Survival of HIV-infected adolescents on antiretroviral therapy in Uganda: findings from a nationally representative cohort in Uganda.
Adolescents have been identified as a high-risk group for poor adherence to and defaulting from combination antiretroviral therapy (cART) care. However, data on outcomes for adolescents on cART in resource-limited settings remain scarce. We developed an observational study of patients who started cART at The AIDS Service Organization (TASO) in Uganda between 2004 and 2009. Age was stratified into three groups: children (≤10 years), adolescents (11-19 years), and adults (≥20 years). Kaplan-Meier survival curves were generated to describe time to mortality and loss to follow-up, and Cox regression used to model associations between age and mortality and loss to follow-up. To address loss to follow up, we applied a weighted analysis that assumes 50% of lost patients had died. A total of 23,367 patients were included in this analysis, including 810 (3.5%) children, 575 (2.5%) adolescents, and 21 982 (94.0%) adults. A lower percentage of children (5.4%) died during their cART treatment compared to adolescents (8.5%) and adults (10%). After adjusting for confounding, other features predicted mortality than age alone. Mortality was higher among males (p<0.001), patients with a low initial CD4 cell count (p<0.001), patients with advanced WHO clinical disease stage (p<0.001), and shorter duration of time receiving cART (p<0.001). The crude mortality rate was lower for children (22.8 per 1000 person-years; 95% CI: 16.1, 29.5), than adolescents (36.5 per 1000 person-years; 95% CI: 26.3, 46.8) and adults (37.5 per 1000 person-years; 95% CI: 35.9, 39.1). This study is the largest assessment of adolescents receiving cART in Africa. Adolescents did not have cART mortality outcomes different from adults or children.


[The use of verbal communicative abilities to increase the mean length of utterance in high-functioning autism and Asperger Syndrome].
high-functioning autism (HFA) and Asperger Syndrome (AS) are pervasive developmental disorders that present alterations in the communicative and social skills. to use verbal communicative skill strategies (VCS) to increase the mean length of utterance (MLU) produced by individuals with HFA and AS. participants were three 12-year-old males with HFA or AS. Data was collected from videotape recordings of structured verbal interaction sessions with the researcher and each participant during eight months. In order to verify the effects of the intervention, a multiple baseline research design across the participants was used, being composed by two phases: baseline (BL) and intervention (I). In the BL phase, spontaneous interaction situations occurred between the researcher and each participant. In the first phase of I, the intervention sessions occurred twice a week and gradually worked their way to once a week, but only after each participant had reached the goal of increasing the MLU. The number of sessions decreased gradually to avoid any drop in performance. The strategies which were used were divided in blocks of activities: spontaneous conversation; activities involving specific language difficulties; games with rules; story/report telling; and meta-linguistic activities. the application of the proposed strategies for verbal communicative abilities achieved the purpose of increasing the MLU of all three participants. suggestions are made for further researches that investigate the maintenance of the results in other environments and during the interaction with different communication partners.


Docosahexaenoic acid from a cultured microalga inhibits cell growth and induces apoptosis by upregulating Bax/Bcl-2 ratio in human breast carcinoma MCF-7 cells.
Docosahexaenoic acid (DHA) is an omega-3 fatty acid that comprises 22 carbons and 6 alternative double bonds in its hydrocarbon chain (22:6omega3). Previous studies have shown that DHA from fish oil controls the growth and development of different cancers; however, safety issues have been raised repeatedly about contamination of toxins in fish oil that makes it no longer a clean and safe source of the fatty acid. We investigated the cell growth inhibition of DHA from the cultured microalga Crypthecodinium cohnii (algal DHA [aDHA]) in human breast carcinoma MCF-7 cells. aDHA exhibited growth inhibition on breast cancer cells dose-dependently by 16.0% to 59.0% of the control level after 72-h incubations with 40 to 160 microM of the fatty acid. DNA flow cytometry shows that aDHA induced sub-G(1) cells, or apoptotic cells, by 64.4% to 171.3% of the control levels after incubations with 80 mM of the fatty acid for 24, 48, and 72 h. Western blot studies further show that aDHA did not modulate the expression of proapoptotic Bax protein but induced the downregulation of anti-apoptotic Bcl-2 expression time-dependently, causing increases of Bax/Bcl-2 ratio by 303.4% and 386.5% after 48- and 72-h incubations respectively with the fatty acid. Results from this study suggest that DHA from the cultured microalga is also effective in controlling cancer cell growth and that downregulation of antiapoptotic Bcl-2 is an important step in the induced apoptosis.


Evaluation of inSPOTLA.org: an Internet partner notification service.
This article presents an evaluation of inSPOTLA.org, a sexually transmitted disease partner notification Web site in Los Angeles County primarily targeting men who have sex with men (MSM). Since its launch in 2005, this Web site has received more than 400,000 visitors and resulted in nearly 50,000 e-mail postcards sent. However, there have been limited quantitative data concerning use of the service for actual partner notification. This study investigated awareness and use of inSPOTLA among MSM, as well as the effect of an advertising campaign. Data from 2 cross-sectional surveys using time-location samples were used for the evaluation, with a baseline survey conducted in 2007 and a follow-up conducted in 2009. The advertising campaign was implemented between the surveys in 2008. Awareness of inSPOTLA was 15.8% in the baseline survey and 14.4% in the follow-up survey, with no statistically significant difference. Reported use of inSPOTLA for partner notification was less than 2% in both surveys, again with no significant difference. In addition to the surveys, a high-volume sexual health clinic that serves the MSM population in Los Angeles collected data on reason for visit, including referrals from inSPOTLA, from all patients from 2007 through 2009. In 3 years, 2 individuals stated having received an inSPOTLA e-card as the reason for their visit. While website user statistics seemed to indicate an impressive level of use, our evaluation of inSPOTLA found very limited evidence of program effectiveness for the purpose of actual partner notification among MSM in Los Angeles County.


Ability of Dual-Energy CT to Detect Silicone Gel Breast Implant Rupture and Nodal Silicone Spread.
The purpose of this study is to compare the performance of dual-energy CT (DECT) with that of breast MRI for detection of silicone gel breast implant rupture and nodal spread of silicone. This prospective study enrolled consecutive patients with current or prior silicone gel implants and clinical suspicion of implant rupture or extra-capsular silicone. All patients underwent MRI followed by unenhanced DECT. A breast radiologist not participating in image evaluation established reference standards for implant rupture (intra- or extracapsular) and regional nodal silicone spread (to axillary nodes and internal mammary [IM] and mediastinal nodes) using MRI, surgical findings, and medical records. After undergoing reader training, two radiologists who were blinded to all medical records interpreted randomized images in two sessions, indicating confidence in diagnosis using a 100-point visual scale. A total of 46 patients who had a subpectoral silicone gel implant (n = 31), a subglandular silicone gel implant (n = 14), or a silicone gel implant that was removed (n = 1) underwent MRI and DECT (mean [± SD] volume CT dose index, 8.2 ± 2.0 mGy). Nineteen patients had implant rupture, and 13 of these patients had silicone within the IM or axillary nodes. Pooled data showed no significant difference between MRI and DECT interpretation of intra- or extracapsular rupture of implants (AUC value for intracapsular rupture, 0.958 [for MRI] vs 0.989 [for DECT]; p = 0.28; AUC value for extracapsular rupture, 0.864 [for MRI] vs 0.878 [for DECT]; p = 0.78). No difference was noted in the AUC value for silicone spread to regional lymph nodes: 0.823-0.866 [for MRI] vs 0.892-0.906 [for DECT]; p = 0.34-0.54). DECT performs similar to MRI for the detection of silicone gel implant rupture and the presence of silicone in regional lymph nodes, and it may be an alternative for patients who are unable or unwilling to undergo MRI.


Optimising drug therapy for non-infectious uveitis.
Uveitis encompasses a wide variety of sight-threatening diseases characterized by intraocular inflammation. It is often classified as infectious and non-infectious uveitis. Unlike infectious uveitis, a distinct infectious agent cannot be identified in non-infectious uveitis and disease origin is usually autoimmune, drug related, or idiopathic. Non-infectious uveitis can often have a relapsing-remitting course, making it difficult to treat, and poses a significant challenge to ophthalmologists. The autoimmune nature of non-infectious uveitis warrants the use of anti-inflammatory and immunomodulatory agents for disease control. However, a subset of patients has persistent or recurrent ocular inflammation despite appropriate treatment, stressing the need for newer therapies aimed at more specific inflammatory targets such as tumour necrosis factor (TNF) alpha agents, anti-interleukin agents, and anti-interleukin receptor agents. This article discusses the various medical options available for the treatment of non-infectious uveitis in the light of the most recent evidence. Successful management of non-infectious uveitis requires the clinician carefully balance advantages and disadvantages of each new and old therapy while considering individual circumstances. Counselling regarding the benefits and complications of each therapy can help patients make an informed choice.


Comparison of the effects of rutaecarpine on molecular subtypes of breast cancer.
Natural compounds have gained considerable attention in recent years due to disadvantages and properties of current chemotherapy drugs in cancer therapy. In addition, the impact of these compounds is specific for each type and/or subtypes of cancer due to different treatment response. Rutaecarpine, an alkaloid obtained from Evodia Rutaecarpa Chinese herb, has anticancer activity by inhibiting topoisomerase and/or cyclo-oxygenase-2 levels. However, the effectiveness of rutaecarpine has not been well known in breast cancer in terms of subtype. Therefore, we investigated the potential therapeutic effects of rutaecarpine on two different subtypes of breast cancer cells. The cytotoxic and apoptotic effects of rutaecarpine on MCF-7 and MDA-MB-231 cells were analyzed by WST-1, Annexin V, cell cycle, and acridine orange staining. WST-1 results indicated that rutaecarpine significantly inhibited the growth of both cancer cells for 48 h (P < 0.05). In addition, rutaecarpine treatment caused apoptotic cell death through chromatin condensation and nuclear blebbing and G0/G1 arrest in both breast cancer cells. However, the efficacy of rutaecarpine was more profound in MCF-7 cells than MDA-MB-231 cells. Consequently, rutaecarpine has a potential therapeutic effect on breast cancer. However, the effectiveness of rutaecarpine is dependent on the subtype of breast cancer.


First report of the dagger nematode Xiphinema pachtaicum on onion in Morocco.
In 2018, during a survey in Souss region of Morocco, the dagger nematode Xiphinema pachtaicum was found parasitizing onion, (Allium cepa L.). The populations of dagger nematode were identified on the basis of their morphological and morphometric characters and by sequencing and analysing the D2D2 region of 28S rRNA. Microscopic observation of females demonstrated the occurrence of Xiphinema pachtaicum on onion. The 28S D2D3 sequences shared 99 to 100% similarity with sequence corresponding to X. pachtaicum in GenBank. To our knowledge this is the first report of Xiphinema pachtaichum infecting onion in Morocco. In 2018, during a survey in Souss region of Morocco, the dagger nematode Xiphinema pachtaicum was found parasitizing onion, (Allium cepa L.). The populations of dagger nematode were identified on the basis of their morphological and morphometric characters and by sequencing and analysing the D2D2 region of 28S rRNA. Microscopic observation of females demonstrated the occurrence of Xiphinema pachtaicum on onion. The 28S D2D3 sequences shared 99 to 100% similarity with sequence corresponding to X. pachtaicum in GenBank. To our knowledge this is the first report of Xiphinema pachtaichum infecting onion in Morocco.


Dyssynchrony and electromechanical delay are associated with focal fibrosis in the systemic right ventricle - Insights from echocardiography.
Systemic right ventricular (RV) dysfunction and sudden cardiac death remain problematic late after Mustard operation for transposition of the great arteries. The exact mechanism for that relationship is likely to be multifactorial including myocardial fibrosis. Doppler echocardiography gives further insights into the role of fibrosis shown by late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) in late morbidity. Twenty-two consecutive patients, mean age 28±8years, were studied with 2D echocardiography, and also assessed by LGE CMR. The presence of LGE in 13/22 patients (59%) was related to delayed septal shortening and lengthening (P=0.002 &P=0.049), prolonged systemic RV isovolumic contraction time (P=0.024) and reduced systemic RV free wall and septal excursion (P=0.027 &P=0.005). The systemic RV total isovolumic time was prolonged but not related to extent of LGE. LGE extent was related to markers of electromechanical delay and dyssynchrony (delayed onset of RV free wall shortening and lengthening; r=0.73 &P=0.004 and r=0.62 &P=0.041, respectively, and QRS duration r=0.68, P<0.01) and was inversely related to systolic RV free wall shortening velocity (r=-0.59 &P=0.042). The presence of LGE was also related to lower exercise capacity, ≥mild tricuspid regurgitation and more arrhythmia (P=0.008, P=0.014 and P=0.040). RV free wall excursion and systolic tissue Doppler velocity were related to CMR derived RV ejection fraction (r=0.51, P=0.015, and r=0.77, P=<0.001, respectively). Post Mustard repair, myocardial fibrosis is related to dyssynchrony, RV long axis dysfunction and tricuspid regurgitation. Echocardiographic measurements of systemic RV function can be confidently used in serial follow-up following Mustard operation.


Pityriasis Rubra Pilaris Type V as an Autoinflammatory Disease by CARD14 Mutations.
We found CARD14 mutations (2 de novo novel mutations and another previously reported mutation) in 3 of 3 patients with pityriasis rubra pilaris (PRP) type V, but not in patients with PRP of other types. Our findings, combined with the published literature, suggest that type V PRP, both familial and sporadic, can be caused by CARD14 mutations. Detailed clinical observation revealed that all 3 patients displayed unique patchy macular brown hyperpigmentation. To further determine how often patients with PRP have pathogenic mutations in CARD14 and to elucidate which clinical subtype of PRP is caused by CARD14 mutations. We sequenced the entire coding regions of CARD14 in genomic DNA from patients with 5 clinical subtypes of PRP. The detailed clinical features were analyzed in all the patients. The pathogenicity of each mutation was evaluated by several computational predictions. PRP was classified into 6 subgroups, types I to VI, based on clinical criteria. We categorized all the patients with PRP into the clinical subtypes using the classic PRP classification; 22 cases of PRP with varying subtypes were studied. The prevalence of CARD14 mutations in each subtype of PRP was evaluated. Clinical features and characteristics of patients with PRP with CARD14 mutations were analyzed. Overall 22 patients with PRP were included in our study (12 men, 10 women; mean [SD] age, 26 [18] years). Among 3 patients with PRP type V, all were found to have CARD14 mutations: 2 de novo novel mutations (p.Cys127Ser and p.Gln136Leu), and another previously reported mutation (p.Gly117Ser). All were close to the reported pathogenic domains. In silico analysis of all 3 mutations suggested that they are functionally relevant to pathogenesis. All 3 patients displayed unique patchy macular brown hyperpigmentation additionally to other typical features of PRP. Patients with PRP type I and type IV, 1 patient each, had the rare variants in CARD14. Pityriasis rubra pilaris type V is a distinct variant of PRP that is caused by CARD14 mutations. In addition, a rare variant of CARD14 might also be implicated in the pathophysiology of other forms of PRP.


Layered Wyner-Ziv video coding.
Following recent theoretical works on successive Wyner-Ziv coding (WZC), we propose a practical layered Wyner-Ziv video coder using the DCT, nested scalar quantization, and irregular LDPC code based Slepian-Wolf coding (or lossless source coding with side information at the decoder). Our main novelty is to use the base layer of a standard scalable video coder (e.g., MPEG-4/H.26L FGS or H.263+) as the decoder side information and perform layered WZC for quality enhancement. Similar to FGS coding, there is no performance difference between layered and monolithic WZC when the enhancement bitstream is generated in our proposed coder. Using an H.26L coded version as the base layer, experiments indicate that WZC gives slightly worse performance than FGS coding when the channel (for both the base and enhancement layers) is noiseless. However, when the channel is noisy, extensive simulations of video transmission over wireless networks conforming to the CDMA2000 1X standard show that H.26L base layer coding plus Wyner-Ziv enhancement layer coding are more robust against channel errors than H.26L FGS coding. These results demonstrate that layered Wyner-Ziv video coding is a promising new technique for video streaming over wireless networks.


Gut butyrate-producing organisms correlate to Placenta Specific 8 protein: Importance to colorectal cancer progression.
Tumor metastasis or recurrence often occurs in patients with curative resection of colorectal cancer (CRC). Placental-specific 8 (PLAC8), which has increased expression in stool, may be associated with CRC recurrence. Insights into the role of PLAC8 in CRC recurrence and its clinical significance may support to develop strategies for preventing CRC recurrence and deterioration. Clinical tissues, cell and animal models were used to clarify the roles of PLAC8 in CRC tumorigenesis, invasion, and migration. Next-generation sequencing of 16S ribosomal DNA has been used to assess the gut microbiota in stool of CRC patients. We found that PLAC8 was upregulated in tissues from patients with late-stage CRC. In our in vitro studies, PLAC8 was dynamically regulated in mitotic cells. Overexpressed PLAC8 was nucleated at the centrosome during mitosis, and therefore, PLAC8 overexpression might increase cell growth and migration (all p < 0.05). The tumorigenic and invasive effects of PLAC8 on CRC cells were also confirmed in a xenograft mouse model. We further identified reduced levels of two butyrate-producing organisms, Butyricicoccus and Prevotella spp., in stools from CRC patients. We found that butyrate downregulated PLAC8 expression and induced apoptosis in PLAC8-overexpressing cells. Our data suggests that PLAC8 gene and protein expression and dysbiosis of gut microflora, especially in butyrate-producing microorganisms, may be indicators of CRC progression.


Antenatal HIV screening in Europe: a review of policies.
The increased prevalence of HIV infection in women is leading to a rising number of children born to HIV-infected mothers. As therapeutic possibilities for HIV/AIDS increase, the detection of undiagnosed HIV infections in pregnant women, followed by adequate management, is of crucial interest. Therapeutic protocols are being updated and increasingly applied in most European countries, but there is no structured information on policies and strategies with regard to antenatal HIV screening as such. In order to identify national policies with regard to antenatal HIV screening, a structured questionnaire was sent to key-informants within the ministries of health and national institutes for public health in each of the 25 EU Member States. Information was obtained from all EU Member States with the exception of Cyprus and Luxembourg. Eighteen countries issued a national policy with regard to antenatal HIV screening, 16 opted for a system in which HIV testing is offered to all women attending antenatal services while only two opted for selective screening. None of the 18 countries with a national policy supports a mandatory screening strategy. The voluntary testing strategies are of two types: opting in versus opting out. In almost all EU countries with antenatal HIV screening policies, screening conditions are defined. Policies are in place in most EU countries. Nevertheless, there is a need for more integrated European policies and region-specific recommendations on the performance of antenatal HIV screening as an opportunity for comprehensive HIV/AIDS service delivery. This would enable the different aspects of prevention to be linked and also address both the needs of pregnant women and mothers as well as that of their infants.


A K ATP channel-dependent pathway within alpha cells regulates glucagon release from both rodent and human islets of Langerhans.
Glucagon, secreted from pancreatic islet alpha cells, stimulates gluconeogenesis and liver glycogen breakdown. The mechanism regulating glucagon release is debated, and variously attributed to neuronal control, paracrine control by neighbouring beta cells, or to an intrinsic glucose sensing by the alpha cells themselves. We examined hormone secretion and Ca(2+) responses of alpha and beta cells within intact rodent and human islets. Glucose-dependent suppression of glucagon release persisted when paracrine GABA or Zn(2+) signalling was blocked, but was reversed by low concentrations (1-20 muM) of the ATP-sensitive K(+) (KATP) channel opener diazoxide, which had no effect on insulin release or beta cell responses. This effect was prevented by the KATP channel blocker tolbutamide (100 muM). Higher diazoxide concentrations (>/=30 muM) decreased glucagon and insulin secretion, and alpha- and beta-cell Ca(2+) responses, in parallel. In the absence of glucose, tolbutamide at low concentrations (<1 muM) stimulated glucagon secretion, whereas high concentrations (>10 muM) were inhibitory. In the presence of a maximally inhibitory concentration of tolbutamide (0.5 mM), glucose had no additional suppressive effect. Downstream of the KATP channel, inhibition of voltage-gated Na(+) (TTX) and N-type Ca(2+) channels (omega-conotoxin), but not L-type Ca(2+) channels (nifedipine), prevented glucagon secretion. Both the N-type Ca(2+) channels and alpha-cell exocytosis were inactivated at depolarised membrane potentials. Rodent and human glucagon secretion is regulated by an alpha-cell KATP channel-dependent mechanism. We propose that elevated glucose reduces electrical activity and exocytosis via depolarisation-induced inactivation of ion channels involved in action potential firing and secretion.


Competing E2 and SN2 Mechanisms for the F- + CH3CH2I Reaction.
Anti-E2, syn-E2, inv-, and ret-SN2 reaction channels for the gas-phase reaction of F- + CH3CH2I were characterized with a variety of electronic structure calculations. Geometrical analysis confirmed synchronous E2-type transition states for the elimination of the current reaction, instead of nonconcerted processes through E1cb-like and E1-like mechanisms. Importantly, the controversy concerning the reactant complex for anti-E2 and inv-SN2 paths has been clarified in the present work. A positive barrier of +19.2 kcal/mol for ret-SN2 shows the least feasibility to occur at room temperature. Negative activation energies (-16.9, -16.0, and -4.9 kcal/mol, respectively) for inv-SN2, anti-E2, and syn-E2 indicate that inv-SN2 and anti-E2 mechanisms significantly prevail over the eclipsed elimination. Varying the leaving group for a series of reactions F- + CH3CH2Y (Y = F, Cl, Br, and I) leads to monotonically decreasing barriers, which relates to the gradually looser TS structures following the order F > Cl > Br > I. The reactivity of each channel nearly holds unchanged except for the perturbation between anti-E2 and inv-SN2. RRKM calculation reveals that the reaction of the fluorine ion with ethyl iodide occurs predominately via anti-E2 elimination, and the inv-SN2 pathway is suppressed, although it is energetically favored. This phenomenon indicates that, in evaluating the competition between E2 and SN2 processes, the kinetic or dynamical factors may play a significant role. By comparison with benchmark CCSD(T) energies, MP2, CAM-B3LYP, and M06 methods are recommended to perform dynamics simulations of the title reaction.


Performance of the Framingham risk models and pooled cohort equations for predicting 10-year risk of cardiovascular disease: a systematic review and meta-analysis.
The Framingham risk models and pooled cohort equations (PCE) are widely used and advocated in guidelines for predicting 10-year risk of developing coronary heart disease (CHD) and cardiovascular disease (CVD) in the general population. Over the past few decades, these models have been extensively validated within different populations, which provided mounting evidence that local tailoring is often necessary to obtain accurate predictions. The objective is to systematically review and summarize the predictive performance of three widely advocated cardiovascular risk prediction models (Framingham Wilson 1998, Framingham ATP III 2002 and PCE 2013) in men and women separately, to assess the generalizability of performance across different subgroups and geographical regions, and to determine sources of heterogeneity in the findings across studies. A search was performed in October 2017 to identify studies investigating the predictive performance of the aforementioned models. Studies were included if they externally validated one or more of the original models in the general population for the same outcome as the original model. We assessed risk of bias for each validation and extracted data on population characteristics and model performance. Performance estimates (observed versus expected (OE) ratio and c-statistic) were summarized using a random effects models and sources of heterogeneity were explored with meta-regression. The search identified 1585 studies, of which 38 were included, describing a total of 112 external validations. Results indicate that, on average, all models overestimate the 10-year risk of CHD and CVD (pooled OE ratio ranged from 0.58 (95% CI 0.43-0.73; Wilson men) to 0.79 (95% CI 0.60-0.97; ATP III women)). Overestimation was most pronounced for high-risk individuals and European populations. Further, discriminative performance was better in women for all models. There was considerable heterogeneity in the c-statistic between studies, likely due to differences in population characteristics. The Framingham Wilson, ATP III and PCE discriminate comparably well but all overestimate the risk of developing CVD, especially in higher risk populations. Because the extent of miscalibration substantially varied across settings, we highly recommend that researchers further explore reasons for overprediction and that the models be updated for specific populations.


Validation of the Arabic version of the Perinatal Anxiety Screening Scale (PASS) among antenatal and postnatal women.
Anxiety among women in the perinatal period is common. Assessing the severity of perinatal anxiety will help monitor the progress of the patient through the stages of anxiety and facilitated the treatment. This study assesses the validity and reliability of the "Perinatal Anxiety Screening Scale" (PASS) in the Arabic language. The PASS was translated into Arabic. Two hundred seventeen women in the antenatal and postnatal phase participated (92 antenatal and 125 postnatal) answered to PASS, GHQ12, EPDS-10, and DASS-21. Content validity, factor analysis, internal consistency, and test retest reliability were assessed. Content Validity Index (CVI) and Content Validity Ratio (CVR) were .88 and 0.79; respectively. The scale loaded on four components: acute anxiety, social anxiety, and dissociation; specific fears and trauma; general anxiety and adjustment; and perfectionism and control. Cronbach's Alpha value for the scale was 0.78 and test retest correlation coefficient was 0.94. PASS significantly correlated with EPDS-10 (rho=0.46), GHQ-12(rho=0.58), the three components of DASS-21 (0.47, 0.50, and 0.43; respectively), and experiencing adverse life events. The Arabic translated version of the PASS showed reasonably adequate validity and reliability and can be used to screen for anxiety disorder among women in the perinatal phase.


Obstetric ultrasound scanning by local health workers in a refugee camp on the Thai-Burmese border.
Ultrasound examination of the fetus is a powerful tool for assessing gestational age and detecting obstetric problems but is rarely available in developing countries. The aim of this study was to assess the intraobserver and interobserver agreement of fetal biometry by locally trained health workers in a refugee camp on the Thai-Burmese border. One expatriate doctor and four local health workers participated in the study, which included examinations performed on every fifth pregnant woman with a singleton pregnancy between 16 and 40 weeks' gestation, and who had undergone an early dating ultrasound scan, attending the antenatal clinic in Maela refugee camp. At each examination, two examiners independently measured biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC) and femur length (FL), with one of the examiners obtaining duplicate measurements of each parameter. Intraobserver measurement error was assessed using the intraclass correlation coefficient (ICC) and interobserver error was assessed by the Bland and Altman 95% limits of agreement method. A total of 4188 ultrasound measurements (12 per woman) were obtained in 349 pregnancies at a median gestational age of 27 (range, 16-40) weeks in 2008. The ICC for BPD, HC, AC and FL was greater than 0.99 for all four trainees and the doctor (range, 0.996-0.998). For gestational ages between 18 and 24 weeks, interobserver 95% limits of agreement corresponding to differences in estimated gestational age of less than +/- 1 week were calculated for BPD, HC, AC and FL. Measurements by local health workers showed high levels of agreement with those of the expatriate doctor. Locally trained health workers working in a well organized unit with ongoing quality control can obtain accurate fetal biometry measurements for gestational age estimation. This experience suggests that training of local health workers in developing countries is possible and could allow effective use of obstetric ultrasound imaging.


Determinants of tetanus and seasonal influenza vaccine uptake in adults living in Germany.
The primary objective of this study was to assess determinants of vaccine uptake in adults living in Germany exemplified by one standard vaccination (tetanus) and one vaccination targeting specific risk-groups (seasonal influenza). Data from 21,262 telephone household-interviews representative of the adult population in Germany were collected in 2009 and analysed. A total 73.1% of the adult population had a sufficient tetanus vaccination status according to national recommendations (i.e. last tetanus shot ≤10 years ago). Influenza vaccination coverage in the target population (i.e. persons ≥60 years, chronically ill, healthcare workers) was 44.1%. Persons who received professional vaccination advice within the past five years were more frequently vaccinated against tetanus and influenza than persons without (p< 0.001). Private physicians were identified as the most important source for vaccination advice. Having a statutory health insurance, last physician contact < 1 year ago, and living in the eastern part of Germany were independently associated with higher tetanus and influenza vaccine uptake. Low socio-economic status, two-sided migration background, and the feeling of being insufficiently informed on the benefits of vaccination were independently associated with low uptake of tetanus but not influenza vaccines. Our results show that tetanus vaccination coverage in the general adult population and influenza vaccination coverage in the target population are unsatisfactorily low in Germany. Since physicians' advice has a major impact on the vaccination decision, physician reminder systems could provide a method to increase vaccination coverage in adults. For tetanus, information activities should target population groups with an increased risk of being undervaccinated.


The use of bootstrap resampling to assess the variability of Draize tissue scores.
The acute dermal and ocular effects of chemicals are generally assessed by performing the Draize skin and eye tests, respectively. Because the animal data obtained in these tests are also used for the development and validation of alternative methods for skin and eye irritation, it is important to assess the inherent variability of the animal data, since this variability places an upper limit on the predictive performance that can be expected of any alternative model. The statistical method of bootstrap resampling was used to estimate the variability arising from the use of different animals and time-points, and the estimates of variability were used to determine the maximal extent to which Draize test tissue scores can be predicted.


Isolation and characterization of a minor legumin and its constituent polypeptides from Pisum sativum (pea).
The purification and characterization of a minor legumin species from Pisum sativum is described. Electrophoretic data indicate that it corresponds to a legumin subunit pair previously designated L1. The beta-polypeptides of the minor legumin have a phenylalanine N-terminus. This is the first time that an amino acid other than glycine has been reported as the N-terminus of the basic polypeptides from legumin-like proteins from any plant species. Sequence analyses of the isolated alpha- and beta-polypeptides of the minor legumin show that it does not correspond to any of the three legumin gene families that have previously been defined on the basis of DNA hybridizations and genetic analyses.


Isolation of the Lyme disease spirochete, Borrelia burgdorferi, from Ixodes dammini (Acari: Ixodidae) collected on Prince Edward Island, Canada.
Studies were undertaken to monitor for the presence of Borrelia burgdorferi, the etiologic agent of Lyme disease, on Prince Edward Island, Canada. Gut contents were removed for culturing from seven engorged ticks collected in 1991-1992 including five Ixodes dammini (Spielman, Clifford, Piesman & Corwin) and two I. scapularis (Say) removed from a dog that had recently traveled to the southern United States. B. burgdorferi was recovered from one I. dammini that had been removed from a cat in Charlottetown in October 1991. The cat had not traveled off the island. Immunofluorescent antibody (IFA) studies on sera from 75 dogs, 7 cats, and 8 white-tailed deer (Odocoileus virginianus) collected on Prince Edward Island between 1989 and 1992 revealed one reactor with an IFA titer > or = 1:256. The reactor was a dog with a history of travel to the United States. This report documents the first isolate of B. burgdorferi in Atlantic Canada, possibly because of the introduction of I. dammini on migratory birds. Serological studies do not indicate widespread occurrence of B. burgdorferi on Prince Edward Island.


The Sleep Condition Indicator: a clinical screening tool to evaluate insomnia disorder.
Describe the development and psychometric validation of a brief scale (the Sleep Condition Indicator (SCI)) to evaluate insomnia disorder in everyday clinical practice. The SCI was evaluated across five study samples. Content validity, internal consistency and concurrent validity were investigated. 30 941 individuals (71% female) completed the SCI along with other descriptive demographic and clinical information. Data acquired on dedicated websites. The eight-item SCI (concerns about getting to sleep, remaining asleep, sleep quality, daytime personal functioning, daytime performance, duration of sleep problem, nights per week having a sleep problem and extent troubled by poor sleep) had robust internal consistency (α≥0.86) and showed convergent validity with the Pittsburgh Sleep Quality Index and Insomnia Severity Index. A two-item short-form (SCI-02: nights per week having a sleep problem, extent troubled by poor sleep), derived using linear regression modelling, correlated strongly with the SCI total score (r=0.90). The SCI has potential as a clinical screening tool for appraising insomnia symptoms against Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria.


[Ultraviolet irradiation of blood in combined treatment of traumatic endophthalmitis].
Thirty-five patients (35 eyes) with traumatic endophthalmitis were treated. Ultraviolet exposure of autoblood was used in 16 patients, the rest 19 were treated routinely (antibiotics, etc.). Use of ultraviolet exposure of the blood in combined therapy of traumatic endophthalmitis more rapidly (12.6 vs. 22.1 days) and effectively (93.7 vs. 68.4%) arrested intraocular infection and more often preserved the objective vision (31.3 vs. 10.5%).


Evasion of cellular antiviral responses by human cytomegalovirus TRS1 and IRS1.
During infection with human cytomegalovirus (HCMV), cellular protein synthesis continues even as viral proteins are being synthesized in abundance. Thus, HCMV may have a mechanism for counteracting host cell antiviral pathways that act by shutting off translation. Consistent with this view, HCMV infection of human fibroblasts rescues the replication of a vaccinia virus mutant lacking the double-stranded RNA-binding protein gene E3L (VVdeltaE3L). HCMV also prevents the phosphorylation of the eukaryotic translation initiation factor eIF-2alpha, the activation of RNase L, and the shutoff of viral and cellular protein synthesis that otherwise result from VVdeltaE3L infection. To identify the HCMV gene(s) responsible for these effects, we prepared a library of VVdeltaE3L recombinants containing HCMV genomic fragments. By infecting nonpermissive cells with this library and screening for VV gene expression and replication, we isolated a virus containing a 2.8-kb HCMV fragment that rescues replication of VVdeltaE3L. The fragment comprises the 3' end of the J1S open reading frame through the entire TRS1 gene. Analyses of additional VVdeltaE3L recombinants revealed that the protein encoded by TRS1, pTRS1, as well as the closely related IRS1 gene, rescues VVdeltaE3L replication and prevent the shutoff of protein synthesis, the phosphorylation of eIF-2alpha, and activation of RNase L. These results demonstrate that TRS1 and IRS1 are able to counteract critical host cell antiviral response pathways.


Genetic and clinic predictors of new onset diabetes mellitus after transplantation.
New Onset Diabetes after Transplantation (NODAT) is a frequent complication after solid organ transplantation, with higher incidence during the first year. Several clinical and genetic factors have been described as risk factors of Type 2 Diabetes (T2DM). Additionally, T2DM shares some genetic factors with NODAT. We investigated if three genetic risk scores (w-GRS) and clinical factors were associated with NODAT and how they predicted NODAT development 1 year after transplantation. In both main (n = 725) and replication (n = 156) samples the clinical risk score was significantly associated with NODAT (ORmain: 1.60 [1.36-1.90], p = 3.72*10-8 and ORreplication: 2.14 [1.39-3.41], p = 0.0008, respectively). Two w-GRS were significantly associated with NODAT in the main sample (ORw-GRS 2:1.09 [1.04-1.15], p = 0.001 and ORw-GRS 3:1.14 [1.01-1.29], p = 0.03) and a similar ORw-GRS 2 was found in the replication sample, although it did not reach significance probably due to a power issue. Despite the low OR of w-GRS on NODAT compared to clinical covariates, when integrating w-GRS 2 and w-GRS 3 in the clinical model, the Area under the Receiver Operating Characteristics curve (AUROC), specificity, sensitivity and accuracy were 0.69, 0.71, 0.58 and 0.68, respectively, with significant Likelihood Ratio test discrimination index (p-value 0.0004), performing better in NODAT discrimination than the clinical model alone. Twenty-five patients needed to be genotyped in order to detect one misclassified case that would have developed NODAT 1 year after transplantation if using only clinical covariates. To our knowledge, this is the first study extensively examining genetic risk scores contributing to NODAT development.


Genetic evidence of intercontinental movement of avian influenza in a migratory bird: the northern pintail (Anas acuta).
The role of migratory birds in the movement of the highly pathogenic (HP) avian influenza H5N1 remains a subject of debate. Testing hypotheses regarding intercontinental movement of low pathogenic avian influenza (LPAI) viruses will help evaluate the potential that wild birds could carry Asian-origin strains of HP avian influenza to North America during migration. Previous North American assessments of LPAI genetic variation have found few Asian reassortment events. Here, we present results from whole-genome analyses of LPAI isolates collected in Alaska from the northern pintail (Anas acuta), a species that migrates between North America and Asia. Phylogenetic analyses confirmed the genetic divergence between Asian and North American strains of LPAI, but also suggested inter-continental virus exchange and at a higher frequency than previously documented. In 38 isolates from Alaska, nearly half (44.7%) had at least one gene segment more closely related to Asian than to North American strains of LPAI. Additionally, sequences of several Asian LPAI isolates from GenBank clustered more closely with North American northern pintail isolates than with other Asian origin viruses. Our data support the role of wild birds in the intercontinental transfer of influenza viruses, and reveal a higher degree of transfer in Alaska than elsewhere in North America.


Why the Medical Research Council refused Robert Edwards and Patrick Steptoe support for research on human conception in 1971.
In 1971, Cambridge physiologist Robert Edwards and Oldham gynaecologist Patrick Steptoe applied to the UK Medical Research Council (MRC) for long-term support for a programme of scientific and clinical 'Studies on Human Reproduction'. The MRC, then the major British funder of medical research, declined support on ethical grounds and maintained this policy throughout the 1970s. The work continued with private money, leading to the birth of Louise Brown in 1978 and transforming research in obstetrics, gynaecology and human embryology. The MRC decision has been criticized, but the processes by which it was reached have yet to be explored. Here, we present an archive-based analysis of the MRC decision. We find evidence of initial support for Edwards and Steptoe, including from within the MRC, which invited the applicants to join its new directly funded Clinical Research Centre at Northwick Park Hospital. They declined the offer, preferring long-term grant support at the University of Cambridge, and so exposed the project to competitive funding mode. Referees and the Clinical Research Board saw the institutional set-up in Cambridge as problematic with respect to clinical facilities and patient management; gave infertility a low priority compared with population control; assessed interventions as purely experimental rather than potential treatments, and so set the bar for safety high; feared fatal abnormalities and so wanted primate experiments first; and were antagonized by the applicants' high media profile. The rejection set MRC policy on IVF for 8 years, until, after the birth of just two healthy babies, the Council rapidly converted to enthusiastic support. This analysis enriches our view of a crucial decision, highlights institutional opportunities and constraints and provides insight into the then dominant attitudes of reproductive scientists and clinicians towards human conception research.


Rice Genome-Scale Network Integration Reveals Transcriptional Regulators of Grass Cell Wall Synthesis.
Grasses have evolved distinct cell wall composition and patterning relative to dicotyledonous plants. However, despite the importance of this plant family, transcriptional regulation of its cell wall biosynthesis is poorly understood. To identify grass cell wall-associated transcription factors, we constructed the Rice Combined mutual Ranked Network (RCRN). The RCRN covers >90% of annotated rice (Oryza sativa) genes, is high quality, and includes most grass-specific cell wall genes, such as mixed-linkage glucan synthases and hydroxycinnamoyl acyltransferases. Comparing the RCRN and an equivalent Arabidopsis network suggests that grass orthologs of most genetically verified eudicot cell wall regulators also control this process in grasses, but some transcription factors vary significantly in network connectivity between these divergent species. Reverse genetics, yeast-one-hybrid, and protoplast-based assays reveal that OsMYB61a activates a grass-specific acyltransferase promoter, which confirms network predictions and supports grass-specific cell wall synthesis genes being incorporated into conserved regulatory circuits. In addition, 10 of 15 tested transcription factors, including six novel Wall-Associated regulators (WAP1, WACH1, WAHL1, WADH1, OsMYB13a, and OsMYB13b), alter abundance of cell wall-related transcripts when transiently expressed. The results highlight the quality of the RCRN for examining rice biology, provide insight into the evolution of cell wall regulation, and identify network nodes and edges that are possible leads for improving cell wall composition.


Alteration of canine renal vascular response to hemorrhage by inhibitors of prostaglandin synthesis.
The involvement of prostaglandins in the redistribution of renal cortical blood flow to inner cortical nephrons during hemorrhagic hypotension was studied in the pentobarbital-anesthetized dog. Total renal blood flow and distribution of renal cortical flow were determined with the radioactive microsphere technique by dividing the cortex into four zones of equal thickness, zone 1 being outermost and zone 4 being juxtamedullary. Two inhibitors of prostaglandin synthesis were used: indomethacin 8 mg/kg and aspirin 100 mg/kg. The inhibitor or the vehicle was given intravenously prior to a control period which was followed by a hemorrhage sufficient to decrease arterial pressure by about one-third. The distribution of cortical flow was determined before hemorrhage, during hemorrhagic hypotension, and after transfusion. In the vehicle-treated dogs, total renal blood flow was well maintained, but flow redistributed to favor the inner cortical nephrons. This vasodilation in the inner cortex was blocked by both inhibitors of prostaglandin synthesis resulting in a decrease in total renal blood flow and relative ischemia of the juxtamedullary nephrons. Salicylate levels required to accomplish blockage of inner cortical vasodilaton were less than 7 mg/100 ml. These studies indicate that prostaglandins are responsible for the decreased vascular resistance of the inner cortical nephrons which results in the redistribution of blood flow during hemorrhage, and when prostaglandin synthesis is blocked, the kidney vasculature constricts during hemorrhage.


[Combined exposure to noise and vibration and its effects on workers' hearing].
To assess the exposure of bus drivers to noise and whole-body vibration (WBV) and to examine the possibility of an association between these risk factors for noise-induced hearing loss. A cross-sectional study was carried out among 141 bus drivers who underwent an audiometry test. This group was classified and internally stratified in subgroups of "exposed" and "controls" according to cumulative working time as bus drivers. Their exposure to noise and vibration was assessed. The association between noise-induced hearing loss (NIHL) and the set of explanatory variables was analyzed through logistic regression. The average (+/- standard deviation) weekly noise exposure of front-engine bus drivers was 83.6 +/- 1.9 dB(A), while rear-engine bus drivers were exposed to 77.0 +/- 1.1 dB(A). The weighted average of vibration acceleration was 0.85/m(2). In the best adjusted model, the multivariable analysis showed that age (>44; OR=2.54; 95% CI=1.15-5.62), diabetes (OR=5.46; 95% CI=0.95-31.4), and the level of noise emission [>86.8 dB(A); OR=2.76; 95% CI=1.24-6.15] were risk factors for NIHL. In another model studied, WBV exposure was significant in determining NIHL. Bus drivers were exposed to significant WBV levels. The noise exposure was more pronounced in front engine than in rear-engine vehicles. No association between WBV exposure and NIHL was observed and no interaction was found between WBV and noise exposure. Further studies are required as other model indicated an association between WBV and NIHL.


Lack of collagen α6(IV) chain in mice does not cause severe-to-profound hearing loss or cochlear malformation, a distinct phenotype from nonsyndromic hearing loss with COL4A6 missense mutation.
Congenital hearing loss affects 1 in every 1000 births, with genetic mutations contributing to more than 50% of all cases. X-linked nonsyndromic hereditary hearing loss is associated with six loci (DFNX1-6) and five genes. Recently, the missense mutation (c.1771G>A, p.Gly591Ser) in COL4A6, encoding the basement membrane (BM) collagen α6(IV) chain, was shown to be associated with X-linked congenital nonsyndromic hearing loss with cochlear malformation. However, the mechanism by which the COL4A6 mutation impacts hereditary hearing loss has not yet been elucidated. Herein, we investigated Col4a6 knockout (KO) effects on hearing function and cochlear formation in mice. Immunohistochemistry showed that the collagen α6(IV) chain was distributed throughout the mouse cochlea within subepithelial BMs underlying the interdental cells, inner sulcus cells, basilar membrane, outer sulcus cells, root cells, Reissner's membrane, and perivascular BMs in the spiral limbus, spiral ligament, and stria vascularis. However, the click-evoked auditory brainstem response analysis did not show significant changes in the hearing threshold of Col4a6 KO mice compared with wild-type (WT) mice with the same genetic background. In addition, the cochlear structures of Col4a6 KO mice did not exhibit morphological alterations, according to the results of high-resolution micro-computed tomography and histology. Hence, loss of Col4a6 gene expression in mice showed normal click ABR thresholds and normal cochlear formation, which differs from humans with the COL4A6 missense mutation c.1771G>A, p.Gly591Ser. Therefore, the deleterious effects in the auditory system caused by the missense mutation in COL4A6 are likely due to the dominant-negative effects of the α6(IV) chain and/or α5α6α5(IV) heterotrimer with an aberrant structure that would not occur in cases with loss of gene expression.


Machine perfusion strategies in liver transplantation.
Machine perfusion is a hot topic in liver transplantation and several new perfusion concepts are currently developed. Prior to introduction into routine clinical practice, however, such perfusion approaches need to demonstrate their impact on liver function, post-transplant complications, utilization rates of high-risk organs, and cost benefits. Therefore, based on results of experimental and clinical studies, the community has to recognize the limitations of this technology. In this review, we summarize current perfusion concepts and differences between protective mechanisms of ex- and in-situ perfusion techniques. Next, we discuss which graft types may benefit most from perfusion techniques, and highlight the current understanding of liver viability testing. Finally, we present results from recent clinical trials involving machine liver perfusion, and analyze the value of different outcome parameters, currently used as endpoints for randomized controlled trials in the field.


"People like numbers": a descriptive study of cognitive assessment methods in clinical practice for Aboriginal Australians in the Northern Territory.
Achieving culturally fair assessments of cognitive functioning for Aboriginal people is difficult due to a scarcity of appropriately validated tools for use with this group. As a result, some Aboriginal people with cognitive impairments may lack fair and equitable access to services. The objective of this study was to examine current clinical practice in the Northern Territory regarding cognitive assessment for Aboriginal people thereby providing some guidance for clinicians new to this practice setting. Qualitative enquiry was used to describe practice context, reasons for assessment, and current practices in assessing cognition for Aboriginal Australians. Semi-structured interviews were conducted with 22 clinicians working with Aboriginal clients in central and northern Australia. Results pertaining to assessment methods are reported. A range of standardised tests were utilised with little consistency across clinical practice. Nevertheless, it was recognised that such tests bear severe limitations, requiring some modification and significant caution in their interpretation. Clinicians relied heavily on informal assessment or observations, contextual information and clinical judgement. Cognitive tests developed specifically for Aboriginal people are urgently needed. In the absence of appropriate, validated tests, clinicians have relied on and modified a range of standardised and informal assessments, whilst recognising the severe limitations of these. Past clinical training has not prepared clinicians adequately for assessing Aboriginal clients, and experience and clinical judgment were considered crucial for fair interpretation of test scores. Interpretation guidelines may assist inexperienced clinicians to consider whether they are achieving fair assessments of cognition for Aboriginal clients.


Patient coping and expectations about recovery predict the development of chronic post-surgical pain after traumatic tibial fracture repair.
The association of patient expectations about recovery with the development of chronic post-surgical pain (CPSP) is uncertain. Three hundred and fifty-nine patients enrolled in the SPRINT trial completed the Somatic Preoccupation and Coping (SPOC) questionnaire six weeks after a traumatic tibial fracture repair. The SPOC questionnaire measures patients' somatic complaints, coping, and optimism for recovery. Using adjusted models, we explored the association of SPOC scores with ≥ mild CPSP and ≥ moderate pain interference with activity at one yr after surgery. Of 267 tibial fracture patients with data available for analysis, 147 (55.1%) reported CPSP at one yr. The incidence of CPSP was 37.6% among those with low (≤40) SPOC scores, 54.1% among those with intermediate (41-80) scores, and 81.7% among those with high (>80) scores. Addition of SPOC scores to an adjusted regression model to predict CPSP improved the c-statistic from 0.61 (95% CI 0.55-0.68) to 0.70 (95% CI 0.64-0.76, P=0.005 for the difference) and found the greatest risk was associated with high SPOC scores (OR 6.56, 95% CI 2.90-14.81). Similarly, an adjusted regression model to predict pain interference with function at one yr (c-statistic 0.77, 95% CI 0.71-0.83) found the greatest risk for those with high SPOC scores (OR 10.10, 95% CI 4.26-23.96). Patient's coping and expectations of recovery, as measured by the SPOC questionnaire, is an independent predictor of CPSP and pain interference one yr after traumatic tibial fracture. Future studies should explore whether these beliefs can be modified, and if doing so improves prognosis. NCT 00038129.


FcγRIIb differentially regulates pre-immune and germinal center B cell tolerance in mouse and human.
Several tolerance checkpoints exist throughout B cell development to control autoreactive B cells and prevent the generation of pathogenic autoantibodies. FcγRIIb is an Fc receptor that inhibits B cell activation and, if defective, is associated with autoimmune disease, yet its impact on specific B cell tolerance checkpoints is unknown. Here we show that reduced expression of FcγRIIb enhances the deletion and anergy of autoreactive immature B cells, but in contrast promotes autoreactive B cell expansion in the germinal center and serum autoantibody production, even in response to exogenous, non-self antigens. Our data thus show that FcγRIIb has opposing effects on pre-immune and post-immune tolerance checkpoints, and suggest that B cell tolerance requires the control of bystander germinal center B cells with low or no affinity for the immunizing antigen.


Breast screening and breast cancer survival in Aboriginal and Torres Strait Islander women of Australia.
Aboriginal and Torres Strait Islander people comprise about 2.5% of the Australian population. Cancer registry data indicate that their breast cancer survivals are lower than for other women but the completeness and accuracy of Indigenous descriptors on registries are uncertain. We followed women receiving mammography screening in BreastScreen to determine differences in screening experiences and survivals from breast cancer by Aboriginal and Torres Strait Islander status, as recorded by BreastScreen. This status is self-reported and used in BreastScreen accreditation, and is considered to be more accurate. The study included breast cancers diagnosed during the period of screening and after leaving the screening program. Least square regression models were used to compare screening experiences and outcomes adjusted for age, geographic remoteness, socio-economic disadvantage, screening period and round during 1996-2005. Survival of breast cancer patients from all causes and from breast cancer specifically was compared for the 1991-2006 diagnostic period using linked cancer-registry data. Cox proportional hazards regression was used to adjust for socio-demographic differences, screening period, and where available, tumour size, nodal status and proximity of diagnosis to time of screen. After adjustment for socio-demographic differences and screening period, Aboriginal and Torres Strait Islander women participated less frequently than other women in screening and re-screening although this difference appeared to be diminishing; were less likely to attend post-screening assessment within the recommended 28 days if recalled for assessment; had an elevated ductal carcinoma in situ but not invasive cancer detection rate; had larger breast cancers; and were more likely than other women to be treated by mastectomy than complete local excision. Linked cancer registry data indicated that five-year year survivals of breast cancer cases from all causes of death were 81% for Aboriginal and Torres Strait Islander women, compared with 90% for other women, and that the former had larger breast cancers that were more likely to have nodal spread at diagnosis. After adjusting for socio-demographic factors, tumour size, nodal spread and time from last screen to diagnosis, Aboriginal and Torres Strait Islander women had approximately twice the risk of death from breast cancer as other women. Aboriginal and Torres Strait Islander women have less favourable screening experiences and those diagnosed with breast cancer (either during the screening period or after leaving the screening program) have lower survivals that persist after adjustment for socio-demographic differences, tumour size and nodal status.


Perceptions of hypertension treatment among patients with and without diabetes.
Despite the availability of a wide selection of effective antihypertensive treatments and the existence of clear treatment guidelines, many patients with hypertension do not have controlled blood pressure. We conducted a qualitative study to explore beliefs and perceptions regarding hypertension and gain an understanding of barriers to treatment among patients with and without diabetes. Ten focus groups were held for patients with hypertension in three age ranges, with and without diabetes. The topic guides for the groups were: What will determine your future health status? What do you understand by "raised blood pressure"? How should one go about treating raised blood pressure? People with hypertension tend to see hypertension not as a disease but as a risk factor for myocardial infarction or stroke. They do not view it as a continuous, degenerative process of damage to the vascular system, but rather as a binary risk process, within which you can either be a winner (not become ill) or a loser. This makes non-adherence to treatment a gamble with a potential positive outcome. Patients with diabetes are more likely to accept hypertension as a chronic illness with minor impact on their routine, and less important than their diabetes. Most participants overestimated the effect of stress as a causative factor believing that a reduction in levels of stress is the most important treatment modality. Many believe they "know their bodies" and are able to control their blood pressure. Patients without diabetes were most likely to adopt a treatment which is a compromise between their physician's suggestions and their own understanding of hypertension. Patient denial and non-adherence to hypertension treatment is a prevalent phenomenon reflecting a conscious choice made by the patient, based on his knowledge and perceptions regarding the medical condition and its treatment. There is a need to change perception of hypertension from a gamble to a disease process. Changing the message from the existing one of "silent killer" to one that depicts hypertension as a manageable disease process may have the potential to significantly increase adherence rates.


Clinical characterization and the improved molecular diagnosis of autosomal dominant cone-rod dystrophy in patients with SCA7.
To evaluate the retinal phenotype and genetic features of Chinese patients with spinocerebellar ataxia type 7 (SCA7). Detailed ophthalmic examinations, including electroretinograms, fundus photography, fundus autofluorescence and optical coherence tomography, were performed to analyse the retinal lesions of patients with SCA7. A molecular genetic analysis was completed to confirm the number of CAG repeats in ATXN7 gene on the patients and their family members. Eight patients from three families with SCA7 were included in this study. Trinucleotide repeat was expanded from 43 to 113 in the affected patients. The affected patients were characterized by different degrees of cone-rod dystrophy, which is positively related to the number of CAG repeats and age. All patients complained of progressive bilateral visual loss, and most cases reported visual disturbance earlier than gait movement or dysarthria. A coarse granular appearance of the macular region on scanning laser ophthalmoscopy, hypofluorescence in the macula on autofluorescence, retinal atrophy on optic coherence tomography, depression of multifocal electroretinograms and prominent abnormalities in cone-mediated responses on electrograms are the general features of SCA7-related retinopathy. Hyperreflective dots in the outer retinal layers and choroidal vessel layers are a common sign in optic coherence tomography in the advanced stage. SCA7 shows a cone-rod dystrophy phenotype. The multimodal imaging of the retina is beneficial to detect the early lesions of cone-rod dystrophy related to SCA7.


Activity of paclitaxel in advanced or recurrent squamous cell cancer of the cervix.
Twenty-six patients with squamous cell cancer of the cervix were treated with i.v. paclitaxel, 250 mg/m2 over 3 h every 21 days. They received steroid, H1 and H2 blocker premedications, and granulocyte-colony-stimulating factor (G-CSF) support (5 microgram/kg/day). No prior chemotherapy, except as a radiation sensitizer, was allowed. The median age was 50 (range, 36-81) years, and performance status Zubrod was 1 (range, 0-2). Eight (33%) patients had prior surgery, and 22 (92%) had prior radiation therapy. Twenty-four patients were evaluable for response; 2 were later found to be ineligible. Five patients had partial responses (21%; 95% confidence interval, 6-40%), and 14 (58%; 95% confidence interval, 35-78%) had stable disease. The median duration of response was 10 (range, 3-27+) weeks. The responses were within the radiation port (four responses) and outside of it (one response). The median interval from the start of irradiation to the start of paclitaxel in responding patients was 94 weeks, whereas in patients with stable disease it was 68 weeks, and in patients whose disease progressed it was 46 weeks. Eighty-eight percent of the 105 cycles of paclitaxel were administered at a dose of 250 mg/m2 or higher. Granulocytopenia was brief and noncumulative, with grades 3 and 4 experienced by 5 and 3 patients, respectively. G-CSF was used for a median of 7 (range, 2-14) days/cycle. Anemia was mild, with G3 noted in 3 patients, and thrombocytopenia was not significant. Infections and musculoskeletal pain were mild and infrequent. Sensory (14 patients G1 or G2 and 2 patients G3) and motor (4 patients G1 or G2 and 1 patient G3) neurotoxicity was noted. There was no significant cardiovascular toxicity. Paclitaxel is active in patients with squamous cell cancer of the cervix and is well tolerated at this dose schedule with G-CSF support.


Molecular Evidence of Helicobacter Pylori Infection in Prostate Tumors.
To determine whether Helicobacter pylori (H. pylori) is detectable in both benign prostatic hyperplasia (BPH) and prostate cancer (PCa). Epidemiological studies have shown significant associations between infective chronic prostatitis and prostatic carcinoma. Many bacteria have been found in the prostate of patients with chronic prostatitis, BPH, and PCa. One hundred consecutive patients with prostate diseases were enrolled in the study. Detection of H. pylori DNA in prostate tissue from patients with BPH and PCa was performed using both immunohistochemistry and PCR, and the results were confirmed by DNA sequencing. Odds ratios and the Fisher Exact test were used for the analysis of the associations between the variables. Among the patients, 78% had BPH and 19% had PCa. While immunohistochemistry showed no positive sample for H. pylori, PCR combined with sequencing detected H. pylori DNA in prostate tissue samples from 5 patients. However, statistical analysis of the data showed that BPH and PCa are not significantly associated with the presence of H. pylori DNA in prostate tissue (odds ratio = 0.94, 95% confidence interval = 0.09-23.34, one-tailed Chi-square value = 0.660, p > 0.05). The limitation of this study was the small number of PCa patients. This study provides, for the first time, molecular evidence of the presence of H. pylori DNA in prostatic tissue of patients with BPH and PCa. It paves the way for further comprehensive studies to examine the association of H. pylori infection with BPH and PCa.


Quercetin prevents alcohol-induced liver injury through targeting of PI3K/Akt/nuclear factor-κB and STAT3 signaling pathway.
Quercetin is a type of flavonoid compound, which has potent antioxidant and anti-inflammatory activities, capable of treating a variety of diseases including neurodegenerative diseases, tumors, diabetes and obesity. The present study selected alcohol-induced liver injury model mice and aimed at studying the protective role of quercetin in preventing alcohol-induced liver injury. In alcohol-induced liver injury mice treated with quercetin, it was demonstrated that levels of aspartate transaminase, alanine transaminase, total bilirubin and triglyceride were reduced. In addition to this, the activities of the antioxidant enzymes superoxide dismutase and glutathione peroxidase were increased, malondialdehyde was inhibited, and interleukin (IL)-1β, IL-6, IL-10 and inducible nitric oxide synthase were suppressed. Quercetin additionally suppressed the protein expression levels of B-cell lymphoma (Bcl)-2, Bcl-2 associated X apoptosis regulator, Caspase-3, poly ADP-ribose polymerase, and signal transducer and activator of transcription (STAT) 3 phosphorylation, nuclear factor (NF)-κB and protein kinase B (Akt) phosphorylation levels in alcohol-induced liver injured mice. These results suggested that the protective role of quercetin prevents alcohol-induced liver injury through the phosphoinositide 3-kinase/Akt/NF-κB and STAT3 pathway.


Arabidopsis is susceptible to the cereal ear blight fungal pathogens Fusarium graminearum and Fusarium culmorum.
The fungal pathogens Fusarium graminearum and F. culmorum cause ear blight disease on cereal crops worldwide. The disease lowers both grain quality and grain safety. Disease prevalence is increasing due to changes in cropping practices and the difficulties encountered by plant breeders when trying to introgress the polygene-based resistance. The molecular basis of resistance to Fusarium ear blight in cereal species is poorly understood. This is primarily due to the large size of cereal genomes and the expensive resources required to undertake gene function studies in cereals. We therefore explored the possibility of developing various model floral infection systems that would be more amenable to experimental manipulation and high-throughput gene function studies. The floral tissues of tobacco, tomato, soybean and Arabidopsis were inoculated with Fusarium conidia and this resulted in disease symptoms on anthers, anther filaments and petals in each plant species. However, only in Arabidopsis did this initial infection then spread into the developing siliques and seeds. A survey of 236 Arabidopsis ecotypes failed to identify a single genotype that was extremely resistant or susceptible to Fusarium floral infections. Three Arabidopsis floral mutants that failed to develop anthers and/or functional pollen (i.e. agamous-1, apetala1-3 and dad1) were significantly less susceptible to Fusarium floral infection than wild type. Deoxynivalenol (DON) mycotoxin production was also detected in Fusarium-infected flowers at >1 ppm. This novel floral pathosystem for Arabidopsis appears to be highly representative of a serious cereal crop disease.


Accelerate!
The old ways of setting and implementing strategy are failing us, writes the author of Leading Change, in part because we can no longer keep up with the pace of change. Organizational leaders are torn between trying to stay ahead of increasingly fierce competition and needing to deliver this year's results. Although traditional hierarchies and managerial processes--the components of a company's "operating system"--can meet the daily demands of running an enterprise, they are rarely equipped to identify important hazards quickly, formulate creative strategic initiatives nimbly, and implement them speedily. The solution Kotter offers is a second system--an agile, networklike structure--that operates in concert with the first to create a dual operating system. In such a system the hierarchy can hand off the pursuit of big strategic initiatives to the strategy network, freeing itself to focus on incremental changes to improve efficiency. The network is populated by employees from all levels of the organization, giving it organizational knowledge, relationships, credibility, and influence. It can Liberate information from silos with ease. It has a dynamic structure free of bureaucratic layers, permitting a level of individualism, creativity, and innovation beyond the reach of any hierarchy. The network's core is a guiding coalition that represents each level and department in the hierarchy, with a broad range of skills. Its drivers are members of a "volunteer army" who are energized by and committed to the coalition's vividly formulated, high-stakes vision and strategy. Kotter has helped eight organizations, public and private, build dual operating systems over the past three years. He predicts that such systems will lead to long-term success in the 21st century--for shareholders, customers, employees, and companies themselves.


Absolute Alchemical Free Energy Calculations for Ligand Binding: A Beginner's Guide.
Many thermodynamic quantities can be extracted from computer simulations that generate an ensemble of microstates according to the principles of statistical mechanics. Among these quantities is the free energy of binding of a small molecule to a macromolecule, such as a protein. Here, we present an introductory overview of a protocol that allows for the estimation of ligand binding free energies via molecular dynamics simulations. While we focus on the binding of organic molecules to proteins, the approach is in principle transferable to any pair of molecules.


An orphan esterase ABHD10 modulates probenecid acyl glucuronidation in human liver.
Probenecid, a widely used uricosuric agent, is mainly metabolized to probenecid acyl glucuronide (PRAG), which is considered a causal substance of severe allergic or anaphylactoid reactions. PRAG can be hydrolyzed (deglucuronidated) to probenecid. The purpose of this study was to identify enzymes responsible for probenecid acyl glucuronidation and PRAG deglucuronidation in human livers and to examine the effect of deglucuronidation in PRAG formation. In human liver homogenates (HLHs), the intrinsic clearance (CLint) of PRAG deglucuronidation was much greater (497-fold) than that of probenecid acyl glucuronidation. Evaluation of PRAG formation by recombinant UDP-glucuronosyltransferase (UGT) isoforms and an inhibition study using HLHs as an enzyme source demonstrated that multiple UGT isoforms, including UGT1A1, UGT1A9, and UGT2B7, catalyzed probenecid acyl glucuronidation. We found that recombinant α/β hydrolase domain containing 10 (ABHD10) substantially catalyzed PRAG deglucuronidation activity, whereas carboxylesterases did not. Similar inhibitory patterns by chemicals between HLHs and recombinant ABHD10 supported the major contribution of ABHD10 to PRAG deglucuronidation in human liver. Interestingly, it was demonstrated that the CLint value of probenecid acyl glucuronidation in HLHs was increased by 1.7-fold in the presence of phenylmethylsulfonyl fluoride, which potently inhibited ABHD10 activity. In conclusion, we found that PRAG deglucuronidation catalyzed by ABHD10 suppressively regulates PRAG formation via multiple UGT enzymes in human liver. The balance of activities by these enzymes is important for the formation of PRAG, which may be associated with the adverse reactions observed after probenecid administration.


Prophylactic Treatment with Vitamins C and B2 for Methotrexate-Induced Gastrointestinal Mucositis.
Mucositis is a common side-effect of chemotherapy treatment, inducing alterations in the composition of the gut microbiota. Redox active compounds, such as vitamins B2 and C, have been shown to reduce inflammation and enhance the growth of anaerobic bacteria in the gut. We therefore aimed to (1) validate the ability of these compounds to promote bacterial cell growth in vitro, and (2) determine their prophylactic efficacy in a rat model of methotrexate (MTX)-induced mucositis. Bacterial growth curves were performed to assess the growth kinetics of bacteria exposed to Vitamins C and B2 (0.5 mM). Male wistar rats (150-200 g) received vitamins B2 (12 mg/day) and C (50 mg/day) via daily oral gavage (from day -1 to day 10). MTX (45 mg/Kg) was administrated via I.V. injection (N = 4-8/group) on day 0. Body weight, water/food consumption and diarrhea were assessed daily. Blood and faecal samples were collected longitudinally to assess citrulline levels (mucositis biomarker) and gut microbiota composition. Vitamins C/B2 enhanced the in vitro growth of anaerobic bacteria Blautia coccoides and Roseburia intestinalis. Contrarily to vitamin B2, in vivo administration of Vitamin C significantly attenuated clinical symptoms of mucositis. Despite their influence on the composition of the gut microbiota, both vitamins did not modulate the course of MTX-induced mucositis, as accessed by plasma citrulline. Vitamins B2 and C enhanced anaerobic bacterial growth in vitro, however their ability to mitigate MTX-induced mucositis was limited.


Prevention of stroke in patients with diabetes mellitus and the metabolic syndrome.
The basic principles of stroke prevention are the same in patients with diabetes and/or the metabolic syndrome as in those without. Blood-pressure lowering is highly effective in both primary and secondary prevention of stroke in diabetics, and there is no evidence to suggest that the benefits of lipid-lowering therapy are any less. Antiplatelet agents are effective in secondary prevention and may be indicated in asymptomatic diabetic patients, who have a substantially increased risk of acute vascular events. Uncertainty over optimal management of patients with diabetes, and possibly of those with metabolic syndrome, relates more to the thresholds for initiation of treatment. The decision to initiate treatment should depend on the balance between the absolute risk of potentially preventable events and the risks of any complications of treatment. The absolute risks of ischaemic stroke and acute coronary events are significantly increased in diabetics in population-based cohort studies and the recommended thresholds for instigating blood pressure lowering and lipid lowering are therefore lower than in the general population. Optimization of strategies to prevent vascular complications must be a priority, given the rapid rises in the incidence and prevalence of type 2 diabetes and the metabolic syndrome in most populations across the globe.


Record linkage to correct under-ascertainment of cancers in HIV cohorts: The Sinikithemba HIV clinic linkage project.
The surveillance of HIV-related cancers in South Africa is hampered by the lack of systematic collection of cancer diagnoses in HIV cohorts and the absence of HIV status in cancer registries. To improve cancer ascertainment and estimate cancer incidence, we linked records of adults (aged ≥ 16 years) on antiretroviral treatment (ART) enrolled at Sinikithemba HIV clinic, McCord Hospital in KwaZulu-Natal (KZN) with the cancer records of public laboratories in KZN province using probabilistic record linkage (PRL) methods. We calculated incidence rates for all cancers, Kaposi sarcoma (KS), cervix, non-Hodgkin's lymphoma and non-AIDS defining cancers (NADCs) before and after inclusion of linkage-identified cancers with 95% confidence intervals (CIs). A total of 8,721 records of HIV-positive patients were linked with 35,536 cancer records. Between 2004 and 2010, we identified 448 cancers, 82% (n = 367) were recorded in the cancer registry only, 10% (n = 43) in the HIV cohort only and 8% (n = 38) both in the HIV cohort and the cancer registry. The overall cancer incidence rate in patients starting ART increased from 134 (95% CI 91-212) to 877 (95% CI 744-1,041) per 100,000 person-years after inclusion of linkage-identified cancers. Incidence rates were highest for KS (432, 95% CI 341-555), followed by cervix (259, 95% CI 179-390) and NADCs (294, 95% CI 223-395) per 100,000 person-years. Ascertainment of cancer in HIV cohorts is incomplete, PRL is both feasible and essential for cancer ascertainment.


A case of isolated metastatic hepatocellular carcinoma arising from the pelvic bone.
Reports of metastatic hepatocellular carcinoma (HCC) without a primary liver tumor are rare. Here we present a case of isolated HCC that had metastasized to the pelvic bone without a primary focus. A 73-year-old man presented with severe back and right-leg pain. Radiological examinations, including computed tomography (CT) and magnetic resonance imaging (MRI), revealed a huge mass on the pelvic bone (13×10 cm). He underwent an incisional biopsy, and the results of the subsequent histological examination were consistent with metastatic hepatocellular carcinoma. The tumor cells were positive for cytokeratin (AE1/AE3), hepatocyte paraffin 1, and glypican-3, and negative for CD56, chromogranin A, and synaptophysin on immunohistochemical staining. Examination of the liver by CT, MRI, positron-emission tomography scan, and angiography produced no evidence of a primary tumor. Radiotherapy and transarterial chemoembolization were performed on the pelvic bone, followed by systemic chemotherapy. These combination treatments resulted in tumor regression with necrotic changes. However, multiple lung metastases developed 1 year after the treatment, and the patient was treated with additional systemic chemotherapy.


Psychiatric and Medical Profiles of Autistic Adults in the SPARK Cohort.
This study examined lifetime medical and psychiatric morbidity reported by caregivers of 2917 autistic adults participating in the US research cohort SPARK. Participants were 78.4% male, 47.3% had intellectual disability, and 32.1% had persistent language impairments. Childhood language disorders (59.7%), speech/articulation problems (32.8%), sleep (39.4%) and eating problems (29.4%), motor delays (22.8%) and history of seizure (15.5%) were the most frequently reported clinical features. Over two thirds (67.2%) had been diagnosed with at least one psychiatric disorder (anxiety disorders: 41.1%; ADHD: 38.7%). Compared to verbally fluent participants, those with language impairments had lower frequencies of almost all psychiatric disorders. Female sex and older age were associated with higher medical and psychiatric morbidity.


Competition, facilitation, and niche differentiation in two foliar pathogens.
We studied competition between the obligate biotroph Puccinia triticina (designated here as Puccinia) and the facultative saprophyte Pyrenophora tritici-repentis (designated here as Pyrenophora) in older and younger leaves in a set of three host genotypes selected to be resistant to Puccinia only, Pyrenophora only, or neither. Age-related resistance is important for both of these pathogens. The facultative saprophyte Pyrenophora was generally a stronger competitor than the biotrophic Puccinia, even experiencing facilitation from the presence of Puccinia when Pyrenophora had the advantage of earlier inoculation. Both pathogen species produced the most spores when they were introduced before the competing species and more spores when introduced simultaneously compared to after the competitor. The pre-interactive niche of Puccinia was larger than the post-interactive niche and sporulation by Puccinia was substantially reduced in environments in which Pyrenophora had high sporulation rates. The pre-interactive niche of Pyrenophora was similar to the post-interactive niche and Pyrenophora had proportionally lower reductions in sporulation due to interspecific competition in the pre-interactive niche.


Counseling on Early Childhood Concerns: Sleep Issues, Thumb-Sucking, Picky Eating, School Readiness, and Oral Health.
Family physicians are often a source of information and advice on early childhood concerns regarding sleep, thumb-sucking/pacifier use, picky eating, school readiness, and oral health. Evidence indicates that family variables are important in the genesis of sleep difficulties, and that traditional behavioral methods are not as effective as previously thought. Attention to family psychosocial well-being, especially maternal functioning, is important in addressing childhood sleep difficulties. Thumb-sucking and pacifier use may be associated with negative consequences if they persist, and referral is recommended after four years of age if appropriate behavioral interventions are ineffective. Picky eating is heavily influenced by environmental factors, and food neophobia is a normal stage of development. The main approaches to childhood eating problems include social modeling of normal eating behaviors, repeated exposures to new foods, and positive mealtime experiences. School readiness focuses on supporting the psychosocial variables that are associated with school success. Reading with the child enhances literacy skills. Quality early childhood education programs are also effective in enhancing school success. Delaying school entry is not beneficial and may be detrimental. School readiness includes the schools' role in supporting the learning needs of all children regardless of their abilities and skills. Oral health is increasingly recognized as an important contributor to overall health. Oral health should be incorporated into well-child visits beginning at the eruption of the first tooth.


In Vivo Labelling of Adenovirus DNA Identifies Chromatin Anchoring and Biphasic Genome Replication.
Adenoviruses are DNA viruses with a lytic infection cycle. Following the fate of incoming as well as recently replicated genomes during infections is a challenge. In this study, we used the ANCHOR3 technology based on a bacterial partitioning system to establish a versatile in vivo imaging system for adenoviral genomes. The system allows the visualization of both individual incoming and newly replicated genomes in real time in living cells. We demonstrate that incoming adenoviral genomes are attached to condensed cellular chromatin during mitosis, facilitating the equal distribution of viral genomes in daughter cells after cell division. We show that the formation of replication centers occurs in conjunction with in vivo genome replication and determine replication rates. Visualization of adenoviral DNA revealed that adenoviruses exhibit two kinetically distinct phases of genome replication. Low-level replication occurred during early replication, while high-level replication was associated with late replication phases. The transition between these phases occurred concomitantly with morphological changes of viral replication compartments and with the appearance of virus-induced postreplication (ViPR) bodies, identified by the nucleolar protein Mybbp1A. Taken together, our real-time genome imaging system revealed hitherto uncharacterized features of adenoviral genomes in vivo The system is able to identify novel spatiotemporal aspects of the adenovirus life cycle and is potentially transferable to other viral systems with a double-stranded DNA phase.IMPORTANCE Viruses must deliver their genomes to host cells to ensure replication and propagation. Characterizing the fate of viral genomes is crucial to understand the viral life cycle and the fate of virus-derived vector tools. Here, we integrated the ANCHOR3 system, an in vivo DNA-tagging technology, into the adenoviral genome for real-time genome detection. ANCHOR3 tagging permitted the in vivo visualization of incoming genomes at the onset of infection and of replicated genomes at late phases of infection. Using this system, we show viral genome attachment to condensed host chromosomes during mitosis, identifying this mechanism as a mode of cell-to-cell transfer. We characterize the spatiotemporal organization of adenovirus replication and identify two kinetically distinct phases of viral genome replication. The ANCHOR3 system is the first technique that allows the continuous visualization of adenoviral genomes during the entire virus life cycle, opening the way for further in-depth study.


An activated rasN gene: detected in late but not early passage human PA1 teratocarcinoma cells.
Early passages of the human teratocarcinoma cell line PA1 are not tumorigenic in nude mice, while late passages are. A transforming gene present in late passages of PA1 cells was isolated as a biologically active molecular clone and is a new isolate of the human rasN locus. Its transforming activity is due to a single G---A (G, guanine; A, adenine) point mutation at the codon for amino acid 12 which changes the codon for glycine so that an aspartic acid residue is expressed. In contrast to late passage PA1 cells (passages 106, 330, and 338), DNA from the PA1 cell line at early passages (passage 36) does not yield rasN foci in DNA transfection assays. Thus, the presence of an activated rasN in PA1 cells correlates with enhanced tumorigenicity of the cell line and, more importantly, may have arisen during cell culture in vitro.


Visual Tailoring and Skin Cancer Prevention: Comparing Personalized, Stock, and Non-Ultraviolet Images.
Past research has demonstrated that ultraviolet (UV) photos - which reveal skin damage as dark patches - can increase preventive behaviors. Emerging camera technology facilitates personalized UV photos for interventions, yet little is known about how personalized photos compare to other visuals and what cognitive or affective mechanism explains their persuasive impact. To engage this research line, the current study compared the impact of personalized UV (PUV), stock UV (SUV), and non-UV (NUV) photos and, to advance theorizing on fear appeals, explored underlying affective mechanisms including physiological fear. A sample of 169 undergraduate students participated in a 3 (Visual conditions: PUV, SUV, NUV) × 2 (Efficacy conditions: No efficacy and Efficacy) between-participants message experiment on a computer equipped with iMotions 6.4 that tracked real-time physiological responses (facial expression and skin conductance). Results demonstrated that PUV skin damage photos produced significantly greater self-reported fear and positive valence (detected by facial expression analysis) than NUV and SUV visuals. Mediation analysis demonstrated that fear had a significant indirect effect on the relationship between exposure to PUV skin damage visuals and behavior expectations.


Wake-promoting and sleep-suppressing actions of hypocretin (orexin): basal forebrain sites of action.
The hypocretins (orexins) are a newly identified peptide family comprised of two peptides, hypocretin-1 and hypocretin-2. Recent observations suggest an involvement of these peptides in the regulation of behavioral state. For example, these peptides are found in a variety of brain regions associated with the regulation of forebrain neuronal and behavioral activity states. Furthermore, when infused into the lateral ventricles in awake animals, hypocretin-1 elicits increased duration of waking beyond that observed in vehicle-treated animals. Previous studies have been limited to an examination of the sleep-wake effects of hypocretin-1 in awake animals. Currently, the sleep-wake effects of hypocretin-2 and the extent to which hypocretins can initiate waking in the sleeping animal remain unclear. To better characterize the wake-promoting actions of the hypocretins, the current studies examined the sleep-wake effects of varying doses (0.007, 0.07 and 0.7 nmol) of hypocretin-1 and hypocretin-2 when administered into sleeping rats (e.g. remote-controlled infusions). Infusions of hypocretin-1 and hypocretin-2 into the lateral ventricles elicited a short latency (0.7 nmol hypocretin-1; 93+/-30 s from the start of the 120-s infusion) increase in electroencephalographic, electromyographic, and behavioral indices of waking. These infusions also produced substantial decreases in slow-wave and rapid-eye movement sleep. Hypocretin-1 was more potent than hypocretin-2 in these actions. Interestingly, hypocretin-1 infused into the fourth ventricle elicited less robust waking which occurred with a longer latency than infusions into the lateral ventricles. These latter observations suggest a forebrain site of action participates in hypocretin-1-induced waking. Within the forebrain, a variety of basal forebrain structures, including the medial preoptic area, the medial septal area and the substantia innominata, receive a moderate hypocretin innervation. Therefore, additional studies examined the sleep-wake effects of bilateral hypocretin-1 infusions into these basal forebrain structures. Robust increases in waking were observed following infusions into, but not outside, the medial septal area, the medial preoptic area and the substantia innominata. These results indicate a potentially prominent role of hypocretins in sleep-wake regulation via actions within certain basal forebrain structures and are consistent with studies indicating a prominent role of hypocretins in sleep/arousal disorders.


Global methylation patterns in idiopathic pulmonary fibrosis.
Idiopathic Pulmonary Fibrosis (IPF) is characterized by profound changes in the lung phenotype including excessive extracellular matrix deposition, myofibroblast foci, alveolar epithelial cell hyperplasia and extensive remodeling. The role of epigenetic changes in determining the lung phenotype in IPF is unknown. In this study we determine whether IPF lungs exhibit an altered global methylation profile. Immunoprecipitated methylated DNA from 12 IPF lungs, 10 lung adenocarcinomas and 10 normal histology lungs was hybridized to Agilent human CpG Islands Microarrays and data analysis was performed using BRB-Array Tools and DAVID Bioinformatics Resources software packages. Array results were validated using the EpiTYPER MassARRAY platform for 3 CpG islands. 625 CpG islands were differentially methylated between IPF and control lungs with an estimated False Discovery Rate less than 5%. The genes associated with the differentially methylated CpG islands are involved in regulation of apoptosis, morphogenesis and cellular biosynthetic processes. The expression of three genes (STK17B, STK3 and HIST1H2AH) with hypomethylated promoters was increased in IPF lungs. Comparison of IPF methylation patterns to lung cancer or control samples, revealed that IPF lungs display an intermediate methylation profile, partly similar to lung cancer and partly similar to control with 402 differentially methylated CpG islands overlapping between IPF and cancer. Despite their similarity to cancer, IPF lungs did not exhibit hypomethylation of long interspersed nuclear element 1 (LINE-1) retrotransposon while lung cancer samples did, suggesting that the global hypomethylation observed in cancer was not typical of IPF. Our results provide evidence that epigenetic changes in IPF are widespread and potentially important. The partial similarity to cancer may signify similar pathogenetic mechanisms while the differences constitute IPF or cancer specific changes. Elucidating the role of these specific changes will potentially allow better understanding of the pathogenesis of IPF.


Randomized trial of autologous cellular immunotherapy with sipuleucel-T in androgen-dependent prostate cancer.
Sipuleucel-T, an autologous cellular immunotherapy, was investigated in a randomized, double-blind, controlled trial to determine its biologic activity in androgen-dependent prostate cancer (ADPC). Patients with prostate cancer detectable by serum prostate-specific antigen (PSA) following radical prostatectomy received 3 to 4 months of androgen suppression therapy, and were then randomized (2:1) to receive sipuleucel-T (n = 117) or control (n = 59). The primary endpoint was time to biochemical failure (BF) defined as serum PSA ≥ 3.0 ng/mL. PSA doubling time (PSADT), time to distant failure, immune response, and safety were also evaluated. Median time to BF was 18.0 months for sipuleucel-T and 15.4 months for control (HR = 0.936, P = 0.737). Sipuleucel-T patients had a 48% increase in PSADT following testosterone recovery (155 vs. 105 days, P = 0.038). With only 16% of patients having developed distant failure, the treatment effect favored sipuleucel-T (HR = 0.728, P = 0.421). The most frequent adverse events in sipuleucel-T patients were fatigue, chills, and pyrexia. Immune responses to the immunizing antigen were greater in sipuleucel-T patients at Weeks 4 and 13 (P < 0.001, all) and were sustained prior to boosting as measured in a subset of patients a median of 22.6 months (range: 14.3-67.3 months) following randomization. No significant difference in time to BF could be shown. The finding of increased PSADT in the sipuleucel-T arm is consistent with its biologic activity in ADPC. Long-term follow-up will be necessary to determine if clinically important events, such as distant failure, are affected by therapy. Treatment was generally well tolerated.