The roles of dispersal, fecundity, and predation in the population persistence of an oak (Quercus engelmannii) under global change.
A species' response to climate change depends on the interaction of biotic and abiotic factors that define future habitat suitability and species' ability to migrate or adapt. The interactive effects of processes such as fire, dispersal, and predation have not been thoroughly addressed in the climate change literature. Our objective was to examine how life history traits, short-term global change perturbations, and long-term climate change interact to affect the likely persistence of an oak species--Quercus engelmannii (Engelmann oak). Specifically, we combined dynamic species distribution models, which predict suitable habitat, with stochastic, stage-based metapopulation models, which project population trajectories, to evaluate the effects of three global change factors--climate change, land use change, and altered fire frequency--emphasizing the roles of dispersal and seed predation. Our model predicted dramatic reduction in Q. engelmannii abundance, especially under drier climates and increased fire frequency. When masting lowers seed predation rates, decreased masting frequency leads to large abundance decreases. Current rates of dispersal are not likely to prevent these effects, although increased dispersal could mitigate population declines. The results suggest that habitat suitability predictions by themselves may under-estimate the impact of climate change for other species and locations.


The current state of sickle cell trait: implications for reproductive and genetic counseling.
Sickle cell trait (SCT) is unique among the carrier states that are identified during newborn screening. Unlike other heterozygous states for rare recessive diseases, SCT is exceedingly prevalent throughout regions of the world, making sickle cell disease one of the most common monogenetic diseases worldwide. Because of this high frequency, reproductive counseling is of paramount importance. In addition, unlike other carrier states, SCT seems to be a risk factor for several clinical complications, such as extreme exertional injury, chronic kidney disease, and venous thromboembolism. Increasing knowledge about these clinical outcomes can help inform genetic counseling recommendations. Expanding research and clinical efforts are needed to ensure that the promises of modern and precision medicine can be delivered to the millions of SCT carriers and their children.


Two independent proteomic approaches provide a comprehensive analysis of the synovial fluid proteome response to Autologous Chondrocyte Implantation.
Autologous chondrocyte implantation (ACI) has a failure rate of approximately 20%, but it is yet to be fully understood why. Biomarkers are needed that can pre-operatively predict in which patients it is likely to fail, so that alternative or individualised therapies can be offered. We previously used label-free quantitation (LF) with a dynamic range compression proteomic approach to assess the synovial fluid (SF) of ACI responders and non-responders. However, we were able to identify only a few differentially abundant proteins at baseline. In the present study, we built upon these previous findings by assessing higher-abundance proteins within this SF, providing a more global proteomic analysis on the basis of which more of the biology underlying ACI success or failure can be understood. Isobaric tagging for relative and absolute quantitation (iTRAQ) proteomic analysis was used to assess SF from ACI responders (mean Lysholm improvement of 33; n = 14) and non-responders (mean Lysholm decrease of 14; n = 13) at the two stages of surgery (cartilage harvest and chondrocyte implantation). Differentially abundant proteins in iTRAQ and combined iTRAQ and LF datasets were investigated using pathway and network analyses. iTRAQ proteomic analysis confirmed our previous finding that there is a marked proteomic shift in response to cartilage harvest (70 and 54 proteins demonstrating ≥ 2.0-fold change and p < 0.05 between stages I and II in responders and non-responders, respectively). Further, it highlighted 28 proteins that were differentially abundant between responders and non-responders to ACI, which were not found in the LF study, 16 of which were altered at baseline. The differential expression of two proteins (complement C1s subcomponent and matrix metalloproteinase 3) was confirmed biochemically. Combination of the iTRAQ and LF proteomic datasets generated in-depth SF proteome information that was used to generate interactome networks representing ACI success or failure. Functional pathways that are dysregulated in ACI non-responders were identified, including acute-phase response signalling. Several candidate biomarkers for baseline prediction of ACI outcome were identified. A holistic overview of the SF proteome in responders and non-responders to ACI has been profiled, providing a better understanding of the biological pathways underlying clinical outcome, particularly the differential response to cartilage harvest in non-responders.


Gay men's accounts of unsafe sex.
This paper provides a qualitative analysis of the explanations given by a sample of 78 gay men in England of the most recent occasion on which they engaged in anal intercourse without a condom. Explanations are analysed and interpreted from the sociological perspective of 'accounts': that is, they are not viewed as exact descriptions of the 'real' motives for behaviour but are seen as a powerful resource that can illuminate the knowledge, assumptions and values that inform behaviour. Four distinct types of accounts were identified from the men's descriptions of the circumstances and motivations surrounding their most recent unsafe sexual encounter. These related to: (i) their emotional needs and drives; (ii) the calculus of risk; (iii) issues of trust; and (iv) lapses of control. Each of these types of account is described and the implications of the typology are considered, both for our understanding of the meanings, considerations and constraints surrounding high-risk sexual behaviour and for developing more relevant health education interventions.


Does it matter who organises your health care?
As the prevalence of long-term and multimorbid conditions is increasing, patients increasingly require consultations with multiple health care professionals and coordination of their care needs. This study is based on a 2011 survey of older Australians which draws on sub-populations of people with diabetes aged 50 years or over, people with chronic obstructive pulmonary disease, and members of Nationals Seniors Australia. We develop a composite coordination measure and examine differences in the measure with different care coordination indicators using both descriptive and regression methods. Three categories of respondent-perceived care organisers are used: health care professionals; "no one"; and patients, their partner, relative or friend. Of the 2,540 survey respondents (an overall response rate of 24%), 1,865 provided information on who organised their health care, and composite coordination measures were calculated for 1,614. Multivariate analysis showed the composite score was highest where a health care professional coordinated care, followed by care organised by self or a carer, and then the group reporting no organiser. In moving towards care coordination there are opportunities to improve the care coordination process itself, and the key enablers to improving care coordination appear to be the availability and communication of clinical information and the role of the clinical team.


Evaluation and clinical use of an intraoral inferior alveolar nerve block in the horse.
Local anaesthesia is often required to facilitate invasive procedures in equine dental patients under standing sedation. To show that an intraoral approach can be used to desensitise the inferior alveolar nerve in horses and report complications seen with this technique. The distance of the mandibular foramen from the distal (caudal) edge of the mandibular third molar tooth, rostral edge of the mandibular ramus and ventral margin of the mandible were measured in 26 adult equine skulls of various ages and breeds. Computed tomography (CT) was used to verify the placement of the local anaesthetic with a custom-made device on 4 equine cadaver heads. The technique was applied in 43 clinical cases having procedures performed on the mandibular quadrants using the delivery device. Computed tomography demonstrated that the intraoral approach provided deposition of the local anaesthetic at the mandibular foramen and anatomical localisation of mandibular foramen indicated that anaesthetic solution could be delivered with a 38 mm needle. Clinical patients to lerated invasive dental procedures following the inferior alveolar nerve block with a 5 ml dose of local anaesthetic, without evidence of self-inflicted lingual trauma. The inferior alveolar nerve was successfully desensitised with the intraoral approach with minimal complications. The reduced volume of local anaesthetic and ability to deposit the local anaesthetic in close proximity to the nerve compared with an extraoral technique may decrease the complication of self-inflicted lingual trauma.


nAChRs mediate human embryonic stem cell-derived endothelial cells: proliferation, apoptosis, and angiogenesis.
Many patients with ischemic heart disease have cardiovascular risk factors such as cigarette smoking. We tested the effect of nicotine (a key component of cigarette smoking) on the therapeutic effects of human embryonic stem cell-derived endothelial cells (hESC-ECs). To induce endothelial cell differentiation, undifferentiated hESCs (H9 line) underwent 4-day floating EB formation and 8-day outgrowth differentiation in EGM-2 media. After 12 days, CD31(+) cells (13.7+/-2.5%) were sorted by FACScan and maintained in EGM-2 media for further differentiation. After isolation, these hESC-ECs expressed endothelial specific markers such as vWF (96.3+/-1.4%), CD31 (97.2+/-2.5%), and VE-cadherin (93.7+/-2.8%), form vascular-like channels, and incorporated DiI-labeled acetylated low-density lipoprotein (DiI-Ac-LDL). Afterward, 5x10(6) hESC-ECs treated for 24 hours with nicotine (10(-8) M) or PBS (as control) were injected into the hearts of mice undergoing LAD ligation followed by administration for two weeks of vehicle or nicotine (100 microg/ml) in the drinking water. Surprisingly, bioluminescence imaging (BLI) showed significant improvement in the survival of transplanted hESC-ECs in the nicotine treated group at 6 weeks. Postmortem analysis confirmed increased presence of small capillaries in the infarcted zones. Finally, in vitro mechanistic analysis suggests activation of the MAPK and Akt pathways following activation of nicotinic acetylcholine receptors (nAChRs). This study shows for the first time that short-term systemic administrations of low dose nicotine can improve the survival of transplanted hESC-ECs, and enhance their angiogenic effects in vivo. Furthermore, activation of nAChRs has anti-apoptotic, angiogenic, and proliferative effects through MAPK and Akt signaling pathways.


External validation of models for predicting risk of colorectal cancer using the China Kadoorie Biobank.
In China, colorectal cancer (CRC) incidence and mortality have been steadily increasing over the last decades. Risk models to predict incident CRC have been developed in various populations, but they have not been systematically externally validated in a Chinese population. This study aimed to assess the performance of risk scores in predicting CRC using the China Kadoorie Biobank (CKB), one of the largest and geographically diverse prospective cohort studies in China. Nine models were externally validated in 512,415 participants in CKB and included 2976 cases of CRC. Model discrimination was assessed, overall and by sex, age, site, and geographic location, using the area under the receiver operating characteristic curve (AUC). Model discrimination of these nine models was compared to a model using age alone. Calibration was assessed for five models, and they were re-calibrated in CKB. The three models with the highest discrimination (Ma (Cox model) AUC 0.70 [95% CI 0.69-0.71]; Aleksandrova 0.70 [0.69-0.71]; Hong 0.69 [0.67-0.71]) included the variables age, smoking, and alcohol. These models performed significantly better than using a model based on age alone (AUC of 0.65 [95% CI 0.64-0.66]). Model discrimination was generally higher in younger participants, males, urban environments, and for colon cancer. The two models (Guo and Chen) developed in Chinese populations did not perform better than the others. Among the 10% of participants with the highest risk, the three best performing models identified 24-26% of participants that went on to develop CRC. Several risk models based on easily obtainable demographic and modifiable lifestyle factor have good discrimination in a Chinese population. The three best performing models have a higher discrimination than using a model based on age alone.


[Movement disorders as a prodromal sign in individuals at high risk of psychosis].
The accurate prediction of a transition to psychosis in high-risk and ultra-high-risk (UHR) populations is important because timely preventive interventions may succeed in delaying or even averting psychosis. However, current screening programmes have very low predictive power. Therefore, if prodromal signs are to be really useful they need to be objective and have strong predictive power. We hypothesise that in the prodromal phase movement disorders (MD) are probably better than screening programmes at predicting the development of psychotic disorders. To determine, on the basis of published articles and personal experience, whether, in UHR populations, MD can predict a transition to psychosis more accurately that current screening programmes. We studied the literature using Medline. Our strategy was to search the literature for studies concerning 1. children with schizotypal personality disorder, 2. UHR adolescents and 3. siblings of patients with schizophrenia. Studies relating to the first two groups showed that the severity of MD was related to the severity of the prodromal signs both at baseline and at follow-up. Patients with more (and more severe) MD had a higher risk of transition to a psychotic disorder than patients without MD. Studies relating to the third group showed that the frequency of mechanically measured md was significantly higher in the siblings of patients with schizophrenia than in healthy controls. MD are objective easy-to-measure prodromal signs which might be powerful predictors of a transition to psychosis in (U)HR populations.


Metabolic response of Geobacter sulfurreducens towards electron donor/acceptor variation.
Geobacter sulfurreducens is capable of coupling the complete oxidation of organic compounds to iron reduction. The metabolic response of G. sulfurreducens towards variations in electron donors (acetate, hydrogen) and acceptors (Fe(III), fumarate) was investigated via (13)C-based metabolic flux analysis. We examined the (13)C-labeling patterns of proteinogenic amino acids obtained from G. sulfurreducens cultured with (13)C-acetate. Using (13)C-based metabolic flux analysis, we observed that donor and acceptor variations gave rise to differences in gluconeogenetic initiation, tricarboxylic acid cycle activity, and amino acid biosynthesis pathways. Culturing G. sulfurreducens cells with Fe(III) as the electron acceptor and acetate as the electron donor resulted in pyruvate as the primary carbon source for gluconeogenesis. When fumarate was provided as the electron acceptor and acetate as the electron donor, the flux analysis suggested that fumarate served as both an electron acceptor and, in conjunction with acetate, a carbon source. Growth on fumarate and acetate resulted in the initiation of gluconeogenesis by phosphoenolpyruvate carboxykinase and a slightly elevated flux through the oxidative tricarboxylic acid cycle as compared to growth with Fe(III) as the electron acceptor. In addition, the direction of net flux between acetyl-CoA and pyruvate was reversed during growth on fumarate relative to Fe(III), while growth in the presence of Fe(III) and acetate which provided hydrogen as an electron donor, resulted in decreased flux through the tricarboxylic acid cycle. We gained detailed insight into the metabolism of G. sulfurreducens cells under various electron donor/acceptor conditions using (13)C-based metabolic flux analysis. Our results can be used for the development of G. sulfurreducens as a chassis for a variety of applications including bioremediation and renewable biofuel production.


High-sensitivity C-reactive protein levels in cerebrospinal fluid and serum in severe head injury: relationship to tumor necrosis factor-alpha and interleukin-6.
Recent studies have demonstrated the role of high-sensitivity C-reactive protein (hsCRP) in inflammatory diseases; however, it is unclear whether this molecule has a role after severe head injury (SHI). Our aim was to evaluate the levels of hsCRP in both cerebrospinal fluid (CSF) and serum from patients after SHI. The study focused on 11 patients with SHI, and evaluated CSF and serum levels of hsCRP, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in a 10-day period following the head trauma. The values were compared with those from nine control patients, who had normal pressure hydrocephalus. In the CSF and serum of the patients after SHI, HsCRP was found to be significantly higher, at all times, than in the controls; TNF-alpha and IL-6 levels were also higher in these patients. However, hsCRP levels did not correlate with either TNF-alpha or IL-6. TNF-alpha and IL-6 increased during the period immediately following the SHI, and intrathecal levels were always higher than those of the serum. This study demonstrates for the first time that hsCRP reaches high levels in both CSF and serum in patients with SHI, and it may therefore be used as an inflammatory index. This finding suggests a need for further studies in this area, which are larger in scope than the present study.


Thrombopoietin receptor-independent stimulation of hematopoietic stem cells by eltrombopag.
Eltrombopag (EP), a small-molecule thrombopoietin receptor (TPO-R) agonist and potent intracellular iron chelator, has shown remarkable efficacy in stimulating sustained multilineage hematopoiesis in patients with bone marrow failure syndromes, suggesting an effect at the most immature hematopoietic stem and multipotent progenitor level. Although the functional and molecular effects of EP on megakaryopoiesis have been studied in the past, mechanistic insights into its effects on the earliest stages of hematopoiesis have been limited. We investigated the effects of EP treatment on hematopoietic stem cell (HSC) function using purified primary HSCs in separation-of-function mouse models, including a TPO-R-deficient strain, and stem cells isolated from patients undergoing TPO-R agonist treatment. Our mechanistic studies showed a stimulatory effect on stem cell self-renewal independently of TPO-R. Human and mouse HSCs responded to acute EP treatment with metabolic and gene expression alterations consistent with a reduction of intracellular labile iron pools that are essential for stem cell maintenance. Iron preloading prevented the stem cell stimulatory effects of EP. Moreover, comparative analysis of stem cells in the bone marrow of patients receiving EP showed a marked increase in the number of functional stem cells compared to patients undergoing therapy with romiplostim, another TPO-R agonist lacking an iron-chelating ability. Together, our study demonstrates that EP stimulates hematopoiesis at the stem cell level through iron chelation-mediated molecular reprogramming and indicates that labile iron pool-regulated pathways can modulate HSC function.


Epoetin treatment of anemia associated with cancer therapy: a systematic review and meta-analysis of controlled clinical trials.
Epoetin treatment offers an attractive but costly alternative to red blood cell transfusion for managing anemia associated with cancer therapy. The goal of this review is to facilitate more efficient use of epoetin by 1) quantifying the effects of epoetin on the likelihood of transfusion and on quality of life in patients with cancer treatment-related anemia and 2) evaluating whether outcomes are superior when epoetin treatment is initiated at higher hemoglobin thresholds. Two independent reviewers followed a prospective protocol for identifying studies. Outcomes data were combined with the use of a random-effects meta-analysis model. Double-blind, randomized, controlled trials that minimized patient exclusions were defined as higher quality for sensitivity analysis; randomized but unblinded trials and trials with excessive exclusions were included in the meta-analysis but were defined as lower quality. Twenty-two trials (n = 1927) met inclusion criteria, and 12 (n = 1390) could be combined for estimation of odds of transfusion. Epoetin decreased the percentage of patients transfused by 9%-45% in adults with mean baseline hemoglobin concentrations of 10 g/dL or less (seven trials; n = 1080), by 7%-47% in those with hemoglobin concentrations greater than 10 g/dL but less than 12 g/dL (seven trials; n = 431), and by 7%-39% in those with hemoglobin concentrations of 12 g/dL or higher (five trials; n = 308). In sensitivity analysis, the combined odds ratio for transfusion in epoetin-treated patients as compared with controls was 0.45 (95% confidence interval [CI] = 0.33 to 0.62) in higher quality studies and 0.14 (95% CI = 0.06 to 0.31) in lower quality studies. The number of patients needed to treat to prevent one transfusion is 4.4 for all studies, 5.2 for higher quality studies, and 2.6 for lower quality studies. Only studies with mean baseline hemoglobin concentrations of 10 g/dL or less reported statistically significant effects of epoetin treatment on quality of life; quality-of-life data were insufficient for meta-analysis. No studies addressed epoetin's effects on anemia-related symptoms. We conclude that epoetin reduces the odds of transfusion for cancer patients undergoing therapy. Evidence is insufficient to determine whether initiating epoetin earlier spares more patients from transfusion or results in better quality of life than waiting until hemoglobin concentrations decline to nearly 10 g/dL.


The Sierra Platinum Service for generating peak-calls for replicated ChIP-seq experiments.
Sierra Platinum is a fast and robust peak-caller for replicated ChIP-seq experiments with visual quality-control and -steering. The required computing resources are optimized but still may exceed the resources available to researchers at biological research institutes. Sierra Platinum Service provides the full functionality of Sierra Platinum: using a web interface, a new instance of the service can be generated. Then experimental data is uploaded and the computation of the peaks is started. Upon completion, the results can be inspected interactively and then downloaded for further analysis, at which point the service terminates.


The health of Hispanics in the southwestern United States: an epidemiologic paradox.
Recent reports in the literature on the health status of southwestern Hispanics, most of whom are Mexican Americans, are reviewed critically. The review is organized into the following sections: infant mortality, mortality at other ages, cardiovascular diseases, cancer, diabetes, other diseases, interview data on physical health, and mental health. Despite methodological limitations of much of the research, it can be concluded with some certainty that the health status of Hispanics in the Southwest is much more similar to the health status of other whites than that of blacks although socioeconomically, the status of Hispanics is closer to that of blacks. This observation is supported by evidence on such key health indicators as infant mortality, life-expectancy, mortality from cardiovascular diseases, mortality from major types of cancer, and measures of functional health. On other health indicators, such as diabetes and infectious and parasitic diseases, Hispanics appear to be clearly disadvantaged relative to other whites. Factors explaining the relative advantages or disadvantages of Hispanics include cultural practices, family supports, selective migration, diet, and genetic heritage. The recently completed Hispanic Health and Nutrition Examination Survey will go a long way to provide answers to many questions regarding the health of Hispanics in the Southwest or elsewhere.


Population distribution and ancestry of the cancer protective MDM2 SNP285 (rs117039649).
The MDM2 promoter SNP285C is located on the SNP309G allele. While SNP309G enhances Sp1 transcription factor binding and MDM2 transcription, SNP285C antagonizes Sp1 binding and reduces the risk of breast-, ovary- and endometrial cancer. Assessing SNP285 and 309 genotypes across 25 different ethnic populations (>10.000 individuals), the incidence of SNP285C was 6-8% across European populations except for Finns (1.2%) and Saami (0.3%). The incidence decreased towards the Middle-East and Eastern Russia, and SNP285C was absent among Han Chinese, Mongolians and African Americans. Interhaplotype variation analyses estimated SNP285C to have originated about 14,700 years ago (95% CI: 8,300 - 33,300). Both this estimate and the geographical distribution suggest SNP285C to have arisen after the separation between Caucasians and modern day East Asians (17,000 - 40,000 years ago). We observed a strong inverse correlation (r = -0.805; p < 0.001) between the percentage of SNP309G alleles harboring SNP285C and the MAF for SNP309G itself across different populations suggesting selection and environmental adaptation with respect to MDM2 expression in recent human evolution. In conclusion, we found SNP285C to be a pan-Caucasian variant. Ethnic variation regarding distribution of SNP285C needs to be taken into account when assessing the impact of MDM2 SNPs on cancer risk.


Androgen receptor genomic regulation.
The transcriptional activity of the androgen receptor (AR) is not only critical for the normal development and function of the prostate but also pivotal to the onset and progression of prostate cancer (PCa). The studies of AR transcriptional regulation were previously limited to a handful of AR-target genes. Owing to the development of various high-throughput genomic technologies, significant advances have been made in recent years. Here we discuss the discoveries of genome-wide androgen-regulated genes in PCa cell lines, animal models and tissues using expression microarray and sequencing, the mapping of genomic landscapes of AR using Combining Chromatin Immunoprecipitation (ChIP)-on-chip and ChIP-seq assays, the interplay of transcriptional cofactors in defining AR binding profiles, and the genomic regulation and AR reprogramming in advanced PCa.


Feasibility and Acceptability of Community Coronavirus Disease 2019 Testing Strategies (FACTS) in a University Setting.
During the coronavirus disease 2019 (COVID-19) pandemic in 2020, the UK government began a mass severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing program. This study aimed to determine the feasibility and acceptability of organized regular self-testing for SARS-CoV-2. This was a mixed-methods observational cohort study in asymptomatic students and staff at University of Oxford, who performed SARS-CoV-2 antigen lateral flow self-testing. Data on uptake and adherence, acceptability, and test interpretation were collected via a smartphone app, an online survey, and qualitative interviews. Across 3 main sites, 551 participants (25% of those invited) performed 2728 tests during a follow-up of 5.6 weeks; 447 participants (81%) completed at least 2 tests, and 340 (62%) completed at least 4. The survey, completed by 214 participants (39%), found that 98% of people were confident to self-test and believed self-testing to be beneficial. Acceptability of self-testing was high, with 91% of ratings being acceptable or very acceptable. A total of 2711 (99.4%) test results were negative, 9 were positive, and 8 were inconclusive. Results from 18 qualitative interviews with students and staff revealed that participants valued regular testing, but there were concerns about test accuracy that impacted uptake and adherence. This is the first study to assess feasibility and acceptability of regular SARS-CoV-2 self-testing. It provides evidence to inform recruitment for, adherence to, and acceptability of regular SARS-CoV-2 self-testing programs for asymptomatic individuals using lateral flow tests. We found that self-testing is acceptable and people were able to interpret results accurately.


Structural characterization of the mechanism through which human glutamic acid decarboxylase auto-activates.
Imbalances in GABA (γ-aminobutyric acid) homoeostasis underlie psychiatric and movement disorders. The ability of the 65 kDa isoform of GAD (glutamic acid decarboxylase), GAD65, to control synaptic GABA levels is influenced through its capacity to auto-inactivate. In contrast, the GAD67 isoform is constitutively active. Previous structural insights suggest that flexibility in the GAD65 catalytic loop drives enzyme inactivation. To test this idea, we constructed a panel of GAD65/67 chimaeras and compared the ability of these molecules to auto-inactivate. Together, our data reveal the important finding that the C-terminal domain of GAD plays a key role in controlling GAD65 auto-inactivation. In support of these findings, we determined the X-ray crystal structure of a GAD65/67 chimaera that reveals that the conformation of the catalytic loop is intimately linked to the C-terminal domain.


In vivo quantification of VCAM-1 expression in renal ischemia reperfusion injury using non-invasive magnetic resonance molecular imaging.
Vascular cell adhesion molecule-1 (VCAM-1) is upregulated in ischemia reperfusion injury (IRI), persisting after restoration of blood flow. We hypothesized that microparticles of iron oxide targeting VCAM-1 (VCAM-MPIO) would depict "ischemic memory" and enable in vivo assessment of VCAM-1 expression. Mice subject to unilateral, transient (30 minutes) renal ischemia and subsequent reperfusion received intravenous VCAM-MPIO (4.5 mg iron/kg body weight). Contrast agent bound rapidly (<30 minutes) in IRI-kidneys and appeared as intensely low signal areas by MRI in vivo. Automated segmentation and quantification yielded MPIO contrast volumes of 5991±354×10(6) µm(3) in IRI vs. 87±7×10(6) µm(3) in kidneys with no surgical intervention (P<0.001); 90±8×10(6) µm(3) in IRI kidneys exposed to control (IgG-MPIO) and 625±80×10(6) µm(3), in IRI kidneys pre-treated with a blocking dose of VCAM-1 antibody (P<0.001). In keeping with quantitative MRI data, VCAM-1 mRNA expression in IRI was 65-fold higher than in kidneys without surgical intervention (3.06±0.63 vs. 0.05±0.02, P<0.001). Indeed VCAM-1 mRNA expression and VCAM-MPIO contrast volume were highly correlated (R(2)=0.901, P<0.01), indicating that quantification of contrast volume reflected renal VCAM-1 transcription. Serial imaging showed VCAM-MPIO accumulation at target within 30 minutes, persisting for ≥90 minutes, while unbound VCAM-MPIO was cleared rapidly from blood, with sequestration by mac-3 positive Kupffer cells in the liver and monocyte/macrophages in the spleen. (1) VCAM-MPIO detected VCAM-1 expression and defined its 3-dimensional distribution, revealing "ischemic memory" in renal IRI; (2) automated volumetric quantification of VCAM-MPIO accurately reflected tissue levels of VCAM-1 mRNA; and (3) VCAM-MPIO bound rapidly to target with active sequestration of unbound MPIO in the liver and spleen.


Aggressive primary olfactory neuroblastoma of the sphenoclival region: a case report and literature review.
Olfactory neuroblastoma (ONB) is an uncommon malignant tumor of neural crest origin, which commonly arises in the superior nasal cavity. Ectopic origin of an ONB is exceedingly rare. We describe a rare case of an ectopic sphenoclival ONB with extensive involvement of the central skull base and with development of systemic metastases. To our knowledge, ours is the first case that describes the imaging features of this rare entity on computed tomography (CT), magnetic resonance imaging, 18 F-fluorodeoxyglucose-positron-emission tomography/CT, and digital subtraction angiography. We also describe the histological features, imaging differentials, and treatment options for this tumor along with a brief literature review.


Understanding regional variation in Medicare expenditures for initial episodes of prostate cancer care.
To evaluate the contributions of patient and treatment factors to overall expenditures and regional variation for initial treatment of localized prostate cancer (CaP) in the Medicare program. Using the Surveillance, Epidemiology, and End Results-Medicare database, we identified 47,517 beneficiaries with localized CaP during 2005-2009 and matched noncancer controls. We employed hierarchical generalized linear models to estimate risk-standardized cancer-related expenditures for each hospital referral region. To identify key contributors to the variation, we sequentially added patient characteristics, treatment intensity (the percentage of patients receiving curative treatments), ancillary procedures (biopsy, hormone therapy, and imaging), and specific treatment modalities into the model. We categorized the expenditures according to the type of services to identify their relative impact on the expenditure variations. The mean expenditure on CaP-related care per CaP beneficiary was $15,900, including $1800 on surgery, $11,200 on radiotherapy, and $1900 on ancillary procedures. The expenditure difference between quintiles 5 and 1 was $6200. Patient characteristics explained 8.4% of this difference. Treatment intensity and treatment modalities accounted for an additional 21.2% and 31.2% of the variation, respectively. Between the highest and lowest expenditure quintiles, the difference in radiotherapy expenditure was $5000, whereas that in surgery or ancillary procedures was <$200. There is substantial geographic variation in CaP expenditures, and the specific modality of radiotherapy is the most important contributor to this variation. Efforts to address the CaP care costs, such as bundled payment development, require targeting both treatment intensity and use of costly modalities.


Cardiovascular disease and 1,5-anhydro-d-glucitol.
The serum 1,5-anhydro-d-glucitol (1,5-AG) level rapidly decreases concomitantly with urinary glucose excretion in hyperglycemia. 1,5-AG is a sensitive clinical marker of short-term glycemic control, postprandial hyperglycemia and glucose fluctuation. Increasing evidence about the relationship between cardiovascular disease (CVD) and glucose fluctuations have been published. In this review, we summarize the possibilities and limitations of 1,5-AG as a marker of CVD. Research showed that 1,5-AG level is associated with prevalence of CVD and is also a predictive value for cardiovascular (CV) events. Especially in a high risk population, the predictive value of 1,5-AG for CV events becomes more effective. Besides, 1,5-AG is an effective glycometabolic marker that complements HbA1c in terms of glucose fluctuation. Appropriate use of 1,5-AG might lead to improved prognosis for patients or decrease medical financial burden of the population through early detection of glucose disorder and quality glucose control.


What shapes pulse amplitude of intracranial pressure?
The pulsatile component of intracranial pressure (ICP) has been shown to be a predictor of outcome in normal pressure hydrocephalus (NPH) and traumatic brain injury (TBI). Experimental studies have demonstrated that the pulse amplitude of ICP (AMP(ICP)) is dependent on the mean ICP (mICP), and on the pulse amplitude of the cerebral arterial blood volume (AMP(CaBV)), according to the exponential craniospinal compliance curve. In this study, we compared the influence of mICP and AMP(CaBV) on AMP(ICP) in patients with NPH (infusion study) and TBI (spontaneous recording). We retrospectively analyzed 25 NPH and 43 TBI patients with continuous monitoring of ICP and cerebral blood flow velocity (CBFV), as assessed with transcranial doppler. AMP(CaBV) was extracted from the CBFV waveform. The influence of mICP and AMP(CaBV) on AMP(ICP) were determined using partial coefficients a, b, and c of the multiple regression model: AMP(ICP) = a * mICP + b * AMP(CaBV) + c. AMP(ICP) was more dependent on mICP in NPH patients than in TBI patients (partial coefficient a = 0.93 versus -0.03; p < 0.001). On the contrary, AMP(ICP) was more dependent on AMP(CaBV) in patients with TBI than in those with NPH (b = 0.86 versus 0.10; p < 0.001). This study shows that AMP(ICP) depends mostly on changes in mean ICP during cerebrospinal fluid (CSF) infusion studies in patients with NPH, and on changes in cerebral arterial blood volume (AMP(CaBV)) in TBI patients. Further clinical studies will reveal whether AMP(ICP) is a better indicator of clinical severity and outcome than mICP in TBI and NPH patients.


Chilling Effects: US Immigration Enforcement And Health Care Seeking Among Hispanic Adults.
Aggressive deportation policy enforcement in the US may make undocumented immigrants and those close to them reluctant to seek medical care. With 68 percent of undocumented immigrants coming from Mexico or Central America, US deportation policies particularly affect Hispanic residents. To examine how deportation enforcement relates to health care use in the Hispanic population in general, we matched survey data from the 2011-16 Behavioral Risk Factor Surveillance System to measures of Immigration and Customs Enforcement (ICE) activity. Quasi-experimental analyses demonstrated that Hispanic respondents were less likely to report having had a regular provider or annual checkup following increased ICE activity in their state. In contrast, these behaviors were unchanged among non-Hispanic adults, a group less likely to be affected by deportation enforcement. Parallel results were found among Hispanic and non-Hispanic adults with diabetes, for whom lapses in care may confer significant health risks.


ANP secretion from small cell lung cancer cell lines: a potential model of ANP release.
Although atrial distension is widely accepted as the primary stimulus for atrial natriuretic peptide (ANP) release, a number of agonists are also known to induce its secretion. The mechanisms underlying these processes are not well understood. Studies of this nature are hampered by the inherent difficulty in culturing homogeneous populations of cardiac myocytes in sufficient quantities to perform molecular investigations. For this reason, we have examined the possibility of using other cell types as a model of ANP release. It has been reported that a number of tumor samples from small cell lung cancer (SCLC) patients express the ANP gene. Characterization of a large number of cell lines derived from SCLC tumor samples indicated that two of these cell lines, OS-A and SHP-77, secrete ANP at rates of approximately 10(-20) g.cell-1.min-1. This is a sufficient quantity to facilitate secretion studies using a perifusion system. We have demonstrated that ANP is released through regulated secretory pathways, as the Ca2+ ionophore A-23187, arginine vasopressin (AVP), and the sodium ionophore, monensin, were capable of modifying secretion rates. High-pressure liquid chromatography (HPLC) analysis indicated that the primary secretory product is ANP-(99-126), the circulating form of this hormone. Intracellularly, both ANP-(99-126) and ANP-(1-126) were present, suggesting the synthesis and appropriate cleavage of pro-ANP-(1-126). Because both of these cell lines have doubling times in the range of 3-5 days, they could serve as a rapidly proliferating and easily maintainable supply of homogeneous tissue for release studies.(ABSTRACT TRUNCATED AT 250 WORDS)


Diminished thyroxine-binding globulin in pubertal diabetic children.
To determine the effect of diabetes on thyroid hormone and thyroxine-binding globulin (TBG) concentrations during puberty. Total thyroxine (TT4), free thyroxine (FT4), and TBG levels of 171 thyroid microsomal antibody-negative subjects with normal thyroid-stimulating hormone (TSH) levels were measured and compared with those of nondiabetic adolescents. A random subset of 68 diabetic patients (40 boys and 28 girls) and 51 control subjects (24 boys and 27 girls) were analyzed for puberty-related changes. Most TT4 levels of diabetic subjects (80% of girls and 63% of boys) were below the 50th percentile for the normal range. TT4 increased with age in girls (r = 0.25, P < 0.04) but not in boys. FT4 was within normal limits in both sexes. TBG measurements were below the 50th percentile and 20% were below the 95% CI for both sexes; TT4 correlated with TBG in boys (r = 0.54, P < 0.001) and in girls (r = 0.58, P < 0.001). Duration of diabetes had no effect, whereas TT4 and FT4 levels were higher in girls with the lowest HbA1 levels (r = -0.29, P < 0.01 and r = -0.45, P < 0.01). Levels of TBG were reduced for all male pubertal stages (P < 0.01) and for early and late female pubertal stages (P < 0.01). There was no direct relationship between glucose control or the duration of diabetes and levels of TBG. Because TT4 levels are low and correlate with the low levels of TBG, it is important to measure free thyroid hormone and TSH levels in diabetic adolescents to establish euthyroidism.


[Diverticular disease of the colon: diagnosis and treatment. Consensus Conference, 5th National Congress of the Italian Society of Academic Surgeons].
Diverticular disease (DD) is one of the most common disorders of the colon with an increased prevalence in Western populations. There are still many unsolved issues about indications, timing of surgery and modality of surgical treatment. These topics were discussed during the Consensus Conference (CC). There is still common agreement indicating surgery after the second acute episode of diverticular disease; however, patients younger than 50 years should undergo surgery after the first acute episode, because of a higher risk of recurrence compared to older patients. It is not clear though how to uniformly classify an acute episode (severe, moderate or mild): an accurate clinical and instrumental valuation (based on CT scan) is recommended to establish the real severity of the acute episode before recommending a surgical procedure. In presence of septic complications (abscess or peritonitis) of DD, colonic resection is indicated, but a primary anastomosis could be at risk of failure due to sepsis. Therefore a Hartmann's procedure or protective stoma could be preferable. However, instead of a staged procedure, an appropriate strategy should be to resolve sepsis and perform resection and anastomosis in election. Abscesses smaller than 5 cm intra-meso-colic or para-colic can be successfully treated medically; vice versa larger or pelvic abscesses should undergo percutaneous or laparoscopic drainage, postponing colonic resection in elective conditions. Limited purulent peritonitis can be favourably treated by means of laparoscopic approach and simple lavage and drainage of peritoneal cavity. Diffuse purulent or faecal peritonitis is the most dramatic complication which still has a high risk of mortality and morbidity. Surgical risk is related to clinical conditions, duration of peritonitis, age of patient and comorbidities. Thus it is not possible to state a univocal approach, although Hartmann's procedure keeps being the first choice. On this matter farther randomized studies are required to compare Hartmann's procedure with other techniques (such as primary anastomosis with or without diverting colostomy). A wide left colonic resection (with splenic flexure mobilization) extended beneath sigmoid-rectal junction is recommended to avoid immediate or late complications. Laparoscopic approach is feasible, even for management of complicated diverticular disease, if strict patient selection criteria are followed, duration of the procedure is comparable to open surgery and conversion rate is under 10%.


Investigating attribute non-attendance and its consequences in choice experiments with latent class models.
A growing literature, mainly from transport and environment economics, has started to explore whether respondents violate some of the axioms about individuals' preferences in Discrete Choice Experiments (DCEs) and use simple strategies to make their choices. One of these strategies, termed attribute non-attendance (ANA), consists in ignoring one or more attributes. Using data from a DCE administered to healthcare providers in Ghana to evaluate their potential resistance to changes in clinical guidelines, this study illustrates how latent class models can be used in a step-wise approach to account for all possible ANA strategies used by respondents and explore the consequences of such behaviours. Results show that less than 3% of respondents considered all attributes when choosing between the two hypothetical scenarios proposed, with a majority looking at only one or two attributes. Accounting for ANA strategies improved the goodness-of-fit of the model and affected the magnitude of some of the coefficient and willingness-to-pay estimates. However, there was no difference in the predicted probabilities of the model taking into account ANA and the standard approach. Although the latter result is reassuring about the ability of DCEs to produce unbiased policy guidance, it should be confirmed by other studies.


Pedunculate Oaks (Quercus robur L.) Differing in Vitality as Reservoirs for Fungal Biodiversity.
Ecological significance of trees growing in urban and peri-urban settings is likely to increase in future land-use regimes, calling for better understanding of their role as potential reservoirs or stepping stones for associated biodiversity. We studied the diversity of fungal endophytes in woody tissues of asymptomatic even aged pedunculate oak trees, growing as amenity trees in a peri-urban setting. The trees were classified into three groups according to their phenotypic vitality (high, medium, and low). Endophytes were cultured on potato dextrose media from surface sterilized twigs and DNA sequencing was performed to reveal the taxonomic identity of the morphotypes. In xylem tissues, the frequency and diversity of endophytes was highest in oak trees showing reduced vitality. This difference was not found for bark samples, in which the endophyte infections were more frequent and communities more diverse than in xylem. In general, most taxa were shared across the samples with few morphotypes being recovered in unique samples. Leaf phenolic profiles were found to accurately classify the trees according to their phenotypic vitality. Our results confirm that xylem is more selective substrate for endophytes than bark and that endophyte assemblages in xylem are correlated to the degree of host vitality. Thus, high vitality of trees may be associated with reduced habitat quality to wood-associated endophytes.


Feasibility of Carbon Ion Radiotherapy in the Treatment of Gynecological Melanoma.
Malignant melanoma of the lower genital tract is a rare disease known to have a poor prognosis. Because of the high rate of distant metastasis and unsatisfactory survival benefit, a more conservative treatment approach, instead of extensive surgery, may be warranted. Gynecological melanoma is a radioresistant tumor, an ideal disease to test the biological efficacy of carbon ion radiotherapy (CIRT). To report our preliminary experience with CIRT in the treatment of gynecological melanoma at the National Center of Oncological Hadrontherapy (CNAO). Between January 2016 and February 2017, four patients were admitted for CIRT at CNAO. A case of cervical melanoma was treated with palliative aim because of large volume macroscopic disease, while three cases of vaginal melanoma were irradiated with a total dose of 68.8 Gy (relative biological effectiveness) in 16 fractions delivered over 4 weeks (4 days a week). The age of women ranged between 49 and 72 (median=60.5 years) years. Treatment was well tolerated in all patients and all women completed the scheduled treatment course. During CIRT, toxicity was mild. For patients with vaginal disease, local control was 10.23 and 12.6 months, while that for cervical malignant melanoma was 7.3 months. All patients experienced systemic progression, with median distant metastasis-free survival of 11.7 months. The median overall survival for the whole patient group was 11.41 months. In our first experiences, CIRT appears to be a safe non-invasive option for malignant melanoma of the lower genital tract, but more data and longer follow-up are necessary in order to evaluate the effectiveness and late effects.


Type I and III collagen turnover is increased in axial spondyloarthritis and psoriatic arthritis. Associations with disease activity and diagnostic capacity.
To investigate the turnover of type I and III collagen by neo-epitope markers in patients with axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA). Patients with PsA (n=101) or axSpA (n=110) and healthy subjects (n=120) were included. Demographic and clinical data were recorded. Markers of type I and III collagen were quantified by RIA (ICTP) or ELISA (C1M and C3M). Non-parametric statistics were applied for intergroup comparisons and correlation studies. The diagnostic potential of these marker molecules was assessed by ROC analysis. C1M and C3M, which originate from soft connective tissues, were significantly higher in axSpA and PsA as compared with healthy control subjects. CIM and C3M correlated with ASDAS and DAS28. Overall, ICTP, which arises from bone degradation, did not differ between disease versus healthy. However, ICTP was lower in HLA-B27 positive than in HLA-B27 negative patients with axSpA. There was no association between bone and soft connective tissue collagen I markers (ICTP and C1M), while C1M and C3M were highly correlated (p<0.0001). C1M discriminated between healthy and diseased with AUCs of 0.83 for PsA and 0.79 for axSpA. C3M AUCs were 0.77 for PsA and 0.78 for axSpA. Type I and III collagen remodelling in soft connective tissue is increased in axSpA and PsA and associates with disease activity. Bone collagen degradation is lower in HLA-B27 positive compared with HLA-B27 negative axSpA, which may represent an aspect of enhanced enthesopathic bone proliferation in HLA-B27 carriers. C1M and C3M distinguish well between healthy and diseased individuals.


Effects of atomoxetine on growth after 2-year treatment among pediatric patients with attention-deficit/hyperactivity disorder.
Treatment for attention-deficit/hyperactivity disorder is maintained typically over periods of months or years and, as a result, the potential effects on growth of pharmacotherapy for this disorder have been an area of concern. This meta-analysis examined the effect on growth of atomoxetine, now approved in the United States for the treatment of attention-deficit/hyperactivity disorder. Patients (N = 412) were 6 to 16 years of age at the start of the treatment period and received atomoxetine treatment (maximal dose: 1.8 mg/kg per day) for >or=2 years. Weight and height measurements were analyzed both as actual values and after conversion to percentiles and z scores with growth charts from the Centers for Disease Control and Prevention. Expected weight and height at the end point were calculated through extrapolation from patients' baseline percentiles with the growth charts. Results indicated that, after 2 years, observed weight and height were close to those predicted on the basis of the patients' baseline weight and height. Weight increased an average of 10.8 kg, a decrease relative to baseline normative weight of 2.7 percentiles, corresponding to 0.87 kg. Height increased an average of 13.3 cm, a decrease relative to baseline normative heights of 2.2 percentiles, corresponding to 0.44 cm. For both weight and height, the quartile of patients who were smallest at baseline had an increase in end-point percentile, whereas patients in the highest quartile had a decrease. These findings suggested that, at the group level, there was only a minimal effect on height after 2 years of treatment with atomoxetine and, for patients most at risk (the lowest quartile), there seemed to be no effect.


Mesangial cells express PDGF mRNAs and proliferate in response to PDGF.
Platelet-derived growth factor (PDGF) is a potent mitogen for cells of mesenchymal origin and is released and/or synthesized by platelets, macrophages, endothelial cells, and rat mesangial cells. In the present investigation, we found that human glomerular mesangial cells in culture release a PDGF-like protein which competes for 125I-PDGF binding to human foreskin fibroblasts and is mitogenic for these fibroblasts. The competing and to a lesser extent the mitogenic activities present in the conditioned medium are partially recognized by an anti-PDGF antibody. Northern blot analysis of poly(A)+ RNA from human mesangial cells demonstrates the expression of both PDGF A- and B-chain mRNAs. PDGF also binds to mesangial cells in a specific manner and stimulates DNA synthesis and cell proliferation. These data suggest that a PDGF-like protein secreted by mesangial cells or released from platelets, monocytes, or endothelial cells during glomerular inflammation may function as an autocrine or a paracrine growth factor for these cells. The biological role of PDGF in mediating proliferative and other inflammatory events in the glomerulus remains to be identified.


Effects of different types of written vaccination information on COVID-19 vaccine hesitancy in the UK (OCEANS-III): a single-blind, parallel-group, randomised controlled trial.
The effectiveness of the COVID-19 vaccination programme depends on mass participation: the greater the number of people vaccinated, the less risk to the population. Concise, persuasive messaging is crucial, particularly given substantial levels of vaccine hesitancy in the UK. Our aim was to test which types of written information about COVID-19 vaccination, in addition to a statement of efficacy and safety, might increase vaccine acceptance. For this single-blind, parallel-group, randomised controlled trial, we aimed to recruit 15 000 adults in the UK, who were quota sampled to be representative. Participants were randomly assigned equally across ten information conditions stratified by level of vaccine acceptance (willing, doubtful, or strongly hesitant). The control information condition comprised the safety and effectiveness statement taken from the UK National Health Service website; the remaining conditions addressed collective benefit, personal benefit, seriousness of the pandemic, and safety concerns. After online provision of vaccination information, participants completed the Oxford COVID-19 Vaccine Hesitancy Scale (outcome measure; score range 7-35) and the Oxford Vaccine Confidence and Complacency Scale (mediation measure). The primary outcome was willingness to be vaccinated. Participants were analysed in the groups they were allocated. p values were adjusted for multiple comparisons. The study was registered with ISRCTN, ISRCTN37254291. From Jan 19 to Feb 5, 2021, 15 014 adults were recruited. Vaccine hesitancy had reduced from 26·9% the previous year to 16·9%, so recruitment was extended to Feb 18 to recruit 3841 additional vaccine-hesitant adults. 12 463 (66·1%) participants were classified as willing, 2932 (15·6%) as doubtful, and 3460 (18·4%) as strongly hesitant (ie, report that they will avoid being vaccinated for as long as possible or will never get vaccinated). Information conditions did not alter COVID-19 vaccine hesitancy in those willing or doubtful (adjusted p values >0·70). In those strongly hesitant, COVID-19 vaccine hesitancy was reduced, in comparison to the control condition, by personal benefit information (mean difference -1·49, 95% CI -2·16 to -0·82; adjusted p=0·0015), directly addressing safety concerns about speed of development (-0·91, -1·58 to -0·23; adjusted p=0·0261), and a combination of all information (-0·86, -1·53 to -0·18; adjusted p=0·0313). In those strongly hesitant, provision of personal benefit information reduced hesitancy to a greater extent than provision of information on the collective benefit of not personally getting ill (-0·97, 95% CI -1·64 to -0·30; adjusted p=0·0165) or the collective benefit of not transmitting the virus (-1·01, -1·68 to -0·35; adjusted p=0·0150). Ethnicity and gender were found to moderate information condition outcomes. In the approximately 10% of the population who are strongly hesitant about COVID-19 vaccines, provision of information on personal benefit reduces hesitancy to a greater extent than information on collective benefits. Where perception of risk from vaccines is most salient, decision making becomes centred on the personal. As such, messaging that stresses the counterbalancing personal benefits is likely to prove most effective. The messaging from this study could be used in public health communications. Going forwards, the study highlights the need for future health campaigns to engage with the public on the terrain that is most salient to them. National Institute for Health Research (NIHR) Oxford Biomedical Research Centre and NIHR Oxford Health Biomedical Research Centre.


AS04, an aluminum salt- and TLR4 agonist-based adjuvant system, induces a transient localized innate immune response leading to enhanced adaptive immunity.
Adjuvant System 04 (AS04) combines the TLR4 agonist MPL (3-O-desacyl-4'-monophosphoryl lipid A) and aluminum salt. It is a new generation TLR-based adjuvant licensed for use in human vaccines. One of these vaccines, the human papillomavirus (HPV) vaccine Cervarix, is used in this study to elucidate the mechanism of action of AS04 in human cells and in mice. The adjuvant activity of AS04 was found to be strictly dependent on AS04 and the HPV Ags being injected at the same i.m. site within 24 h of each other. During this period, AS04 transiently induced local NF-kappaB activity and cytokine production. This led to an increased number of activated Ag-loaded dendritic cells and monocytes in the lymph node draining the injection site, which further increased the activation of Ag-specific T cells. AS04 was also found to directly stimulate those APCs in vitro but not directly stimulate CD4(+) T or B lymphocytes. These AS04-induced innate responses were primarily due to MPL. Aluminum salt appeared not to synergize with or inhibit MPL, but rather it prolonged the cytokine responses to MPL at the injection site. Altogether these results support a model in which the addition of MPL to aluminum salt enhances the vaccine response by rapidly triggering a local cytokine response leading to an optimal activation of APCs. The transient and confined nature of these responses provides further supporting evidence for the favorable safety profile of AS04 adjuvanted vaccines.


Targeting Krüppel-like factor 5 (KLF5) for cancer therapy.
Krüppel-like factor 5 (KLF5) belongs to a family of zinc-finger-containing transcription factors which are involved in regulating expression of a wide range of genes, thereby affecting diverse cellular functions. The activities of KLF5 are regulated by multiple signaling pathways including Wnt, Ras, TGFβ, Hippo, Notch, retinoid acid receptor, and hormone receptors. The expression of KLF5 is frequently abnormal in human cancers and the functions of KLF5 are context dependent. Accumulating evidence suggests that KLF5 represents a novel therapeutic target for cancer therapy. In this review, we discuss the potential biological functions of KLF5 associated with several key signaling pathways that are relevant to cancer as well as the involvement of KLF5 in various human cancers. We also describe the progress in the discovery and development of small molecules targeting KLF5 as potential therapeutics that may benefit cancer patients. The challenges and future research directions on the drug discovery of KLF5 ligands are also presented.


Association of schizophrenia in 22q11.2 deletion syndrome and gray matter volumetric deficits in the superior temporal gyrus.
Individuals with 22q11.2 deletion syndrome are known to be at high risk of developing schizophrenia. Previous imaging studies have provided limited data on the relation of schizophrenia expression in 22q11.2 deletion syndrome to specific regional brain volumetric changes. The authors hypothesized that the main structural brain finding associated with schizophrenia expression in 22q11.2 deletion syndrome, as for schizophrenia in the general population, would be gray matter volumetric deficits, especially in the temporal lobes. MR brain images from 29 patients with 22q11.2 deletion syndrome and schizophrenia and 34 comparison subjects with 22q11.2 deletion syndrome and no history of psychosis were analyzed using a voxel-based morphometry method that also yielded volumes for related region-of-interest analyses. The authors compared data from the two groups using an analysis of covariance model correcting for total intracranial volume, age, sex, IQ, and history of congenital cardiac defects. The false discovery rate threshold was set at 0.05 to account for multiple comparisons. Voxel-based morphometry analyses identified significant gray matter reductions in the left superior temporal gyrus (Brodmann's area 22) in the schizophrenia group. There were no significant between-group differences in white matter or CSF volumes. Region-of-interest analyses showed significant bilateral gray matter volume reductions in the temporal lobes and superior temporal gyri in the schizophrenia group. The structural brain expression of schizophrenia associated with the highly penetrant 22q11.2 deletion involves lower gray matter volumes in temporal lobe regions. These structural MRI findings in a 22q11.2 deletion syndrome form of schizophrenia are consistent with those from studies involving schizophrenia samples from the general population. The results provide further support for 22q11.2 deletion syndrome as a genetic subtype and as a useful neurodevelopmental model of schizophrenia.


Development of a multiplex ARMS test for mutations in the HFE gene associated with hereditary haemochromatosis.
Genetic testing for hereditary haemochromatosis is likely to be a significant workload for diagnostic laboratories. The C282Y and H63D mutations in the HFE gene associated with hereditary haemochromatosis have previously been detected using a number of methods including alterations in the restriction digest pattern of polymerase chain reaction (PCR) amplified products. An amplification refractory mutation system (ARMS) has been developed that will simultaneously detect both hereditary haemochromatosis mutations. Comparison of the results obtained from the analysis of 46 samples referred for hereditary haemochromatosis testing showed no discrepancies between ARMS and restriction enzyme digestion. Furthermore, consistent results were obtained by ARMS from both blood and buccal mouthwash samples. The ARMS test is quicker and less expensive in terms of consumables and scientist time than restriction enzyme analysis, and is therefore suited to the routine diagnostic analysis of hereditary haemochromatosis.


Music and dance as a coalition signaling system.
Evidence suggests that humans might have neurological specializations for music processing, but a compelling adaptationist account of music and dance is lacking. The sexual selection hypothesis cannot easily account for the widespread performance of music and dance in groups (especially synchronized performances), and the social bonding hypothesis has severe theoretical difficulties. Humans are unique among the primates in their ability to form cooperative alliances between groups in the absence of consanguineal ties. We propose that this unique form of social organization is predicated on music and dance. Music and dance may have evolved as a coalition signaling system that could, among other things, credibly communicate coalition quality, thus permitting meaningful cooperative relationships between groups. This capability may have evolved from coordinated territorial defense signals that are common in many social species, including chimpanzees. We present a study in which manipulation of music synchrony significantly altered subjects' perceptions of music quality, and in which subjects' perceptions of music quality were correlated with their perceptions of coalition quality, supporting our hypothesis. Our hypothesis also has implications for the evolution of psychological mechanisms underlying cultural production in other domains such as food preparation, clothing and body decoration, storytelling and ritual, and tools and other artifacts.


Fungal rhinosinusitis: what every allergist should know.
The interaction between fungi and the sinonasal tract results in a diverse range of diseases with an equally broad spectrum of clinical severity. The classification of these interactions has become complex, and this review seeks to rationalize and simplify the approach to fungal diseases of the nose and paranasal sinuses. These conditions may be discussed under two major headings: non-invasive disease (localized fungal colonization, fungal ball and allergic fungal rhinosinusitis) and invasive disease (acute invasive rhinosinusitis, chronic invasive rhinosinusitis and granulomatous invasive rhinosinusitis). A diagnosis of fungal rhinosinusitis is established by combining findings on history, clinical examination, laboratory testing, imaging and histopathology. The immunocompetence of the patient is of great importance, as invasive fungal rhinosinusitis is uncommon in immunocompetent patients. With the exception of localized fungal colonization, treatment of all forms of fungal rhinosinusitis relies heavily on surgery. Systemic antifungal agents are a fundamental component in the treatment of invasive forms, but are not indicated for the treatment of the non-invasive forms. Antifungal drugs may have a role as adjuvant therapy in allergic fungal rhinosinusitis, but evidence is poor to support recommendations. Randomized controlled trials need to be performed to confirm the benefit of immunotherapy in the treatment of allergic fungal rhinosinusitis. In this article, we will summarize the current literature, addressing the controversies regarding the diagnosis and management of fungal rhinosinusitis, and focussing on those aspects which are important for clinical immunologists and allergists.


Electroencephalogram abnormalities in panic disorder patients: a study of symptom characteristics and pathology.
Since the 1980s, a high EEG abnormality rate has been reported for patients with panic disorder. However, how the EEG abnormalities of panic disorder patients are related to the clinical features and pathology of these patients has yet to be clarified. In this study we investigated whether or not EEG abnormalities are related to the 13 symptoms in the DSM-IV criteria for a diagnosis of panic attacks. Subjects were 70 patients diagnosed with panic disorder.Logistic regression analysis was performed with EEG findings as dependent variables and age, sex and with or without the 13 symptoms as independent variables. (1)EEG findings for panic disorder patients with EEG abnormalities: Of the 17 patients, 13 had repeated slow waves in the θ-band; the most prevalent EEG abnormality found in this study. Paroxysmal abnormality interpreted as epileptiform was found in only two cases. (2)Nausea or abdominal distress (37.7% vs 82.45%, OR-12.5), derealization or depersonalization (7.5% vs 47.1%, OR = 13.9,) and paresthesias (43.4% vs 64.7%, OR = 7.9,) were extracted by multivariate analysis as factors related to EEG abnormalities. Of the 70 patients studied, 17 had EEG abnormalities. Among these 17 cases, "repeated slow waves in the θ-band" was the most common abnormality. The factors identified as being related to EEG abnormalities are nausea or abdominal distress, derealization or depersonalization, and paresthesias. The study indicated that physiological predispositions are closely related to panic attacks.


The chronostratigraphy of the Haua Fteah cave (Cyrenaica, northeast Libya).
The 1950s excavations by Charles McBurney in the Haua Fteah, a large karstic cave on the coast of northeast Libya, revealed a deep sequence of human occupation. Most subsequent research on North African prehistory refers to his discoveries and interpretations, but the chronology of its archaeological and geological sequences has been based on very early age determinations. This paper reports on the initial results of a comprehensive multi-method dating program undertaken as part of new work at the site, involving radiocarbon dating of charcoal, land snails and marine shell, cryptotephra investigations, optically stimulated luminescence (OSL) dating of sediments, and electron spin resonance (ESR) dating of tooth enamel. The dating samples were collected from the newly exposed and cleaned faces of the upper 7.5 m of the ∼14.0 m-deep McBurney trench, which contain six of the seven major cultural phases that he identified. Despite problems of sediment transport and reworking, using a Bayesian statistical model the new dating program establishes a robust framework for the five major lithostratigraphic units identified in the stratigraphic succession, and for the major cultural units. The age of two anatomically modern human mandibles found by McBurney in Layer XXXIII near the base of his Levalloiso-Mousterian phase can now be estimated to between 73 and 65 ka (thousands of years ago) at the 95.4% confidence level, within Marine Isotope Stage (MIS) 4. McBurney's Layer XXV, associated with Upper Palaeolithic Dabban blade industries, has a clear stratigraphic relationship with Campanian Ignimbrite tephra. Microlithic Oranian technologies developed following the climax of the Last Glacial Maximum and the more microlithic Capsian in the Younger Dryas. Neolithic pottery and perhaps domestic livestock were used in the cave from the mid Holocene but there is no certain evidence for plant cultivation until the Graeco-Roman period.


Non-thermal extremely low frequency magnetic field effects on opioid related behaviors: Snails to humans, mechanisms to therapy.
In 1984, it was initially discovered in mice that an extremely low frequency magnetic field (ELF-MF) could attenuate opiate induced analgesia. In the past 30 years, we defined some of ELF-MF exposure and subject state conditions that can both increase and decrease nociception in snails and mice and can induce analgesia in humans. In our search for mechanisms and our desire to translate our findings to the treatment of chronic pain in humans, we pioneered the use of electroencephalography and magnetic resonance imaging to monitor effects during exposure. We have contributed to an understanding of the phenomena but a considerable amount remains to be done by us and those who have undertaken corroboratory and complimentary work. As the recipient of the 2013 d'Arsonval Award, I was invited to prepare an article for Bioelectromagnetics that highlights research findings that led to the award. Here, I have focused on our main findings associated with the effects of nociception of exposure to ELF-MF. To enrich the value of this contribution, I have put our research into the context of work of others. Further, I have suggested future directions of research and the potential for linkages and synergies associated with the extensive literature on animal orientation. Hence, it needs to be acknowledged that this is a report of our contributions and not intended as a balanced review.


First Report of Powdery Mildew of Pumpkin Caused by Golovinomyces cichoracearum in Neelum Valley, Azad Kashmir.
During July 2011, a severe powdery mildew outbreak was recorded in pumpkin (Cucurbita moschata Duch.) fields in economically poor areas in the Neelum Valley (Leswa, Mir Pura, Jura, Kundal Shahi, and Bela). Disease symptoms included grayish white circular to irregular patches consisting of epiphytic mycelia and conidia on both surfaces of the leaves of infected vines. Fungal mycelia and conidiophores were also visible in white powdery patches on the main stems, leaves, and petioles of affected plants. Leaves became necrotic with age. Powdery mildew symptoms were more severe on pumpkin vines located in the shade, and severely affected vines collapsed. A voucher specimen (IR00027) has been deposited in First Fungal Culture Bank of the Pakistan (FCBP), Institute of Agriculture Sciences, University of the Punjab, Lahore, Pakistan. For morphological observation, a clear tape strip was used to remove fungal tissue from infected leaves. The tape was mounted on microscope slides with water and examined with a light microscope (2). Conidiophores were unbranched, cylindrical, erect and arose singly on hyphal cells, 110 to 200 × 6 to 12 μm, composed of a foot cell and three to eight barrel-shaped conidia formed in chains with a sinuate edge, followed with a basal septum at the branching point or slightly displaced from the mycelium. Foot cells were 50 to 80 × 6 to 12 μm, and slightly swollen with constriction at the base. Conidia were cylindrical to doliiform, 30 to 50 × 14 to 20 μm and produced in chains. The length/breadth ratio of the conidia was 1.8 to 2.6. Fibrosin bodies were absent in both conidiophores and conidia. No cleistothecia were observed. Identification of the causal agent as Golovinomyces cichoracearum (DC.) V.P. Heluta (synonym Erysiphe cichoracearum) was based on morphology (1). Pathogenicity was determined using field-infected plant leaves transported to a greenhouse. Fresh conidia of field isolates of G. cichoracearum were transferred by a sterile brush from the affected leaves to fully expanded four to five healthy leaves of three 40-day-old vines. For the control, three vines were stroked with a clean sterile brush and control plants were placed 100 m away from the inoculated plants. For disease development 20°C and 80% relative humidity was maintained in the greenhouse. A plastic sheet was placed around each vine for a week and removed later. Inoculated vines developed visible white spots of powdery mildew on the leaves after 10 days in the greenhouse, whereas control plants remained asymptomatic. Fungal colony and conidial morphology on the leaves of inoculated plants were as described above. Previously, G. cichoracearum has been reported on other cucurbits (3) in the plains of Pakistan. To our knowledge, this is the first report of occurrence of G. cichoracearum as a causal agent of powdery mildew on pumpkin in Neelum Valley, Azad Kashmir. References: (1) U. Braun. Beih. Nova Hedwigia 89:1, 1987. (2) J. C. Correll et al. Plant Dis. 71:248, 1987. (3) A. Wahid et al. Pak. J. Agric. Res. 9:209, 1988.


Management of horses with focus on blanketing and clipping practices reported by members of the Swedish and Norwegian equestrian community.
Limited information is available on the extent to which blankets are used on horses and the owners' reasoning behind clipping the horse's coat. Research on the effects of those practices on horse welfare is scarce but results indicate that blanketing and clipping may not be necessary from the horse's perspective and can interfere with the horse's thermoregulatory capacities. Therefore, this survey collected robust, quantitative data on the housing routines and management of horses with focus on blanketing and clipping practices as reported by members of the Swedish and Norwegian equestrian community. Horse owners were approached via an online survey, which was distributed to equestrian organizations and social media. Data from 4,122 Swedish and 2,075 Norwegian respondents were collected, of which 91 and 84% of respondents, respectively, reported using blankets on horses during turnout. Almost all respondents owning warmblood riding horses used blankets outdoors (97% in Sweden and 96% in Norway) whereas owners with Icelandic horses and coldblood riding horses used blankets significantly less ( < 0.05). Blankets were mainly used during rainy, cold, or windy weather conditions and in ambient temperatures of 10°C and below. The horse's coat was clipped by 67% of respondents in Sweden and 35% of Norwegian respondents whereby owners with warmblood horses and horses primarily used for dressage and competition reported clipping the coat most frequently. In contrast to scientific results indicating that recovery time after exercise increases with blankets and that clipped horses have a greater heat loss capacity, only around 50% of respondents agreed to these statements. This indicates that evidence-based information on all aspects of blanketing and clipping has not yet been widely distributed in practice. More research is encouraged, specifically looking at the effect of blankets on sweaty horses being turned out after intense physical exercise and the effect of blankets on social interactions such as mutual grooming. Future efforts should be tailored to disseminate knowledge more efficiently, which can ultimately stimulate thoughtful decision-making by horse owners concerning the use of blankets and clipping the horse's coat.


Challenges in comparing risk-adjusted bypass surgery mortality results: results from the Cooperative Cardiovascular Project.
We sought to evaluate the predictive accuracy of four bypass surgery mortality clinical risk models and to examine the extent to which hospitals' risk-adjusted surgical outcomes vary depending on which risk-adjustment method is applied. Cardiovascular "report cards" often compare risk-adjusted surgical outcomes; however, it is unclear to what extent the risk-adjustment process itself may affect these metrics. As part of the Cooperative Cardiovascular Project's Pilot Revascularization Study, we compared the predictive accuracy of four bypass clinical risk models among 3,654 Medicare patients undergoing surgery at 28 hospitals in Alabama and Iowa. We also compared the agreement in hospital-level risk-adjusted bypass outcome performance ratings depending on which of the four risk models was applied. Although the four risk models had similar discriminatory abilities (C-index, 0.71 to 0.74), certain models tended to overpredict mortality in higher-risk patients. There was high correlation between a hospital's risk-adjusted mortality rates regardless of which of the four models was used (correlation between risk-adjusted rating, 0.93 to 0.97). In contrast, there was limited agreement in which hospitals were identified as "performance outliers" depending on which risk-adjustment model was used and how outlier status was defined. A hospital's risk-adjusted bypass surgery mortality rating, relative to its peers, was consistent regardless of the risk-adjustment model applied, supporting their use as a means of provider performance feedback. Designation of performance outliers, however, can vary significantly depending on the benchmark and methods used for this determination.


Midlife Cardiorespiratory Fitness, Incident Cancer, and Survival After Cancer in Men: The Cooper Center Longitudinal Study.
Cardiorespiratory fitness (CRF) as assessed by formalized incremental exercise testing is an independent predictor of numerous chronic diseases, but its association with incident cancer or survival following a diagnosis of cancer has received little attention. To assess the association between midlife CRF and incident cancer and survival following a cancer diagnosis. This was a prospective, observational cohort study conducted at a preventive medicine clinic. The study included 13 949 community-dwelling men who had a baseline fitness examination. All men completed a comprehensive medical examination, a cardiovascular risk factor assessment, and incremental treadmill exercise test to evaluate CRF. We used age- and sex-specific distribution of treadmill duration from the overall Cooper Center Longitudinal Study population to define fitness groups as those with low (lowest 20%), moderate (middle 40%), and high (upper 40%) CRF groups. The adjusted multivariable model included age, examination year, body mass index, smoking, total cholesterol level, systolic blood pressure, diabetes mellitus, and fasting glucose level. Cardiorespiratory fitness levels were assessed between 1971 and 2009, and incident lung, prostate, and colorectal cancer using Medicare Parts A and B claims data from 1999 to 2009; the analysis was conducted in 2014. The main outcomes were (1) incident prostate, lung, and colorectal cancer and (2) all-cause mortality and cause-specific mortality among men who developed cancer at Medicare age (≥65 years). Compared with men with low CRF, the adjusted hazard ratios (HRs) for incident lung, colorectal, and prostate cancers among men with high CRF were 0.45 (95% CI, 0.29-0.68), 0.56 (95% CI, 0.36-0.87), and 1.22 (95% CI, 1.02-1.46), respectively. Among those diagnosed as having cancer at Medicare age, high CRF in midlife was associated with an adjusted 32% (HR, 0.68; 95% CI, 0.47-0.98) risk reduction in all cancer-related deaths and a 68% reduction in cardiovascular disease mortality following a cancer diagnosis (HR, 0.32; 95% CI, 0.16-0.64) compared with men with low CRF in midlife. There is an inverse association between midlife CRF and incident lung and colorectal cancer but not prostate cancer. High midlife CRF is associated with lower risk of cause-specific mortality in those diagnosed as having cancer at Medicare age.


Evidence for the influence of diet on cranial form and robusticity.
The evolutionary significance of cranial form and robusticity in early Homo has been variously attributed to allometry, encephalization, metabolic factors, locomotor activity, and masticatory forces. However, the influence of such factors is variably understood. To evaluate the effect of masticatory loading on neurocranial form, sibling groups of weanling white rabbits were divided into two cohorts of 10 individuals each and raised on either a soft diet or a hard/tough diet for 16 weeks until subadulthood. Micro-CT was used to quantify and visualize morphological variation between treatment groups. Results reveal trends (P < 0.10) for greater outer table thickness of the frontal bones, zygomatic height, and cranial globularity in rabbits raised on a hard/tough diet. Furthermore, analyses of three-dimensional coordinate landmark data indicate that the basicrania of hard/tough diet rabbits exhibit more robust middle cranial fossae and pterygoid plates, as well as altered overall morphology of the caudal cranial fossa. Thus, long term increases in masticatory loads may result in thickening of the bones of the neurocranial vault and/or altering the curvature of the walls. Differences in cranial regions not directly associated with the generation or resistance of masticatory forces (i.e., frontal bone, basicranium) may be indirectly correlated with diet-induced variation in maxillomandibular morphology. These findings also suggest that long-term variation in masticatory forces associated with differences in dietary properties can contribute to the complex and multifactorial development of neurocranial morphology.


The effect of substrate on thermodynamic and kinetic anisotropies in atomic thin films.
Glasses have a wide range of technological applications. The recent discovery of ultrastable glasses that are obtained by depositing the vapor of a glass-forming liquid onto the surface of a cold substrate has sparked renewed interest in the effects of confinements on physicochemical properties of liquids and glasses. Here, we use molecular dynamics simulations to study the effect of substrate on thin films of a model glass-forming liquid, the Kob-Andersen binary Lennard-Jones system, and compute profiles of several thermodynamic and kinetic properties across the film. We observe that the substrate can induce large oscillations in profiles of thermodynamic properties such as density, composition, and stress, and we establish a correlation between the oscillations in total density and the oscillations in normal stress. We also demonstrate that the kinetic properties of an atomic film can be readily tuned by changing the strength of interactions between the substrate and the liquid. Most notably, we show that a weakly attractive substrate can induce the emergence of a highly mobile region in its vicinity. In this highly mobile region, structural relaxation is several times faster than in the bulk, and the exploration of the potential energy landscape is also more efficient. In the subsurface region near a strongly attractive substrate, however, the dynamics is decelerated and the sampling of the potential energy landscape becomes less efficient than the bulk. We explain these two distinct behaviors by establishing a correlation between the oscillations in kinetic properties and the oscillations in lateral stress. Our findings offer interesting opportunities for designing better substrates for the vapor deposition process or developing alternative procedures for situations where vapor deposition is not feasible.


Cytomorphology of adrenocortical carcinoma and comparison with renal cell carcinoma.
To review the cytomorphologic features of adrenocortical carcinoma (ACC), correlate them with histology and compare them with the cytomorphologic features of very similar renal cell carcinoma (RCC) on fine needle aspiration (FNA) smears. Cytomorphologic features in 7 cases of ACC in FNA smears were analyzed and compared with those in 10 cases of RCC. Five cases of ACC and five of RCC were later confirmed on histopathology. Parameters analyzed pertained mainly to architectural, cytoplasmic and nuclear features. The presence of cells in sheets with a central, thin-walled vascular core (endocrine vascular pattern); monomorphic cell population; eccentric nuclei; focal dramatic anisonucleosis; and focal spindling with crushing was a prominent feature of ACC in contrast to RCC, which showed mainly an acinar pattern with only a focal endocrine pattern, well-defined cytoplasmic angles and projections, and cytoplasmic vacuolations; pleomorphism, if present, was gradual and seen uniformly in all the cells. Univariate analysis using the chi 2 test showed the presence of endocrine architecture; focal dramatic anisonucleosis; crushed spindle fragments; eccentric nuclei; and absence of cytoplasmic vacuolizations as significant differentiating features in favor of ACC (P < .05). A cytomorphologic comparison of ACC with RCC showed that differentiation is possible by a set of statistically significant features that not only have diagnostic value but, as with crushed spindle fragments, also have prognostic significance.


Database resources of the National Center for Biotechnology Information: update.
In addition to maintaining the GenBank(R) nucleic acid sequence database, the National Center for Biotechnology Information (NCBI) provides data analysis and retrieval resources for the data in GenBank and other biological data made available through NCBI's website. NCBI resources include Entrez, PubMed, PubMed Central, LocusLink, the NCBI Taxonomy Browser, BLAST, BLAST Link (BLink), Electronic PCR, OrfFinder, Spidey, RefSeq, UniGene, HomoloGene, ProtEST, dbMHC, dbSNP, Cancer Chromosome Aberration Project (CCAP), Entrez Genomes and related tools, the Map Viewer, Model Maker, Evidence Viewer, Clusters of Orthologous Groups (COGs) database, Retroviral Genotyping Tools, SARS Coronavirus Resource, SAGEmap, Gene Expression Omnibus (GEO), Online Mendelian Inheritance in Man (OMIM), the Molecular Modeling Database (MMDB), the Conserved Domain Database (CDD) and the Conserved Domain Architecture Retrieval Tool (CDART). Augmenting many of the web applications are custom implementations of the BLAST program optimized to search specialized data sets. All of the resources can be accessed through the NCBI home page at: http://www.ncbi.nlm.nih.gov.


Percutaneous application of fibrin sealant in surgically recalcitrant urinomas following oncocytoma resection.
Surgical application of fibrin sealant is well established as a hemostatic agent. However, reports of its percutaneous application and its uses within the urinary tract are limited. Presented below are two patients with recalcitrant urinomas despite diversion therapy following partial nephrectomy for oncocytomas. Both patients were successfully treated with percutaneous application of fibrin sealant via a sheath at the time of percutaneous perinephric drain removal. Follow-up imaging demonstrated resolution of the urinomas with stabilization of creatinine. Percutaneous application of fibrin sealant may be considered as an alternative treatment for recalcitrant urinomas prior to surgical intervention, though more studies are required to confirm its effectiveness and safety.


Cone Calix[4]arenes with Orientable Glycosylthioureido Groups at the Upper Rim: An In-Depth Analysis of Their Symmetry Properties.
The two glycoclusters α- and β-d-mannosylthioureidocalix[4]arenes 1 and 2 in the cone geometry have been submitted to a conformational investigation with the DFT approach at the standard B3LYP/6-31G(d) level and using a water continuum solvent model. After a reasoned choice of the level of calculation and the evaluation of the properties of the monomeric components of 1 and 2, the intrinsic conformational properties of cone calix[4]arenes with orientable groups at the upper rim were thoroughly analyzed. From the possible combinations of the directions that the groups may assume, 10 different geometries derive, all chiral. These geometries are interchangeable through two different processes, named breathing equilibrium and arrow rotation, that allow a dense network connection among them. When the modeling of whole macrocycles 1 and 2 was performed, a huge difference in their conformational behavior that heavily influences the presentation mode of their saccharidic moieties was found.


Appendectomy is more frequent but not a risk factor in Crohn's disease while being protective in ulcerative colitis: a comparison of surgical procedures in inflammatory bowel disease.
Appendectomy was shown to be protective in patients with ulcerative colitis (UC). There are fewer data in Crohn's disease (CD). Other operations were less studied. The aim of this study was to investigate the prevalence of appendectomy, cholecystectomy, and tonsillectomy, including their timing, in patients with inflammatory bowel disease in comparison to controls. Two hundred seventy-one patients with UC and 260 with CD, 475 clinic controls, and 428 community controls were interviewed. Appendectomy was found in 5.5% patients with UC, in 11% of clinic controls (p < 0.05), and 7.7% of community controls (p = not significant). The differences were more significant for appendectomy before onset of disease. Appendectomy was performed in 19.2% of patients with CD, in 10.9% of clinic controls, and in 10.1% of community controls (p < 0.01). However, there were no significant differences when only appendectomy before onset of disease was considered. Cholecystectomy was found in 1.5% of patients with UC, in 6.1% of clinic controls (p < 0.01), and in 4.5% of community controls (p = not significant). The difference remained significant when confined to operations performed before disease onset. No such difference was found in patients with CD. No significant difference was found in the prevalence of tonsillectomy between patients and controls. Appendectomy is protective in UC; it is more frequent, but not a risk factor in CD. The role of cholecystectomy should be investigated further.


Oxidative stress in industrial fungi.
Fungi are amongst the most industrially important microorganisms in current use within the biotechnology industry. Most such fungal cultures are highly aerobic in nature, a character that has been frequently referred to in both reactor design and fungal physiology. The most fundamentally significant outcome of the highly aerobic growth environment in fermenter vessels is the need for the fungal culture to effectively combat in the intracellular environment the negative consequences of high oxygen transfer rates. The use of oxygen as the respiratory substrate is frequently reported to lead to the development of oxidative stress, mainly due to oxygen-derived free radicals, which are collectively termed as reactive oxygen species (ROS). Recently, there has been extensive research on the occurrence, extent, and consequences of oxidative stress in microorganisms, and the underlying mechanisms through which cells prevent and repair the damage caused by ROS. In the present study, we critically review the current understanding of oxidative stress events in industrially relevant fungi. The review first describes the current state of knowledge of ROS concisely, and then the various antioxidant strategies employed by fungal cells to counteract the deleterious effects, together with their implications in fungal bioprocessing are also discussed. Finally, some recommendations for further research are made.


Predicting soil fumigant air concentrations under regional and diverse agronomic conditions.
SOFEA (SOil Fumigant Exposure Assessment system; Dow AgroSciences, Indianapolis, IN) is a new stochastic numerical modeling tool for evaluating and managing human inhalation exposure potential associated with the use of soil fumigants. SOFEA calculates fumigant concentrations in air arising from volatility losses from treated fields for large agricultural regions using multiple transient source terms (treated fields), geographical information systems (GIS) information, agronomic specific variables, user-specified buffer zones, and field reentry intervals. A modified version of the USEPA Industrial Source Complex Short Term model (ISCST3) is used for air dispersion calculations. Weather information, field size, application date, application rate, application type, soil incorporation depth, pesticide degradation rates in air, tarp presence, field retreatment, and other sensitive parameters are varied stochastically using Monte Carlo techniques to mimic region and crop specific agronomic practices. Regional land cover, elevation, and population information can be used to refine source placement (treated fields), dispersion calculations, and risk assessments. This paper describes the technical algorithms of SOFEA and offers comparisons of simulation predictions for the soil fumigant 1,3-dichloropropene (1,3-D) to actual regional air monitoring measurements from Kern, California. Comparison of simulation results to daily air monitoring observations is remarkable over the entire concentration distribution (average percent deviation of 44% and model efficiency of 0.98), especially considering numerous inputs such as meteorological conditions for SOFEA were unavailable and approximated by neighboring regions. Both current and anticipated and/or forecasted fumigant scenarios can be simulated using SOFEA to provide risk managers and product stewards the necessary information to make sound regulatory decisions regarding the use of soil fumigants in agriculture.


Survival patterns in lung and pleural cancer in Europe 1999-2007: Results from the EUROCARE-5 study.
Survival of patients diagnosed with lung and pleura cancer is a relevant health care indicator which is related to the availability and access to early diagnosis and treatment facilities. Aim of this paper is to update lung and pleural cancer survival patterns and time trends in Europe using the EUROCARE-5 database. Data on adults diagnosed with lung and pleural cancer from 87 European cancer registries in 28 countries were analysed. Relative survival (RS) in 2000-2007 by country/region, age and gender, and over time trends in 1999-2007 were estimated. Lung cancer survival is poor everywhere in Europe, with a RS of 39% and 13% at 1 and 5years since diagnosis, respectively. A geographical variability is present across European areas with a maximum regional difference of 12 and 5 percentage points in 1-year and 5-year RS respectively. Pleural cancer represents 4% of cases included in the present study with 7% 5-year RS overall in Europe. Most pleural cancers (83%) are microscopically verified mesotheliomas. Survival for both cancers decreases with advancing age at diagnosis for both cancers. Slight increasing trends are described for lung cancer. Survival over time is higher for squamous cell carcinoma and adenocarcinomas than for small and large cell carcinoma; and better among women than men. Despite the generalised although slight increase, survival of lung and pleural cancer patients still remains poor in European countries. Priority should be given to prevention, with tobacco control policies across Europe for lung cancer and banning asbestos exposure for pleural cancer, and in early diagnosis and better treatment. The management of mesothelioma needs a multidisciplinary team and standardised health care strategies.