Tomotherapy treatment plan quality assurance: the impact of applied criteria on passing rate in gamma index method.
Pretreatment patient plan verification with gamma index (GI) metric analysis is standard procedure for intensity modulated radiation therapy (IMRT) treatment. The aim of this paper is to evaluate the variability of the local and global gamma index obtained during standard pretreatment quality assurance (QA) measurements for plans performed with Tomotherapy unit. The QA measurements were performed with a 3D diode array, using variable passing criteria: 3%∕3 mm, 2%∕2 mm, 1%∕1 mm, each with both local and global normalization. The authors analyzed the pretreatment QA results for 73 verifications; 37 were prostate cancer plans, 16 were head and neck plans, and 20 were other clinical sites. All plans were treated using the Tomotherapy Hi-Art System. Pretreatment QA plans were performed with the commercially available 3D diode array ArcCHECK™. This device has 1386 diodes arranged in a helical geometry spaced 1 cm apart. The dose measurements were acquired on the ArcCHECK™ and then compared with the calculated dose using the standard gamma analysis method. The gamma passing rate (%GP), defined as the percentage of points satisfying the condition GI < 1, was calculated for different criteria (3%∕3 mm, 2%∕2 mm, 1%∕1 mm) and for both global and local normalization. In the case of local normalization method, the authors set three dose difference threshold (DDT) values of 2, 3, and 5 cGy. Dose difference threshold is defined as the minimum absolute dose error considered in the analysis when using local normalization. Low-dose thresholds (TH) of 5% and 10% were also applied and analyzed. Performing a paired-t-test, the authors determined that the gamma passing rate is independent of the threshold values for all of the adopted criteria (5%TH vs 10%TH, p > 0.1). Our findings showed that mean %GPs for local (or global) normalization for the entire study group were 93% (98%), 84% (92%), and 66% (61%) for 3%∕3 mm, 2%∕2 mm, and 1%∕1 mm criteria, respectively. DDT was equal to 2 cGy for the local normalization analysis cases. The authors observed great variability in the resulting %GP. With 3%∕3 mm gamma criteria, the overall passing rate with local normalization was 4.6% less on the average than with global one, as expected. The wide difference between %GP calculated with global or local approach is also confirmed by an unpaired t-test statistical analysis. The variability of %GP obtained confirmed the necessity to establish defined agreement criteria that could be universal and comparable between institutions. In particular, while the gamma passing rate does not depend on the choice of threshold, the choice of DDT strongly influences the gamma passing rate for local calculations. The difference between global and local %GP was statistically significant for prostate and other treatment sites when DDT was changed from 2 to 3 cGy.


Light pollution simulations for planar ground-based light sources.
The light pollution model is employed to analyze spatial behavior of luminance at the night sky under cloudless and overcast conditions. Enhanced light excess is particularly identified at cloudy skies, because the clouds efficiently contribute to the downward luminous flux. It is evident that size of ground-based light sources can play an important role in the case of overcast sky conditions. Nevertheless, the realistically sized light sources are rarely embedded into light pollution modeling, and rather they are replaced by simple point sources. We discuss the discrepancies between sky luminance distributions when at first the planar light sources are considered and at second the point-source approximation is accepted. The found differences are noticeable if the size of the light source, distance to the observer, and altitude of a cloudy layer are comparable one to the other. Compared with point-source approximation, an inclusion of the size factor into modeling the light sources leads to partial elimination of the steep changes of sky luminance (typical for point sources of light). The narrow and sharp light pillars normally presented on the sky illuminated by point light sources can disappear or fuse together when two or more nearby light sources are considered with their real sizes. Sky elements situated close to the horizon will glow efficiently if luminous flux originates from two-dimensional ground-based entities (such as cities or villages).


An evaluation of objective measures for intelligibility prediction of time-frequency weighted noisy speech.
Existing objective speech-intelligibility measures are suitable for several types of degradation, however, it turns out that they are less appropriate in cases where noisy speech is processed by a time-frequency weighting. To this end, an extensive evaluation is presented of objective measure for intelligibility prediction of noisy speech processed with a technique called ideal time frequency (TF) segregation. In total 17 measures are evaluated, including four advanced speech-intelligibility measures (CSII, CSTI, NSEC, DAU), the advanced speech-quality measure (PESQ), and several frame-based measures (e.g., SSNR). Furthermore, several additional measures are proposed. The study comprised a total number of 168 different TF-weightings, including unprocessed noisy speech. Out of all measures, the proposed frame-based measure MCC gave the best results (ρ = 0.93). An additional experiment shows that the good performing measures in this study also show high correlation with the intelligibility of single-channel noise reduced speech.


Alterations in cyst fluid genetics following endoscopic ultrasound-guided pancreatic cyst ablation with ethanol and paclitaxel.
Endoscopic ultrasound (EUS)-guided ethanol lavage with paclitaxel injection has been shown to be effective for the treatment of pancreatic cystic neoplasms; however, the evidence for effectiveness is based primarily on cyst resolution on imaging. The aim of this study was to evaluate changes in pancreatic cyst fluid DNA following EUS-guided pancreatic cyst ablation (PCA) with ethanol and paclitaxel. In a single-center, prospective study, patients with suspected benign pancreatic cysts (15 - 50 mm in diameter; ≤ 5 compartments) underwent EUS-PCA with ethanol and paclitaxel followed 3 months later by repeat EUS-FNA, cyst aspiration for repeat DNA analysis, and possible repeat EUS-PCA. Abdominal imaging was repeated 3 - 4 months and 12 months after the second EUS. Changes in baseline pancreatic cyst fluid DNA, procedural complications, and radiographic changes in cyst volume were evaluated. A total of 22 patients (median age 67 years; 15 women) with cysts in the head or uncinate (n = 10), body or neck (n = 8), and tail (n = 4), measuring a median diameter of 25 mm (range 15 - 43 mm), underwent one (n = 22) or two (n = 9) EUS-PCA procedures. Baseline cyst DNA included mutations in 11 patients (50 %). Postablation cyst fluid (n = 19) showed elimination of all baseline mutations in eight patients, new mutations in three, and no changes in eight without a baseline mutation. The largest per-protocol postablation image-defined volume change (n = 20) from either of the follow-up abdominal imaging studies (n = 20) demonstrated complete response ( < 5 % original volume) in 10 patients (50 %), partial response (5 % - 25 % original volume) in 5 (25 %), and a persistent cyst (> 25 % original volume) in 5 (25 %). During a median follow-up of 27 months (range 17 - 42 months), adverse events from all EUS-PCAs (n = 31) included abdominal pain alone in four patients (13 %), pancreatitis in three (10 %), peritonitis in one (3 %), and gastric wall cyst in one (3 %). The adverse events were classified as moderately severe in four patients (three with pancreatitis, one with peritonitis). EUS-PCA with ethanol and paclitaxel may possibly eliminate mutant DNA in neoplastic pancreatic cysts. This technique leads to complete or partial image-defined resolution in 75 % of cysts but may lead to rare adverse events. ClinicalTrials.gov (NCT01643460).


Vitamin k dependent proteins and the role of vitamin k2 in the modulation of vascular calcification: a review.
Vascular calcification, a cause of cardiovascular morbidity and mortality, is an actively regulated process involving vitamin K dependent proteins (VKDPs) among others. Vitamin K is an essential micronutrient, present in plants and animal fermented products that plays an important role as a cofactor for the post-translational γ-carboxylation of glutamic acid residues in a number of proteins. These VKDPs require carboxylation to become biologically active, and they have been identified as having an active role in vascular cell migration, angiogenesis and vascular calcification. This paper will review the process of vascular calcification and delineate the role that vitamin K2 plays in the modulation of that process, through the activation of VKDPs. One such VKDP is Matrix Gla Protein (MGP), which when activated inhibits osteogenic factors, thereby inhibiting vascular and soft tissue calcification.


Effect of the enantiomeric structure of hydrophobic polymers on the encapsulation properties of a second near infrared (NIR-II) fluorescent dye for in vivo deep imaging.
Over-thousand-nanometer (OTN) near-infrared (NIR) fluorophores are useful for biological deep imaging because of the reduced absorption and scattering of OTN-NIR light in biological tissues. IR-1061, an OTN-NIR fluorescent dye, has a hydrophobic and cationic backbone in its molecular structure, and a non-polar counter ion, BF4 -. Because of its hydrophobicity, IR-1061 needs to be encapsulated in a hydrophobic microenvironment, such as a hydrophobic core of polymer micelles, shielded with a hydrophilic shell for bioimaging applications. Previous studies have shown that the affinity of dyes with hydrophobic core polymers is dependent on the polarity of the core polymer, and that this characteristic is important for designing dye-encapsulated micelles to be used in bioimaging. In this study, the dye-polymer affinity was investigated using hydrophobic polymer films with different chiral structures of poly(lactic acid). IR-1061 showed higher affinity for l- and d-lactic acid copolymers (i.e., poly(dl-lactic acid) (PDLLA)) than to poly(l-lactic acid) (PLLA), as IR-1061 shows less dimerization in PDLLA than in PLLA. In contrast, the stability of IR-1061 in PDLLA was less than that in PLLA due to the influence of hydroxyl groups. Choosing hydrophobic core polymers for their robustness and dye affinity is an effective strategy to prepare OTN-NIR fluorescent probes for in vivo deep imaging.


Incidental Learning of Gender Agreement in L2.
Incidental learning of grammar has been an area of interest for many decades; nevertheless, existing research has primarily focused on artificial or semi-artificial languages. The present study examines the incidental acquisition of the grammar of a natural language by exposing adult speakers of an ungendered L1 (English) to the gender agreement patterns in Russian (a language that was novel to the learners). Both receptive and productive knowledge and the mediating role of working memory (WM) in learning were measured. Speakers of the ungendered language were able to successfully acquire receptive but not productive grammatical knowledge in a new language under incidental exposure. WM was engaged in production but not in a grammaticality judgment task in the incidental learning condition, indicating cognitive effort during knowledge retrieval.


[Cardiac dyssynchrony correlates with left ventricular remodeling after myocardial Infarction].
Cardiac dyssynchrony is common in advanced heart failure (HF), but the changes in cardiac synchrony after myocardial infarction (MI) have not been adequately descríbed. To study the relationship between cardiac synchrony and left ventricular remodeling after acute myocardial infarction. Forty nine patients aged 59+/-10 years (77% men) with a first episode of a ST segment elevation MI, were studied. Scintigraphic left ventricular function and synchrony analyses were performed at baseline and after a six months follow-up. Determinations were compared with 33 healthy subjects. At baseline, patients with MIhad a decreased left ventricular ejection fraction (LVEF) and significant dyssynchrony, when compared with controls. LVEF was 36.4%+/-10%, left ventricular end-diastolic volume (LVEDV) 127+/-38 mL, interventricular delay (IEV) 29+/-35 miliseconds (ms), and intraventricular delay (IAV), 234+/-89 ms. After 6 months, LVEF significantly improved (38%+/-10%, p =0.042) without significant changes in LVEDV (129+/-32 mL, p =0.97), IEV (24+/-17, p =0.96) or IAV (231+/-97, p =0.34). At baseline there were significant correlations between IAV and LVEF, and between IAV and LVEDV (r =0.48, p =0.001 and r =0.41, p =0.004, respectively). These correlations remained significant after 6 months. There was a positive correlation between IAV and LVEDV changes at six months (r =0.403, p =0.04). The development of cardiac dyssynchrony correlates with adverse left ventricular remodeling after MI .


Ethics of deliberation, consent and coercion in psychiatry.
In psychiatry, caregivers try to get free and informed consent of patients, but often feel required to restrict freedom and to use coercion. The present article develops ethical advice given by an Ethics Committee for Mental Health Care. The advice recommends an ethical ideal of shared deliberation, consisting of information, motivation, consensus and evaluation. For the exceptional use of coercion, the advice develops three criteria, namely incapacity to deliberate, threat of serious harm and proportionality between harm and coercion. The article also discusses the viewpoints of the ethical advice and of the European Convention on Human Rights and Biomedicine: is the advice in agreement with the Convention and can the advice refine the guidelines of the Convention for the particular context of psychiatry? Although the Convention emphasises the autonomy of the individual patient, whereas the advice focuses on the relationships between the partners involved, the advice enjoys a complementary and supportive function in the application of the Convention.


The diverticulated crop of adult Phormia regina.
The crop of adult Phormia regina consists of a duct that diverges from the esophagus, just in front of the cardia, and extends ventrally and posteriorly into the thorax and abdomen where it forms a bilobed sac. Flattened epithelial cells produce the cuticular lining of the crop. When empty, or partially full, the epithelial cells and cuticular lining form folds extending into the lumen, thus providing for expansion as the crop sac fills. Covering the sac on the hemolymph side is a layer of anastomosed, intrinsic muscles connected to one another by intercellular cytoplasmic bridges. Mitochondria are located at the periphery of the sarcomere. Also inside the sarcomere are glycogen, sarcoplasmic reticula, and transverse tubular systems (T-system). I, A, and Z-bands are present and the Z-bands are not in register making the muscle-type supercontractile. Important structures, not previously researched and associated with the crop muscles, are the crop nerves. Coming off the corpora cardiaca, and running down each side of the crop duct, is a pair of nerves, each housing several axons. These nerves extend to and branch over the crop sac. Here they penetrate the muscle mass and form neuromuscular junctions where electron-dense droplets of neurosecretion are released. Based on the literature, and research in our laboratory, it has now been shown that these nerves carry adipokinetic hormone, Drosophila insulin-like peptide, and a dromyosuppressin-like neuropeptide.


Exploring genetic responsibility for the self, family and kin in the case of hereditary raised cholesterol.
This paper explores the notion of genetic responsibility, i.e. the responsibility to know and manage one's own genome for oneself and the sake of others, focusing particularly on responsibilities to family and kin. It also considers wider ideas about the emergence of new forms of biological subjectivities with which the concept of genetic responsibility is associated. The paper draws on a UK-based study concerned with lay constructions of familial hypercholesterolaemia (FH), a treatable inherited form of high cholesterol, which involved qualitative interviews with 31 people with the condition recruited through a specialist outpatient clinic. The paper is an attempt to open out discussions about the significance of genetic responsibility and biological subjectivity. I argue that in this study, FH was not associated with a notable family narrative of illness or a strongly defined specific disease community, and no clear sense emerged of obligations to kin or others derived through genetic risks or genetic connections. While responsibilities concerned with the welfare of oneself and one's existing offspring were enunciated, obligations to other potential or actual kin, e.g. to tell and encourage kin to manage their risks, were much less clearly defined. Drawing on these findings, I start to address questions about the pervasiveness of genetic responsibility and genetic identity and the contexts in which they might be significant.


Mapping Solanum chacoense mediated Colorado potato beetle (Leptinotarsa decemlineata) resistance in a self-compatible F2 diploid population.
A major QTL on chromosome 2 associated with leptine biosynthesis and Colorado potato beetle resistance was identified in a diploid S. chacoense F2 population using linkage mapping and bulk-segregant analysis. We examined the genetic features underlying leptine glycoalkaloid mediated Colorado potato beetle (Leptinotarsa decemlineata) host plant resistance in a diploid F2 mapping population of 233 individuals derived from Solanum chacoense lines USDA8380-1 and M6. The presence of foliar leptine glycoalkaloids in this population segregated as a single dominant gene and displayed continuous distribution of accumulated quantity in those individuals producing the compound. Using biparental linkage mapping, a major overlapping QTL region with partial dominance effects was identified on chromosome 2 explaining 49.3% and 34.1% of the variance in Colorado potato beetle field resistance and leptine accumulation, respectively. Association of this putative resistance region on chromosome 2 was further studied in an expanded F2 population in a subsequent field season. Loci significantly associated with leptine synthesis colocalized to chromosome 2. Significant correlation between increased leptine content and decreased Colorado potato beetle defoliation suggests a single QTL on chromosome 2. Additionally, a minor QTL with overdominance effects explaining 6.2% associated with Colorado potato beetle resistance donated by susceptible parent M6 was identified on chromosome 7. Bulk segregant whole genome sequencing of the same F2 population detected QTL associated with Colorado potato beetle resistance on chromosomes 2, 4, 6, 7, and 12. Weighted gene co-expression network analysis of parental lines and resistant and susceptible F2 individuals identified a tetratricopeptide repeat containing protein with a putative regulatory function and a previously uncharacterized acetyltransferase within the QTL region on chromosome 2, possibly under the control of a regulatory Tap46 subunit within the minor QTL on chromosome 12.


Single-molecule avidin-biotin association reaction studied by force-clamp spectroscopy.
Using single-molecule force-clamp spectroscopy, where the distance between the AFM tip and the sample surface is fixed and a few parallel avidin-biotin complexes are kept stretched by a certain force, we were able to observe the formation of single avidin-biotin bonds. Perspectives to use such an approach to study association reactions at single-molecule level in the conditions resembling those characteristic for some processes in vivo (e.g. virus-cell membrane attachment) are briefly discussed.


Exploring Locality in Molecular Dirac-Coulomb-Breit Calculations: A Perspective.
The Dirac-Coulomb-Breit (DCB) operator is widely recognized for its ability to accurately capture relativistic effects and spin-physics in molecular calculations. However, due to its high computational cost, there is a need to develop low-scaling approximations without compromising accuracy. To tackle this challenge, it becomes essential to gain a deeper understanding of the DCB operator's behavior. This work aims to explore local integral approximations, shedding light on the locality of the parts of the charge-current distribution due to the small component. In particular, we propose an atomic Breit approximation that leverages an analysis of the behavior observed in a series of gold chains. Through benchmark studies of metal complexes, we evaluated the accuracy and performance of the proposed atomic Breit approximation. This work provides a comprehensive understanding of the behavior of the charge-current distribution in terms of its contributions from its AO basis constituents, facilitating the development of low-scaling methods that strike a balance between computational efficiency and accuracy.


Improving outcomes in lung cancer: the value of the multidisciplinary health care team.
Lung cancer is a major worldwide health burden, with high disease-related morbidity and mortality. Unlike other major cancers, there has been little improvement in lung cancer outcomes over the past few decades, and survival remains disturbingly low. Multidisciplinary care is the cornerstone of lung cancer treatment in the developed world, despite a relative lack of evidence that this model of care improves outcomes. In this article, the available literature concerning the impact of multidisciplinary care on key measures of lung cancer outcomes is reviewed. This includes the limited observational data supporting improved survival with multidisciplinary care. The impact of multidisciplinary care on other benchmark measures of quality lung cancer treatment is also examined, including staging accuracy, access to diagnostic investigations, improvements in clinical decision making, better utilization of radiotherapy and palliative care services, and improved quality of life for patients. Health service research suggests that multidisciplinary care improves care coordination, leading to a better patient experience, and reduces variation in care, a problem in lung cancer management that has been identified worldwide. Furthermore, evidence suggests that the multidisciplinary model of care overcomes barriers to treatment, promotes standardized treatment through adherence to guidelines, and allows audit of clinical services and for these reasons is more likely to provide quality care for lung cancer patients. While there is strengthening evidence suggesting that the multidisciplinary model of care contributes to improvements in lung cancer outcomes, more quality studies are needed.


Acute inhibition of fatty acid import inhibits GLUT4 transcription in adipose tissue, but not skeletal or cardiac muscle tissue, partly through liver X receptor (LXR) signaling.
Insulin-mediated glucose uptake is highly sensitive to the levels of the facilitative GLUT protein GLUT4. Transcription of the GLUT4 gene is repressed in states of insulin deficiency and insulin resistance and can be induced by states of enhanced energy output, such as exercise. The cellular signals that regulate GLUT4 transcription are not well understood. We hypothesized that changes in energy substrate flux regulate GLUT4 transcription. To test this hypothesis, we used transgenic mice in which expression of the chloramphenicol acetyltransferase (CAT) gene is driven by a functional 895-bp fragment of the human GLUT4 promoter, thereby acting as a reporter for transcriptional activity. Mice were treated with a single dose of etomoxir, which inhibits the transport of long-chain fatty acids into mitochondria and increases basal, but not insulin-mediated, glucose flux. GLUT4 and transgenic CAT mRNA were measured. Etomoxir treatment significantly reduced CAT and GLUT4 mRNA transcription in adipose tissue, but did not change transcription in heart and skeletal muscle. Downregulation of GLUT4 transcription was cell autonomous, since etomoxir treatment of 3T3-L1 adipocytes resulted in a similar downregulation of GLUT4 mRNA. GLUT4 transcriptional downregulation required the putative liver X receptor (LXR) binding site in the human GLUT4 gene promoter in adipose tissue and 3T3-L1 adipocytes. Treatment of 3T3-L1 adipocytes with the LXR agonist, TO901317, partially restored GLUT4 expression in etomoxir-treated cells. Our data suggest that long-chain fatty acid import into mitochondria in adipose tissue may produce ligands that regulate expression of metabolic genes.


Sex differences in HPV immunity among adults without cancer.
The incidence of human papillomavirus (HPV)-associated head and neck cancers is rising, particularly among men. Whether observed epidemiological differences in sex are explained by differences in sexual exposure and/or by immune response is unclear. In this cross-sectional, multi-institutional study, seroprevalence of antibodies to HPV L1 capsid antigen was compared by patient characteristics among 374 adult patients without cancer. A significantly higher seroprevalence was observed among women compared with men for HPV16 (OR = 2.96, 95% CI = 1.21-7.21) and HPV18 (OR = 2.84, 95% CI = 1.06-7.60) L1 antibodies. This difference persisted for HPV16 after controlling for lifetime and recent sexual behavior. After controlling for sex, HPV16 and HPV18 L1 seroprevalence was also significantly associated with higher number of lifetime (HPV16 OR = 1.05, 95% CI = 1.01-1.08; HPV18 OR = 1.04, 95% CI = 1.01-1.08) and recent (HPV16 OR = 1.54, 95% CI = 1.15-2.07; HPV18 OR = 1.40, 95% CI = 1.07-1.82) oral but not vaginal sexual partners. These findings potentially suggest a more robust immune response to HPV16/18 among women compared with men that may not be explained by differences in number of sexual partners, and thereby presumably HPV exposure. The independent association of HPV16/18 L1 seroprevalence with higher number of oral sexual partners suggests a possible role for site of mucosal exposure in the HPV immune response.


Online quantitative proteomics p-value calculator for permutation-based statistical testing of peptide ratios.
The utility of high-throughput quantitative proteomics to identify differentially abundant proteins en-masse relies on suitable and accessible statistical methodology, which remains mostly an unmet need. We present a free web-based tool, called Quantitative Proteomics p-value Calculator (QPPC), designed for accessibility and usability by proteomics scientists and biologists. Being an online tool, there is no requirement for software installation. Furthermore, QPPC accepts generic peptide ratio data generated by any mass spectrometer and database search engine. Importantly, QPPC utilizes the permutation test that we recently found to be superior to other methods for analysis of peptide ratios because it does not assume normal distributions.1 QPPC assists the user in selecting significantly altered proteins based on numerical fold change, or standard deviation from the mean or median, together with the permutation p-value. Output is in the form of comma separated values files, along with graphical visualization using volcano plots and histograms. We evaluate the optimal parameters for use of QPPC, including the permutation level and the effect of outlier and contaminant peptides on p-value variability. The optimal parameters defined are deployed as default for the web-tool at http://qppc.di.uq.edu.au/ .


Expression of a mitochondrial progesterone receptor (PR-M) in leiomyomata and association with increased mitochondrial membrane potential.
Clinical evidence supports a role for progestins in the growth of leiomyomata (fibroids). The mechanism(s) for this is thought to involve gene regulation via the nuclear progesterone receptors. Recently a mitochondrial progesterone receptor (PR-M) has been identified with evidence of a progesterone/progestin-dependent increase in cellular respiration. This observation raises a possible new mechanism whereby progesterone/progestin may affect the growth of fibroids. The goals of this research were to determine differential expression of PR-M in normal myometrium compared with the edge of a fibroid within the same uterus, to demonstrate a progestin-dependent increase in mitochondria membrane potential using an immortalized human myometrial cell line and to examine mitochondrial membrane potential in transfected cells expressing the complete coding sequence of PR-M. Protein levels of PR-M, PR-B, PR-A, mitochondrial porin, and glyceraldehyde-3-phosphate dehydrogenase were determined in the myometrium and adjacent edge of a fibroid in 10 subjects undergoing hysterectomy for benign indications. Mitochondrial membrane potential was determined by fluorescent emission of 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolecarbocyanide iodine in hTERT-HM cells treated with R5020 and in transfected hTERT-HM cells determined by the fluorescent emission of tetramethylrhodamine methyl ester. Higher levels of PR-M and mitochondrial porin were found in the fibroid edge compared with adjacent myometrium. Progestin increased mitochondrial membrane potential in hTERT-HM cells, which was not affected by a translation inhibitor. This effect was exaggerated in hTERT-HM cells expressing PR-M after transient transfection. These studies suggest a mechanism whereby progesterone/progestin may affect the growth of fibroids by altering mitochondrial activity.


HLA-G expression levels influence the tolerogenic activity of human DC-10.
Human leukocyte antigen (HLA)-G is a non-classical HLA class I molecule with known immune-modulatory functions. Our group identified a subset of human dendritic cells, named DC-10, that induce adaptive interleukin-10-producing T regulatory type 1 (Tr1) cells via the interleukin-10-dependent HLA-G/ILT4 pathway. In this study we aimed at defining the role of HLA-G in DC-10-mediated Tr1 cell differentiation. We analyzed phenotype, functions, and genetic variations in the 3' untranslated region of the HLA-G locus of in vitro-differentiated DC-10 from 67 healthy donors. We showed that HLA-G expression on DC-10 is donor-dependent. Functional studies demonstrated that DC-10, independently of HLA-G expression, secrete interleukin-10 and negligible levels of interleukin-12. Interestingly, DC-10 with high HLA-G promote allo-specific anergic T cells that contain a significantly higher frequency of Tr1 cells, defined as interleukin-10-producing (P=0.0121) or CD49b(+)LAG-3(+) (P=0.0031) T cells, compared to DC-10 with low HLA-G. We found that the HLA-G expression on DC-10 is genetically imprinted, being associated with specific variations in the 3' untranslated region of the gene, and it may be finely tuned by microRNA-mediated post-transcriptional regulation. These data highlight the important role of HLA-G in boosting DC-10 tolerogenic activity and confirm that interleukin-10 production by DC-10 is necessary but not sufficient to promote Tr1 cells at high frequency. These new insights into the role of HLA-G in DC-10-mediated induction of Tr1 cells provide additional information for clinical use in Tr1- or DC-10-based cell therapy approaches.


Performance of severity of illness classification for Clostridium difficile infection to predict need-for-colectomy or inpatient death.
In current state of practice, disease severity assessment for Clostridium difficile infection (CDI) lacks consensus between different organizations. In the latest guidelines for management of CDI, authors have proposed a new disease severity classification. This classification has been derived from expert opinion and includes previously reported patient related factors that predict unfavorable outcome in CDI. To evaluate the performance of new disease severity classification to predict CDI-related colectomy or in-patient deaths. This observational study was performed at a 300-bed community hospital catering to a suburban population. All the adult patients discharged during October 2005 through September 2012 and diagnosed with CDI were included in the study. Cases of CDI were identified using the billing database. Demographic and clinical characteristics of CDI cases were extracted from medical chart reviews performed by two physician researchers. Cases were classified as mild-to-moderate, severe, or severe and complicated CDI. Major outcomes measured were in-patient deaths and colectomy attributed to CDI. For risk stratification, each variable of severe and complicated CDI was counted. In total, 59,897 patients were discharged from our hospital during the study period; 894 of them were diagnosed with CDI. Mean age of CDI cases was 74 years (standard deviation 15 years), 345 (39%) were male, and median length of hospital stay was 7 days (interquartile range 4-13). One hundred ninety-one patients (21%) were classified as mild-to-moderate, 93 patients (10%) as severe, and 610 patients (68%) as severe and complicated. In total, 14 patients underwent colectomy for CDI and 53 patients expired. In 35 of these patients, the cause of death was thought to be CDI. The combined outcome (CDI-related colectomy and/or death in hospital) occurred in 47 patients. None of the patients in mild-to-moderate disease or severe disease had combined outcome. On severe and complicated cases, as the score increased, rate of combined outcome increased significantly (z-12.7, p<0.0001). On plotting receiver-operating curve, the simple variable count had area under the curve of 0.91. The newly proposed disease severity classification for CDI categorized more than two-thirds of patients as severe and complicated. Increase in number of severe and complicated classifying variables increases the chance of adverse outcomes significantly. Patients meeting only one variable could be potentially treated as a severe case instead of severe and complicated. This data needs to validated prospectively before could be used in clinical practice.


Assessment of carbon footprint of milk production and identification of its major determinants in smallholder dairy farms in Karnataka, India.
Indian dairy enterprise is dominated by smallholder dairy farms that contribute 72% of the country's total milk production. These smallholder dairy farms are often considered to emit substantial greenhouse gases (GHG) but are poor in productive performances. Therefore, it is crucial to estimate the carbon footprint (CF) of milk production of the smallholder Indian dairy farms. The primary objectives of the study were: 1) Assessing the CF of milk production of smallholder dairy farms through life cycle analysis in south-interior Karnataka, India; 2) Identifying the hotspots of GHG emissions and significant factors influencing the CF of milk production in smallholder dairy production system. The study accounted GHG emissions from different sources and considered multiple functions of the smallholder production system. Estimations were made based on primary data collected from 47 farms and associated secondary data. For estimating the CF of milk production, the emissions of carbon dioxide (CO2), methane (CH4) and nitrous oxide (N2O) on CO2-equivalent (CO2-eq) basis from feed production, enteric fermentation, manure management, transport and energy usage were allocated to fat-protein-corrected milk (FPCM) based on mass balance, price (crop by-products and residues) and feed digestibility. Principal component analysis and stepwise linear regression analysis were performed to identify the major factors influencing the CF. The average total GHG emissions (kg CO2-eq yr-1 farm-1) attributable to milk production based on mass, economic and digestibility allocations were 8936, 8641 and 8759, respectively. The contributions of CH4, N2O and CO2 to the total farm GHG emission were 70.6, 20.5 and 7.69%, respectively. The major emission hotspots were CH4 emission from enteric fermentation (66.8%) and GHG emission from feed production (23.0%). The average CF of cradle-to-dairy cooperative milk production varied from 1.45 to 1.81 kg CO2-eq kg FPCM-1. The CF of milk production was more than 2-fold greater, when milk yield was below 3500 kg lactating cow-1 yr-1. The FPCM yield 100 kg body weight-1, dry matter intake and CH4 emission from manure management were the strongest determinants of the CF and explained 83.4% of the observed variation. The study emphasized the importance of considering multiple functions of a mixed crop-livestock-based dairy production system for estimating CF per unit of product. The results suggest that maintaining high-yielding dairy animals and adopting appropriate feeding strategies for better feed utilization are the possible effective interventions for reducing the CF of milk production.


Osteogenic Differentiation of Human Mesenchymal Stem Cells by the Single Action of Luminescent Polyurea Oxide Biodendrimers.
Polyurea oxide (PURO) biodendrimers are a class of dendrimers that can trigger osteogenic differentiation of human mesenchymal stem cells (hMSCs). PURO biodendrimers are prepared by simple, solventless oxidation of polyurea dendrimers using hydrogen peroxide as the oxidant in quantitative yield, retaining both biocompatibility (up to 10 mg/mL for higher generations) and the non-traditional intrinsic luminescence. The effect of PURO biodendrimers in the differentiation of hMSCs was found by the single addition to a standard growth medium for MSCs differentiation (without differentiation inducers). After 21 days of incubation, the formation of osteoblasts was confirmed by the alizarin red staining assay and alkaline phosphatase activity. This is the first report of in vitro osteodifferentiation fully regulated by synthetic soft polymers such as dendrimers. Current osteogenic differentiation protocols rely on an in vitro inducing formulation (including dexamethasone, ascorbic acid, and β-glycerophosphate), which lacks therapeutic potential in vivo. The outstanding role of dendrimers in nanomedicine, under clinic translation, combined with this feature is envisaged to foster PURO dendrimers as an important strategy in cell therapy and regenerative medicine.


The Psychedelic Personality: Personality Structure and Associations in a Sample of Psychedelics Users.
Research on the relationship between personality and psychedelics use has found evidence of a two-way influence where the personality structure predicts individual responses to psychedelics, and psychedelics use results in lasting changes to the individual's personality structure. This study used brief personality measures in the form of the Ten-Item Personality Inventory (TIPI) and a simplified version of the Risk Taking Index (RTI) in order to measure personality traits in a sample of psychedelics users (N = 319). The participants in the study scored consistently higher than norms on each of the Big Five traits except Extraversion, and on every dimension of risk taking in the RTI. In multivariate logistic regression analyses, personality structure was associated with characteristics of the psychedelic experience that included the feelings of fear, love, and peace as well as states of perceived contact with non-ordinary beings and transcendent forces.


Dose-dependent effects of melengestrol acetate (MGA) on plasma levels of estradiol, progesterone and luteinizing hormone in cycling heifers and influences on oestrogen residues in edible tissues.
Melengestrol acetat (MGA) is widely used as a growth promoting feed additive in cattle breeding in the USA and several other non-European countries. To explore the physiological effects of MGA four heifers were fed during 8 weeks with 0.5 mg MGA daily as registered in the USA and two heifers each received 0, 1.5 or 5 mg/day, respectively. Plasma samples were collected twice a week and concentrations of MGA, progesterone (P4) and estradiol-17beta (E2-17beta) were quantified. The pulsatile secretion of luteinizing hormone (LH) was investigated in 6-hour profiles before and during treatment. After slaughter the reproductive organs were examined and oestrogen residues in edible tissues were measured. Four days after the beginning of MGA feeding MGA concentrations in plasma reached levels of 30 and 100-400 pg/mL depending on the dose received. Three weeks after the beginning of MGA feeding P4 plasma concentrations had dropped to base levels below 0.3 ng/mL in all three treatment groups. Mean plasma E2-17beta levels increased in physiological range from 1 to 5 pg/mL during 0.5 mg MGA/day feeding with many acyclic peaks. Overdosed MGA decreased E2 levels and suppressed cyclic peaks. Number and size of ovarian follicles were not altered by any treatment. Mean LH levels and pulse frequencies increased significantly during labelled treatment (0.5 mg/day), while higher doses had reducing effects. The development of corpus luteum was suppressed. E2-17beta residues in fat increased about 300% following labelled MGA treatment.


Midterm evaluation of hemodynamics of the Top Hat supraannular aortic valve.
The CarboMedics Top Hat supraannular aortic valve provides an orifice-to-annulus ratio of 1:1 in most patients, and enhances patient outcomes. This study compared the midterm echocardiographic parameters of 52 patients undergoing aortic valve replacement with a Top Hat valve with those in other studies of Top Hat or CarboMedics intraannular valves. Echocardiography was performed 6-48 months after surgery with Top Hat sizes 21-27. Parameters evaluated included mean gradient, peak gradient, effective orifice area, and effective orifice area index. Preoperative and postoperative echocardiographic measurements were compared in 38 patients with aortic valve stenosis. Hemodynamic data were comparable to those of other studies, but the Top Hat prosthesis implanted was significantly larger (by a mean of 3.29 mm) than the valve size indicated using an intraannular valve sizer in 48 patients. Mean effective orifice area improved significantly from 0.73 cm(2) preoperatively to 2.04 cm(2) postoperatively. In patients with preoperative aortic valve stenosis, postoperative mean peak gradient was significantly reduced. The larger orifice-to-annulus ratio of the Top Hat valve improved hemodynamic parameters assessed by echocardiography up to 4 years postoperatively, with a lower transvalvular gradient, hence decreased left ventricular workload.


[Serum glycoside level in old age. Problems of course control in glycoside therapy].
Many intoxications--up to 20%--and the often described "digitalis-incompatibility of old age" require a strict indication for this long term therapy and a critical discussion to conceptions like "old age-heart" and "insufficiency of old age-heart". The factors of uncertainty for efficient therapy -- unknown rates of resorption and elimination, mistakes in dosage by patients and interaction with other medicaments on account of the multimorbidity of old age -- demand a better control than only clinical observation and electrocardiography. In 25 patients the serum glycoside concentration was evaluated during several weeks at constant dose by radioimmunoassay and analyzed. Digoxin-assay has to be available as an "emergency-measure", since the early diagnosis of digitalis intoxication in old patients is often very difficult because of the ambiguous clinical picture. 63 patients of different age with normal function of the kidneys (endogenous creatinin-clearance, nephrography with iodine-131-hippuran) were treated with 0,75 mg digoxin/die orally and the serum glycoside concentration was evaluated after 8, 24 and 48 hours by radioimmunoassay; we only found a dependence on weight, but not on the age of our patients. In old age, digoxin is metabolized in the same way as in young age, but because of frequent kidney diseases, kidney function should be assessed carefully before long term digoxin therapy.


Crohn's disease presenting as enterovesical fistula.
Enterovesical fistulae in Crohn's disease are relatively rare. We present the first report of a child presenting with an enterovesical fistula as the initial presentation of Crohn's disease. Management comprises of timely diagnosis, and treatment involving surgical resection with adjunctive medical management including immunomodulators. This case highlights the need to be aware of the rare but important occurrence of Crohn's enterovesical fistula as a cause for urinary symptoms in a child with inadequate weight gain.


Predicting the peak growth velocity in the individual child: validation of a new growth model.
Predicting the peak growth velocity in an individual patient with adolescent idiopathic scoliosis is essential or determining the prognosis of the disorder and timing of the (surgical) treatment. Until the present time, no accurate method has been found to predict the timing and magnitude of the pubertal growth spurt in the individual child. A mathematical model was developed in which the partial individual growth velocity curve was linked to the generic growth velocity curve. The generic curve was shifted and stretched or shrunk, both along the age axis and the height velocity axis. The individual age and magnitude of the PGV were obtained from the new predicted complete growth velocity curve. Predictions were made using 2, 1.5, 1 and 0.5 years of the available longitudinal data of the individual child, starting at different ages. The predicted values of 210 boys and 162 girls were compared to the child's own original values of the PGV. The individual differences were compared to differences obtained when using the generic growth velocity curve as a standard. Using 2 years of data as input for the model, all predictions of the age of the PGV in boys and girls were significantly better in comparison to using the generic values. Using only 0.5 years of data as input, the predictions with a starting age from 13 to 15.5 years in boys and from 9.5 to 14.5 years in girls were significantly better. Similar results were found for the predictions of the magnitude of the PGV. This model showed highly accurate results in predicting the individual age and magnitude of the PGV, which can be used in the treatment of patients with adolescent idiopathic scoliosis.


Risk perception, worry, and test acceptance in average-risk women who undergo ovarian cancer screening.
We evaluated baseline knowledge of ovarian cancer risk and perceptions toward ovarian cancer screening (OCS) by initiating the normal risk ovarian screening study. Average-risk, postmenopausal women were enrolled between 2001 and 2011 as they entered the normal risk ovarian screening study. Participants completed baseline surveys of risk perception, cancer worry (Cancer Worry Scale), anxiety (State-Trait Anxiety Inventory), health and well-being survey (SF-36 HEALTH SURVEY), and acceptability of OCS. Of the 1242 women who were enrolled, 925 women (74.5%) completed surveys. The respondents estimated a mean lifetime risk of ovarian cancer of 29.9%, which is much higher than the actual risk of 1.4% for women in the United States. Only 2.8% of participants correctly estimated their risk; 35.4% of the participants reported their lifetime risk to be ≥50%. Cancer worry was low, with a median Cancer Worry Scale score of 7 of 24. Anxiety was comparable with published norms for women in this age group, with median STAI-State and STAI-Trait scores of 30 and 29 of 80, respectively. Overall, women reported good physical and mental well-being. In terms of OCS acceptability, 97.2% of respondents agreed or strongly agreed that "the benefits of screening outweigh the difficulties." Very few women were reluctant to undergo OCS because of time constraints (1.1%), pain (2.0%), or embarrassment (1.9%). Average-risk women who underwent OCS highly overestimated their risk of ovarian cancer. Despite this, participants reported low cancer worry and anxiety. The discrepancy between knowledge of and attitudes toward ovarian cancer risk highlights the need for educational efforts in this area.


Reproductive decision-making: a qualitative study among couples at increased risk of having a child with retinoblastoma.
Little is known about the reproductive decision-making process of couples with an increased risk of having a child with retinoblastoma (Rb). A qualitative study was conducted to explore the impact of prospective risk on reproductive decisions, factors influencing these decisions, and the needs of couples with regard to reproductive counselling. Fourteen couples of childbearing age who received genetic counselling between 2002 and 2006 participated in semi-structured interviews in 2008. The risk of having a child with Rb ranged from less than 1% to 50%. In most cases, the diagnosis of Rb influenced subsequent family planning. Prenatal diagnosis was used by two couples, while others refrained from having more children. Reproductive decisions were influenced by the burden of the disease for the patient and family members, the impact of ophthalmological screening under anaesthesia, and couples' perceived risk, which did not always relate to their actual risk. Reproductive choices with regard to the number of children wanted changed over time. Our findings indicate topics to be discussed during genetic counselling of couples at increased risk for a child with Rb. We suggest continued access to genetic counselling also after the initial diagnosis and treatment.


Dietary intake of energy, nutrients and water in elderly people living at home or in nursing home.
There is a lack of detailed information on dietary intake in elderly people at an individual level, which is crucial for improvement of nutritional support. The aim of this study was to investigate the dietary intake in elderly people in two types of living situations. Observational study, analysing prospective data. The dietary intake was studied in elderly people living at home or in nursing home, in different cities of Sweden. A total of 264 elderly people (mean age 84) participated in the observational study. Dietary intake was measured using weighed food records and food diaries, comparing females and males. The observed dietary intake was related to Recommended intake and Lower intake level. All dietary intake and patient characteristic variables showed large individual differences (ranges). We found no significant differences (p>0.05) between those living at home and nursing home residents regarding the average intake of energy, protein and water when expressed as total intake per kg of body weight. A very low daily intake of energy (<20 kcal/kg body weight/day) was observed in 16% of the participants. For vitamin D and iron, 19% and 15%, respectively, had intakes below the Lower intake level. There was no correlation between intake of energy, protein or water and resident characteristics such as age, autonomy, morbidity, nutritional state or cognition. The large individual differences (ranges) in energy, nutrients and water show that the use of mean values when analysing dietary intake data from elderly people is misleading. From a clinical perspective it is more important to consider the individual intake of energy, nutrients and water. Ageism is intrinsic in the realm of 'averageology'.


Cat exposure in early life decreases asthma risk from the 17q21 high-risk variant.
Early-life exposure to cats and dogs has shown diverging associations with childhood asthma risk, and gene-environment interaction is one possible explanation. We investigated interactions between cat and dog exposure and single nucleotide polymorphism rs7216389 variants in the chromosome 17q21 locus, the strongest known genetic risk factor for childhood asthma. Genotyping was performed in 377 children from the at-risk Copenhagen Prospective Studies on Asthma in Childhood2000. The primary end point was the development of asthma until age 12 years. The secondary end point was the number of episodes with pneumonia and bronchiolitis from 0 to 3 years of age. Exposures included cat and dog ownership from birth and cat and dog allergen levels in bedding at age 1 year. Replication was performed in the unselected COPSAC2010 cohort with follow-up until 5 years of age. Cat and/or dog exposure from birth was associated with a lower prevalence of asthma among children with the rs7216389 high-risk TT genotype (adjusted hazard ratio, 0.16; 95% CI, 0.04-0.71; P = .015), with no effect in those with the CC/CT genotype (adjusted P = .283), demonstrating interaction between cat and dog exposure and the rs7216389 genotype (adjusted P = .044). Cat allergen levels were inversely associated with asthma development in children with the TT genotype (adjusted hazard ratio, 0.83; 95% CI, 0.71-0.97; P = .022), supporting the cat-rs7216389 genotype interaction (adjusted P = .008). Dog allergen exposure did not show such interaction. Furthermore, the TT genotype was associated with higher risk of pneumonia and bronchiolitis, and this increased risk was likewise decreased in children exposed to cat. Replication showed similar effects on asthma risk. The observed gene-environment interaction suggests a role of early-life exposure, especially to cat, for attenuating the risk of childhood asthma, pneumonia, and bronchiolitis in genetically susceptible subjects.


Normalizing Transantiago: on the challenges (and limits) of repairing infrastructures.
This article looks to propose a new way to understand the repair of failing large sociotechnical systems. Leaving aside romantic valuations, repair always involves a certain degree of normalization. Derived from conceptualizations by Foucault, repair as normalization is understood as a particular form of power that, first, recognizes a certain normal state to which the failing system should evolve and, second, develops different strategies to reach it, usually involving the deployment of particular disciplinary devices. The ultimate aim of such practices is usually not only the improvement of the system but centrally the maintenance of a certain kind of power. In order to show the empirical usability of such conceptualization, the article analyzes the case of Transantiago, a thoroughgoing reform of the public transport system of Santiago, Chile. The start of Transantiago in February 2007 was marred by multiple failures, becoming one of the biggest public controversies in the country in recent decades. Given this, several different strategies were developed to repair such failures, understanding them explicitly as normalization. The article analyzes two particular strategies: attempts to change the negative 'public perception' about Transantiago through the use of quantitative indicators and the introduction of an unexpected type of infrastructure to increase the overall speed of the system. Finally, the conclusion analyzes how the conception of repair as normalization can help us better understand the complexities involved in dealing with failing large sociotechnical systems such as Transantiago, pointing to the need to sometimes move beyond repair.


Basic fibroblast growth factor stimulates matrix metalloproteinase-13 via the molecular cross-talk between the mitogen-activated protein kinases and protein kinase Cdelta pathways in human adult articular chondrocytes.
Excessive release of basic fibroblast growth factor (bFGF) during loading and/or injury of the cartilage matrix may contribute to the onset or progression of osteoarthritis. This pathological role may be related to the ability of bFGF to decrease proteoglycan synthesis and to antagonize the activity of anabolic growth factors in cartilage such as insulin-like growth factor-1 and bone morphogenetic protein 7 (BMP7 or OP-1). Matrix metalloproteinase-13 (MMP-13), a catabolic cartilage-degrading enzyme, is dramatically up-regulated by inflammatory cytokines or by fibronectin fragments in articular chondrocytes. In this study, we investigated MMP-13 production by bFGF using human articular chondrocytes. Endogenous concentration of bFGF in synovial fluids collected from arthritis patients and asymptomatic subjects showed a good linear correlation with the endogenous levels of MMP-13. bFGF stimulation of MMP-13 was mediated at the transcriptional level and, at least in part, by stimulation of interleukin-1 production. Also, our findings suggest that bFGF stimulation of MMP-13 required the activation of multiple MAPKs (ERK, p38, and JNK) by bFGF, and more importantly, bFGF activation of protein kinase C (PKC) delta played a key role in the MMP-13 stimulation. Indeed, PKCdelta is the only isoform associated with MMP-13 stimulation among the PKC isoforms tested. PKCdelta controls the bFGF response by regulating multiple MAPK pathways. Our results suggest that PKCdelta activation is a principal rate-limiting event in the bFGF-dependent stimulation of MMP-13 in human adult articular chondrocytes. We propose that deregulation of cross-talk between MAPK and PKCdelta signaling may contribute to the etiology of osteoarthritis in human patients.


Sildenafil promotes eNOS activation and inhibits NADPH oxidase in the transgenic sickle cell mouse penis.
Sickle cell disease (SCD)-associated vasculopathy in the penis is characterized by aberrant nitric oxide and phosphodiesterase (PDE) 5 signaling, and by increased oxidative stress. Preliminary clinical trials show that continuous treatment with PDE5 inhibitor sildenafil unassociated with sexual activity decreases priapic activity in patients with SCD. However, the mechanism of its vasculoprotective effect in the penis remains unclear. We evaluated whether continuous administration of PDE5 inhibitor sildenafil promotes eNOS function at posttranslational levels and decreases superoxide-producing enzyme NADPH oxidase activity in the sickle cell mouse penis. SCD transgenic mice were used as an animal model of SCD. WT mice served as controls. Mice received treatment with the PDE5 inhibitor sildenafil (100 mg/kg/day) or vehicle for 3 weeks. eNOS phosphorylation on Ser-1177 (positive regulatory site), eNOS interactions with heat-shock protein 90 (HSP90) (positive regulator), phosphorylated AKT (upstream mediator of eNOS phosphorylation on Ser-1177), an NADPH oxidase catalytic subunit gp91(phox), and a marker of oxidative stress (4-hydroxy-2-nonenal [HNE]) were measured by Western blot. Effect of continuous sildenafil treatment on eNOS posttranslational activation, NADPH oxidase catalytic subunit, and oxidative stress in the penis of the sickle cell mouse. Continuous treatment with sildenafil reversed (P < 0.05) the abnormalities in protein expressions of P-eNOS (Ser-1177), eNOS/HSP90 interaction, P-AKT, protein expression of gp91(phox), and 4-HNE, in the sickle cell mouse penis. Sildenafil treatment of WT mice did not affect any of these parameters. Our findings that sildenafil enhances eNOS activation and inhibits NADPH oxidase function in the sickle cell mouse penis offers a vasculoprotective molecular basis for the therapeutic effect of sildenafil in the penis in association with SCD.


[Use of indicator of nursing assistance to base qualification program].
Descriptive-exploratory study, aiming to propose a program of qualification for the nursing staff, based on an indicator of healthcare quality related to the newborn's skin integrity during a given period of hospital internment. Data from 121 newborns, collected during their stays at a neonatal unit of a university hospital according to the acquired skin injuries, associated risk factors and injury records in files of the nursing assistance system. 230 skin injuries were identified, with the most frequent types being ecchymosis, perineal erythemas, moniliasis, and, in lower amounts, infiltrations, bruises, erosion, fissures, excoriations, abscesses and impetigo. The results served as the base for the elaboration of a qualification program supported on the principles of the collective planning and development of technical-scientific, ethical-political and socio-educational competences. The development of this study made it evident that it is important to apply indicators of quality as one of the tools to evaluate the management of healthcare provision.


Effect of breakfast timing on the cognitive functions of elementary school students.
To study the effect of breakfast timing on selected cognitive functions of elementary school students. A 2-week randomized control intervention trial. Five elementary schools. The subjects comprised 569 children, 51% of them boys, aged 11 to 13 years; the children were in grades 5 through 6 (17 classes). The subjects lived in different areas and had different socioeconomic backgrounds. Each subject was tested twice, by 2 versions of the Rey Auditory-Verbal Learning Test, 2 alternative forms of the logical memory subtest of the revised Wechsler Memory Scale, and 2 versions of the Benton Visual Retention Test. On the first test, before any nutritional intervention, the subjects were asked to complete a questionnaire about their food intake on the day of testing. Two thirds of the subjects received 200 ml of 3%-fat milk and 30 g of sugared cornflakes for the next 14 days, and all the subjects were reexamined on the 15th day. Scoring on the different tests was compared with baseline scores. After 15 days, children who ate breakfast at school scored notably higher on most of the test modules than did children who ate breakfast at home and children who did not at breakfast. Our results indicate that routinely eating breakfast 2 hours prior to being tested does not improve cognitive functions in 11- to 13-year-old elementary school students, but food supplementation 30 minutes prior to taking a test notably improves scoring. We suggest further studies on the relationship between meal content, feeding time, and scholastic performance.


External Validation of Robust Radiomic Signature to Predict 2-Year Overall Survival in Non-Small-Cell Lung Cancer.
Lung cancer is the second most fatal disease worldwide. In the last few years, radiomics is being explored to develop prediction models for various clinical endpoints in lung cancer. However, the robustness of radiomic features is under question and has been identified as one of the roadblocks in the implementation of a radiomic-based prediction model in the clinic. Many past studies have suggested identifying the robust radiomic feature to develop a prediction model. In our earlier study, we identified robust radiomic features for prediction model development. The objective of this study was to develop and validate the robust radiomic signatures for predicting 2-year overall survival in non-small cell lung cancer (NSCLC). This retrospective study included a cohort of 300 stage I-IV NSCLC patients. Institutional 200 patients' data were included for training and internal validation and 100 patients' data from The Cancer Image Archive (TCIA) open-source image repository for external validation. Radiomic features were extracted from the CT images of both cohorts. The feature selection was performed using hierarchical clustering, a Chi-squared test, and recursive feature elimination (RFE). In total, six prediction models were developed using random forest (RF-Model-O, RF-Model-B), gradient boosting (GB-Model-O, GB-Model-B), and support vector(SV-Model-O, SV-Model-B) classifiers to predict 2-year overall survival (OS) on original data as well as balanced data. Model validation was performed using 10-fold cross-validation, internal validation, and external validation. Using a multistep feature selection method, the overall top 10 features were chosen. On internal validation, the two random forest models (RF-Model-O, RF-Model-B) displayed the highest accuracy; their scores on the original and balanced datasets were 0.81 and 0.77 respectively. During external validation, both the random forest models' accuracy was 0.68. In our study, robust radiomic features showed promising predictive performance to predict 2-year overall survival in NSCLC.


Plasmacytoid dendritic cells in cutaneous sarcoidosis.
While absent from normal skin, plasmacytoid dendritic cells (pDCs) infiltrate the skin in several infectious, inflammatory, and neoplastic entities. In addition to providing anti-viral resistance, pDCs link the innate and adaptive immune responses. Sarcoidosis is an idiopathic multi-system granulomatous disease characterized by epitheliod granulomas. Its underlying immunopathogenesis involves hyperactivity of cell-mediated immune system with involvement of CD4+ T-helper cells of the Th1 subtype. Recently, pDCs have been shown to contribute to other cutaneous granulomatous disorders such as granuloma annulare (GA). Here, we intend to investigate pDC occurrence and activity in cutaneous sarcoidosis. Twenty cutaneous sarcoidosis cases and a comparable group of 20 cases of GA were retrieved from our database and were immunohistochemically tested for pDC occurrence and activity using anti-BDCA-2 and anti-MxA antibodies, respectively. Fifteen cases of cutaneous lupus erythrematosus (LE) were used as a comparison group. A semi-quantitative scoring system was used. pDCs were present in all cutaneous sarcoidosis in peri-vascular and/or peri-adnexal location admixed with lymphocytes. pDC numbers in sarcoidosis were comparable to those in GA, while pDCs were significantly more abundant in LE. MxA expression was mostly patchy in cutaneous sarcoidosis and GA cases, while LE cases showed diffuse and strong MxA expression. In conclusion, we have shown that pDCs are recruited into the skin lesions of sarcoidosis and GA. Despite the diminished type I IFN production demonstrated in our study, the consistent presence of pDCs in all cutaneous sarcoidosis cases speaks in favor of some role of these cells in the pathogenesis of granulomatous disorders. (Sarcoidosis Vasc Diffuse Lung Dis 2018; 35: 55-61).


Psychopathology as a predictor of medical service utilization for youth in residential treatment.
Rising health care costs have led to an emphasis on identifying factors that contribute to medical service utilization. Previous research has suggested an association between youth psychopathology and service utilization; however, prospective studies among high-risk populations are needed. The current study examined youth psychopathology as a predictor of subsequent medical service utilization among a large sample (N = 536) of youth entering residential treatment. Youth psychopathology and medical status were assessed at intake, and medical service utilization was tracked across the duration of the residential placement. Results indicated that higher levels of psychopathology predicted greater youth medical service utilization, even after controlling for the presence of a diagnosed medical condition. Internalizing problems was a significant independent predictor of utilization, but externalizing problems was not. These findings highlight the association between mental health and medical service utilization and suggest that effective behavioral health services may be helpful in reducing costly medical service needs.


Human complex exploration strategies are enriched by noradrenaline-modulated heuristics.
An exploration-exploitation trade-off, the arbitration between sampling a lesser-known against a known rich option, is thought to be solved using computationally demanding exploration algorithms. Given known limitations in human cognitive resources, we hypothesised the presence of additional cheaper strategies. We examined for such heuristics in choice behaviour where we show this involves a value-free random exploration, that ignores all prior knowledge, and a novelty exploration that targets novel options alone. In a double-blind, placebo-controlled drug study, assessing contributions of dopamine (400 mg amisulpride) and noradrenaline (40 mg propranolol), we show that value-free random exploration is attenuated under the influence of propranolol, but not under amisulpride. Our findings demonstrate that humans deploy distinct computationally cheap exploration strategies and that value-free random exploration is under noradrenergic control.


Effects of a chronic l-arginine supplementation on the arginase pathway in aged rats.
While ageing is frequently associated with l-arginine deficiency, clinical and experimental studies provided controversial data on the interest of a chronic l-arginine supplementation with beneficial, no or even deleterious effects. It was hypothesized that these discrepancies might relate to a deviation of l-arginine metabolism towards production of l-ornithine rather than nitric oxide as a result of age-induced increase in arginase activity. This study investigated the effect of ageing on arginase activity/expression in target tissues and determined whether l-arginine supplementation modulated the effect of ageing on arginase activity. Arginase activity and expression were measured in the heart, vessel, brain, lung, kidney and liver in young rats (3-months old) and aged Wistar rats (22-24-months-old) with or without l-arginine supplementation (2.25% in drinking water for 6weeks). Plasma levels of l-arginine and l-ornithine were quantified in order to calculate the plasma l-arginine/l-ornithine ratio, considered as a reflection of arginase activity. Cardiovascular parameters (blood pressure, heart rate) and aortic vascular reactivity were also studied. Ageing dramatically reduced plasma l-arginine and l-arginine/l-ornithine ratio, decreased liver and kidney arginase activities but did not change activities in other tissues. l-Arginine supplementation normalized plasma l-arginine and l-arginine/l-ornithine ratio, improved endothelial function and decreased systolic blood pressure. These effects were associated with decreased arginase activity in aorta along with no change in the other tissues except in the lung in which activity was increased. A strong mismatch was therefore observed between arginase activity and expression in analyzed tissues. The present study reveals that ageing selectively changes arginase activity in clearance tissues, but does not support a role of the arginase pathway in the potential deleterious effect of the l-arginine supplementation in aged patients. Moreover, our data argue against the use of the measurement of plasma l-arginine/l-ornithine ratio to estimate arginase activity in aged patients.


Estrogen-Related Receptor Alpha: An Under-Appreciated Potential Target for the Treatment of Metabolic Diseases.
The estrogen-related receptor alpha (ESRRA) is an orphan nuclear receptor (NR) that significantly influences cellular metabolism. ESRRA is predominantly expressed in metabolically-active tissues and regulates the transcription of metabolic genes, including those involved in mitochondrial turnover and autophagy. Although ESRRA activity is well-characterized in several types of cancer, recent reports suggest that it also has an important role in metabolic diseases. This minireview focuses on the regulation of cellular metabolism and function by ESRRA and its potential as a target for the treatment of metabolic disorders.


Assessment of a Cultural Competency Program in Podiatric Medical Education.
Des Moines University College of Podiatric Medicine and Surgery (CPMS) is implementing a cultural competency program for third-year podiatric medical students. This study assessed the effectiveness of the new educational program on cultural competency at CPMS by comparing pretest and posttest scores of students from the CPMS graduating classes of 2013 and 2014. Students from the class of 2013 completed a 10-week online course on cultural competency, and the class of 2014 students did not. A pretest and posttest survey was used to assess cultural competency. The questions were categorized to assess either knowledge acquisition or attitudinal change. The 2013 students completed the pretest before the course and a posttest after completing the course. Without taking the course, 2014 students completed the same pretest and posttest separated by 10 weeks. A repeated-measures analysis of variance was used to compare the knowledge acquisition scores and attitudinal change scores. The repeated-measures analysis of variance revealed a significant interaction effect of taking the attitudinal change course (F(1,77) = 15.2; P < .001). The course did not show a significant interaction on knowledge acquisition (F(1,77) = 0.72; P > .05). The analysis showed a statistically significant improvement in attitudinal change scores. The study suggests that there needs to be a greater knowledge acquisition component to the cultural competency course at CPMS.


Patient reported differences in dry eye disease between men and women: impact, management, and patient satisfaction.
Dry eye disease affects women twice as often as men, but there is little information on whether dry eye treatments, treatment satisfaction, or the impact of dry eye disease on patients' lives and vision might differ by sex. Questionnaire survey of 4000 participants in the Women's Health Study and the Physicians' Health Studies I and II with a prior report of a diagnosis of DED. Among participants who re-confirmed a diagnosis of dry eye disease, we assessed symptoms, treatments, patient satisfaction and impact of dry eye disease, and analyzed differences between men and women using regression models. The final study population consisted of 1,518 women (mean age 70.7 years) and 581 men (mean age 76.7 years), with a mean reported duration of dry eye disease of 10.5 years and 10.1 years, respectively. The frequency and severity of dry eye disease symptoms were higher among women (each P<0.0001), and women reported a greater impact on everyday activities (P<0.0001). Women were more likely to use artificial tears (P<0.0001) use them more often (P<0.0001), and to use Restasis® (P<0.0001), omega-3 fatty acids (P=0.0006), and have punctal occlusion (P=0.005). Women spent more money per month on dry eye treatments (P<0.0001), but reported greater dissatisfaction with treatment side effects (P=0.001), and the amount of time before treatments started working (P=0.03). These data show that dry eye disease is generally experienced as being more severe among women, having a greater impact on their self-assessed well-being.


Influencing the secretion of myogenic factors from mesenchymal stem cells.
Mounting evidence indicates that the regenerative effect of mesenchymal stem cells in skeletal muscle is related to the secretion of factors that stimulate resident myogenic cells. However, the environmental cues that affect the secreted factors of mesenchymal stem cells are not well understood. A recent publication demonstrated that secretion of factors is dependent on cell substrate, with mesenchymal stem cells grown on laminin providing more pro-myogenic factors than those grown on collagen, and that cellular strain may also play a role. Conditioned media from mesenchymal stem cells grown on laminin and subjected to strain provided the quickest and largest stimulation to myogenic cell proliferation. The influence of cell substrate and mechanical perturbation on mesenchymal stem cells therefore appears key to secretion of factors that support myogenesis.


Episodic and Chronic Migraine in Primary Care.
To inform migraine care model development by assessing differences between patients with chronic migraine (CM) and episodic migraine (EM) in the current state of treatment, disability, patient satisfaction, and quality improvement opportunities. Efficient and focused use of scarce resources will be needed to address challenges within large populations of migraine patients. We deployed a cross-sectional survey study of randomly selected migraine patients within a community primary care practice. There were 516 survey respondents (516/1804 [30%] response rate). CM patients were more likely than EM patients to report care from a neurologist (76/110 [69%] vs 229/406 [56%]; P = .0026), and higher disability according to the Migraine Disability Assessment and Headache Impact Test - 6 questionnaires (P < .0001). CM patients were less likely than EM patients to report overall satisfaction with care (16/110 [38%] vs 156/406 [66%], P = .0002), satisfaction with access to care (17/110 [33%] vs 176/406 [68%], P < .0001), and advice they needed (16/110 [31%] vs 160/406 [62%], P < .0001). Most patients with migraine had been offered triptan medications 377/516 (78%). Overall, 156/516 (31%) of individuals were currently taking any medication for migraine prevention, and 208/516 (40%) including botulinum toxin injections. CM patients were more likely to be taking preventive medication (39/110 [36%] vs 117/406 [29%], P = .0191) and report familiarity with the diagnosis of medication-overuse headache than patients with EM (80/110 [81%] vs 256/406 [69%], P = .0178). We observed differences between patients with chronic and EM and expected care delivery improvement opportunities for migraine patients in primary care. CM patients report higher levels of disability and less satisfaction with access to perceived needed medical advice and care. These findings support the need to further develop and study novel care models to efficiently and effectively deliver high-quality care and expertise in limited supply to a diverse migraine population.


Passive Sensing of Health Outcomes Through Smartphones: Systematic Review of Current Solutions and Possible Limitations.
Technological advancements, together with the decrease in both price and size of a large variety of sensors, has expanded the role and capabilities of regular mobile phones, turning them into powerful yet ubiquitous monitoring systems. At present, smartphones have the potential to continuously collect information about the users, monitor their activities and behaviors in real time, and provide them with feedback and recommendations. This systematic review aimed to identify recent scientific studies that explored the passive use of smartphones for generating health- and well-being-related outcomes. In addition, it explores users' engagement and possible challenges in using such self-monitoring systems. A systematic review was conducted, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, to identify recent publications that explore the use of smartphones as ubiquitous health monitoring systems. We ran reproducible search queries on PubMed, IEEE Xplore, ACM Digital Library, and Scopus online databases and aimed to find answers to the following questions: (1) What is the study focus of the selected papers? (2) What smartphone sensing technologies and data are used to gather health-related input? (3) How are the developed systems validated? and (4) What are the limitations and challenges when using such sensing systems? Our bibliographic research returned 7404 unique publications. Of these, 118 met the predefined inclusion criteria, which considered publication dates from 2014 onward, English language, and relevance for the topic of this review. The selected papers highlight that smartphones are already being used in multiple health-related scenarios. Of those, physical activity (29.6%; 35/118) and mental health (27.9; 33/118) are 2 of the most studied applications. Accelerometers (57.7%; 67/118) and global positioning systems (GPS; 40.6%; 48/118) are 2 of the most used sensors in smartphones for collecting data from which the health status or well-being of its users can be inferred. One relevant outcome of this systematic review is that although smartphones present many advantages for the passive monitoring of users' health and well-being, there is a lack of correlation between smartphone-generated outcomes and clinical knowledge. Moreover, user engagement and motivation are not always modeled as prerequisites, which directly affects user adherence and full validation of such systems.


Chronic insomnia is associated with a shift of interleukin-6 and tumor necrosis factor secretion from nighttime to daytime.
Chronic insomnia, by far the most commonly encountered sleep disorder in medical practice, is characterized by difficulty falling or staying asleep at night and increased fatigue during the day. Interleukin-6 (IL-6) and tumor necrosis factor (TNF) are fatigue-inducing cytokines, and the daytime secretion of IL-6 is negatively influenced by the quantity and quality of the previous night's sleep. We hypothesize that the poor quality of insomniacs' sleep is associated with a hypersecretion of these 2 cytokines during the daytime, which, in turn, correlates with the fatigue experienced by these patients. Eleven young insomniacs (6 men and 5 women) and 11 (8 men and 3 women) age- and body mass index (BMI)-matched healthy controls participated in the study. Subjects were recorded in the sleep laboratory for 4 consecutive nights and serial 24-hour plasma measures of IL-6 and TNF were obtained during the 4th day. Insomniacs compared to controls slept poorly (sleep latency and wake were increased, whereas percentage sleep time was decreased during baseline nights, all P <.05). The mean 24-hour IL-6 and TNF secretions were not different between insomniacs and controls. However, the difference in the change (increase) of IL-6 plasma levels from midafternoon (2 PM) to evening (9 PM) between insomniacs and controls was significant (P <.01). Furthermore, cosinor analysis showed a significant shift of the major peak of IL-6 secretion from nighttime (4 AM) to evening (7 PM) in insomniacs compared to controls (P <.05). Also, while TNF secretion in controls showed a distinct circadian rhythm with a peak close and prior to the offset of sleep (P <.05), such a rhythm was not present in insomniacs. Finally, daytime secretion of TNF in insomniacs was characterized by a regular rhythm of 4 hours (P <.05); such a distinct periodicity was not present in controls. We conclude that chronic insomnia is associated with a shift of IL-6 and TNF secretion from nighttime to daytime, which may explain the daytime fatigue and performance decrements associated with this disorder. The daytime shift of IL-6 and TNF secretion, combined with a 24-hour hypersecretion of cortisol, an arousal hormone, may explain the insomniacs' daytime fatigue and difficulty falling asleep.


Implementation of a guideline-based clinical pathway of care to improve health outcomes following whiplash injury (Whiplash ImPaCT): protocol of a randomised, controlled trial.
Whiplash-associated disorders (WAD) are a huge worldwide health and economic burden. The propensity towards developing into chronic, disabling conditions drives the rise in health and economic costs associated with treatment, productivity loss and compulsory third party insurance claims. Current treatments fail to address the well-documented heterogeneity of WAD and often result in poor outcomes. A novel approach is to evaluate whether the care provided according to the estimated risk of poor prognosis improves health outcomes while remaining cost-effective. (1) Does a guideline-based clinical pathway of care improve health outcomes after whiplash injury compared to usual care? (2) Does risk of recovery have a differential effect on health outcomes for the clinical pathway of care? (3) Is the clinical pathway of care intervention cost-effective? (4) What are the variations in professional practice between usual care and the clinical pathway of care? Multi-centre, randomised, controlled trial conducted over two Australian states: Queensland and New South Wales. 236 people with WAD (grade I-III, within 6 weeks of injury) and their primary healthcare providers. A clinical pathway of care, with care matched to the predicted risk of poor recovery. Participants at low risk of ongoing pain and disability (hence, predicted to fully recover) will receive up to three sessions of guideline-based advice and exercise with their primary healthcare provider. Participants at medium/high risk of developing ongoing pain and disability will be referred to a specialist (defined as a practitioner with expertise in whiplash) who will conduct a more in-depth physical and psychological assessment. As a result, the specialist will liaise with the original primary healthcare provider and determine one of three further pathways of care. Usual care provided by the primary healthcare provider that is based on clinical judgment. Primary (global rating of change and neck-related disability) and secondary (self-efficacy, pain intensity, general health and disability and psychological health) outcomes will be collected using validated scales. Direct (eg, professional care, transportation costs, time spent for care, co-payments) and indirect (eg, lost economic productivity) costs will be obtained through an electronic cost diary. Health and cost outcomes will be assessed at baseline, 3, 6 and 12 months after randomisation. Professional practice outcomes will be evaluated through questionnaires completed by healthcare providers and their patients at 3 months. Potential participants (patients) will be identified through emergency departments, primary health clinics and advertisements. Eligible participants will complete baseline assessments and will be categorised into low or medium/high risk of poor recovery using a clinical prediction rule. After this assessment, participants will be randomly allocated to either a control group (n=118) or intervention group (n=118), stratified by risk subgroup and treatment site. The participants' nominated primary healthcare providers will be informed of their involvement in the trial. Consent will be obtained from the primary healthcare providers to participate and to obtain information about professional practice. Participants in the intervention group will additionally have access to an interactive website that provides information about whiplash and recovery relative to their risk category. Analysis will be conducted on an intention-to-treat basis. Outcomes will be analysed independently through cross-sectional analyses using generalised linear models methods, with an appropriate link function, to test for an intervention effect, adjusted for the baseline values. The risk category will be tested for its association with treatment effect by adding risk group to the regression equation. Cost-effectiveness will be calculated using utility weights and the resulting measure will be cost per quality-adjusted life year (QALY) saved. Professional practice outcomes will be analysed using descriptive statistics. This research is significant as it will be the first study to address the heterogeneity of whiplash by implementing a clinical pathway of care that matches evidence-based interventions to projected risk of poor recovery. The results of this trial have the potential to change clinical practice for WAD, thereby maximising treatment effects, improving patient outcomes, reducing costs and maintaining the compulsory third party system.


Melatonin and oral cavity.
While initially the oral cavity was considered to be mainly a source of various bacteria, their toxins and antigens, recent studies showed that it may also be a location of oxidative stress and periodontal inflammation. Accordingly, this paper focuses on the involvement of melatonin in oxidative stress diseases of oral cavity as well as on potential therapeutic implications of melatonin in dental disorders. Melatonin has immunomodulatory and antioxidant activities, stimulates the proliferation of collagen and osseous tissue, and acts as a protector against cellular degeneration associated with aging and toxin exposure. Arising out of its antioxidant actions, melatonin protects against inflammatory processes and cellular damage caused by the toxic derivates of oxygen. As a result of these actions, melatonin may be useful as a coadjuvant in the treatment of certain conditions of the oral cavity. However, the most important effect of melatonin seems to result from its potent antioxidant, immunomodulatory, protective, and anticancer properties. Thus, melatonin could be used therapeutically for instance, locally, in the oral cavity damage of mechanical, bacterial, fungal, or viral origin, in postsurgical wounds caused by tooth extractions and other oral surgeries. Additionally, it can help bone formation in various autoimmunological disorders such as Sjorgen syndrome, in periodontal diseases, in toxic effects of dental materials, in dental implants, and in oral cancers.


Repair of UV-induced pyrimidine dimers in Drosophila melanogaster cells in vitro.
Tissue culture cells of Drosophila melanogaster were given various doses of ultraviolet light. The results indicate that Drosophila cells do have a dark-repair excision mechanism which is not sensitive to caffeine. Pyrimidine dimers were destroyed by photoreactivating illumination in these cells and this destruction probably represents monomerization of the pyrimidine dimers.


Amyloid peptide pores and the beta sheet conformation.
Over 20 clinical syndromes have been described as amyloid diseases. Pathologically, these illnesses are characterized by the deposition in various tissues of amorphous, Congo red stainingdeposits, referred to as amyloid. Under polarizing light microscopy, these deposits exhibit characteristic green birefringence. X-ray diffraction reveals cross-beta structure of extended amyloid fibrils. Although there is always a major protein in amyloid deposits, the predominant protein differs in each ofthe clinical syndromes. All the proteins exhibit the characteristic nonnative beta-sheet state. These proteins aggregate spontaneously into extended fibrils and precipitate out of solution. At least a dozen of these peptides have been demonstrated to be capable of channel formation in lipid bilayers and it has been proposed that this represents a pathogenic mechanism. Remarkably, the channels formed by these various peptides exhibit a number of common properties including irreversible, spontaneous insertion into membranes, production oflarge, heterogeneous single-channel conductances, relatively poor ion selectivity, inhibition of channel formation by Congo red and related dyes and blockade of inserted channels by zinc. In vivo amyloid peptides have been shown to disrupt intracellular calcium regulation, plasma membrane potential, mitochondrial membrane potential and function and long-term potentiation in neurons. Amyloid peptides also cause cytotoxicity. Formation of the beta sheet conformation from native protein structures can be induced by high protein concentrations, metal binding, acidic pH, amino acid mutation and interaction with lipid membranes. Most amyloid peptides interact strongly with membranes and this interaction is enhanced by conditions which favor beta-sheet formation. Formation of pores in these illnesses appears to be a spontaneous process and available evidence suggests several steps are critical. First, destabilization of the native structure and formation of the beta-sheet conformation must occur. This may occur in solution or may be facilitated by contact with lipid membranes. Oligomerization of the amyloid protein is then mediated by the beta strands. Amyloid monomers and extended fibrils appear to have little potential for toxicity whereas there is much evidence implicating amyloid oligomers of intermediate size in the pathogenesis of amyloid disease. Insertion of the oligomer appears to take place spontaneously although there may be a contribution of acidic pH and/or membrane potential. Very little is known about the structure of amyloid pores, but given that the amyloid peptides must acquire beta-sheet conformation to aggregate and polymerize, it has been hypothesized that amyloid pores may in fact be beta-sheet barrels similar to the pores formed by alpha-latrotoxin, Staphylococcal alpha-hemolysin, anthrax toxin and clostridial perfringolysin.


Age-related changes in refractive index distribution and power of the human lens as measured by magnetic resonance micro-imaging in vitro.
We report a new technique for non-invasively mapping the refractive index distribution through the eye lens using magnetic resonance micro-imaging. The technique is applied to map the refractive index distribution throughout the sagittal plane of 18 human eye lenses ranging in age from 14 to 82 years in vitro. The results are compared with standard models for the human eye lens. They confirm that the refractive index distribution, when plotted as a function of normalised lens radius, is a function of lens age and differs both between the equatorial and axial directions and between the anterior and posterior halves of the optical axis. The refractive index of the lens nucleus exhibits a significant reduction with age amounting to 3.4+/-0.6 x 10(-4) years(-1). The contribution of the gradient index (GRIN) to the lens power decreases by 0.286+/-0.067 D/year, accounting almost entirely for the estimated overall change in lens power with age for these lenses, which were probably in their most accommodated state. The results provide experimental verification of hypothesised changes in the GRIN that have previously been invoked as contributing to presbyopia and support the hypothesis that changes in the GRIN are sufficient to offset effects of increasing curvature of human lenses with age in their unaccommodated state.


Acceleration of the ventricular response during atrial fibrillation in the Wolff-Parkinson-White syndrome after verapamil.
We examined the electrophysiologic effects of verapamil in eight patients with the Wolff-Parkinson-White syndrome. Verapamil shortened the antegrade effective refractory period of the accessory pathway in three patients and abbreviated the shortest cycle length with 1:1 conduction over the accessory pathway in two patients. More significantly, verapamil decreased the shortest RR interval between preexcited ventricular complexes during atrial fibrillation (279 +/- 20 msec vs 236 +/- 18 msec, mean +/- SEM; p less than 0.01). After verapamil, two patients required cardioversion for hemodynamic deterioration after acceleration of the ventricular response during atrial fibrillation. In the four patients with predominantly preexcited ventricular complexes during atrial fibrillation the ventricular rate accelerated after verapamil, whereas in patients with predominantly normal ventricular complexes, the average ventricular rate decreased or did not change after verapamil. Verapamil may result in significant acceleration of ventricular response during atrial fibrillation in the Wolff-Parkinson-White syndrome. The safety of verapamil in individual patients with the Wolff-Parkinson-White syndrome should be established by electrophysiologic testing before its use.


HSF1, a versatile factor in tumorogenesis.
HSF1 is an essential factor in the acute response to proteotoxic stress, in which it causes rapid transcription of heat shock protein (HSP) genes in order to permit survival of cells and restoration of global protein quality. In addition to this property however, HSF1 is chronically activated or overexpressed in a wide range of cancers and is essential for multiple pathways of malignant transformation. Studies in recent years indicate a remarkable pleiotropy in the properties of HSF1 in cancer. HSF1 functions as a transcription factor for HSP genes, reminiscent of its role in the stress response, and the resultant elevation in HSP levels leads to a reduction in programmed cell death and senescence and permits overexpression of mutated oncogenic protein clients required to fuel tumor growth. In addition HSF1 plays a role as a signal modulator, stimulating kinase activity, regulating energy metabolism and permitting the development of polyploidy in cancer cells. HSF1 can also function as an inhibitor of transcription and in cooperation with NuRD family factors can repress genes that oppose metastasis. Inhibitors of HSF1 are undergoing selection and future studies may see the testing of HSF1 as a target in cancer therapy.


Vitamin D status, liver enzymes, and incident liver disease and mortality: a general population study.
Vitamin D deficiency is common among patients with liver diseases. Both cholestatic and non-cholestatic liver diseases can cause vitamin D deficiency. Whether vitamin D status can also affect liver function is poorly understood. To investigate the association between vitamin D status, liver enzymes, and incident liver disease, we included a total of 2,649 individuals from the Monica10 study conducted in 1993-1994. Vitamin D status as assessed by serum 25-hydroxyvitamin, serum alanine transaminase (ALT), aspartate transaminase (AST), and gamma glutamyl transferase (GGT) were measured at baseline. Information on fatal and non-fatal liver disease was obtained from the Danish National Patient Register and The Danish Registry of Causes of Death, respectively. Median follow-up time was 16.5 years, and there were 62 incident cases of fatal and non-fatal liver disease. Multivariable Cox regression analyses with age as underlying time axis and delayed entry showed a statistically significant inverse association between vitamin D status and incident liver disease with a hazard ratio = 0.88 (95 % confidence interval 0.79-0.99) per 10 nmol/l higher vitamin D status at baseline (adjusted for gender, season, alcohol consumption, smoking, physical activity, dietary habits, education, body mass index, and ALT). The risk of having a high level of ALT, AST, or GGT tended to be higher for lower vitamin D levels, although not statistically significant. In this general population study, vitamin D status was inversely associated with incident liver disease. Further studies are needed to determine whether patients in risk of developing impaired liver function should be screened for vitamin D deficiency for preventive purposes.