapies. The creation of expression profiles and signatures will allow the evaluation of cancer phenotypes and give insight into determining those with increased risk of cancer, identification of critical pathways involved in the development of cancer, prediction of disease outcome, and assessment of the response of cancer to established and novel therapies. This review focuses on highlighting recent work in genomics and on its role in evaluating potential genetic modifiers of prostate cancer and novel biomarkers that may help with prostate cancer diagnosis, its potential to provide a better understanding of prostate cancer behavior and transition to metastatic disease, and its role in current and new therapies in prostate cancer. This framework has the exciting potential to be predictive and provide personalized and individual treatment to the large number of men diagnosed with prostate cancer each year.


Risk of second cancer after treatment of aggressive non-Hodgkin's lymphoma; an EORTC cohort study.
Second cancer has been associated with non-Hodgkin's Lymphoma (NHL) treatment, but few studies have addressed this issue considering specific treatments. We estimated risk by standardized incidence ratios (SIR) and absolute excess risk (AER) based on general population rates (European Network of Cancer Registries) in 748 patients (aged 15-82 years) treated for aggressive NHL in four successive EORTC (European Organization for Research on Treatment of Cancer) trials. All patients received fully-dosed CHOP-like chemotherapy, 65% received involved-field radiotherapy and 14% high-dose treatment. Half of the patients needed salvage treatment and 37% were followed for more than 10 years. The cause of death was NHL in 79% of the patients; 4% died of second cancer (median survival 8.9 (0.8- 20.5) years). Cumulative incidences (death from any cause being a competing event) were 5% and 11% for solid cancer and 1% and 3% for acute myeloid leukemia/myelodysplastic syndrome at 10 and 15 years, respectively. Cancer risk appeared age-related: in young patients high risks were observed for leukemia (SIR 16.7,95% CI 1.4-93.1,AER 5.0), Hodgkin's lymphoma (SIR 60.1,95% CI 12.4-175.2, AER 15.7), colorectal cancer (SIR 12.5, 95% CI 2.6-36.5, AER 14.7) and lung cancer (SIR 15.4; 95% CI 4.2-39.4, AER 19.8), while risk in patients older than 45 years matched than that in the normal population. The risk of cancer was significantly raised by smoking and salvage treatment. Half of the patients die of aggressive NHL before living long enough to experience second cancer. Only young patients have a high risk of second cancer during follow-up beyond 10 years.


Methylation of FKBP5 and SLC6A4 in Relation to Treatment Response to Mindfulness Based Stress Reduction for Posttraumatic Stress Disorder.
Mindfulness Based Stress Reduction (MBSR) is an effective non-pharmacologic treatment for veterans with PTSD. Extensive work has identified epigenetic factors related to PTSD disease risk and pathophysiology, but how these factors influence treatment response is unclear. Serotonin signaling and hypothalamic-pituitary-adrenal (HPA) axis functioning may be perturbed in PTSD and are molecular pathways targeted by PTSD treatments. To identify potential biomarkers for treatment response, we utilized genomic DNA isolated from peripheral blood samples from veterans with PTSD who were responders (n = 11) or non-responders (n = 11) to MBSR as part of a clinical trial. We assessed methylation levels at CpG sites in regions of the serotonin transporter (SLC6A4) previously associated with expression and depression outcomes, as well as the Intron 7 region of the FK506 binding protein 5 (FKBP5) containing known glucocorticoid response elements suggested to regulate this gene. Selected subjects were matched across MBSR responder status by baseline symptoms, age, sex, current smoking status, and current antidepressant use. Percent methylation was compared between responders and non-responders at baseline (pre-MBSR treatment). Additionally, percent change in methylation from baseline to post-treatment was compared between responders and non-responders. There was a significant time x responder group interaction for methylation in FKBP5 intron 7 bin 2 [F (1, 19) = 7.492, p = 0.013] whereby responders had a decrease in methylation and non-responders had an increase in methylation from before to after treatment in this region. Analyses of the three CpG sites within bin 2 revealed a significant time x responder group interaction for CpG_35558513 [F (1, 19) = 5.551, p = 0.029] which resides in a known glucocorticoid response element (GRE). Decreases in FKBP5 methylation after treatment in responders as compared to increases in non-responders suggest that effective meditation intervention may be associated with stress-related pathways at the molecular level. These preliminary findings suggest that DNA methylation signatures within FKBP5 are potential indicators of response to meditation treatment in PTSD and require validation in larger cohorts.


Administrative and professional issues for the occupational therapist in home health care.
Administrative and professional issues for the occupational therapist working in home health care include contractual relationships, referral systems, third-party reimbursement, documentation, equipment, and ethics. In this paper, the regulations for third-party reimbursement by Medicare, Medicaid, and Blue Cross for occupational therapy in home health care are explained, including the Medicare definition of homebound status and the requirement that treatment be restorative. The effect of such regulations on occupational therapy treatment planning and documentation of services is discussed. Coverage of frequently ordered equipment by Medicare and Medicaid is explained. Both the issues related to standards of practice, including the length and frequency of occupational therapy treatment sessions, and the expected duration of treatment are discussed. The effect on the professional relationship of treating patients in their own environments is examined. Changes in third-party reimbursement for inpatient care have presented occupational therapists with the challenge of working with acutely ill patients in their homes.


The OMACS-PIL study: a randomised controlled trial within the OMACS observational study.
There has been little research to investigate whether the appearance of paper patient information leaflets (PILs) used to describe research studies to potential participants influences their decision to take part. Embedding a study within a trial (SWAT) is an efficient way of answering this type of methodological question. We included a randomised SWAT within a large cohort study, Outcome Monitoring after Cardiac Surgery (OMACS), to address this question. Potential participants for the OMACS study were randomised to receive one of three PILs, which were identical in content but with varying formatting and use of colour: PIL A (enhanced format), PIL B (hybrid format) and PIL C (standard format). Consent to OMACS was the primary outcome. Consent rates using the three different PIL formats were collected and compared. Qualitative feedback on the different formats was obtained from a public and patient involvement (PPI) group. For the SWAT, 1517 PILs were sent to potential participants, of whom 640 (42%) consented to take part in OMACS. PIL B had the highest recruitment rate, with 45% of patients consenting to participation; 40% and 41% of patients consented to participation after receiving PILs A and C, respectively. Compared to PIL C, the consent rate was 4% higher with PIL B (45% versus 41%, 95% confidence interval (CI) -2% to + 10%, p = 0.16) and 1% lower with PIL A (40% versus 41%, 95% CI - 7% to + 5%, p = 0.72). Consent rates were similar for all three PIL formats. PIL B is being used for the remainder of the host study and will be used to inform the design of PILs for other research studies, as it was the preferred format of the PPI group. International Clinical Trials Registry, ISRCTN90204321. Registered on 21 January 2015.


Interactions of two major metabolites of prasugrel, a thienopyridine antiplatelet agent, with the cytochromes P450.
The biotransformation of prasugrel to R-138727 (2-[1-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-mercapto-3-piperidinylidene]acetic acid) involves rapid deesterification to R-95913 (2-[2-oxo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]-1-cyclopropyl-2-(2-fluorophenyl)ethanone) followed by cytochrome P450 (P450)-mediated formation of R-138727, the metabolite responsible for platelet aggregation. For identification of the P450s responsible for the formation of the active metabolite, the current studies were conducted with R-95913 as the substrate. Incubations required supplementation with reduced glutathione. Hyperbolic kinetics (K(m) 21-30 microM), consistent with a single enzyme predominating, were observed after incubations with human liver microsomes. Correlation analyses revealed a strong relationship between R-138727 formation and CYP3A-mediated midazolam 1'-hydroxylation (r(2) = 0.98; p < 0.001) in a bank of characterized human liver microsomal samples. The human lymphoblast-expressed enzymes capable of forming R-138727, in rank order of rates, were CYP3A4>CYP2B6>CYP2C19 approximately CYP2C9>CYP2D6. A monoclonal antibody to CYP2B6 and the CYP3A inhibitor ketoconazole substantially inhibited R-138727 formation, whereas inhibitors of CYP2C9 (sulfaphenazole) and CYP2C19 (omeprazole) did not. Scaling of in vitro intrinsic clearance values from expressed enzymes to the whole liver using a relative abundance approach indicated that either CYP3A4 alone or CYP3A4 and CYP2B6 are the major contributors to R-138727 formation. R-95913 and R-138727 were also examined for their ability to inhibit metabolism mediated by five P450s. R-138727 did not inhibit the P450s tested. In vitro, R-95913 inhibited CYP2C9, CYP2C19, CYP2D6, and CYP3A, with K(i) values ranging from 7.2 microM to 82 microM, but did not inhibit CYP1A2. These K(i) values exceed circulating concentrations in humans by 3.8- to 43-fold. Therefore, neither R-95913 nor R-138727 is expected to substantially inhibit the P450-mediated metabolism of coadministered drugs.


Do neotropical migrant butterflies navigate using a solar compass?
Many tropical butterfly species are well-known for their migratory behaviour. Although these insects can maintain a constant direction throughout the day, the physiological mechanisms of orientation are unknown. It has been argued that tropical migrant butterflies must use a time-compensated sun compass to accomplish their journey, but the crucial experimental manipulations to test this hypothesis have not been conducted. This study reports the results of clock-shift experiments performed with two species of migrating butterflies (Pieridae: Aphrissa statira and Phoebis argante) captured during flight across Lake Gatun, Panama. The observed constant flight bearing of natural controls suggests that these species are capable of performing time-compensated celestial navigation. Our clock-shift experiments suggest that a sun compass is involved. Individuals submitted to a 4 h advance shift took significantly different mean orientations on release compared with control butterflies. The direction of this difference was consistent with the use of a sun compass. The magnitude was approximately half the predicted value if the vanishing bearing of released butterflies was used as the variable to evaluate the effect of time-shifting and approximately three-quarters of that predicted if the estimated heading was the variable used. Mean vanishing bearings of control and experimental butterflies did not correspond to predicted values. This difference can be attributed largely to the combined effects of wind and handling.


Effect of engaging abutment position in implant-borne, screw-retained three-unit fixed cantilevered prostheses.
To investigate the effects of internally connected engaging component position in screw-retained fixed cantilevered prostheses. Twenty-one three-unit fixed dental prostheses (FDPs) were cast in high-palladium alloy in three groups. In group A, engaging components were incorporated into the units away from the cantilevered segment; proximal units received nonengaging components. In group B, these positions were reversed. Control specimens were fabricated using all nonengaging components. Specimens were attached to internally connected 3.5 (diameter) × 13 mm (length) implants, torqued to 32 Ncm, and embedded into epoxy resin. Specimens were tested in cyclic fatigue with a 2 Hz sine wave and 0.1 min/max load ratio. Load amplitude started at 1.8 N and increased by 1.8 N every 60 cycles until fracture. Log-rank statistic, ANOVA, Spearman's correlation, and LIFETEST procedures were used to evaluate level of statistical significance within the results. In the control group, the mean number of cycles to fracture was 31,205 ± 2639. Mean axial force at fracture was 932 ± 78 N. In group A, these numbers were 38,160 ± 4292 and 1138 ± 128 N, and in group B, 31,810 ± 3408 and 949 ± 101 N. Statistical significance levels for number of cycles to fracture were: Control versus group A, p = 0.0117, and groups A versus B, p = 0.0156 (statistically significant). Control versus group B, p = 0.357 (not statistically significant). Log-rank statistic for the survival curves is greater than would be expected by chance; there was a statistically significant difference between survival curves (p = 0.012). The location and mode of failure were noteworthy (always in the abutment screw). The position of the engaging component had significant effects on the results. Within the limitations of this investigation, it can be concluded that using an engaging abutment in a screw-retained fixed cantilevered FDP provides a mechanical advantage, and engaging the implant furthest from the cantilever when designing a screw-retained cantilever FDP increased resistance to fracture of the distal abutment screw.


[Adenosine deaminase. A pluridisciplinary enzyme].
Adenosine deaminase is an enzyme that actively participates in the metabolism of the adenine nucleotides. It catalyzes the irreversible hydrolytic deamination of deoxyadenosine and adenosine with the production of deoxyinosine and inosine respectively and of ammonia. This enzyme thus plays an important role in lympho-monocyte maturation and activation. The increase in its activity in different biological fluids (pleural, pericardial, peritoneal, intra-articular and cerebrospinal fluids) has been used as a rapid diagnostic test in tuberculosis infection. In human immunodeficiency virus infection, it was verified that enzymatic activity progressively increases in serum and blood cells, accompanying the natural evolution of the disease. The physiopathological mechanism has not been definitely established but the CD4+ lymphocytes and macrophages are pointed to as being accountable for the enzyme's increase in activity. For this reason, adenosine deaminase could be a marker of the cellular immune response. The study of adenosine deaminase activity in blood cells elucidated the diagnosis of severe combined immunodeficiency (due to a congenital lack of the enzyme) in 30 to 50% of the cases. One type of congenital hemolytic anemia is due to an exaggerated enzymatic activity in red blood cells.


Different subtypes of pseudohypoparathyroidism in the same family with an unusual psychiatric presentation of the index case.
A 13 year old Asian girl presenting with apparent hysterical paralysis and subsequent rapid cycling bipolar mood disorder was found to have biochemical evidence of pseudohypoparathyroidism type II. The mood disorder responded to treatment of the pseudohypoparathyroidism with a vitamin D analogue. Investigation of her parents and siblings showed phenotypes consistent with two distinct types of pseudohypoparathyroidism (type I and type II) in different family members.


Exposure to asbestos: correlation between blood levels of mesothelin and frequency of micronuclei in peripheral blood lymphocytes.
Inhalation of asbestos, a mineral extensively used in a variety of applications, is strongly associated with malignant mesothelioma (MM), a fatal cancer of the pleura. Soluble mesothelin-related peptides (SMRP) are a promising biomarker suggested for the screening of MM in healthy asbestos-exposed subjects. In the present study a comparison of micronucleus (Mn) frequencies in peripheral blood lymphocytes (PBL) between 44 asbestos-exposed and 22 control individuals has been performed, and the correlation with serum SMRP has been examined. SMRP levels were found to be significantly higher in subjects exposed to asbestos and in their various subgroups than in controls. Concerning micronucleated lymphocytes, a statistically significant difference from controls was seen in the percentages of both micronucleated mononucleated lymphocytes (MnMNL) and micronucleated binucleated lymphocytes (MnBNL), but the difference was markedly higher for the percentage of micronucleated polynucleated lymphocytes (MnPNL). With respect to the correlation between the frequency of the three types of micronucleated lymphocytes and serum-SMRP values of asbestos-exposed subjects, it was statistically significant for MnMNL, but not for MnBNL and MnPNL.


Effects of in vitro corticosteroids on B cell activation, proliferation, and differentiation.
The present study demonstrates the graded effect of in vitro corticosteroids (CSs) on the different phases of B cell activation, proliferation, and differentiation. Early events such as activation and proliferation of high-dose anti-mu or Staphylococcus aureus-stimulated B cells are profoundly suppressed by the presence of in vitro CSs. The suppressed proliferative response may be mediated by a direct effect on B cells and/or modulation of accessory cell function. Later events in the B cell cycle such as the proliferative response to B cell growth factor after either in vivo or in vitro activation are less sensitive to the suppressive effects of in vitro CSs. The final events in the B cell cycle; namely, the differentiation to the immunoglobulin-producing state, is not suppressed by in vitro CSs. Indeed, depending on the systems employed, there is either no effect or enhancement of immunoglobulin secretion by the presence of in vitro CSs. The graded effect of in vitro CSs on the discrete phases of the B cell activation, proliferation, and differentiation cycle provide new insights into the complex nature of CS-induced modulation of human B cell responses.


Evolving a polymerase for hydrophobic base analogues.
Hydrophobic base analogues (HBAs) have shown great promise for the expansion of the chemical and coding potential of nucleic acids but are generally poor polymerase substrates. While extensive synthetic efforts have yielded examples of HBAs with favorable substrate properties, their discovery has remained challenging. Here we describe a complementary strategy for improving HBA substrate properties by directed evolution of a dedicated polymerase using compartmentalized self-replication (CSR) with the archetypal HBA 5-nitroindole (d5NI) and its derivative 5-nitroindole-3-carboxamide (d5NIC) as selection substrates. Starting from a repertoire of chimeric polymerases generated by molecular breeding of DNA polymerase genes from the genus Thermus, we isolated a polymerase (5D4) with a generically enhanced ability to utilize HBAs. The selected polymerase. 5D4 was able to form and extend d5NI and d5NIC (d5NI(C)) self-pairs as well as d5NI(C) heteropairs with all four bases with efficiencies approaching, or exceeding, those of the cognate Watson-Crick pairs, despite significant distortions caused by the intercalation of the d5NI(C) heterocycles into the opposing strand base stack, as shown by nuclear magnetic resonance spectroscopy (NMR). Unlike Taq polymerase, 5D4 was also able to extend HBA pairs such as Pyrene: varphi (abasic site), d5NI: varphi, and isocarbostyril (ICS): 7-azaindole (7AI), allowed bypass of a chemically diverse spectrum of HBAs, and enabled PCR amplification with primers comprising multiple d5NI(C)-substitutions, while maintaining high levels of catalytic activity and fidelity. The selected polymerase 5D4 promises to expand the range of nucleobase analogues amenable to replication and should find numerous applications, including the synthesis and replication of nucleic acid polymers with expanded chemical and functional diversity.


Adsorbate-driven morphological changes on Cu(111) nano-pits.
Adsorbate-driven morphological changes of pitted-Cu(111) surfaces have been investigated following the adsorption and desorption of CO and H. The morphology of the pitted-Cu(111) surfaces, prepared by Ar(+) sputtering, exposed a few atomic layers deep nested hexagonal pits of diameters from 8 to 38 nm with steep step bundles. The roughness of pitted-Cu(111) surfaces can be healed by heating to 450-500 K in vacuum. Adsorption of CO on the pitted-Cu(111) surface leads to two infrared peaks at 2089-2090 and 2101-2105 cm(-1) for CO adsorbed on under-coordinated sites in addition to the peak at 2071 cm(-1) for CO adsorbed on atop sites of the close-packed Cu(111) surface. CO adsorbed on under-coordinated sites is thermally more stable than that of atop Cu(111) sites. Annealing of the CO-covered surface from 100 to 300 K leads to minor changes of the surface morphology. In contrast, annealing of a H covered surface to 300 K creates a smooth Cu(111) surface as deduced from infrared data of adsorbed CO and scanning tunnelling microscopy (STM) imaging. The observation of significant adsorbate-driven morphological changes with H is attributed to its stronger modification of the Cu(111) surface by the formation of a sub-surface hydride with a hexagonal structure, which relaxes into the healed Cu(111) surface upon hydrogen desorption. These morphological changes occur ∼150 K below the temperature required for healing of the pitted-Cu(111) surface by annealing in vacuum. In contrast, the adsorption of CO, which only interacts with the top-most Cu layer and desorbs by 200 K, does not significantly change the morphology of the pitted-Cu(111) surface.


Association between alcohol use and HIV status: findings from Zambia and Zimbabwe.
To conduct statistical analysis to assess the association between alcohol use and HIV status using Demographic Health Survey data from Zambia (2013-2014) and Zimbabwe (2015-2016). The study showed an association between alcohol use and HIV status using nationally representative population-based surveys. The surveys were conducted among men (15-54 years) and women (15-49 years) in 2013-2014 and 2015-2016 in Zambia and Zimbabwe respectively. HIV prevalence in the two countries was higher among males and females who drank alcohol compared to those who did not. This study reinforces the existing knowledge base on the association between alcohol use and HIV sero-status and calls for further research to explore the causal pathways between alcohol consumption and HIV status.


In vitro comparison of Nyvad's system and ICDAS-II with Lesion Activity Assessment for evaluation of severity and activity of occlusal caries lesions in primary teeth.
This in vitro study of occlusal surfaces on primary molars aimed to: (1) evaluate the reproducibility of the Nyvad and ICDAS-II visual systems in detecting caries; (2) to test the accuracy of the systems in estimating lesion depth, and (3) to examine the association between the Nyvad system and the Lesion Activity Assessment system, an adjunct to ICDAS-II. Two samples of extracted primary molars (sample 1, n = 38; sample 2, n = 69) were evaluated independently by 2 examiners. In this in vitro study, evaluation of plaque in the Nyvad system was not possible. Histology (sample 2) was used to validate lesion depth. Area under ROC curves (A(z)), sensitivity, specificity and percent agreement of both systems were calculated at D1, D2 and D3 thresholds. Both systems showed kappa for intra- and inter-examiner agreement >0.86 and good correlation with histology: Spearman rho = 0.73 (Nyvad) and 0.78 (ICDAS-II). They presented similar performances except that ICDAS-II showed significantly higher sensitivity (Nyvad 0.89; ICDAS 0.92) and A(z) (Nyvad 0.85; ICDAS 0.90) for the D1 threshold. The correlation between the systems for lesion activity (Cramer's V) was 0.71. Therefore, both visual systems are reliable and can estimate caries lesion depth on primary teeth. Under in vitro conditions, there is no major difference between the Nyvad system and Lesion Activity Assessment in assessing caries activity.


Biomechanical comparison of axial load between cannulated locking screws and noncannulated cortical locking screws.
The goal of this study was to compare the biomechanical stability of cannulated locking screws and noncannulated cortical locking screws in a periarticular locking plate. Twelve fresh-frozen porcine tibias with a 1-cm gap created distal to the tibial plateau were used to simulate an unstable proximal tibial fracture. All specimens were fixed with a periarticular proximal lateral tibial locking plate and divided into 2 groups based on whether the proximal metaphyseal screw holes of the plate were inserted with either cannulated locking screws or noncannulated cortical locking screws. An axial compressive load was applied to cause failure in each specimen using a materials testing instrument. The axial stiffness and maximum failure strength in axial loading were recorded. Axial stiffness of the constructs using noncannulated cortical locking screw was significantly higher than that of the constructs using cannulated locking screws (P=.006). Axial failure strength of the constructs using noncannulated cortical locking screw was significantly higher than that of the constructs using cannulated locking screws (P=.002). The failure mode observed in all specimens was a permanent screw-bending deformity over the head-shaft junction of proximal metaphyseal screws, irrespective of whether they were cannulated or noncannulated cortical locking screws. Fixation with noncannulated cortical locking screws offered more stability than cannulated locking screws with regard to axial stiffness and failure strength in a porcine model with unstable proximal tibial fractures.


Single-dose cefuroxime axetil versus multiple-dose cefaclor in the treatment of acute urinary tract infections.
Eighty-nine college women with acute urinary tract infections were treated orally with either 1,000 mg of cefuroxime axetil in a single dose (n = 59) or 250 mg of cefaclor three times a day for 7 days (n = 30). At 1 week posttherapy, 88% of the patients in the cefuroxime axetil group and 97% in the cefaclor group were clinically and bacteriologically cured (P greater than 0.10). There was no statistically significant difference between the cure rates of the two treatment groups. However, this study has only a 50% power to detect a 10% difference. Therefore, there is a substantial possibility of a type II error, i.e., failing to find a difference that is actually present. At 4 weeks posttherapy, 78% of the patients in the cefuroxime group and 80% in the cefaclor group remained cured. By 36 weeks posttherapy, the cumulative rate of recurrence in both treatment groups was 60%. Of the patients with a positive antibody-coated bacteria test, fewer achieved a short-term cure after single-dose treatment with cefuroxime axetil than those with a negative antibody-coated bacteria test (67 versus 96%; P less than 0.01).


NUFIP and the HSP90/R2TP chaperone bind the SMN complex and facilitate assembly of U4-specific proteins.
The Sm proteins are loaded on snRNAs by the SMN complex, but how snRNP-specific proteins are assembled remains poorly characterized. U4 snRNP and box C/D snoRNPs have structural similarities. They both contain the 15.5K and proteins with NOP domains (PRP31 for U4, NOP56/58 for snoRNPs). Biogenesis of box C/D snoRNPs involves NUFIP and the HSP90/R2TP chaperone system and here, we explore the function of this machinery in U4 RNP assembly. We show that yeast Prp31 interacts with several components of the NUFIP/R2TP machinery, and that these interactions are separable from each other. In human cells, PRP31 mutants that fail to stably associate with U4 snRNA still interact with components of the NUFIP/R2TP system, indicating that these interactions precede binding of PRP31 to U4 snRNA. Knock-down of NUFIP leads to mislocalization of PRP31 and decreased association with U4. Moreover, NUFIP is associated with the SMN complex through direct interactions with Gemin3 and Gemin6. Altogether, our data suggest a model in which the NUFIP/R2TP system is connected with the SMN complex and facilitates assembly of U4 snRNP-specific proteins.


Left lower-quadrant pain: guidelines from the American College of Radiology appropriateness criteria.
The differential diagnosis of left lower-quadrant pain includes gastrointestinal, gynecologic, and renal/ureteric pathology. Imaging is helpful in evaluating left lower-quadrant pain, and is generally guided by the clinical presentation. Acute sigmoid diverticulitis should be suspected when the clinical triad of left lower-quadrant pain, fever, and leukocytosis is present. The severity of disease varies from mild pericolonic and peridiverticular inflammation to severe inflammatory changes with complications such as perforation, peritonitis, or abscess or fistula formation. Computed tomography is the preferred test in evaluating clinically suspected diverticulitis. It is used to evaluate the severity and extent of disease and to identify complications, but it also may diagnose other causes of left lower-quadrant pain that can mimic diverticulitis. Magnetic resonance imaging can be used to assess left lower-quadrant pain. It has superior resolution of soft tissues and does not expose the patient to ionizing radiation, but it is expensive and requires more time to perform. Transabdominal ultrasonography with graded compression is another effective technique but is limited by its high operator dependency and technical difficulties in scanning patients who are obese. Pelvic ultrasonography is the preferred imaging modality in women of childbearing age. Radiography with contrast enema is less sensitive than computed tomography in diagnosing diverticulitis and is seldom used.


Ten Years of Gabor-Domain Optical Coherence Microscopy.
Gabor-domain optical coherence microscopy (GDOCM) is a high-definition imaging technique leveraging principles of low-coherence interferometry, liquid lens technology, high-speed imaging, and precision scanning. GDOCM achieves isotropic 2 μm resolution in 3D, effectively breaking the cellular resolution limit of optical coherence tomography (OCT). In the ten years since its introduction, GDOCM has been used for cellular imaging in 3D in a number of clinical applications, including dermatology, oncology and ophthalmology, as well as to characterize materials in industrial applications. Future developments will enhance the structural imaging capability of GDOCM by adding functional modalities, such as fluorescence and elastography, by estimating thicknesses on the nano-scale, and by incorporating machine learning techniques.


Ectopic expression of cancer/testis antigen SSX2 induces DNA damage and promotes genomic instability.
SSX cancer/testis antigens are frequently expressed in melanoma tumors and represent attractive targets for immunotherapy, but their role in melanoma tumorigenesis has remained elusive. Here, we investigated the cellular effects of SSX2 expression. In A375 melanoma cells, SSX2 expression resulted in an increased DNA content and enlargement of cell nuclei, suggestive of replication aberrations. The cells further displayed signs of DNA damage and genomic instability, associated with p53-mediated G1 cell cycle arrest and a late apoptotic response. These results suggest a model wherein SSX2-mediated replication stress translates into mitotic defects and genomic instability. Arrest of cell growth and induction of DNA double-strand breaks was also observed in MCF7 breast cancer cells in response to SSX2 expression. Additionally, MCF7 cells with ectopic SSX2 expression demonstrated typical signs of senescence (i.e. an irregular and enlarged cell shape, enhanced β-galactosidase activity and DNA double-strand breaks). Since replication defects, DNA damage and senescence are interconnected and well-documented effects of oncogene expression, we tested the oncogenic potential of SSX2. Importantly, knockdown of SSX2 expression in melanoma cell lines demonstrated that SSX2 supports the growth of melanoma cells. Our results reveal two important phenotypes of ectopic SSX2 expression that may drive/support tumorigenesis: First, immediate induction of genomic instability, and second, long-term support of tumor cell growth.


Polyphosphate is involved in cell cycle progression and genomic stability in Saccharomyces cerevisiae.
Polyphosphate (polyP) is a linear chain of up to hundreds of inorganic phosphate residues that is necessary for many physiological functions in all living organisms. In some bacteria, polyP supplies material to molecules such as DNA, thus playing an important role in biosynthetic processes in prokaryotes. In the present study, we set out to gain further insight into the role of polyP in eukaryotic cells. We observed that polyP amounts are cyclically regulated in Saccharomyces cerevisiae, and those mutants that cannot synthesise (vtc4Δ) or hydrolyse polyP (ppn1Δ, ppx1Δ) present impaired cell cycle progression. Further analysis revealed that polyP mutants show delayed nucleotide production and increased genomic instability. Based on these findings, we concluded that polyP not only maintains intracellular phosphate concentrations in response to fluctuations in extracellular phosphate levels, but also muffles internal cyclic phosphate fluctuations, such as those produced by the sudden demand of phosphate to synthetize deoxynucleotides just before and during DNA duplication. We propose that the presence of polyP in eukaryotic cells is required for the timely and accurate duplication of DNA.


Body mass index in relation to oesophageal and oesophagogastric junction adenocarcinomas: a pooled analysis from the International BEACON Consortium.
Previous studies suggest an association between obesity and oesophageal (OA) and oesophagogastric junction adenocarcinomas (OGJA). However, these studies have been limited in their ability to assess whether the effects of obesity vary by gender or by the presence of gastro-oesophageal reflux (GERD) symptoms. Individual participant data from 12 epidemiological studies (8 North American, 3 European and 1 Australian) comprising 1997 OA cases, 1900 OGJA cases and 11 159 control subjects were pooled. Logistic regression was used to estimate study-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between body mass index (BMI, kg/m(2)) and the risk of OA and OGJA. Random-effects meta-analysis was used to combine these ORs. We also investigated effect modification and synergistic interaction of BMI with GERD symptoms and gender. The association of OA and OGJA increased directly with increasing BMI (P for trend <0.001). Compared with individuals with a BMI <25, BMI ≥40 was associated with both OA (OR 4.76, 95% CI 2.96-7.66) and OGJA (OR 3.07, 95% CI 1.89-4.99). These associations were similar when stratified by gender and GERD symptoms. There was evidence for synergistic interaction between BMI and GERD symptoms in relation to OA/OGJA risk. These data indicate that BMI is directly associated with OA and OGJA risk in both men and women and in those with and without GERD symptoms. Disentangling the relationship between BMI and GERD will be important for understanding preventive efforts for OA and OGJA.


Failure criterion of silver nanowire electrodes on a polymer substrate for highly flexible devices.
Nanomechanical characteristics of standalone silver nanowires (Ag NWs) are a key issue for providing a failure criterion of advanced flexible electrodes that are trending towards smaller radius of curvatures (ROCs). Through in-situ tensile and buckling tests of pentagonal Ag NWs, we demonstrated that the intrinsic fracture strain provides a significant criterion to predict the mechanical and electrical failure of Ag NW electrodes under various strain modes, because the decrease in fracture strain limits figure of merit of flexible devices. The Ag NW electrodes on a polymer substrate exhibited a strain-dependent electrical failure owing to the unique deformation characteristics with a size-dependent brittle-to-ductile transition of the five-fold twinned Ag NWs. All the Ag NWs greater than approximately 40 nm in diameter exhibited brittle fracture with a size-independent stress-strain response under tensile and buckling modes, which leads to the electrical failure of flexible electrodes at the almost same threshold ROC. Meanwhile, the higher ductility of Ag NWs less than 40 nm in diameter resulted in much smaller threshold ROCs of the electrodes due to the highly extended fracture strains, which can afford a high degree of freedom for highly flexible devices.


Host hindrance to HIV-1 replication in monocytes and macrophages.
Monocytes and macrophages are targets of HIV-1 infection and play critical roles in multiple aspects of viral pathogenesis. HIV-1 can replicate in blood monocytes, although only a minor proportion of circulating monocytes harbor viral DNA. Resident macrophages in tissues can be infected and function as viral reservoirs. However, their susceptibility to infection, and their capacity to actively replicate the virus, varies greatly depending on the tissue localization and cytokine environment. The susceptibility of monocytes to HIV-1 infection in vitro depends on their differentiation status. Monocytes are refractory to infection and become permissive upon differentiation into macrophages. In addition, the capacity of monocyte-derived macrophages to sustain viral replication varies between individuals. Host determinants regulate HIV-1 replication in monocytes and macrophages, limiting several steps of the viral life-cycle, from viral entry to virus release. Some host factors responsible for HIV-1 restriction are shared with T lymphocytes, but several anti-viral mechanisms are specific to either monocytes or macrophages. Whilst a number of these mechanisms have been identified in monocytes or in monocyte-derived macrophages in vitro, some of them have also been implicated in the regulation of HIV-1 infection in vivo, in particular in the brain and the lung where macrophages are the main cell type infected by HIV-1. This review focuses on cellular factors that have been reported to interfere with HIV-1 infection in monocytes and macrophages, and examines the evidences supporting their role in vivo, highlighting unique aspects of HIV-1 restriction in these two cell types.


Holographic control of motive shape in plasmonic nanogap arrays.
Here we demonstrate that 4-beam holographic lithography can be utilized to create plasmonic nanogaps that are 70 times smaller than the laser wavelength (488 nm). This was achieved by controlling phase, polarization, and laser beam intensity in order to tune the relative spacing of the two sublattices in the interference pattern of a compound-lattice in combination with the nonlinear resist response. Exemplarily, twin and triplet motive features were designed and patterned into polymer in a single exposure step and then transferred into gold nanogap arrays resulting in an average gap size of 22 nm and smallest features down to 7 nm. These results extend the utility of high-throughput, wafer-scale holographic lithography into the realm of nanoplasmonics.


Gene Expression Correlation and Gene Ontology-Based Similarity: An Assessment of Quantitative Relationships.
The Gene Ontology and annotations derived from the S. cerivisiae Genome Database were analyzed to calculate functional similarity of gene products. Three methods for measuring similarity (including a distance-based approach) were implemented. Significant, quantitative relationships between similarity and expression correlation of pairs of genes were detected. Using a known gene expression dataset in yeast, this study compared more than three million pairs of gene products on the basis of these functional properties. Highly correlated genes exhibit strong similarity based on information originating from the gene ontology taxonomies. Such a similarity is significantly stronger than that observed between weakly correlated genes. This study supports the feasibility of applying gene ontology-driven similarity methods to functional prediction tasks, such as the validation of gene expression analyses and the identification of false positives in protein interaction studies.


Remnant signal peptides on non-exported enzymes: implications for the evolution of prokaryotic respiratory chains.
The twin-arginine translocation (Tat) pathway is a prokaryotic protein targeting system dedicated to the transmembrane translocation of folded proteins. Substrate proteins are directed to the Tat translocase by signal peptides bearing a conserved SRRxFLK 'twin-arginine' motif. In Escherichia coli, most of the 27 periplasmically located Tat substrates are cofactor-containing respiratory enzymes, and many of these harbour a molybdenum cofactor at their active site. Molybdenum cofactor-containing proteins are not exclusively located in the periplasm, however, with the major respiratory nitrate reductase (NarG) and the biotin sulfoxide reductase (BisC), for example, being located at the cytoplasmic side of the membrane. Interestingly, both NarG and BisC contain 'N-tail' regions that bear some sequence similarity to twin-arginine signal peptides. In this work, we have examined the relationship between the non-exported N-tails and the Tat system. Using a sensitive genetic screen for Tat transport, variant N-tails were identified that displayed Tat transport activity. For the NarG 36-residue N-tail, six amino acid changes were needed to induce transport activity. However, these changes interfered with binding by the NarJ biosynthetic chaperone and impaired biosynthesis of the native enzyme. For the BisC 36-residue N-tail, only five amino acid substitutions were needed to restore Tat transport activity. These modifications also impaired in vivo BisC activity, but it was not possible to identify a biosynthetic chaperone for this enzyme. These data highlight an intimate genetic and evolutionary link between some non-exported redox enzymes and those transported across membranes by the Tat translocation system.


Associations of serum insulin-like growth factor-I and insulin-like growth factor-binding protein 3 levels with biomarker-calibrated protein, dairy product and milk intake in the Women's Health Initiative.
It is well established that protein-energy malnutrition decreases serum insulin-like growth factor (IGF)-I levels, and supplementation of 30 g of whey protein daily has been shown to increase serum IGF-I levels by 8 % after 2 years in a clinical trial. Cohort studies provide the opportunity to assess associations between dietary protein intake and IGF axis protein levels under more typical eating conditions. In the present study, we assessed the associations of circulating IGF axis protein levels (ELISA, Diagnostic Systems Laboratories) with total biomarker-calibrated protein intake, as well as with dairy product and milk intake, among postmenopausal women enrolled in the Women's Health Initiative (n 747). Analyses were carried out using multivariate linear regression models that adjusted for age, BMI, race/ethnicity, education, biomarker-calibrated energy intake, alcohol intake, smoking, physical activity and hormone therapy use. There was a positive association between milk intake and free IGF-I levels. A three-serving increase in milk intake per d (approximately 30 g of protein) was associated with an estimated average 18·6 % higher increase in free IGF-I levels (95 % CI 0·9, 39·3 %). However, total IGF-I and insulin-like growth factor-binding protein 3 (IGFBP-3) levels were not associated with milk consumption and nor were there associations between biomarker-calibrated protein intake, biomarker-calibrated energy intake, and free IGF-I, total IGF-I or IGFBP-3 levels. The findings of the present study carried out in postmenopausal women are consistent with clinical trial data suggesting a specific relationship between milk consumption and serum IGF-I levels, although in the present study this association was only statistically significant for free, but not total, IGF-I or IGFBP-3 levels.


Attempted and completed incidents of stranger-perpetrated child sexual abuse and abduction.
To establish the prevalence, typology and nature of attempted or completed incidents of stranger-perpetrated sexual abuse or abduction of children "away from home". A questionnaire was completed by 2,420 children (83% response rate) aged 9-16 years in 26 elementary and high schools in North-West England. Of these children, 19.0% (n=461) reported that they had been the victims of any attempted or completed sexual abuse or abduction incident away from home at some point in their lives. Of these children, 161 (6.7% of the original sample) reported that the "last" incident had been perpetrated by a stranger. Based upon these last incidents, four main types of attempted or completed CSA or abduction incident were identified: indecent exposure (40.8% of victims), touching (25.8%), and abduction (23.1%), each occurring on their own; and incidents involving multiple types of act (10.2%). The majority of these abductions (91.1%) and touching incidents (50.9%) were attempted as opposed to completed. Rates of victimization were generally higher among girls than boys (10.4% vs. 4.2%, p<.001). A sizeable minority of victims had experienced sexual abuse or abduction previously (28.8%). The large majority of incidents were carried out by males (88.2%). Most incidents occurred when children were accompanied by their peers (67.9%). Many victims were frightened by their experience (46.9% very frightened) and the large majority made a disclosure (79.9%). Only a minority of incidents were reported to the police (33.3%). Incidents of attempted and completed stranger CSA and abduction are distinct from CSA and abduction by known persons, go against stereotypes, are complex, and give rise to a number of key issues that may have implications for prevention and intervention. Professionals involved in child protection should undertake work to reduce the risk of existing victims of CSA or abduction becoming victims of stranger CSA or abduction, and the risk of attempted incidents becoming completed ones. They also need to encourage the disclosure and reporting of attempted and completed stranger CSA and abduction incidents.


Hypertonic saline versus mannitol for the treatment of elevated intracranial pressure: a meta-analysis of randomized clinical trials.
Randomized trials have suggested that hypertonic saline solutions may be superior to mannitol for the treatment of elevated intracranial pressure, but their impact on clinical practice has been limited, partly by their small size. We therefore combined their findings in a meta-analysis. We searched for relevant studies in MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, and ISI Web of Knowledge. Randomized trials were included if they directly compared equiosmolar doses of hypertonic sodium solutions to mannitol for the treatment of elevated intracranial pressure in human subjects undergoing quantitative intracranial pressure measurement. Two investigators independently reviewed potentially eligible trials and extracted data using a preformed data collection sheet. Disagreements were resolved by consensus or by a third investigator if needed. We collected data on patient demographics, type of intracranial pathology, baseline intracranial pressure, osms per treatment dose, quantitative change in intracranial pressure, and prespecified adverse events. Our primary outcome was the proportion of successfully treated episodes of elevated intracranial pressure. Five trials comprising 112 patients with 184 episodes of elevated intracranial pressure met our inclusion criteria. In random-effects models, the relative risk of intracranial pressure control was 1.16 (95% confidence interval, 1.00-1.33), and the difference in mean intracranial pressure reduction was 2.0 mm Hg (95% confidence interval, -1.6 to 5.7), with both favoring hypertonic saline over mannitol. A mild degree of heterogeneity was present among the included trials. There were no significant adverse events reported. We found that hypertonic saline is more effective than mannitol for the treatment of elevated intracranial pressure. Our meta-analysis is limited by the small number and size of eligible trials, but our findings suggest that hypertonic saline may be superior to the current standard of care and argue for a large, multicenter, randomized trial to definitively establish the first-line medical therapy for intracranial hypertension.


Empiric antimicrobial therapy for pediatric skin and soft-tissue infections in the era of methicillin-resistant Staphylococcus aureus.
The goal was to compare the clinical effectiveness of monotherapy with beta-lactams, clindamycin, or trimethoprim-sulfamethoxazole in the outpatient management of nondrained noncultured skin and soft-tissue infections (SSTIs), in a methicillin-resistant Staphylococcus aureus (MRSA)-endemic region. A retrospective, nested, case-control trial was conducted with a cohort of patients from 5 urban pediatric practices in a community-acquired MRSA-endemic region. All subjects were treated as outpatients with oral monotherapy for nondrained noncultured SSTIs between January 2004 and March 2007. The primary outcome was treatment failure, defined as a drainage procedure, hospitalization, change in antibiotic, or second antibiotic prescription within 28 days. Of 2096 children with nondrained noncultured SSTIs, 104 (5.0%) were identified as experiencing treatment failure and were matched to 480 control subjects. Compared with beta-lactam therapy, clindamycin was equally effective but trimethoprim-sulfamethoxazole was associated with an increased risk of failure. Other factors independently associated with failure included initial treatment in the emergency department, presence or history of fever, and presence of either induration or a small abscess. Compared with beta-lactams, clindamycin monotherapy conferred no benefit, whereas trimethoprim-sulfamethoxazole was associated with an increased risk of treatment failure in a cohort of children with nondrained noncultured SSTIs who were treated as outpatients. Even in regions with endemic community-acquired MRSA, beta-lactams may still be appropriate, first-line, empiric therapy for children presenting with these infections.


A Thermal Imaging Solution for Early Detection of Pre-ulcerative Diabetic Hotspots.
Foot ulcers are a common complication of diabetes and are the leading cause of amputation amongst those with diabetes. Research has shown that, an increase of two degrees Celsius in the skin temperature on the plantar surface of the foot can be an early indication of injury or inflammation. Early detection and treatment of a hotspot region may reduce the risk of an ulcer developing. This paper presents a thermography-based approach for detecting temperature hotspots on the foot. The system comprises a bespoke application and a thermal camera attachment which captures RGB images and a temperature matrix. Web-based services process the captured data and detect whether any regions of higher temperature are present on the foot, in comparison to the other foot. The accuracy of this system has been verified through a pilot study. Hotspots were simulated on the feet of 10 healthy participants. The results indicated that hotspots were correctly detected for 60% of the participants. We discuss some reasons why the results were inaccurate for the remaining four participants. Furthermore, we also suggest some potential enhancements to the system with the aim of increasing the precision of the results.


Withdrawal of hormone therapy and increased risk of cardiovascular disease.
Many menopause specialists follow the principle of prescribing postmenopausal hormone therapy (HT) for the shortest duration needed, in order to decrease the risk of some related serious adverse effects, such as breast cancer. Based on several large studies, it seems, however, that withdrawal of HT may be associated with immediate, though small increased risk of coronary heart disease and stroke. Cessation of HT correlates with increased risk of fractures as well. This information should be relayed to hormone users while discussing the continuation of HT with their health-care provider, but, since the potential cardiovascular harm is actually very small, it should not deter symptomatic women from using HT when needed.


Antibiotic microbial resistance (AMR) removal efficiencies by conventional and advanced wastewater treatment processes: A review.
The World Health Organization (WHO) has identified the spread of antibiotic resistance as one of the major risks to global public health. An important transfer route into the aquatic environment is the urban water cycle. In this paper the occurrence and transport of antibiotic microbial resistance in the urban water cycle are critically reviewed. The presence of antibiotic resistance in low impacted surface water is being discussed to determine background antibiotic resistance levels, which might serve as a reference for treatment targets in the absence of health-based threshold levels. Different biological, physical and disinfection/oxidation processes employed in wastewater treatment and their efficacy regarding their removal of antibiotic resistant bacteria and antibiotic resistance geness (ARGs) were evaluated. A more efficient removal of antibiotic microbial resistance abundances from wastewater effluents can be achieved by advanced treatment processes, including membrane filtration, ozonation, UV-irradiation or chlorination, to levels typically observed in urban surface water or low impacted surface water.


Cotesia kariyai larvae need an anchor to emerge from the host Pseudaletia separata.
Mature larvae of the gregarious endoparasitoid Cotesia kariyai construct cocoons for pupation approximately 10 days after parasitization and emerge from their host Pseudaletia separata under a long day photo-regime (16L8D) at 25 +/- 1 degrees C. The parasitoid larvae make capsules in the host hemocoel just prior to their emergence. These capsules function as "anchors," which enable them to press against the host integument from inside the host. It was predicted that this anchor might be composed of silk proteins secreted from the parasitoid larvae, because a previous study showed that the anchor was made up of a glycoprotein and that the silk gland of parasitoid larvae developed from 2nd larval stage. Fibroin-like proteins in C. kariyai larva mainly consist of two proteins with molecular masses of the 300.6 and 46.7 kDa estimated by SDS-PAGE. The fibroin-like proteins with the same molecular mass were detected from the anchor proteins just prior to parasitoid emergence. These results indicate that the anchor was assembled with fibroin-like proteins and was formed just before parasitoid emergence while in the host body cavity. Injection of bovine pancreatic trypsin inhibited the emergence of parasitoid larvae from the host because the anchor was decomposed by trypsin. Trypsin activity in the parasitized host hemolymph increased only after parasitoid emergence.


Carbonate Apatite Containing Statin Enhances Bone Formation in Healing Incisal Extraction Sockets in Rats.
The purpose of this study was to evaluate the feasibility of using apatite blocks fabricated by a dissolution⁻precipitation reaction of preset gypsum, with or without statin, to enhance bone formation during socket healing after tooth extraction. Preset gypsum blocks were immersed in a Na₃PO₄ aqueous solution to make hydroxyapatite (HA) low crystalline and HA containing statin (HAFS), or in a mixed solution of Na₂HPO₄ and NaHCO₃ to make carbonate apatite (CO) and CO containing statin (COFS). The right mandibular incisors of four-week-old male Wistar rats were extracted and the sockets were filled with one of the bone substitutes or left untreated as a control (C). The animals were sacrificed at two and four weeks. Areas in the healing socket were evaluated by micro-computed tomography (micro-CT) and histological analyses. The bone volume, trabecular thickness, and trabecular separation were greatest in the COFS group, followed by the CO, HAFS, HA, and C groups. The bone mineral density of the COFS group was greater than that of the other groups when evaluated in the vertical plane. The results of this study suggest that COFS not only allowed, but also promoted, bone healing in the socket. This finding could be applicable for alveolar bone preservation after tooth extraction.


The crystallisation of copper(ii) phenylphosphonates.
The crystal structures and syntheses of four different copper(ii) phenylphosphonates, the monophenylphosphonates α-, β-, and γ-Cu(O3PC6H5)·H2O (α-CuPhPmH (1) β-CuPhPmH (2) and γ-CuPhPmH (3)), and the diphosphonate Cu(HO3PC6H5)2·H2O (CuPhP2mH (4)), are presented. The compounds were synthesized from solution at room temperature, at elevated temperature, under hydrothermal conditions, and mechanochemical conditions. The structures of α-CuPhPmH (1) and CuPhP2mH (4) were solved from powder X-ray diffraction data. The structure of β-CuPhPmH (2) was solved by single crystal X-ray analysis. The structures were validated by extended X-ray absorption fine structure (EXAFS) and DTA analyses. Disorder of the crystal structure was elucidated by electron diffraction. The relationship between the compounds and their reaction pathways were investigated by in situ synchrotron measurements.


L-arginine destabilizes oral multi-species biofilm communities developed in human saliva.
The amino acid L-arginine inhibits bacterial coaggregation, is involved in cell-cell signaling, and alters bacterial metabolism in a broad range of species present in the human oral cavity. Given the range of effects of L-arginine on bacteria, we hypothesized that L-arginine might alter multi-species oral biofilm development and cause developed multi-species biofilms to disassemble. Because of these potential biofilm-destabilizing effects, we also hypothesized that L-arginine might enhance the efficacy of antimicrobials that normally cannot rapidly penetrate biofilms. A static microplate biofilm system and a controlled-flow microfluidic system were used to develop multi-species oral biofilms derived from pooled unfiltered cell-containing saliva (CCS) in pooled filter-sterilized cell-free saliva (CFS) at 37° C. The addition of pH neutral L-arginine monohydrochloride (LAHCl) to CFS was found to exert negligible antimicrobial effects but significantly altered biofilm architecture in a concentration-dependent manner. Under controlled flow, the biovolume of biofilms (μm(3)/μm(2)) developed in saliva containing 100-500 mM LAHCl were up to two orders of magnitude less than when developed without LAHCI. Culture-independent community analysis demonstrated that 500 mM LAHCl substantially altered biofilm species composition: the proportion of Streptococcus and Veillonella species increased and the proportion of Gram-negative bacteria such as Neisseria and Aggregatibacter species was reduced. Adding LAHCl to pre-formed biofilms also reduced biovolume, presumably by altering cell-cell interactions and causing cell detachment. Furthermore, supplementing 0.01% cetylpyridinium chloride (CPC), an antimicrobial commonly used for the treatment of dental plaque, with 500 mM LAHCl resulted in greater penetration of CPC into the biofilms and significantly greater killing compared to a non-supplemented 0.01% CPC solution. Collectively, this work demonstrates that LAHCl moderates multi-species oral biofilm development and community composition and enhances the activity of CPC. The incorporation of LAHCl into oral healthcare products may be useful for enhanced biofilm control.


Cognitive remediation in schizophrenia.
Cognitive deficits are routinely evident in schizophrenia, and are of sufficient magnitude to influence functional outcomes in work, social functioning and illness management. Cognitive remediation is an evidenced-based non-pharmacological treatment for the neurocognitive deficits seen in schizophrenia. Narrowly defined, cognitive remediation is a set of cognitive drills or compensatory interventions designed to enhance cognitive functioning, but from the vantage of the psychiatric rehabilitation field, cognitive remediation is a therapy which engages the patient in learning activities that enhance the neurocognitive skills relevant to their chosen recovery goals. Cognitive remediation programs vary in the extent to which they reflect these narrow or broader perspectives but six meta-analytic studies report moderate range effect sizes on cognitive test performance, and daily functioning. Reciprocal interactions between baseline ability level, the type of instructional techniques used, and motivation provide some explanatory power for the heterogeneity in patient response to cognitive remediation.


Periodic movements of the legs during sleep associated with rises in systemic blood pressure.
We report the relationship between periodic leg movements during sleep and recurrent rises in systemic blood pressure in a patient with narcolepsy. The mean increase in systolic blood pressure following leg movements was 23%, which is of the same order as the rises seen in patients with obstructive sleep apnea. Following treatment with temazepam, the swings in blood pressure were unchanged despite considerably less electroencephalographic evidence of cortical arousal.


[Stem cells in orthopaedics].
Sharing new ideas and approaches is needed to advance basic scientific research as well as the clinical application of stem cells. In this newsletter we present the current knowledge in stem cell research and therapy within the field of orthopaedics, presenting the definitions, types and sources of the stem cells. The second part of this newsletter focuses on the clinical application of stem cells in the therapy of tissues with very limited capacity for self-regeneration; this includes tendons and ligaments, particularly found in rotator cuff rupture. The sever problems associated with articular cartilage repair have lead to the need for the development of clinical research, with the aim of finding efficient clinical applications of stem cell therapy in cartilage defects and osteoarthritis. However in addition to this, such therapy could be used for the regeneration of bone, as in bone defect repair. The clinical outcome of stem cell therapy is a promising option for the treatment of cartilage, bone and tendon defects; however an increased sample size and additional long-term prospective randomised studies are needed to confirm these preliminary results.


Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer.
This randomized phase III trial compared the efficacy and safety of capecitabine with or without bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. Patients were randomly assigned to receive capecitabine (2,500 mg/m2/d) twice daily on day 1 through 14 every 3 weeks, alone or in combination with bevacizumab (15 mg/kg) on day 1. The primary end point was progression-free survival (PFS), as determined by an independent review facility. From November 2000 to March 2002, 462 patients were enrolled. Treatment arms were balanced. No significant differences were found in the incidence of diarrhea, hand-foot syndrome, thromboembolic events, or serious bleeding episodes between treatment groups. Of other grade 3 or 4 adverse events, only hypertension requiring treatment (17.9% v 0.5%) was more frequent in patients receiving bevacizumab. Combination therapy significantly increased the response rates (19.8% v 9.1%; P = .001); however, this did not result in a longer PFS (4.86 v 4.17 months; hazard ratio = 0.98). Overall survival (15.1 v 14.5 months) and time to deterioration in quality of life as measured by the Functional Assessment Of Cancer Treatment--Breast were comparable in both treatment groups. Bevacizumab was well tolerated in this heavily pretreated patient population. Although the addition of bevacizumab to capecitabine produced a significant increase in response rates, this did not translate into improved PFS or overall survival.


Graduate-entry medical students: older and wiser but not less distressed.
Australia has a growing number of graduate-entry medical courses. It is known that undergraduate medical students have high levels of psychological distress; however, little is known about graduate-entry medical students. We examined whether graduate-entry medical students had higher levels of psychological distress than the same-age general population. Psychological distress was assessed in 122 graduate-entry medical students in an Australian graduate-entry medical school using the 21-item Depression Anxiety and Stress Scale. Mean scores and the proportion of students with scores in the highly distressed range were compared with non-clinical population norms. Scores were also compared across demographic characteristics. Medical students reported higher mean depression, anxiety and stress scores than the general population and were more likely to score in the moderate to extremely high range for anxiety (45% vs. 13%; p<0.001) and stress (17% vs. 13%; p=0.003). Anxiety and stress were higher in students aged ≥30 years than in younger students. Despite their maturity, graduate-entry students experienced high psychological distress. Anxiety and stress were higher, not lower, with increasing age. Our results suggest that graduate-entry medical students warrant the same level of concern as their school-leaving counterparts. Further interventions to support these students during medical school are warranted.


Targeting insulin-like growth factor-binding protein-3 by microRNA-125b promotes tumor invasion and poor outcomes in non-small-cell lung cancer.
Insulin-like growth factor-binding protein-3 acts as a tumor suppressor that inhibits the PI3K/AKT signaling pathway due to blocking insulin growth factor-1 binding to its receptor. We hypothesized that insulin-like growth factor-binding protein-3 might be targeted by microRNA-125b and promote tumor invasion and poor outcome in non-small-cell lung cancer via activation of the PI3K/AKT signaling pathway. Real-time polymerase chain reaction and immunohistochemistry were performed to determine the level of microRNA-125b, insulin-like growth factor-binding protein-3 messenger RNA, and phosphorylated-AKT expression in 105 tumors from non-small-cell lung cancer patients. Low insulin-like growth factor-binding protein-3 messenger RNA levels and positive phosphorylated-AKT expression were more commonly found in patients with high microRNA-125b tumors than low microRNA-125b tumors. A poorer overall survival and relapse-free survival were observed in patients with high microRNA-125b tumors than low-microRNA-125b tumors in p53-mutated patients, but not in p53-wild-type patients. Mechanistically, microRNA-125b promotes invasion ability in p53-mutated cells via the PI3K/AKT activation by targeting of insulin-like growth factor-binding protein-3, but this effect was not observed in p53-wild-type cells. An increase in phosphorylated-AKT expression due to targeting of insulin-like growth factor-binding protein-3 by microRNA-125b was responsible for cell invasion in p53-mutated cells. In conclusion, the microRNA-125b level promotes invasive ability in p53-mutated cells via PI3K/AKT activation by targeting of insulin-like growth factor-binding protein-3, thereby resulting in p53-mutated non-small-cell lung cancer patients with poor outcomes.


Piecewise approximation of contours through scale-space selection of dominant points.
This paper describes a method of approximating a shape contour with a polygon. The polygon vertices are extracted from the curvature extremes, through a scale-space description of the contour, via linear diffusion. These vertices are located on the contour points where the sharper changes of the contour directions occur. Using a proper strategy, a set of extremes that result in a given approximation level is chosen. By adding new vertices, the approximation level can be improved, and a scalable representation of the contour is identified. This method results in an approximation that discriminates local from global geometric features and provides a good visual representation of the original contour. This polygonal approximation method is used for scalable encoding of the shape contours. In this regard, an encoding technique suitable for scalable polygonal approximation has been developed. We show that encoding the approximated polygons result in a good relation between the distortion and the bitrate. Finally, we show that in addition to coding this method can be efficiently used for shape comparison and shape retrieval.


Effect of clopidogrel on early failure of arteriovenous fistulas for hemodialysis: a randomized controlled trial.
The arteriovenous fistula is the preferred type of vascular access for hemodialysis because of lower thrombosis and infection rates and lower health care expenditures compared with synthetic grafts or central venous catheters. Early failure of fistulas due to thrombosis or inadequate maturation is a barrier to increasing the prevalence of fistulas among patients treated with hemodialysis. Small, inconclusive trials have suggested that antiplatelet agents may reduce thrombosis of new fistulas. To determine whether clopidogrel reduces early failure of hemodialysis fistulas. Randomized, double-blind, placebo-controlled trial conducted at 9 US centers composed of academic and community nephrology practices in 2003-2007. Eight hundred seventy-seven participants with end-stage renal disease or advanced chronic kidney disease were followed up until 150 to 180 days after fistula creation or 30 days after initiation of dialysis, whichever occurred later. Participants were randomly assigned to receive clopidogrel (300-mg loading dose followed by daily dose of 75 mg; n = 441) or placebo (n = 436) for 6 weeks starting within 1 day after fistula creation. The primary outcome was fistula thrombosis, determined by physical examination at 6 weeks. The secondary outcome was failure of the fistula to become suitable for dialysis. Suitability was defined as use of the fistula at a dialysis machine blood pump rate of 300 mL/min or more during 8 of 12 dialysis sessions. Enrollment was stopped after 877 participants were randomized based on a stopping rule for intervention efficacy. Fistula thrombosis occurred in 53 (12.2%) participants assigned to clopidogrel compared with 84 (19.5%) participants assigned to placebo (relative risk, 0.63; 95% confidence interval, 0.46-0.97; P = .018). Failure to attain suitability for dialysis did not differ between the clopidogrel and placebo groups (61.8% vs 59.5%, respectively; relative risk, 1.05; 95% confidence interval, 0.94-1.17; P = .40). Clopidogrel reduces the frequency of early thrombosis of new arteriovenous fistulas but does not increase the proportion of fistulas that become suitable for dialysis. Trial Registration clinicaltrials.gov Identifier: NCT00067119.


Applied climate-change analysis: the climate wizard tool.
Although the message of "global climate change" is catalyzing international action, it is local and regional changes that directly affect people and ecosystems and are of immediate concern to scientists, managers, and policy makers. A major barrier preventing informed climate-change adaptation planning is the difficulty accessing, analyzing, and interpreting climate-change information. To address this problem, we developed a powerful, yet easy to use, web-based tool called Climate Wizard (http://ClimateWizard.org) that provides non-climate specialists with simple analyses and innovative graphical depictions for conveying how climate has and is projected to change within specific geographic areas throughout the world. To demonstrate the Climate Wizard, we explored historic trends and future departures (anomalies) in temperature and precipitation globally, and within specific latitudinal zones and countries. We found the greatest temperature increases during 1951-2002 occurred in northern hemisphere countries (especially during January-April), but the latitude of greatest temperature change varied throughout the year, sinusoidally ranging from approximately 50 degrees N during February-March to 10 degrees N during August-September. Precipitation decreases occurred most commonly in countries between 0-20 degrees N, and increases mostly occurred outside of this latitudinal region. Similarly, a quantile ensemble analysis based on projections from 16 General Circulation Models (GCMs) for 2070-2099 identified the median projected change within countries, which showed both latitudinal and regional patterns in projected temperature and precipitation change. The results of these analyses are consistent with those reported by the Intergovernmental Panel on Climate Change, but at the same time, they provide examples of how Climate Wizard can be used to explore regionally- and temporally-specific analyses of climate change. Moreover, Climate Wizard is not a static product, but rather a data analysis framework designed to be used for climate change impact and adaption planning, which can be expanded to include other information, such as downscaled future projections of hydrology, soil moisture, wildfire, vegetation, marine conditions, disease, and agricultural productivity.


Effects of acute exposure to the radiofrequency fields of cellular phones on plasma lipid peroxide and antioxidase activities in human erythrocytes.
Radiofrequency fields of cellular phones may affect biological systems by increasing free radicals, which appear mainly to enhance lipid peroxidation, and by changing the antioxidase activities of human blood thus leading to oxidative stress. To test this, we have investigated the effect of acute exposure to radiofrequency fields of commercially available cellular phones on some parameters indicative of oxidative stress in 12 healthy adult male volunteers. Each volunteer put the phone in his pocket in standby position with the keypad facing the body. The parameters measured were lipid peroxide and the activities of superoxide dismutase (SOD), total glutathione peroxidase (GSH-Px) and catalase. The results obtained showed that the plasma level of lipid peroxide was significantly increased after 1, 2 and 4 h of exposure to radiofrequency fields of the cellular phone in standby position. Moreover, the activities of SOD and GSH-Px in human erythrocytes showed significant reduction while the activity of catalase in human erythrocytes did not decrease significantly. These results indicate that acute exposure to radiofrequency fields of commercially available cellular phones may modulate the oxidative stress of free radicals by enhancing lipid peroxidation and reducing the activation of SOD and GSH-Px, which are free radical scavengers. Therefore, these results support the interaction of radiofrequency fields of cellular phones with biological systems.


Pharmacological suppression of hepcidin increases macrophage cholesterol efflux and reduces foam cell formation and atherosclerosis.
We recently reported that lowering of macrophage free intracellular iron increases expression of cholesterol efflux transporters ABCA1 and ABCG1 by reducing generation of reactive oxygen species. In this study, we explored whether reducing macrophage intracellular iron levels via pharmacological suppression of hepcidin can increase macrophage-specific expression of cholesterol efflux transporters and reduce atherosclerosis. To suppress hepcidin, increase expression of the iron exporter ferroportin, and reduce macrophage intracellular iron, we used a small molecule inhibitor of bone morphogenetic protein (BMP) signaling, LDN 193189 (LDN). LDN (10 mg/kg IP b.i.d.) was administered to mice, and its effects on atherosclerosis, intracellular iron, oxidative stress, lipid efflux, and foam cell formation were measured in plaques and peritoneal macrophages. Long-term LDN administration to apolipoprotein E-/- mice increased ABCA1 immunoreactivity within intraplaque macrophages by 3.7-fold (n=8; P=0.03), reduced Oil Red O-positive lipid area by 50% (n=8; P=0.02), and decreased total plaque area by 43% (n=8; P=0.001). LDN suppressed liver hepcidin transcription and increased macrophage ferroportin, lowering intracellular iron and hydrogen peroxide production. LDN treatment increased macrophage ABCA1 and ABCG1 expression, significantly raised cholesterol efflux to ApoA-1, and decreased foam cell formation. All preceding LDN-induced effects on cholesterol efflux were reversed by exogenous hepcidin administration, suggesting modulation of intracellular iron levels within macrophages as the mechanism by which LDN triggers these effects. These data suggest that pharmacological manipulation of iron homeostasis may be a promising target to increase macrophage reverse cholesterol transport and limit atherosclerosis.


Active and inactive renin in pregnancy and in women on estrogen-containing oral contraceptives.
Total and active renin concentrations (TRC and ARC) were determined in pregnant women and in women on estrogen-containing oral contraceptives to study the variation of plasma renin forms in pregnancy. TRC was already elevated in the first trimester. After that TRC increased consistently reaching the maximum in the third trimester. The ratio of inactive renin concentrations (IRC) to TRC was between 20 and 30% throughout gestation. Therefore, it was supposed that the development of the placenta or the enlargement of the uterus do not affect the ratio of IRC to TRC too much. In women on oral contraceptives in whom plasma renin activity was increased due to elevation of renin substrate, the ratio of IRC to TRC was almost the same as that in normal controls. From these results, it was suggested that the development of the placenta and the enlargement of the uterus do not play an important role in the variation of plasma renin forms, although remarkable changes are observed in the renin substrate and total amounts of renin in pregnancy.


Micro-CT evaluation of two different root canal filling techniques.
The aim of this study was to compare the frequency and volume of voids in root canals obturated with two different filling techniques using micro-computed tomography (micro-CT). Forty single-rooted permanent teeth were selected and decoronated. The roots were instrumented with WaveOne (Dentsply Maillefer, Ballaigues, Switzerland) to a large size until working length and irrigated with 5.25% sodium hypochlorite and 17% EDTA. Then, the samples were filled using a single-cone (n = 20) or the GuttaCore technique (n = 20). The presence and volume (mm3) of voids (internal, external, and combined) was calculated in the coronal, medium, and apical thirds using micro-CT (SkyScan 1072; SkyScan, Kartuizersweg, Belgium). Statistical analyses were performed using the χ2-test and Kruskal-Wallis tests (p<0.05). The frequency and total volume of voids in the middle third and the external voids in the coronal third were statistically significant (p<0.05). Within the same group, both techniques (single-cone and Guttacore) showed statistically significant differences in external and internal voids (p<0.05). The GuttaCore technique showed better results in the coronal and medium thirds than the single-cone technique. Our results showed that the single-cone and GuttaCore techniques were comparable in the apical third (p>0.05).


Reactivity of autoantibodies and DNA/anti-DNA complexes with a novel 110-kilodalton phosphoprotein in systemic lupus erythematosus and other diseases.
Utilizing nonionic detergent lysates of human lymphoid and non-lymphoid cells as substrate, IgM and/or IgG antibodies to a 110-kDa/isoelectric point 5.4 phosphoprotein (110K) was demonstrated in serum from patients with SLE or certain other systemic autoimmune disorders by immunoblotting and immunoprecipitation. Ig of this specificity was not demonstrable in serum from normal individuals, but, in a limited survey, was detected in serum from patients with acute hepatitis A or infectious mononucleosis. 110K shares a number of properties with nucleolin, i.e., identical Mr and isoelectric point, localization in both the nucleus and the cytosol, increased expression in rapidly dividing cells, and shown to be distinct from already defined autoantigens of similar size, i.e., topoisomerase I, PM-Scl, and RNA polymerase I. Because 110K could bind denatured DNA, as demonstrated by its specific absorption by DNA-cellulose and by its reactivity with monoclonal anti-ssDNA antibody in the presence of denatured DNA, special efforts were made to distinguish reactivity of pre-formed DNA/anti-DNA complexes in SLE serum from that due to specific anti-110K autoantibodies. Although binding to 110K could be mediated by DNA and anti-DNA in some SLE sera, the accumulated evidence supports the existence of a major new autoantibody system in SLE, other autoimmune diseases, and certain virus infections.


[Strengths and difficulties in emotional adjustment of Aymara children from the perspective of children, parents and teachers].
To describe capabilities and difficulties in emotional adjustment experienced by children living in the Chilean Aymara city of Arica. 610 students between 5th and 8th grade, in addition to their parents and teachers were surveyed using the Strengths and Difficulties Questionnaire (SDQ), comparing Aymara children to those without indigenous heritage. 25 items divided into five scales were evaluated: Emotional, behavioral problems, hyperactivity, relationship problems with peers and prosocial behaviors, classifying the respondents into three levels, Normal, Border and Abnormal. There were no significant differences among the groups studied, where discrepancies in almost all cases show a slight effect (d≥|0.2|). Also, no relevant effects were observed regarding the type of assessor on the assessment of each dimension. Despite this, it was observed that Aymara children showed lower scores than their peers in "behavioral problems" according to their teachers, but this difference was also mild (partial η2>0.01). Aymara Children showed similar strengths and difficulties than non-Aymara students in situations that require emotional adjustment.


Investigating the genetic and environmental bases of biases in threat recognition and avoidance in children with anxiety problems.
Adults with anxiety show biased categorization and avoidance of threats. Such biases may emerge through complex interplay between genetics and environments, occurring early in life. Research on threat biases in children has focuses on a restricted range of biases, with insufficient focus on genetic and environmental origins. Here, we explore differences between children with and without anxiety problems in under-studied areas of threat bias. We focused both on associations with anxious phenotype and the underlying gene-environmental correlates for two specific processes: the categorisation of threat faces and avoidance learning. Two-hundred and fifty 10-year old MZ and DZ twin pairs (500 individuals) completed tasks assessing accuracy in the labelling of threatening facial expressions and in the acquisition of avoidant responses to a card associated with a masked threatening face. To assess whether participants met criteria for an anxiety disorder, parents of twins completed a self-guided computerized version of the Development and Well-being Assessment (DAWBA). Comparison of MZ and DZ twin correlations using model-fitting were used to compute estimates of genetic, shared and non-shared environmental effects. Of the 500 twins assessed, 25 (5%) met diagnostic criteria for a current anxiety disorder. Children with anxiety disorders were more accurate in their ability to recognize disgust faces than those without anxiety disorders, but were commensurate on identifying other threatening face emotions (angry, fearful, sad). Children with anxiety disorders but also more strongly avoided selecting a conditioned stimulus than non-anxious children. While recognition of socially threatening faces was moderately heritable, avoidant responses were heavily influenced by the non-shared environment. These data add to other findings on threat biases in anxious children. Specifically, we found biases in the labelling of some negative-valence faces and in the acquisition of avoidant responses. While non-shared environmental effects explained all of the variance on threat avoidance, some of this may be due to measurement error.