Systematic Functional Characterization of Candidate Causal Genes for Type 2 Diabetes Risk Variants.
Most genetic association signals for type 2 diabetes risk are located in noncoding regions of the genome, hindering translation into molecular mechanisms. Physiological studies have shown a majority of disease-associated variants to exert their effects through pancreatic islet dysfunction. Systematically characterizing the role of regional transcripts in β-cell function could identify the underlying disease-causing genes, but large-scale studies in human cellular models have previously been impractical. We developed a robust and scalable strategy based on arrayed gene silencing in the human β-cell line EndoC-βH1. In a screen of 300 positional candidates selected from 75 type 2 diabetes regions, each gene was assayed for effects on multiple disease-relevant phenotypes, including insulin secretion and cellular proliferation. We identified a total of 45 genes involved in β-cell function, pointing to possible causal mechanisms at 37 disease-associated loci. The results showed a strong enrichment for genes implicated in monogenic diabetes. Selected effects were validated in a follow-up study, including several genes (ARL15, ZMIZ1, and THADA) with previously unknown or poorly described roles in β-cell biology. We have demonstrated the feasibility of systematic functional screening in a human β-cell model and successfully prioritized plausible disease-causing genes at more than half of the regions investigated.


Measurements of the phase shift on reflection for low-order infrared Fabry-Perot interferometer dielectric stack mirrors.
A simple technique based on a Fizeau interferometer to measure the absolute phase shift on reflection for a Fabry-Perot interferometer dielectric stack mirror is described. Excellent agreement between the measured and predicted phase shift on reflection was found. Also described are the salient features of low-order Fabry-Perot interferometers and the demonstration of a near ideal low-order (1-10) Fabry-Perot interferometer through minimizing the phase dispersion on reflection of the dielectric stack. This near ideal performance of a low-order Fabry-Perot interferometer should enable several applications such as compact spectral imagers for solid and gas detection. The large free spectral range of such systems combined with an active control system will also allow simple interactive tuning of wavelength agile laser sources such as CO(2) lasers, external cavity diode lasers, and optical parametric oscillators.


Evidence that the cAMP pathway controls emergence of both primary and appressorial germ tubes of barley powdery mildew.
Development of conidia of barley powdery mildew involves the formation of a primary germ tube (PGT), an appressorial germ tube (AGT), and an appressorium. Previously, it was found that cyclic AMP (cAMP) was involved in these developmental processes. Comparison of development on the host surface with two types of cellulose membrane revealed that frequency of PGT emergence was surface independent. On one type of cellulose, where the frequencies of both AGT and appressorial differentiation were similar to that on the host surface, cAMP levels and protein kinase A (PKA) activities had a biphasic pattern with peaks at 15 min and 4 h after inoculation (prior to PGT and AGT emergence, respectively). The effect of manipulating cAMP levels was tested on another type of cellulose membrane, which stimulated a lower degree of AGT and appressorial formation than the host surface. Cholera toxin and forskolin, activators of adenylyl cyclase, significantly increased PGT emergence, but cAMP did not. Cholera toxin, forskolin, and cAMP increased the frequency of AGT and appressorial formation, but in a time-dependent manner.


Enhancement of light extraction efficiency of organic light emitting diodes using nanostructured indium tin oxide.
Improved outcoupling efficiency of organic light emitting diodes (OLEDs) is demonstrated by incorporating a nanostructured indium tin oxide (NSITO) film between a conducting anode and a glass substrate. NSITO film was fabricated using rf-sputtering at oblique angle (85°). Significant reduction in refractive index and improved transmission of NSITO film was observed. OLEDs were then fabricated onto NSITO film to extract the ITO-glass waveguided modes. Extraction efficiency was enhanced by 80% without introducing any detrimental effects to operating voltage, current density, and angular invariance of emission spectra of OLEDs.


Complex two-gene modulation of lung disease severity in children with cystic fibrosis.
Although cystic fibrosis (CF) is a monogenic disease, its clinical manifestations are influenced in a complex manner. Severity of lung disease, the main cause of mortality among CF patients, is likely modulated by several genes. The mannose-binding lectin 2 (MBL2) gene encodes an innate immune response protein and has been implicated as a pulmonary modifier in CF. However, reports have been conflicting, and interactions with other modifiers have not been investigated. We therefore evaluated the association of MBL2 with CF pulmonary phenotype in a cohort of 1,019 Canadian pediatric CF patients. MBL2 genotypes were combined into low-, intermediate-, and high-expression groups based on MBL2 levels in plasma. Analysis of age at first infection with Pseudomonas aeruginosa demonstrated that MBL2 deficiency was significantly associated with earlier onset of infection. This MBL2 effect was amplified in patients with high-producing genotypes of transforming growth factor beta 1 (TGFB1). Similarly, MBL2 deficiency was associated with more rapid decline of pulmonary function, most significantly in those carrying the high-producing TGFB1 genotype. These findings provide evidence of gene-gene interaction in the pathogenesis of CF lung disease, whereby high TGF-beta1 production enhances the modulatory effect of MBL2 on the age of first bacterial infection and the rate of decline of pulmonary function.


Interleukin-8 induction by Helicobacter pylori in gastric epithelial cells is dependent on apurinic/apyrimidinic endonuclease-1/redox factor-1.
Helicobacter pylori infection causes inflammation and increases the expression of IL-8 in human gastric epithelial cells. H. pylori activates NF-kappaB and AP-1, essential transcriptional factors in H. pylori-induced IL-8 gene transcription. Although colonization creates a local oxidative stress, the molecular basis for the transition from infection to the expression of redox-sensitive cytokine genes is unknown. We recently reported that the expression of apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE-1/Ref-1), which repairs oxidative DNA damage and reductively activates transcription factors including AP-1 and NF-kappaB, is increased in human gastric epithelia during H. pylori infection. In this study, we examine whether APE-1/Ref-1 functions in the modulation of IL-8 gene expression in H. pylori-infected human gastric epithelial cells. Small interfering RNA-mediated silencing of APE-1/Ref-1 inhibited basal and H. pylori-induced AP-1 and NF-kappaB DNA-binding activity without affecting the nuclear translocation of these transcription factors and also reduced H. pylori-induced IL-8 mRNA and protein. In contrast, overexpression of APE-1/Ref-1 enhanced basal and H. pylori-induced IL-8 gene transcription, and the relative involvement of AP-1 in inducible IL-8 promoter activity was greater in APE-1/Ref-1 overexpressing cells than in cells with basal levels of APE-1/Ref-1. APE-1/Ref-1 inhibition also reduced other H. pylori-induced chemokine expression. By implicating APE-1/Ref-1 as an important regulator of gastric epithelial responses to H. pylori infection, these data elucidate a novel mechanism controlling transcription and gene expression in bacterial pathogenesis.


Extensive characterization of NF-κB binding uncovers non-canonical motifs and advances the interpretation of genetic functional traits.
Genetic studies have provided ample evidence of the influence of non-coding DNA polymorphisms on trait variance, particularly those occurring within transcription factor binding sites. Protein binding microarrays and other platforms that can map these sites with great precision have enhanced our understanding of how a single nucleotide polymorphism can alter binding potential within an in vitro setting, allowing for greater predictive capability of its effect on a transcription factor binding site. We have used protein binding microarrays and electrophoretic mobility shift assay-sequencing (EMSA-Seq), a deep sequencing based method we developed to analyze nine distinct human NF-κB dimers. This family of transcription factors is one of the most extensively studied, but our understanding of its DNA binding preferences has been limited to the originally described consensus motif, GGRRNNYYCC. We highlight differences between NF-κB family members and also put under the spotlight non-canonical motifs that have so far received little attention. We utilize our data to interpret the binding of transcription factors between individuals across 1,405 genomic regions laden with single nucleotide polymorphisms. We also associated binding correlations made using our data with risk alleles of disease and demonstrate its utility as a tool for functional studies of single nucleotide polymorphisms in regulatory regions. NF-κB dimers bind specifically to non-canonical motifs and these can be found within genomic regions in which a canonical motif is not evident. Binding affinity data generated with these different motifs can be used in conjunction with data from chromatin immunoprecipitation-sequencing (ChIP-Seq) to enable allele-specific analyses of expression and transcription factor-DNA interactions on a genome-wide scale.


Current status of health index in Tehran: A multidimensional approach.
Background: Health is an essential component of human rights and the rights are interdependent, indivisible, and correlated. The present study aimed at codifying a multidimensional health index according to multistage index development and describing the status of this index in 22 municipal districts of Tehran. Methods: This study was conducted using the data collected in the second round of Urban HEART Project of Tehran (2012-2013). The sample size was 34 700. To develop a multidimensional health index (MDHI), the nine steps of the Organization for Economic Cooperation and Development (OECD) were followed, from codifying theoretical framework to introducing the index. Results: According to the constructed MDHI, the districts no. 13, 10, 17, 1, 3, 4, and 22 had the best status and the district no. 8 the worst status. With respect to physical health, the districts no. 13, 17, 1, 3, 10, and 18 had the best status and the district no. 8 the worst. Concerning mental health, the districts no. 3, 6, 1, and 10 had the best status and the districts no. 8 and 12 the worst status. With respect to social health, the districts no. 10, 22, and 21 had the best status and the districts no. 6, 7, 12, and 14 the worst status. The analysis of sensitivity indicated that the MDHI was more sensitive towards physical health. Based on the mean, minimum, and maximum scores on each indicator of the questionnaires, the physical, mental, social, and MDHI status of Tehran residents (2012-2013) was high-medium, medium, low-medium, and high-medium, respectively. Conclusion: The right to health should be widely investigated, as it is a primary principle needed for sustainable development, which can be accomplished when the attitudes of different organizations towards the health construct are multidimensional rather than unidimensional.


Time to Refocus Assessment of Vision in Older Adults? Contrast Sensitivity but Not Visual Acuity Is Associated With Gait in Older Adults.
The relationship between measures of visual function and gait related risk factors for falls is unclear. In this study, we examine the relationship between visual function (visual acuity [VA] and contrast sensitivity [CS] at multiple spatial frequencies) and quantitative spatiotemporal gait, using a large, nationally representative sample of community dwelling older adults. Participants aged 50 and over were recruited as part of The Irish Longitudinal Study on Ageing (TILDA). VA was measured with the LogMAR chart according to the Early Treatment of Diabetic Retinopathy Study protocol. CS was measured at five spatial frequencies ranging 1.5 to 18 cycles per degree (cpd) using the Functional Acuity Contrast Test. Gait speed, cadence, and stride length were measured using the GAITRite system. Multivariate analysis examined associations between gait and visual performance parameters adjusting for socioeconomic, physical, cognitive, and mental health covariates. Data from 4,678 participants were analyzed (age 61.7 ± 8.3 years, 54.1% woman). Poorer CS at 1.5 cpd and 3.0 cpd (low spatial frequency) was independently associated with decreased stride length (CS at 1.5 cpd: β = .031; p = .001 and CS at 3.0 cpd: β = .020; p = .001) but not cadence or gait speed. There was no evidence of an association between VA and any of the gait variables considered (p > .05). Reduced CS, at low spatial frequencies, is independently associated with shorter stride length, while VA is not associated with any gait measures. This evidence suggests that it may be necessary to consider refocus of the assessment of vision to include the most appropriate measures.


Computer automated detection of head orientation for prevention of wrong-side treatment errors.
A medical error can occur when a patient is positioned in a medical imaging device such as an MRI scanner if information regarding their orientation is improperly entered into the device control software. If such an error is not detected and corrected, the erroneous orientation data will be stored in the image header information and will propagate with the images throughout the medical enterprise. Presented here is a fully automated algorithm for computing patient head orientation from the image data and detecting errors in image orientation labeling. This will enable errors in orientation labeling to be corrected at their source when they occur, thus preventing later medical treatment errors related to laterality.


Environmental improvements brought by the legal interventions in the homes of poorly controlled inner-city adult asthmatic patients: a proof-of-concept study.
Domestic contamination with mold, cockroaches, rodents, and dust worsens asthma severity. This violates warranty of habitability laws in most of the states, but patients often find it beyond their means to remedy their housing situation. We aimed to study the effect of a medical-legal collaborative intervention to force landlords into providing better living conditions for patients with poorly controlled asthma. We retrospectively studied charts of adult patients aged 18 years or older with poorly controlled asthma (moderate or severe persistent) despite maximum medical therapy. Additionally, patients had self-reported domestic allergen exposures such as mold, cockroaches, mice or rats, and dust. The patients received legal assistance to improve their domestic environments, including fixing leaks, exterminating pests, or providing a different apartment. Post-intervention change in peak expiratory flow rate (PEFR), asthma severity class, medications, emergency department (ED) visits, hospitalizations, and requirement for systemic steroids for symptom control was assessed. Data were available for 12 patients (9-12 months pre-intervention and 6-12 months post-intervention). Analysis of paired data revealed that mean PEFR rose by 38.6 LPM (95% CI: 9.9-67.3; p = .014). The number of ED visits and hospital admissions declined from 22 ED visits and 11 admissions to 2 ED visits and 1 admission (91% reduction), respectively. Of the 11 patients requiring systemic steroids, only three required these post-intervention. All patients had reductions in the dose and/or number of medications. During post-intervention, 11 (91.7%) patients dropped ≥2 classes in asthma severity. Medical-legal collaboration is highly effective in improving the control of inner-city asthmatics by effecting improvements in the domestic environment.


Endometriosis and ovarian cancer: potential benefits and harms of screening and risk-reducing surgery.
Although endometriosis is well recognized as a benign gynecologic condition, its association with ovarian cancer (OVCA) has frequently been reported. Review articles on this topic are voluminous, yet there seems to be no consensus as to whether endometriosis is truly a precursor of OVCA and whether any screening or risk-reducing surgery should be instituted, on the basis of our current knowledge. In this review, published data are compiled and critically appraised. Through this critical appraisal, it seems clear that the strongest evidence seems to come from prevalence data. This type of data also suggests a reduced risk of certain histotypes (mainly type II) of OVCA in women with endometriosis. This may explain the rather moderate increase in risk as shown in epidemiologic studies. Even with this moderate increase in OVCA risk, caution should be exercised because of apparent bias in favor of publication of positive results, extensive heterogeneities among prevalence estimates, and inverse relationship between estimates and sizes of the studies. Many molecular studies are conflicting, and earlier studies showing molecular aberrations involved in genomic instability and mutation that enable malignant transformation are not replicated in later studies. Given the low incidence of OVCA and the rather moderate increase in risk of mostly type I tumors, screening seems to be ill-advised, and risk-reducing surgery such as salpingectomy with or without oophorectomy does not seem to yield any substantial benefit to women with endometriosis.


A class of learning algorithms for principal component analysis and minor component analysis.
Principal component analysis (PCA) and minor component analysis (MCA) are a powerful methodology for a wide variety of applications such as pattern recognition and signal processing. In this paper, we first propose a differential equation for the generalized eigenvalue problem.We prove that the stable points of this differential equation are the eigenvectors corresponding to the largest eigenvalue. Based on this generalized differential equation, a class of PCA and MCA learning algorithms can be obtained. We demonstrate that many existing PCA and MCA learning algorithms are special cases of this class, and this class includes some new and simpler MCA learning algorithms. Our results show that all the learning algorithms of this class have the same order of convergence speed, and they are robust to implementation error.


Effect of Biofermentation with Taxifolin on Physicochemical and Microbiological Properties of Cold-Smoked Pork Sausages.
The aim of this work is to evaluate the effect of taxifolin on the physicochemical and microbiological properties of cold-smoked pork sausages produced using different commercial starter cultures with Leuconostoc carnosum and with a mixture of Pediococcus pentosaceus and Staphylococcus xylosus. Ultra performance liquid chromatography analysis demonstrated that after 181 days of storage total taxifolin content was the highest in samples with taxifolin and L. carnosum (60%), compared to the first day of storage. The sausages with taxifolin and the mixture of P. pentosaceus and S. xylosus (56%) followed next. Taxifolin improved the hygienic quality of sausages without significant effect on the growth of lactic acid bacteria. The accumulation of biogenic amines, including histamine and putrescine, was more effectively reduced in sausages inoculated with the taxifolin and P. pentosaceus and S. xylosus mixture. Using this mixture, the rate of lipolysis and lipid oxidation were effectively slowed down. Samples with taxifolin and L. carnosum showed the highest free radical scavenging activity on the first day of the study ((77.4±1.3) %) (p<0.05 in all samples). Mixtures containing taxifolin and starter cultures bound free radicals better than taxifolin alone. The colour parameters (L*, a* and b*) of preparations and final products were significantly influenced by taxifolin and starter cultures and storage time (p<0.05 in all samples).


Clustering of vertically constrained passive particles in homogeneous isotropic turbulence.
We analyze the dynamics of small particles vertically confined, by means of a linear restoring force, to move within a horizontal fluid slab in a three-dimensional (3D) homogeneous isotropic turbulent velocity field. The model that we introduce and study is possibly the simplest description for the dynamics of small aquatic organisms that, due to swimming, active regulation of their buoyancy, or any other mechanism, maintain themselves in a shallow horizontal layer below the free surface of oceans or lakes. By varying the strength of the restoring force, we are able to control the thickness of the fluid slab in which the particles can move. This allows us to analyze the statistical features of the system over a wide range of conditions going from a fully 3D incompressible flow (corresponding to the case of no confinement) to the extremely confined case corresponding to a two-dimensional slice. The background 3D turbulent velocity field is evolved by means of fully resolved direct numerical simulations. Whenever some level of vertical confinement is present, the particle trajectories deviate from that of fluid tracers and the particles experience an effectively compressible velocity field. Here, we have quantified the compressibility, the preferential concentration of the particles, and the correlation dimension by changing the strength of the restoring force. The main result is that there exists a particular value of the force constant, corresponding to a mean slab depth approximately equal to a few times the Kolmogorov length scale η, that maximizes the clustering of the particles.


Brain-derived neurotrophic factor, a new soluble biomarker for malignant pleural mesothelioma involved in angiogenesis.
Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer related to asbestos exposure. The discovery of soluble biomarkers with diagnostic/prognostic and/or therapeutic properties would improve therapeutic care of MPM patients. Currently, soluble biomarkers described present weaknesses preventing their use in clinic. This study aimed at evaluating brain-derived neurotrophic factor (BDNF), we previously identified using transcriptomic approach, in MPM. We observed that high BDNF expression, at the mRNA level in tumors or at the protein level in pleural effusions (PE), was a specific hallmark of MPM samples. This protein presented significant but limited diagnostic properties (area under the curve (AUC) = 0.6972, p < 0.0001). Interestingly, high BDNF gene expression and PE concentration were predictive of shorter MPM patient survival (13.0 vs 8.3 months, p < 0.0001, in PE). Finally, BDNF did not affect MPM cell oncogenic properties but was implicated in PE-induced angiogenesis. In conclusion, BDNF appears to be a new interesting biomarker for MPM and could also be a new therapeutic target regarding its implication in angiogenesis.


Norwegian translation, cultural adaption and testing of the Person-centred Practice Inventory - Staff (PCPI-S).
Person-centred health care has widespread recognition, but there are few instruments aimed at measuring the provision of person-centred practice among health care professionals across a range of settings. The Person-centred Practice Inventory - Staff (PCPI-S) is a new instrument for this purpose, theoretically aligned with McCormack & McCance's person-centred framework, which has been translated and culturally adapted into Norwegian. The study used a two-stage research design involving: translation and cultural adaption of the PCPI-S from English to Norwegian language (phase 1), and a quantitative cross sectional survey following psychometric evaluation (phase 2). Confirmatory factor analysis was used to examine the theoretical measurement model. The translation and cultural adaption was carried out according to ten recommend steps. Discrepancies were addressed and revised by all translators until consensus was reached on a reconciled version of the translation. A sample of 258 health care staff participated in the survey. The model fit statistics were overall positive; the model requires minor modifications and these are mostly confined to correlated errors. The translation and cultural adaption process of the PCPI-S from English to Norwegian language was a demanding process in order to retain the conceptual meanings of the original instrument. Overall, the psychometric properties of the tool were acceptable, but testing on a larger sample size is recommended.


Maternal alcohol use and risk of orofacial cleft birth defects.
Maternal alcohol use during pregnancy is a known cause of birth defects associated with the fetal alcohol syndrome, but its role in more common, isolated, craniofacial birth defects is not well understood. A population-based, case-control study of orofacial clefts was conducted in Iowa using births during 1987-1991. Cases were identified by the Iowa Birth Defects Registry and classified as having a cleft lip with or without cleft palate (CLP) or cleft palate only (CP) and whether the cleft was isolated or occurred with other birth defects. Controls were selected from normal Iowa births. Maternal alcohol use during pregnancy was classified according to self-reported drinks consumed per month. Results are based on 302 controls and the following numbers in each case group: 118 isolated CLP, 56 isolated CP, 51 CLP with multiple defects, and 62 CP with multiple defects. Compared to women who did not drink alcohol during pregnancy, the relative odds of isolated CLP rose with increasing level of maternal drinking as follows: 1-3 drinks per months, 1.5; 4-10 drinks per month, 3.1; more than 10 drinks per month, 4.7 (chi-square test for trend, P = 0.003). Adjustment for maternal smoking, vitamin use, education, and household income did not substantially alter these results. No significant association was found between alcohol use and isolated cleft palate or clefts in children with multiple birth defects. Alcohol use during pregnancy may be a cause of isolated cleft lip with or without cleft palate.


Development of a database of organ doses for paediatric and young adult CT scans in the United Kingdom.
Despite great potential benefits, there are concerns about the possible harm from medical imaging including the risk of radiation-related cancer. There are particular concerns about computed tomography (CT) scans in children because both radiation dose and sensitivity to radiation for children are typically higher than for adults undergoing equivalent procedures. As direct empirical data on the cancer risks from CT scans are lacking, the authors are conducting a retrospective cohort study of over 240,000 children in the UK who underwent CT scans. The main objective of the study is to quantify the magnitude of the cancer risk in relation to the radiation dose from CT scans. In this paper, the methods used to estimate typical organ-specific doses delivered by CT scans to children are described. An organ dose database from Monte Carlo radiation transport-based computer simulations using a series of computational human phantoms from newborn to adults for both male and female was established. Organ doses vary with patient size and sex, examination types and CT technical settings. Therefore, information on patient age, sex and examination type from electronic radiology information systems and technical settings obtained from two national surveys in the UK were used to estimate radiation dose. Absorbed doses to the brain, thyroid, breast and red bone marrow were calculated for reference male and female individuals with the ages of newborns, 1, 5, 10, 15 and 20 y for a total of 17 different scan types in the pre- and post-2001 time periods. In general, estimated organ doses were slightly higher for females than males which might be attributed to the smaller body size of the females. The younger children received higher doses in pre-2001 period when adult CT settings were typically used for children. Paediatric-specific adjustments were assumed to be used more frequently after 2001, since then radiation doses to children have often been smaller than those to adults. The database here is the first detailed organ-specific paediatric CT scan database for the UK. As well as forming the basis for the UK study, the results and description of the methods will also serve as a key resource for paediatric CT scan studies currently underway in other countries.


Preliminary results of two dose-finding studies of paclitaxel (Taxol) and carboplatin in non-small cell lung and ovarian cancers: a European Cancer Centre effort.
Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given as a 24-hour infusion, and carboplatin have activity in advanced non-small cell lung cancer (NSCLC) and ovarian cancer. Two dose-finding studies were initiated to identify the optimal doses for the paclitaxel/carboplatin combination when paclitaxel is given in a 3-hour infusion. The fact that the pharmacologic interaction between paclitaxel and cisplatin increases the toxicity of paclitaxel when cisplatin is given before it also prompted an investigation of the influence of drug sequence on toxicity and pharmacokinetics in the NSCLC trial. Thirty-three patients with advanced NSCLC and 11 with advanced ovarian cancer previously untreated by chemotherapy have been enrolled to date. In the NSCLC trial escalating doses of paclitaxel were given in combination with a fixed carboplatin dose of 300 mg/m2, while both drugs were escalated in the ovarian cancer study. In both studies paclitaxel was infused over 3 hours and carboplatin over 30 minutes, and cycles were repeated every 4 weeks. The most frequent side effect has been neutropenia, although this did not result in any infectious episodes. Alopecia and mild emesis also have been frequently encountered. Mild skin reactions have been reported in a few patients. Bone pain and myalgia occur more frequently at the highest paclitaxel doses. No difference in toxicity has been observed thus far between the two drug sequences in the NSCLC study. Both studies are still accruing patients as the maximum tolerated doses of paclitaxel in combination with carboplatin have not yet been reached (carboplatin 300 mg/m2 with paclitaxel 175 mg/m2 in the NSCLC study; carboplatin 400 mg/m2 with paclitaxel 150 mg/m2 in the ovarian cancer study). An investigation of maximum tolerated doses with granulocyte colony-stimulating factor support is planned thereafter.


Low serum levels of dehydroepiandrosterone may cause deficient IL-2 production by lymphocytes in patients with systemic lupus erythematosus (SLE).
The principal cause of IL-2 deficiency, a common feature of both murine lupus and human SLE, remains obscure. Recent studies of our own as well as others have shown that dehydroepiandrosterone (DHEA), an intermediate compound in testosterone synthesis, significantly up-regulates IL-2 production of T cells, and that administration of exogenous DHEA or IL-2 via a vaccinia construct to murine lupus dramatically reverses their clinical autoimmune diseases. Thus, we have examined serum levels of DHEA in patients with SLE to test whether abnormal DHEA activity is associated with IL-2 deficiency of the patients. We found that nearly all of the patients examined have very low levels of serum DHEA. The decreased DHEA levels were not simply a reflection of a long term corticosteroid treatment which may cause adrenal atrophy, since serum samples drawn at the onset of disease, which are devoid of corticosteroid treatment, also contained low levels of DHEA. In addition, exogenous DHEA restored impaired IL-2 production of T cells from patients with SLE in vitro. These results indicate that defects of IL-2 synthesis of patients with SLE are at least in part due to the low DHEA activity in the serum.


Metabolite differences between glutamate carboxypeptidase II gene knockout mice and their wild-type littermates after traumatic brain injury: a 7-tesla 1H-MRS study.
Traumatic brain injury (TBI) is a complex condition and remains a prominent public and medical health issue in individuals of all ages. A rapid increase in extracellular glutamate occurs after TBI, leading to glutamate-induced excitotoxicity, which causes neuronal damage and further functional impairments. Although inhibition of glutamate carboxypeptidase II (GCP II) is considered a potential approach for reducing glutamate-induced excitotoxicity after TBI, further detailed evidence regarding its efficacy is required. Therefore, in this study, we examined the differences in the metabolite status between wild-type (WT) and GCP II gene-knockout (KO) mice after TBI using proton magnetic resonance spectroscopy (1H-MRS) and T2-weighted magnetic resonance (MR) imaging with a 7-tesla imaging system, and brain water-content analysis. Evaluation of glutamate and N-acetylaspartate concentrations revealed a decrease in both levels in the ipsilateral hippocampus at 24 h post-TBI; however, the reduction in glutamate and N-acetylaspartate levels was less marked in GCP II-KO mice than in WT mice (p < 0.05). T2 MR data and brain water-content analysis demonstrated that the extent of cortical edema and brain swelling was less in KO than in WT mice after TBI (p < 0.05). Using two non-invasive methods, 1H-MRS and T2 MR imaging, as well as in vitro brain-water content measurements, we demonstrated that the mechanism underlying the neuroprotective effects of GCP II-KO against brain swelling in TBI involves changes in glutamate and N-acetylaspartate levels. This knowledge may contribute towards the development of therapeutic strategies for TBI.


Assessment of dietary exposure to some persistent organic pollutants in the Republic of Karakalpakstan of Uzbekistan.
A 1999 study heightened long-standing concerns over persistent organic pollutant contamination in the Aral Sea area, detecting elevated levels in breast milk and cord blood of women in Karakalpakstan (western Uzbekistan). These findings prompted a collaborative research study aimed at linking such human findings with evidence of food chain contamination in the area. An international team carried out analyses of organochlorine and organophosphate pesticides, polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs), and polychlorinated dibenzofurans (PCDFs) on samples of 12 foods commonly produced and consumed in Karakalpakstan. Analysis consistently detected long-lasting organochlorine pesticides and their metabolites in all foods of animal origin and in some vegetables such as onions and carrots--two low-cost components of many traditional dishes. Levels of PCBs were relatively low in all samples except fish. Analyses revealed high levels of PCDDs and PCDFs (together often termed "dioxins") in sheep fat, dairy cream, eggs, and edible cottonseed oil, among other foodstuffs. These findings indicate that food traditionally grown, sold, and consumed in Karakalpakstan is a major route of human exposure to several persistent toxic contaminants, including the most toxic of dioxins, 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD). Intake estimations demonstrate that consumption of even small amounts of locally grown food may expose consumers to dioxin levels that considerably exceed the monthly tolerable dioxin intake levels set by the World Health Organization. Data presented in this study allow a first assessment of the risk associated with the consumption of certain food products in Karakalpakstan and highlight a critical public health situation.


A 24-month evaluation of amalgam and resin-based composite restorations: Findings from The National Dental Practice-Based Research Network.
Knowing which factors influence restoration longevity can help clinicians make sound treatment decisions. The authors analyzed data from The National Dental Practice-Based Research Network to identify predictors of early failures of amalgam and resin-based composite (RBC) restorations. In this prospective cohort study, the authors gathered information from clinicians and offices participating in the network. Clinicians completed a baseline data collection form at the time of restoration placement and annually thereafter. Data collected included patient factors, practice factors and dentist factors, and the authors analyzed them by using mixed-model logistic regression. A total of 226 practitioners followed up 6,218 direct restorations in 3,855 patients; 386 restorations failed (6.2 percent) during the mean (standard deviation) follow-up of 23.7 (8.8) months. The number of tooth surfaces restored at baseline helped predict subsequent restoration failure; restorations with four or more restored surfaces were more than four times more likely to fail. Restorative material was not associated significantly with longevity; neither was tooth type. Older patient age was associated highly with failure (P < .001). The failure rate for children was 4 percent, compared with 10 percent for people 65 years or older. Dentist's sex and practice workload were associated significantly with restoration longevity. In this prospective cohort study, these factors were significantly predictive of failure for amalgam and RBC restorations: patient's age, a higher number of surfaces restored at baseline, the dentist's sex and the practice workload. Material choice was not significantly predictive in these early results. Practical Implications. If clinicians can recognize and identify the risk factors associated with early restoration failure, more effective treatment plans may be offered to the patient.


Industrial pollution and mortality from digestive cancers at the small area level in a Spanish industrialized province.
The province of Cadiz, Spain, is a highly industrialized area with numerous registered industrial plants, which has led to major concern regarding the possible influence of these facilities on the high rate of cancer-related mortality observed. Our objective was to evaluate the association between digestive cancer mortality and proximity to industrial installations in the province of Cadiz over the period 1992-2014 and to analyse this risk according to different categories of carcinogenic substances. An ecological study at the census tract level was carried out. Mortality due to digestive cancer (involving the oral cavity, pharynx, oesophagus, stomach, liver, pancreas, gallbladder, colon and rectum) was analysed. Using the spatial Besag, York and Mollié (BYM) approach, we assessed the relative risk of dying from these cancers for people living between 500 m and 5 km from industrial installations. The models were adjusted to account for socioeconomic deprivation. We detected a significant, excess risk of dying due to cancer in the following organs (expressed as relative risk with 95% confidence intervals): colon/rectum (1.13; 1.04-1.22 at 4 km), stomach (1.13; 1.00-1.29 at 2 km), liver (1.28; 1.02-1.61 at 1 km), pancreas (1.19; 1.03-1.39 at 2 km), oral and pharyngeal (1.40; 1.08-1.82 at 1 km), oesophagus (2.05; 1.18-3.56 at 500 m) and gallbladder (2.80; 1.14-6.89 at 500 m) for men; and from colorectal (1.21; 1.00-1.46 at 1 km), stomach (1.15; 1.01-1.31 at 4 km) and liver (1.58; 1.20- 2.07 at 1 km) cancers for women. The results support the hypothesis of an association between several digestive cancers and proximity to polluting industrial plants.


Management of anaphylaxis due to COVID-19 vaccines in the elderly.
Older adults, especially men and/or those with diabetes, hypertension, and/or obesity, are prone to severe COVID-19. In some countries, older adults, particularly those residing in nursing homes, have been prioritized to receive COVID-19 vaccines due to high risk of death. In very rare instances, the COVID-19 vaccines can induce anaphylaxis, and the management of anaphylaxis in older people should be considered carefully. An ARIA-EAACI-EuGMS (Allergic Rhinitis and its Impact on Asthma, European Academy of Allergy and Clinical Immunology, and European Geriatric Medicine Society) Working Group has proposed some recommendations for older adults receiving the COVID-19 vaccines. Anaphylaxis to COVID-19 vaccines is extremely rare (from 1 per 100,000 to 5 per million injections). Symptoms are similar in younger and older adults but they tend to be more severe in the older patients. Adrenaline is the mainstay treatment and should be readily available. A flowchart is proposed to manage anaphylaxis in the older patients.


Large margin low rank tensor analysis.
We present a supervised model for tensor dimensionality reduction, which is called large margin low rank tensor analysis (LMLRTA). In contrast to traditional vector representation-based dimensionality reduction methods, LMLRTA can take any order of tensors as input. And unlike previous tensor dimensionality reduction methods, which can learn only the low-dimensional embeddings with a priori specified dimensionality, LMLRTA can automatically and jointly learn the dimensionality and the low-dimensional representations from data. Moreover, LMLRTA delivers low rank projection matrices, while it encourages data of the same class to be close and of different classes to be separated by a large margin of distance in the low-dimensional tensor space. LMLRTA can be optimized using an iterative fixed-point continuation algorithm, which is guaranteed to converge to a local optimal solution of the optimization problem. We evaluate LMLRTA on an object recognition application, where the data are represented as 2D tensors, and a face recognition application, where the data are represented as 3D tensors. Experimental results show the superiority of LMLRTA over state-of-the-art approaches.


Acute alterations in biochemistry, morphology and contractility of rat isolated urinary bladder via increased intra-abdominal pressure.
To determine the acute effects of increased intra-abdominal pressure (IAP) on the biochemistry, morphology and contractility of the rat isolated urinary bladder using an experimental laparoscopy model. We divided 24 adult female Sprague-Dawley rats into three groups. The control group (group I) was not subjected to increased IAP. In groups II and III, IAPs of 10 and 20 mm Hg, respectively, were established by carbon dioxide pneumoperitoneum for 60 min. Thirty minutes after desufflation, the rat urinary bladder dome was removed for in vitro pharmacological investigation, measurement of malondialdehyde (MDA) levels and histopathological examination. Statistical comparisons between groups were performed. Tissue MDA levels in groups II and III were significantly higher than in the control group. In group II, only the lamina propria was significantly damaged. However, the epithelium, lamina propria, and serosa were significantly damaged in group III. Acetylcholine potentiated contractions in both IAP groups. Increased responses to electrical field stimulation in the IAP groups were significant only in group II. In this experimental model, 10 and 20 mm Hg of IAP induced by pneumoperitoneum increased MDA levels and caused important changes in the morphology and contractile response of the urinary bladder.


High resolution age-structured mapping of childhood vaccination coverage in low and middle income countries.
The expansion of childhood vaccination programs in low and middle income countries has been a substantial public health success story. Indicators of the performance of intervention programmes such as coverage levels and numbers covered are typically measured through national statistics or at the scale of large regions due to survey design, administrative convenience or operational limitations. These mask heterogeneities and 'coldspots' of low coverage that may allow diseases to persist, even if overall coverage is high. Hence, to decrease inequities and accelerate progress towards disease elimination goals, fine-scale variation in coverage should be better characterized. Using measles as an example, cluster-level Demographic and Health Surveys (DHS) data were used to map vaccination coverage at 1 km spatial resolution in Cambodia, Mozambique and Nigeria for varying age-group categories of children under five years, using Bayesian geostatistical techniques built on a suite of publicly available geospatial covariates and implemented via Markov Chain Monte Carlo (MCMC) methods. Measles vaccination coverage was found to be strongly predicted by just 4-5 covariates in geostatistical models, with remoteness consistently selected as a key variable. The output 1 × 1 km maps revealed significant heterogeneities within the three countries that were not captured using province-level summaries. Integration with population data showed that at the time of the surveys, few districts attained the 80% coverage, that is one component of the WHO Global Vaccine Action Plan 2020 targets. The elimination of vaccine-preventable diseases requires a strong evidence base to guide strategies and inform efficient use of limited resources. The approaches outlined here provide a route to moving beyond large area summaries of vaccination coverage that mask epidemiologically-important heterogeneities to detailed maps that capture subnational vulnerabilities. The output datasets are built on open data and methods, and in flexible format that can be aggregated to more operationally-relevant administrative unit levels.


Particle extinction measured at ambient conditions with differential optical absorption spectroscopy. 1. system setup and characterization.
We describe an instrument for measuring the particle extinction coefficient at ambient conditions in the spectral range from 270 to 1000 nm. It is based on a differential optical absorption spectroscopy (DOAS) system, which was originally used for measuring trace-gas concentrations of atmospheric absorbers in the ultraviolet-visible wavelength range. One obtains the particle extinction spectrum by measuring the total atmospheric extinction and subtracting trace-gas absorption and Rayleigh scattering. The instrument consists of two nested Newton-type telescopes, which are simultaneously used for emitting and detecting light, and two arrays of retroreflectors at the ends of the two light paths. The design of this new instrument solves crucial problems usually encountered in the design of such instruments. The telescope is actively repositioned during the measurement cycle. Particle extinction is simultaneously measured at several wavelengths by the use of two grating spectrometers. Optical turbulence causes lateral movement of the spot of light in the receiver telescope. Monitoring of the return signals with a diode permits correction for this effect. Phase-sensitive detection efficiently suppresses background signals from the atmosphere as well as from the instrument itself. The performance of the instrument was tested during a measurement period of 3 months from January to March 2000. The instrument ran without significant interruption during that period. A mean accuracy of 0.032 km(-1) was found for the extinction coefficient for an 11-day period in March.


Salivary Duct Carcinoma Arising in a Warthin Tumor of the Parotid Gland: A Rare Case Report with Review of Literature and PD-L1 Expression.
Warthin's tumor is the second most common neoplasm of the parotid gland and consists of 2 components, including lymphoid stroma and glandular epithelium. Malignant transformation in this tumor is mostly seen in the lymphoid component; however, the carcinomatous transformation of the epithelial component is extremely rare. Cases of latter reported in the literature include squamous cell carcinoma, adenocarcinoma, mucoepidermoid carcinoma, oncocytic carcinoma, Merkel cell carcinoma, and undifferentiated carcinoma. We describe an extremely rare case of salivary duct carcinoma arising in a Warthin tumor in a 64-year-old male. Patient presented with an enlarging left parotid mass, biopsy of which showed salivary duct carcinoma. He subsequently underwent left parotidectomy along with left level II-IV lymph node dissection. Histology revealed both in situ as well as invasive salivary duct carcinoma arising from Warthin tumor. Immunohistochemistry showed tumor cells positive for CK7, AR, and GATA3, while p63 highlighted the myoepithelial cell layer in the in situ component. Her2 was 2+ by immunohistochemistry. In addition, PD-L1 IHC revealed positive expression with a combined positive score of 20%.


Constitutive production of c-di-GMP is associated with mutations in a variant of Pseudomonas aeruginosa with altered membrane composition.
Most bacteria can form multicellular communities called biofilms on biotic and abiotic surfaces. This multicellular response to surface contact correlates with an increased resistance to various adverse environmental conditions, including those encountered during infections of the human host and exposure to antimicrobial compounds. Biofilm formation occurs when freely swimming (planktonic) cells encounter a surface, which stimulates the chemosensory-like, surface-sensing system Wsp and leads to generation of the intracellular second messenger 3',5'-cyclic-di-guanosine monophosphate (c-di-GMP). We identified adaptive mutations in a clinical small colony variant (SCV) of Pseudomonas aeruginosa and correlated their presence with self-aggregating growth behavior and an enhanced capacity to form biofilms. We present evidence that a point mutation in the 5' untranslated region of the accBC gene cluster, which encodes components of an enzyme responsible for fatty acid biosynthesis, was responsible for a stabilized mRNA structure that resulted in reduced translational efficiency and an increase in the proportion of short-chain fatty acids in the plasma membrane. We propose a model in which these changes in P. aeruginosa serve as a signal for the Wsp system to constitutively produce increased amounts of c-di-GMP and thus play a role in the regulation of adhesion-stimulated bacterial responses.


Ultrasensitive 1D field-effect phototransistors: CH3NH3PbI3 nanowire sensitized individual carbon nanotubes.
Field-effect phototransistors were fabricated based on individual carbon nanotubes (CNTs) sensitized by CH3NH3PbI3 nanowires (MAPbI3NWs). These devices represent light responsivities of R = 7.7 × 10(5) A W(-1) under low-lighting conditions in the nW mm(-2) range, unprecedented among CNT-based photodetectors. At high incident power (∼1 mW mm(-2)), light soaking results in a negative photocurrent, turning the device insulating. We interpret the phenomenon as a result of efficient free photoexcited charge generation and charge transfer of photoexcited holes from the perovskite to the carbon nanotube. The charge transfer improves conductance by increasing the number of carriers, but leaves electrons behind. At high illumination intensity their random electrostatic potential quenches mobility in the nanotube.


Induction of the Wnt antagonist Dickkopf-1 is involved in stress-induced hippocampal damage.
The identification of mechanisms that mediate stress-induced hippocampal damage may shed new light into the pathophysiology of depressive disorders and provide new targets for therapeutic intervention. We focused on the secreted glycoprotein Dickkopf-1 (Dkk-1), an inhibitor of the canonical Wnt pathway, involved in neurodegeneration. Mice exposed to mild restraint stress showed increased hippocampal levels of Dkk-1 and reduced expression of β-catenin, an intracellular protein positively regulated by the canonical Wnt signalling pathway. In adrenalectomized mice, Dkk-1 was induced by corticosterone injection, but not by exposure to stress. Corticosterone also induced Dkk-1 in mouse organotypic hippocampal cultures and primary cultures of hippocampal neurons and, at least in the latter model, the action of corticosterone was reversed by the type-2 glucocorticoid receptor antagonist mifepristone. To examine whether induction of Dkk-1 was causally related to stress-induced hippocampal damage, we used doubleridge mice, which are characterized by a defective induction of Dkk-1. As compared to control mice, doubleridge mice showed a paradoxical increase in basal hippocampal Dkk-1 levels, but no Dkk-1 induction in response to stress. In contrast, stress reduced Dkk-1 levels in doubleridge mice. In control mice, chronic stress induced a reduction in hippocampal volume associated with neuronal loss and dendritic atrophy in the CA1 region, and a reduced neurogenesis in the dentate gyrus. Doubleridge mice were resistant to the detrimental effect of chronic stress and, instead, responded to stress with increases in dendritic arborisation and neurogenesis. Thus, the outcome of chronic stress was tightly related to changes in Dkk-1 expression in the hippocampus. These data indicate that induction of Dkk-1 is causally related to stress-induced hippocampal damage and provide the first evidence that Dkk-1 expression is regulated by corticosteroids in the central nervous system. Drugs that rescue the canonical Wnt pathway may attenuate hippocampal damage in major depression and other stress-related disorders.


Efficacy and acceptability of tadenan (Pygeum africanum extract) in the treatment of benign prostatic hyperplasia (BPH): a multicentre trial in central Europe.
Pygeum africanum extract is available as Tadenan in many countries, including those in central and eastern Europe, for the treatment of mild to moderate BPH. Its efficacy and acceptability have been demonstrated in numerous open and placebo-controlled studies in large populations. The present open three-centre efficacy and safety study was conducted according to common protocol at urology clinics in the Czech and Slovak Republics and in Poland, in order to confirm the therapeutic profile of Pygeum africanum in conditions of daily practice, using International Prostate Symptom Score (IPSS) and flowmetry assessments. Men aged 50-75 years and in compliance with the selection criteria (including IPSS > or = 12, quality of life (QoL) score > or = 3, and maximum urinary flow < or = 15 ml/s) were first examined then recalled after two weeks during which no treatment was provided (washout and check of stability). If still compliant, they were entered at this point into a two-month period of treatment with Pygeum africanum extract 50 mg twice daily. There followed a further one-month period without treatment, the objective being to evaluate the persistence of any effects observed during the previous two months of Pygeum africanum administration. The primary efficacy parameter investigated was IPSS; the other efficacy parameters were QoL, nocturnal frequency, maximum urinary flow, average urinary flow, post-voiding residual volume and prostatic volume, after one and two months of Pygeum africanum treatment and one month after stopping treatment. A total of 85 patients were evenly distributed between the three centres and completed the entire study. At inclusion their mean IPSS was 16.17, QoL was 3.60 and nocturia was 2.6 times per night. The changes in subjective scores, IPSS and QoL after the two-month treatment period were highly statistically significant with mean improvements of 40% and 31%, respectively. Nocturnal frequency was reduced by 32% and the mean reduction was again highly statistically significant. Mean maximum urinary flow, average urinary flow and urine volume were also statistically significantly improved, but the modest improvement in post-voiding volume did not reach statistical significance. The improvements, which exceeded those observed with placebo in earlier studies, were maintained after one month without treatment indicating an interesting persistence of clinically useful activity. Prostatic volume and quality of sexual life remained unchanged throughout. No treatment-related adverse effects were observed. In conclusion, under conditions of daily practice, Pygeum africanum extract induces significant improvement in IPSS and uroflowmetry parameters. These positive effects are accompanied by a very satisfactory safety profile with the overall result of a substantial improvement in QoL.


Worldwide human papillomavirus etiology of cervical adenocarcinoma and its cofactors: implications for screening and prevention.
Most cancers of the uterine cervix are squamous cell carcinomas. Although the incidence of such carcinomas of the uterine cervix has declined over time, that of cervical adenocarcinoma has risen in recent years. The extent to which human papillomavirus (HPV) infection and cofactors may explain this differential trend is unclear. We pooled data from eight case-control studies of cervical cancer that were conducted on three continents. A total of 167 case patients with invasive cervical adenocarcinoma (112 with adenocarcinoma and 55 with adenosquamous carcinoma) and 1881 hospital-based control subjects were included. HPV DNA was analyzed in cervical specimens with the GP5+/6+ general primer system followed by type-specific hybridization for 33 HPV genotypes. Blood samples were analyzed for chlamydial and herpes simplex virus 2 (HSV-2) serology. Multivariable unconditional logistic regression modeling was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs). All tests of statistical significance were two-sided. The adjusted overall odds ratio for cervical adenocarcinoma in HPV-positive women compared with HPV-negative women was 81.3 (95% CI = 42.0 to 157.1). HPV 16 and HPV 18 were the two most commonly detected HPV types in case patients and control subjects. These two types were present in 82% of the patients. Cofactors that showed clear statistically significant positive associations with cervical adenocarcinoma overall and among HPV-positive women included never schooling, poor hygiene, sexual behavior-related variables, long-term use of hormonal contraception, high parity, and HSV-2 seropositivity. Parity had a weaker association with adenocarcinoma and only among HPV-positive women. Use of an intrauterine device (IUD) had a statistically significant inverse association with risk of adenocarcinoma (for ever use of an IUD compared with never use, OR = .41 [95% CI = 0.18 to 0.93]). Smoking and chlamydial seropositivity were not associated with disease. HPV appears to be the key risk factor for cervical adenocarcinoma. HPV testing in primary screening using current mixtures of HPV types and HPV vaccination against main HPV types should reduce the incidence of this cancer worldwide.


Subcellular compartmentalization of adeno-associated virus type 2 assembly.
Using immunofluorescence and in situ hybridization techniques, we studied the intracellular localization of adeno-associated virus type 2 (AAV-2) Rep proteins, VP proteins, and DNA during the course of an AAV-2/adenovirus type 2 coinfection. In an early stage, the Rep proteins showed a punctate distribution pattern over the nuclei of infected cells, reminiscent of replication foci. At this stage, no capsid proteins were detectable. At later stages, the Rep proteins were distributed more homogeneously over the nuclear interior and finally became redistributed into clusters slightly enriched at the nuclear periphery. During an intermediate stage, they also appeared at an interior part of the nucleolus for a short period, whereas most of the time the nucleoli were Rep negative. AAV-2 DNA colocalized with the Rep proteins. All three capsid proteins were strongly enriched in the nucleolus in a transient stage of infection, when the Rep proteins homogeneously filled the nucleoplasm. Thereafter, they became distributed over the whole nucleus and colocalized in nucleoplasmic clusters with the Rep proteins and AAV-2 DNA. While VP1 and VP2 strongly accumulated in the nucleus, VP3 was almost equally distributed between the nucleus and cytoplasm. Capsids, visualized by a conformation-specific antibody, were first detectable in the nucleoli and then spread over the whole nucleoplasm. This suggests that nucleolar components are involved in initiation of capsid assembly whereas DNA packaging occurs in the nucleoplasm. Expression of a transfected full-length AAV-2 genome followed by adenovirus infection showed all stages of an AAV-2/adenovirus coinfection, whereas after expression of the cap gene alone, capsids were restricted to the nucleoli and did not follow the nuclear redistribution observed in the presence of the whole AAV-2 genome. Coexpression of Rep proteins released the restriction of capsids to the nucleolus, suggesting that the Rep proteins are involved in nuclear redistribution of AAV capsids during viral infection. Capsid formation was dependent on the concentration of expressed capsid protein.


CCL2/MCP-I genotype-phenotype relationship in latent tuberculosis infection.
Among the known biomarkers, chemokines, secreted by activated macrophages and T cells, attract groups of immune cells to the site of infection and may determine the clinical outcome. Association studies of CCL-2/MCP-1 -2518 A/G functional SNP linked to high and low phenotypes with tuberculosis disease susceptibility have shown conflicting results in tuberculosis. Some of these differences could be due the variability of latent infection and recent exposure in the control groups. We have therefore carried out a detailed analysis of CCL-2 genotype SNP -2518 (A/G transition) with plasma CCL-2 levels and related these levels to tuberculin skin test positivity in asymptomatic community controls with no known exposure to tuberculosis and in recently exposed household contacts of pulmonary tuberculosis patients. TST positivity was linked to higher concentrations of plasma CCL2 (Mann Whitney U test; p = 0.004) and was more marked when the G allele was present in TST+ asymptomatic controls (A/G; p = 0.01). Recent exposure also had a significant effect on CCL-2 levels and was linked to the G allele (p = 0.007). Therefore association studies for susceptibility or protection from disease should take into consideration the PPD status as well as recent exposure of the controls group used for comparison. Our results also suggest a role for CCL-2 in maintaining the integrity of granuloma in asymptomatic individuals with latent infection in high TB burden settings. Therefore additional studies into the role of CCL-2 in disease reactivation and progression are warranted.


PIK3CA Cooperates with KRAS to Promote MYC Activity and Tumorigenesis via the Bromodomain Protein BRD9.
Tumor formation is generally linked to the acquisition of two or more driver genes that cause normal cells to progress from proliferation to abnormal expansion and malignancy. In order to understand genetic alterations involved in this process, we compared the transcriptomes of an isogenic set of breast epithelial cell lines that are non-transformed or contain a single or double knock-in (DKI) of PIK3CA (H1047R) or KRAS (G12V). Gene set enrichment analysis revealed that DKI cells were enriched over single mutant cells for genes that characterize a MYC target gene signature. This gene signature was mediated in part by the bromodomain-containing protein 9 (BRD9) that was found in the SWI-SNF chromatin-remodeling complex, bound to the MYC super-enhancer locus. Small molecule inhibition of BRD9 reduced MYC transcript levels. Critically, only DKI cells had the capacity for anchorage-independent growth in semi-solid medium, and CRISPR-Cas9 manipulations showed that PIK3CA and BRD9 expression were essential for this phenotype. In contrast, KRAS was necessary for DKI cell migration, and BRD9 overexpression induced the growth of KRAS single mutant cells in semi-solid medium. These results provide new insight into the earliest transforming events driven by oncoprotein cooperation and suggest BRD9 is an important mediator of mutant PIK3CA/KRAS-driven oncogenic transformation.


Culture-negative endocarditis due to Bartonella quintana.
Bartonella spp. was first described as a possible cause of culture-negative endocarditis in 1993, and has since emerged as a significant cause of this condition worldwide. We describe a complicated case of culture-negative endocarditis in an immune-competent male patient, which was confirmed on resected heart valves to have been caused by Bartonella quintana by broad-range 16S ribosomal RNA polymerase chain reaction. The objective of this report is to highlight the clinical, diagnostic and therapeutic challenges of Bartonella endocarditis.


Annual summary of vital statistics--1998.
Most vital statistics indicators of the health of Americans were stable or showed modest improvements between 1997 and 1998. The preliminary birth rate in 1998 was 14.6 births per 1000 population, up slightly from the record low reported for 1997 (14.5). The fertility rate, births per 1000 women aged 15 to 44 years, increased 1% to 65.6 in 1998, compared with 65.0 in 1997. The 1998 increases, although modest, were the first since 1990, halting the steady decline in the number of births and birth and fertility rates in the 1990s. Fertility rates for total white, non-Hispanic white, and Native American women each increased from 1% to 2% in 1998. The fertility rate for black women declined 19% from 1990 to 1996, but has changed little since 1996. The rate for Hispanic women, which dropped 2%, was lower than in any year for which national data have been available. Birth rates for women 30 years or older continued to increase. The proportion of births to unmarried women remained about the same at one third. The birth rate for teen mothers declined again for the seventh consecutive year, and the use of timely prenatal care (82.8%) improved for the ninth consecutive year, especially for black (73.3%) and Hispanic (74.3%) mothers. The number and rate of multiple births continued their dramatic rise; the number of triplet and higher-order multiple births jumped 16% between 1996 and 1997, accounting, in part, for the slight increase in the percentage of low birth weight (LBW) births. LBW continued to increase from 1997 to 1998 to 7.6%. The infant mortality rate (IMR) was unchanged from 1997 to 1998 (7.2 per 1000 live births). The ratio of the IMR among black infants to that for white infants (2.4) remained the same in 1998 as in 1997. Racial differences in infant mortality remain a major public health concern. In 1997, 65% of all infant deaths occurred to the 7.5% of infants born LBW. Among all of the states, Maine, Massachusetts, and New Hampshire had the lowest IMRs. State-by-state differences in IMR reflect racial composition, the percentage LBW, and birth weight-specific neonatal mortality rate for each state. The United States continues to rank poorly in international comparisons of infant mortality. Expectation of life at birth increased slightly to 76.7 years for all gender and race groups combined. Death rates in the United States continue to decline, including a drop in mortality from human immunodeficiency virus. The age-adjusted death rate for suicide declined 6% in 1998; homicide declined 14%. Death rates for children from all major causes declined again in 1998. A large proportion of childhood deaths, however, continue to occur as a result of preventable injuries.


Role of ketamine for analgesia in adults and children.
Ketamine an N-methyl-D-aspartate (NMDA) receptor blocking agent and a dissociative anesthetic with neurostimulatory side effects. In recent years, multiple research trials as well as systematic reviews and meta-analyses suggest the usefulness of ketamine as a strong analgesic used in subanesthetic intravenous doses, and also as a sedative. In addition, ketamine was noted to possess properties of anti-tolerance, anti-hyperalgesia and anti-allodynia most likely secondary to inhibition of the NMDA receptors. Tolerance, hyperalgesia and allodynia phenomena are the main components of opioid resistance, and pathological pain is often seen in the clinical conditions involving neuropathic pain, opioid-induced hyperalgesia, and central sensitization with allodynia or hyperalgesia. All these conditions are challenging to treat. In low doses, ketamine does not have major adverse dysphoric effects and also has the favorable effects of reduced incidence of opioid-induced nausea and vomiting. Therefore, ketamine can be a useful adjunct for pain control after surgery. Additional studies are required to determine the role of ketamine in the immediate postoperative period after surgical interventions known to produce severe pain and in the prevention and treatment of chronic pain.


Characterization of a cis-Golgi matrix protein, GM130.
Antisera raised to a detergent- and salt-resistant matrix fraction from rat liver Golgi stacks were used to screen an expression library from rat liver cDNA. A full-length clone was obtained encoding a protein of 130 kD (termed GM130), the COOH-terminal domain of which was highly homologous to a Golgi human auto-antigen, golgin-95 (Fritzler et al., 1993). Biochemical data showed that GM130 is a peripheral cytoplasmic protein that is tightly bound to Golgi membranes and part of a larger oligomeric complex. Predictions from the protein sequence suggest that GM130 is an extended rod-like protein with coiled-coil domains. Immunofluorescence microscopy showed partial overlap with medial- and trans-Golgi markers but almost complete overlap with the cis-Golgi network (CGN) marker, syntaxin5. Immunoelectron microscopy confirmed this location showing that most of the GM130 was located in the CGN and in one or two cisternae on the cis-side of the Golgi stack. GM130 was not re-distributed to the ER in the presence of brefeldin A but maintained its overlap with syntaxin5 and a partial overlap with the ER-Golgi intermediate compartment marker, p53. Together these results suggest that GM130 is part of a cis-Golgi matrix and has a role in maintaining cis-Golgi structure.


3D nitrogen-doped graphene aerogel-supported Fe3O4 nanoparticles as efficient electrocatalysts for the oxygen reduction reaction.
Three-dimensional (3D) N-doped graphene aerogel (N-GA)-supported Fe(3)O(4) nanoparticles (Fe(3)O(4)/N-GAs) as efficient cathode catalysts for the oxygen reduction reaction (ORR) are reported. The graphene hybrids exhibit an interconnected macroporous framework of graphene sheets with uniform dispersion of Fe(3)O(4) nanoparticles (NPs). In studying the effects of the carbon support on the Fe(3)O(4) NPs for the ORR, we found that Fe(3)O(4)/N-GAs show a more positive onset potential, higher cathodic density, lower H(2)O(2) yield, and higher electron transfer number for the ORR in alkaline media than Fe(3)O(4) NPs supported on N-doped carbon black or N-doped graphene sheets, highlighting the importance of the 3D macropores and high specific surface area of the GA support for improving the ORR performance. Furthermore, Fe(3)O(4)/N-GAs show better durability than the commercial Pt/C catalyst.


Additional evidence for lack of transmission of HIV infection by close interpersonal (casual) contact.
To further study the possibility of transmission of HIV infection by close personal but non-sexual, non-parenteral contact we have continued to enroll and evaluate household contacts of adult patients with AIDS. Two hundred and six household contacts of 90 patients with AIDS were evaluated with detailed interviews, physical examinations, and detection of HIV antibodies and p24 antigen from 1984 to 1987; 118 of these contacts were re-evaluated 6-12 months after cessation of household contact or death of the patient. The median duration of household contact from 18 months prior to symptoms in the AIDS patients to last contact was 23 months (range 3-101 months). The median time elapsed from first contact during this period to the last evaluation was 38 months (range 13-66 months). No household contact had signs or symptoms suggesting HIV infection. All 206 were negative for serum antibodies to HIV and HIV p24 antigen, despite extensive sharing of household facilities and items and personal interactions with AIDS patients. This study continues to show that household members without other risks remain at minimal to no risk for HIV transmission (95% confidence interval, 0-1.44) despite prolonged and substantial close non-sexual contact with AIDS patients, and after re-evaluation at a median of 10.9 months after initial evaluation.


Small female rib cage fracture in frontal sled tests.
The 2 objectives of this study are to (1) examine the rib and sternal fractures sustained by small stature elderly females in simulated frontal crashes and (2) determine how the findings are characterized by prior knowledge and field data. A test series was conducted to evaluate the response of 5 elderly (average age 76 years) female postmortem human subjects (PMHS), similar in mass and size to a 5th percentile female, in 30 km/h frontal sled tests. The subjects were restrained on a rigid planar seat by bilateral rigid knee bolsters, pelvic blocks, and a custom force-limited 3-point shoulder and lap belt. Posttest subject injury assessment included identifying rib cage fractures by means of a radiologist read of a posttest computed tomography (CT) and an autopsy. The data from a motion capture camera system were processed to provide chest deflection, defined as the movement of the sternum relative to the spine at the level of T8. A complementary field data investigation involved querying the NASS-CDS database over the years 1997-2012. The targeted cases involved belted front seat small female passenger vehicle occupants over 40 years old who were injured in 25 to 35 km/h delta-V frontal crashes (11 to 1 o'clock). Peak upper shoulder belt tension averaged 1,970 N (SD = 140 N) in the sled tests. For all subjects, the peak x-axis deflection was recorded at the sternum with an average of -44.5 mm or 25% of chest depth. The thoracic injury severity based on the number and distribution of rib fractures yielded 4 subjects coded as Abbreviated Injury Scale (AIS) 3 (serious) and one as AIS 5 (critical). The NASS-CDS field data investigation of small females identified 205 occupants who met the search criteria. Rib fractures were reported for 2.7% of the female occupants. The small elderly test subjects sustained a higher number of rib cage fractures than expected in what was intended to be a minimally injurious frontal crash test condition. Neither field studies nor prior laboratory frontal sled tests conducted with 50th percentile male PMHS predicted the injury severity observed. Although this was a limited study, the results justify further exploration of the risk of rib cage injury for small elderly female occupants.


Vocational Rehabilitation: Supporting Ill or Disabled Individuals in (to) Work: A UK Perspective.
Work is important for one's self-esteem, social standing and ability to participate in the community as well as for the material advantages it brings to individuals and their families. The evidence suggests that the benefits of employment outweigh the risks of work and are greater than the risks of long-term unemployment or sickness absence. Individuals may be born with physical or intellectual disadvantages (e.g., cerebral palsy), or they may be acquired during childhood or adult life. Some progressive conditions may present in childhood or adolescence (e.g., some muscular dystrophies) and these need to be distinguished from those presenting later in life (e.g., trauma, stroke). Vocational rehabilitation (VR) thus takes three forms: preparing those with a disability, health or mental health condition for the world of work, job retention for those in work and assisting those out of work into new work. Important components of VR consist of the attributes of the individual, the skills/knowledge of their health professionals, the knowledge and attitudes of actual or potential employers and the assistance that is provided by the state or other insurance facility. Charities are playing an increasing role.


Non-linear effects of cathodal transcranial direct current stimulation (tDCS) of the primary motor cortex on implicit motor learning.
Transcranial direct current stimulation (tDCS) of 1 mA for 13 min was reported to create a linear inter-dependency between the intensity and duration of the current and the effects of the stimulation. tDCS on the primary motor cortex (M1) has been shown to have an effect on both motor-evoked potential (MEP) and motor learning. However, recent findings have shown that the known linear effect is invalid in a 2 mA stimulation for 20 min, where cathodal stimulation led to excitability, rather than inhibition, as measured by MEP changes. Here we aim to replicate the non-linear effect of cathodal stimulation over the M1, using a cognitive task. Twenty-two healthy subjects participated in three sessions, where they were administered with a 2 mA anodal and cathodal stimulation for 20 min over the left M1, and a sham stimulation, while performing the serial reaction time task (SRTT). The overall analysis failed to show any effects of either polarity of tDCS on SRTT performance and hence did not replicate previous findings. However, given our goal to replicate the previously reported reversed polarity effects on MEP, we conducted an exploratory analysis to see whether there were any more subtle signs of a change in sign of the cathodal effect compared with anodal. Anodal stimulation led to faster performance than cathodal stimulation before 13 min of stimulation have passed, however, after 13 min, the pattern had switched, and performance under cathodal stimulation was faster. We conclude that cathodal tDCS has a non-linear effect, and the known polarity-dependent effects of tDCS shift after 13 min of stimulation, leading to an increased, rather than decreased, excitability.


Summarizing performance for genome scale measurement of miRNA: reference samples and metrics.
The potential utility of microRNA as biomarkers for early detection of cancer and other diseases is being investigated with genome-scale profiling of differentially expressed microRNA. Processes for measurement assurance are critical components of genome-scale measurements. Here, we evaluated the utility of a set of total RNA samples, designed with between-sample differences in the relative abundance of miRNAs, as process controls. Three pure total human RNA samples (brain, liver, and placenta) and two different mixtures of these components were evaluated as measurement assurance control samples on multiple measurement systems at multiple sites and over multiple rounds. In silico modeling of mixtures provided benchmark values for comparison with physical mixtures. Biomarker development laboratories using next-generation sequencing (NGS) or genome-scale hybridization assays participated in the study and returned data from the samples using their routine workflows. Multiplexed and single assay reverse-transcription PCR (RT-PCR) was used to confirm in silico predicted sample differences. Data visualizations and summary metrics for genome-scale miRNA profiling assessment were developed using this dataset, and a range of performance was observed. These metrics have been incorporated into an online data analysis pipeline and provide a convenient dashboard view of results from experiments following the described design. The website also serves as a repository for the accumulation of performance values providing new participants in the project an opportunity to learn what may be achievable with similar measurement processes. The set of reference samples used in this study provides benchmark values suitable for assessing genome-scale miRNA profiling processes. Incorporation of these metrics into an online resource allows laboratories to periodically evaluate their performance and assess any changes introduced into their measurement process.


Optimal noise suppression in Fresnel incoherent correlation holography (FINCH) configured for maximum imaging resolution.
An optimal setup in the sense of imaging resolution for the Fresnel incoherent correlation holography (FINCH) system is proposed and analyzed. Experimental results of the proposed setup in reflection mode suffer from low signal-to-noise ratio (SNR) due to a granular noise. SNR improvement is achieved by two methods that rely on increasing the initial amount of phase-shifted recorded holograms. In the first method, we average over several independent complex-valued digital holograms obtained by recording different sets of three digital phase-shifted holograms. In the second method, the least-squares solution for solving a system of an overdetermined set of linear equations is approximated by utilizing the Moore-Penrose pseudoinverse. These methods improve the resolution of the reconstructed image due to their ability to reveal fine and weak details of the observed object.


Chronic electromagnetic field exposure decreases HSP70 levels and lowers cytoprotection.
Electromagnetic field (EMF) exposures have been shown to induce heat shock proteins (HSPs), which help to maintain the conformation of cellular proteins during periods of stress. We have previously reported that short-term exposure of chick embryos to either 60 Hz (extremely low frequency: ELF), or radio-frequency (RF: 915 MHz) EMFs induce protection against hypoxia. Experiments presented in the current report are based on a study in which long-term (4 days), continuous exposure to ELF-EMFs decreased protection against ultraviolet radiation. Based on this result, it was hypothesized that de-protection against hypoxia should also occur following long-term, continuous, or daily, repeated exposures to EMFs. To test this hypothesis, chick embryos were exposed to ELF-EMFs (8 microT) continuously for 4 days, or to ELF or RF (3.5 mW incident power)-EMFs repeated daily (20, 30, or 60 min once or twice daily for 4 days). Several of the exposure protocols yielded embryos that had statistically significant decreases in protection against hypoxic stress (continuous and 30 or 60 min ELF twice daily; or 30 or 60 min once daily RF). This is consistent with our finding that following 4 days of ELF-EMF exposure, HSP70 levels decline by 27% as compared to controls. In addition, the superposition of ELF-EMF noise, previously shown to minimize ELF-EMF induced hypoxia protection, inhibited hypoxia de-protection caused by long term, continuous ELF or daily, repeated RF exposures. This EMF-induced decrease in HSP70 levels and resulting decline in cytoprotection suggests a mechanism by which daily exposure (such as might be experienced by mobile phone users) could enhance the probability of cancer and other diseases.


Stem and leaf gas exchange and their responses to fire in a north Australian tropical savanna.
We measured stem CO2 efflux and leaf gas exchange in a tropical savanna ecosystem in northern Australia, and assessed the impact of fire on these processes. Gas exchange of mature leaves that flushed after a fire showed only slight differences from that of mature leaves on unburned trees. Expanding leaves typically showed net losses of CO2 to the atmosphere in both burned and unburned trees, even under saturating irradiance. Fire caused stem CO2 efflux to decline in overstory trees, when measured 8 weeks post-fire. This decline was thought to have resulted from reduced availability of C substrate for respiration, due to reduced canopy photosynthesis caused by leaf scorching, and to priority allocation of fixed C towards reconstruction of a new canopy. At the ecosystem scale, we estimated the annual above-ground woody-tissue CO2 efflux to be 275 g C m(-2) ground area year(-1) in a non-fire year, or approximately 13% of the annual gross primary production. We contrasted the canopy physiology of two co-dominant overstory tree species, one of which has a smooth bark on its branches capable of photosynthetic re-fixation (Eucalyptus miniata), and the other of which has a thick, rough bark incapable of re-fixation (Eucalyptus tetrodonta). Eucalyptus miniata supported a larger branch sapwood cross-sectional area in the crown per unit subtending leaf area, and had higher leaf stomatal conductance and photosynthesis than E. tetrodonta. Re-fixation by photosynthetic bark reduces the C cost of delivering water to evaporative sites in leaves, because it reduces the net C cost of constructing and maintaining sapwood. We suggest that re-fixation allowed leaves of E. miniata to photosynthesize at higher rates than those of E. tetrodonta, while the two invested similar amounts of C in the maintenance of branch sapwood.


Obstacles to compassion-giving among nursing and midwifery managers: an international study.
To explore nursing and midwifery managers' views regarding obstacles to compassion-giving across country cultures. The benefit of compassionate leadership is being advocated, but despite the fact that health care is invariably conducted within culturally diverse workplaces, the interconnection of culture, compassion and leadership is rarely addressed. Furthermore, evidence on how cultural factors hinder the expression of compassion among nursing and midwifery managers is lacking. Cross-sectional, exploratory, international online survey involving 1 217 participants from 17 countries. Managers' responses on open-ended questions related to barriers for providing compassion were entered and thematically analysed through NVivo. Three key themes related to compassion-giving obstacles emerged across countries: 1. related to the managers' personal characteristics and experiences; 2. system-related; and 3. staff-related. Obstacles to compassion-giving among managers vary across countries. An understanding of the variations across countries and cultures of what impedes compassion to flourish in health care is important. Nursing mangers should wisely use their power by adopting leadership styles that promote culturally competent and compassionate workplaces with respect for human rights. Policymakers should identify training and mentoring needs to enable the development of managers' practical wisdom. Appropriate national and international policies should facilitate the establishment of standards and guidelines for compassionate leadership, in the face of distorted organizational cultures and system-related obstacles to compassion-giving.


The influence of the microtubule inhibitor, methyl benzimidazol-2-yl-carbamate (MBC) on nuclear division and the cell cycle in Saccharomyces cerevisiae.
Methyl benzimidazol-2-yl-carbamate (MBC), at a concentration of 100 microM, has a pronounced effect on the growth of Saccharomyces cerevisiae, resulting in the accumulation of cells as large doublets. We have determined a specific execution point for the effect of MBC on the yeast cell cycle, and have shown that this execution point is between the cycle events of spindle pole body duplication and spindle pole body separation. An ultrastructural examination of the MBC-treated cells revealed the absence of cytoplasmic and spindle microtubules. MBC treatment also produced an altered spindle pole body morphology, causing the disappearance of the outer component. Nuclear size was also markedly increased in the MBC-induced doublet cells, although the septa were completely absent from these doublet cells. It is proposed that MBC inhibits microtubule polymerization, rather than causing the depolymerization of stable microtubules.


Important role of insulin and flow in stimulating glucose uptake in contracting skeletal muscle.
The relative role of contractions, insulin, and increased supply of glucose and insulin, via an increase in blood flow, in stimulating glucose uptake in skeletal muscle during contractions was studied in isolated perfused rat hindlimbs. Hindlimbs were perfused with a standard perfusate medium containing 6 mmol/l glucose and four different insulin concentrations (0, 100, 500, and 20,000 microU/ml). Contractions were induced by supramaximal intermittent electrical stimulation of the sciatic nerve. Three different perfusion protocols were used: 1) muscles were stimulated to contract without concomitantly increasing perfusate flow; 2) flow was increased in the absence of electrical stimulation; and 3) muscles were stimulated to contract together with a flow increase. Both contractions and increased flow of perfusate, applied as separate stimuli, increased (P < 0.05) glucose uptake in the absence of insulin. Yet when submaximal insulin concentrations were added to the perfusate, the stimulatory action of both contractions and increased blood flow on muscle glucose uptake was augmented. The higher the submaximal insulin concentration, the greater the increment (P < 0.05). This effect, however, faded at supramaximal insulin concentration. Electrical stimulation associated with an increase in perfusion flow rate produced a greater (P < 0.05) rise in glucose uptake than did contractions alone. In fact, stimulation of muscle glucose uptake by contractions and increased flow proved to be additive at any insulin concentration. We conclude that contractions and increased blood flow act as additional stimuli to muscle glucose uptake at any insulin concentration.(ABSTRACT TRUNCATED AT 250 WORDS)


[Presence of B cell clones in acute myelomonocytic leukemia].
The coexistence of acute myeloid leukemia and chronic lymphocytic leukemia in the same patient is rare. The majority of the cases correspond to patients that developed acute leukemia during the evolutionary course of a chronic lymphatic leukemia following treatment with chemotherapy drugs. We report a case of acute myelomonocytic leukemia concurrent with untreated B-cell chronic lymphocytic leukemia in which the use of flow cytometry analysis with a large panel of monoclonal antibodies, allowed the demonstration of different pathological populations and determine immunophenotyping patterns. Published cases of simultaneous chronic lymphocytic leukemia and acute leukemia are reviewed. The use of multiparametric flow cytometry to differentiate the populations demonstrates the utility of this technology in the diagnosis of these hematological malignancies.


Barriers and Facilitating Factors for Implementation of Genetic Services: A Public Health Perspective.
More than 15 years after the publication of the sequence of the human genome, the resulting changes in health care have been modest. At the same time, some promising examples in genetic services become visible, which contribute to the prevention of chronic disease such as cancer. These are discussed to identify barriers and facilitating factors for the implementation of genetic services. Examples from oncogenetics illustrate a high risk of serious disease where prevention is possible, especially in relatives. Some 5% of breast cancers and colorectal cancers are attributable to an inherited predisposition. These cancers occur at a relatively young age. DNA testing of relatives of affected patients may facilitate primary and secondary prevention. Training of non-genetic health care workers and health technology assessment are needed, as is translational research in terms of bringing genomics to health care practice while monitoring and evaluating. Stratified screening programs could include cascade screening and risk assessment based on family history. New roles and responsibilities will emerge. A clear assessment of the values implied is needed allowing to balance the pros and cons of interventions to further the responsible innovation of genetic services.


Photochemical-biological treatment of a real industrial biorecalcitrant wastewater containing 5-amino-6-methyl-2-benzimidazolone.
5-amino-6-methyl-2-benzimidazolone (AMBI), used in the manufacture of dyes, was characterised as a biorecalcitrant compound by means of different biodegradability tests. In order to enhance the biodegradability of this important pollutant, the application of Advanced Oxidation Process (AOPs) as a pretreatment was explored. Some experiments were addressed to find the most efficient AOP. The systems H2O2/hv, TiO2/H2O2/hv, Fe3+/hv, Fe3+/H2O2 and Fe3+/H2O2/hv were compared. The photo-Fenton system was the most efficient and the optimal conditions (AMBI, Fe3+, H2O2 concentrations) for the degradation of AMBI were found. During the photo-Fenton degradation, experiments were also made to obtain information concerning the evolution of: (a) organic carbon and initial compound concentration; (b) the oxidation state; (c) the toxicity; (d) the biodegradability; and (e) the chemical nature of the intermediates. These analyses show that the solution resulting from the treatment of AMBI is biologically compatible and complete mineralisation can be performed by biological means. A combined photochemical (Fenton) and biological flow reactor for the degradation of AMBI was successfully operated in continuous mode at laboratory scale. 100% of the initial concentration of AMBI and 80.3% of Dissolved Organic Carbon (DOC) were removed in 3.5 hours of total residence time. Finally, some field experiments under direct sunlight carried out at the Plataforma Solar de Almeria, Spain, demonstrated that this solar catalytic system is an effective treatment for this kind of industrial wastewater.


Robust Intensity Modulated Proton Therapy (IMPT) Increases Estimated Clinical Benefit in Head and Neck Cancer Patients.
To compare the clinical benefit of robust optimized Intensity Modulated Proton Therapy (minimax IMPT) with current photon Intensity Modulated Radiation Therapy (IMRT) and PTV-based IMPT for head and neck cancer (HNC) patients. The clinical benefit is quantified in terms of both Normal Tissue Complication Probability (NTCP) and target coverage in the case of setup and range errors. For 10 HNC patients, PTV-based IMRT (7 fields), minimax and PTV-based IMPT (2, 3, 4, 5 and 7 fields) plans were tested on robustness. Robust optimized plans differed from PTV-based plans in that they target the CTV and penalize possible error scenarios, instead of using the static isotropic CTV-PTV margin. Perturbed dose distributions of all plans were acquired by simulating in total 8060 setup (±3.5 mm) and range error (±3%) combinations. NTCP models for xerostomia and dysphagia were used to predict the clinical benefit of IMPT versus IMRT. The robustness criterion was met in the IMRT and minimax IMPT plans in all error scenarios, but this was only the case in 1 of 40 PTV-based IMPT plans. Seven (out of 10) patients had relatively large NTCP reductions in minimax IMPT plans compared to IMRT. For these patients, xerostomia and dysphagia NTCP values were reduced by 17.0% (95% CI; 13.0-21.1) and 8.1% (95% CI; 4.9-11.2) on average with minimax IMPT. Increasing the number of fields did not contribute to plan robustness, but improved organ sparing. The estimated clinical benefit in terms of NTCP of robust optimized (minimax) IMPT is greater than that of IMRT and PTV-based IMPT in HNC patients. Furthermore, the target coverage of minimax IMPT plans in the presence of errors was comparable to IMRT plans.


Not all proteinuria is created equal.
Albuminuria acts as a marker of progressive chronic kidney disease and as an indicator for initiation of hypertension treatment via modulation of the renin-angiotensin-aldosterone system with angiotensin receptor blockers or angiotensin-converting enzyme inhibitors. However, the true significance of albuminuria has yet to be fully defined. Is it merely a marker of underlying pathophysiology, or does it play a causal role in the progression of kidney disease? The answer remains under debate. In this issue of the JCI, Bedin et al. used next-generation sequencing data to identify patients with chronic proteinuria who had biallelic variants in the cubilin gene (CUBN). Through investigation of these pathogenic mutations in CUBN, the authors have further illuminated the clinical implications of albuminuria.


Evaluation of duration of corneal anesthesia induced with ophthalmic 0.5% proparacaine hydrochloride by use of a Cochet-Bonnet aesthesiometer in clinically normal horses.
To measure duration of corneal anesthesia and time and degree of maximal anesthetic effect of 0.5% proparacaine hydrochloride by use of a Cochet-Bonnet aesthesiometer in horses. 10 clinically normal adult horses. Baseline corneal touch threshold (CTT) was measured in millimeters for 1 randomly selected eye of each horse by use of the aesthesiometer by applying the filament to the cornea at maximum length (60 mm) and decreasing in 5-mm increments until a consistent blink response was elicited. Following baseline CTT measurement, 0.2 mL of 0.5% proparacaine hydrochloride was instilled in the selected eye. The CTT was measured within 1 minute following proparacaine administration and every 5 minutes thereafter for 60 minutes. A mixed-model ANOVA with tested eye varying between subjects and measurement time varying within subject was used to test for main effects and any interaction between these factors. A contrast between means of baseline and each subsequent CTT identified the duration of corneal anesthesia as the time at which there was no difference from baseline. Maximal anesthetic effect occurred at the time with the lowest mean CTT. Duration of corneal anesthesia achieved by use of proparacaine was 25 minutes, and maximal anesthetic effect occurred within 5 minutes, although CTT never went to 0 in any horse at any time. Duration of corneal anesthesia in horses was shorter than in dogs, and degree of maximal effect was less than in cats and dogs, most likely because of increased sensitivity of the equine cornea, compared with corneal sensitivity in those species.