Environmental supportiveness for physical activity in English schoolchildren: a study using Global Positioning Systems.
There is increasing evidence that the environment plays a role in influencing physical activity in children and adults. As children have less autonomy in their behavioural choices, neighbourhood environment supportiveness may be an important determinant of their ability to be active. Yet we know rather little about the types of environment that children use for bouts of physical activity. This study uses accelerometery and global positioning system technologies to identify the charactieristics of environments being used for bouts of continuous moderate to vigorous physical activity (MVPA) in a sample of English schoolchildren. The study used a convenience sample of 100 children from SPEEDY (Sport, Physical activity and Eating behaviour: Environmental Determinants in Young people), a cohort of 2064 9-10 year-olds from Norfolk, England, recruited in 2007. Children wore an ActiGraph GT1M accelerometer and a Garmin Forerunner 205 GPS unit over four consecutive days. Accelerometery data points were matched to GPS locations and bouts (5 minutes or more) of MVPA were identified. Bout locations were overlaid with a detailed landcover dataset developed in a GIS to identify the types of environment supporting MVPA. Findings are presented using descriptive statistics. Boys were also more active than girls, spending an average of 20 (SD 23) versus 11 (SD 15) minutes per day in MVPA bouts. Children who spent more time outside the home were more active (p = 0.002), especially girls and children living in rural locations (both p < 0.05). Children tended to be active close to home, with 63% of all bout time occurring inside neighbourhoods, although boys (p = 0.05) and rural children (p = 0.01) were more likely to roam outside their neighbourhood. Amongst urban children, gardens (28% of bout time) and the street environment (20%) were the most commonly used environments for MVPA bouts. Amongst rural children farmland (22%) and grassland (18%) were most frequently used. The study has developed a new methodology for the identification of environments in which bouts of continuous physical activity are undertaken. The results highlight the importance of the provision of urban gardens and greenspaces, and the maintenance of safe street environments as places for children to be active.


Fluvastatin Inhibits HMG-CoA Reductase and Prevents Non-Small Cell Lung Carcinogenesis.
Lung cancer is the leading cause of cancer-related death worldwide. However, promising agents for lung cancer prevention are still very limited. Identification of preventive targets and novel effective preventive agents is urgently needed for clinical applications. In this study, we found that fluvastatin targeted 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR), which a rate-limiting enzyme in the mevalonate pathway, and inhibited non-small cell lung cancer (NSCLC) tumorigenesis. Initially, we demonstrated that HMGCR is overexpressed in human lung adenocarcinoma tissues compared with normal tissues. Knockdown of HMGCR in NSCLC cells attenuated growth and induced apoptosis in vitro and in vivo Furthermore, we found that fluvastatin, an inhibitor of HMGCR, suppressed NSCLC cell growth and induced apoptosis. Intriguingly, fluvastastin functions by inhibiting the HMGCR-driven Braf/MEK/ERK1/2 and Akt signaling pathways. Notably, fluvastatin attenuated tumor growth in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis and in a patient-derived xenograft lung tumor model. Overall, our findings suggest that fluvastatin might be promising chemopreventive or potential therapeutic drug against NSCLC tumorigenesis, providing hope for rapid clinical translation.


The Asplenic Patient: Post-Insult Immunocompetence, Infection, and Vaccination.
Splenic injury can occur through multiple mechanisms and may result in various degrees of residual immunocompetence. Functionally or anatomically asplenic patients are at higher risk for infection, particularly with encapsulated bacteria. Vaccination is recommended to prevent infection with these organisms; however, the recommendations are routinely updated, and vaccine selection and timing are complex. Review of the pertinent English-language literature, including the recommendations of the U.S. Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices. Overwhelming post-splenectomy infection is associated with high morbidity and mortality rates. Patients requiring splenectomy for trauma-related injury appear to be at lower risk for infection than those undergoing splenectomy for a hematologic or oncologic indication. Initial vaccination is dependent on immunization history but generally should consist of the 13-valent pneumococcal conjugate, quadrivalent meningococcal conjugate, meningococcal serogroup B, and Haemophilus influenzae serotype b (Hib) vaccines. Antimicrobial prophylaxis for certain asplenic patients, such as children under the age of five y, may be indicated. Immunization remains a key measure to prevent overwhelming post-splenectomy infection. Consideration of new recommendations and indications, possible interactions, and timing remains important to including optimal response to the vaccines.


Exploring why quality circles work in primary health care: a realist review protocol.
Quality circles (QCs) are commonly used in primary health care in Europe to consider and improve standard practice over time. They represent a complex social intervention that occurs within the fast-changing system of primary health care. Numerous controlled trials, reviews, and studies have shown small but unpredictable positive effect sizes on behavior change. Although QCs seem to be effective, stakeholders have difficulty understanding how the results are achieved and in generalizing the results with confidence. They also lack understanding of the active components of QCs which result in changes in the behavior of health care professionals. This protocol for a realist synthesis will examine how configurations of components and the contextual features of QCs influence their performance. Stakeholder interviews and a scoping search revealed the processes of QCs and helped to describe their core components and underlying theories. After clarifying their historical and geographical distribution, a purposive and systematic search was developed to identify relevant papers to answer the research questions, which are: understanding why, how, and when QCs work, over what time frame, and in what circumstances. After selecting and abstracting appropriate data, configurations of contexts and mechanisms which influence the outcome of QCs within each study will be identified. Studies will be grouped by similar propositional statements in order to identify patterns and validation from stakeholders sought. Finally, theories will be explored in order to explain these patterns and to help stakeholders maintain and improve QC performance. Analyzing context-mechanism-outcome (CMO) patterns will reveal how QCs work and how contextual factors interact to influence their outcome. The aim is to investigate unique configurations that enable them to improve the performance of health care professionals. Using a standardized reporting system, this realist review will allow the research questions to be answered to the satisfaction of key stakeholders and enable on-going critical examination and dissemination of the findings. PROSPERO registration number: CRD42013004826.


Sexual Positioning Among Men Who Have Sex With Men: A Narrative Review.
Sexual positioning practices among men who have sex with men (MSM) have not received a thorough discussion in the MSM and HIV literature, given that risks for acquiring or transmitting HIV and STIs via condomless anal sex vary according to sexual positioning. MSM bear a disproportionate burden of HIV compared to the general population in the United States; surveillance efforts suggest that HIV and STIs are increasing among domestic and international populations of MSM. We conducted a narrative review, using a targeted literature search strategy, as an initial effort to explore processes through which sexual positioning practices may contribute to HIV/STI transmission. Peer-reviewed articles were eligible for inclusion if they contained a measure of sexual positioning identity and/or behavior (i.e., "top", "bottom," etc.) or sexual positioning behavior (receptive anal intercourse or insertive anal intercourse), or assessed the relationship between sexual positioning identity with HIV risk, anal sex practice, masculinity, power, partner type, or HIV status. A total of 23 articles met our inclusion criteria. This review highlights dynamic psychosocial processes likely underlying sexual decision making related to sexual positioning identity and practices among MSM and MSM who have sex with women (MSMW), and ways these contexts may influence HIV/STI risk. Despite limited focus in the extant literature, this review notes the important role the contextual factors (masculinity stereotypes, power, partner type, and HIV status) likely to play in influencing sexual positioning identity and practices. Through this review we offer an initial synthesis of the literature describing sexual positioning identities and practices and conceptual model to provide insight into important areas of study through future research.


Targeting the stem cell niche: role of collagen XVII in skin aging and wound repair.
The skin epidermis and appendages undergo ongoing renewal throughout life. Stem cells residing in the epidermis and hair follicles are pivotal for sustaining skin homeostasis. The self-renewal ability of stem cells significantly decreases during skin aging but actively increases during wound repair. Residential stem cells reside in niches that provide spatially distinct microenvironments for stem cell maintenance and function. Cell-extracellular matrix (ECM) adhesion is essential for the establishment of niche architecture. Collagen XVII (COL17), as a transmembrane protein constituting hemidesmosomes (HDs), mediates the interactions of stem cells with surrounding cells and the matrix to regulate skin homeostasis, aging and wound repair. This review focuses on the pivotal role of the niche component COL17 in stem cell maintenance and its function in regulation of skin aging and wound repair.


Oral health-related quality of life is linked with subjective well-being and depression in early old age.
Although a body of research has targeted predictors of well-being and depression in old age, the consideration of oral health-related quality of life (OHRQoL) as a predictor of these major psychosocial endpoints has been rare in the previous literature. The objective of this study was to test whether OHRQoL is associated with well-being and depression, after controlling for relevant confounders; also, the mediating role of subjective health, a major predictor of both well-being and depression, has been explored. OHRQoL was measured by two commonly used assessment instruments, the geriatric oral health assessment index (GOHAI) and oral health impact profile (OHIP); well-being was assessed by the Philadelphia Geriatric Center Morale Scale (PGCMS) and depression by the self-rating depression scale (SDS). We used a subsample of 197 participants from the older cohort (1930-1932) of the Interdisciplinary Longitudinal Study of Adult Development. Regression models and structural equations modeling (SEM) were used for the test for study variable relationships. Both GOHAI and OHIP revealed significant associations to both PGCMS and SDS at the bivariate level. In regression analyses considering gender, household situation, subjective health, and both OHRQoL indicators, only OHIP remained a significant predictor of well-being and depression. In addition, supportive evidence for a mediating role of subjective health regarding the linkage between OHRQoL and an overall latent construct of well-being was found in the SEM analysis. In conclusion, OHRQoL is significantly linked with well-being and depression in old age, while subjective health is able to mediate the relationship. The generally underrated role of OHRQoL with respect to well-being and depression in late adulthood deserves more attention.


Does Sagittal Spinopelvic Configuration Influence Vertebral Fracture Type or Localization in Trauma Patients?: A Retrospective Radiologic Analysis.
Retrospective data analysis. The aim of this study was to analyze correlations between spinopelvic configuration and fracture pattern or location in traumatic vertebral fractures. The spinopelvic configuration represented by the pelvic incidence (PI) angle showed to have a strong correlation with the occurrence of degenerative diseases of the thoracolumbar spine. No data are available on whether there is an influence of the PI angle on traumatic vertebral lesions as well. In a consecutive series of patients sustaining traumatic vertebral fractures, we retrospectively analyzed spinopelvic computed tomography data sets of 197 patients (121 male and 76 female patients; mean age, 51 years). Measurements included the PI angle, level of fracture(s), and fracture type according to the AO classification. Statistical analysis was performed to calculate correlation between PI and fracture level and between PI and fracture type. An average of 1.6 fractures per patient was found in the 197 individuals included in our study. PI angle showed a mean of 50.6 degrees for the left hip and a mean of 49.9 degrees for the right hip. There were no significant differences of the PI angle between male and female patients as well. Neither a significant effect of the PI angle on the vertebral fracture level (P=0.64) nor a significant relationship between the PI angle and the fracture type according to the AO classification (P=0.52) was found. The spinopelvic configuration represented by PI angle seems to influence neither the level nor the type of vertebral fractures in trauma patients.


Diabetes and hyperglycemia quality improvement efforts in hospitals in the United States: current status, practice variation, and barriers to implementation.
To determine the status of diabetes and hyperglycemia quality improvement efforts in hospitals in the United States. We designed and administered a survey to a convenience sample of hospitals, and the responses were analyzed statistically. We received 269 responses from 1,151 requested surveys. The sample was similar to hospitals in the United States on the basis of hospital type and geographic region (P = no significant difference) but not on the basis of number of beds (P<.001). Among responding hospitals, 39%, 21%, and 15% had fully implemented inpatient diabetes and hyperglycemia quality improvement programs for critically ill, non-critically ill, and perioperative patients, respectively. Moreover, 77%, 44%, and 49% had fully implemented protocols for hypoglycemia, hyperglycemic crises, and diabetic ketoacidosis, respectively. Variations in glucose target ranges were noted. The responding hospitals had no standard biochemical definition of hypoglycemia; 47% defined hypoglycemia as a glucose level <or=70 mg/dL, but 29%, 8%, 6%, and 4% used <60, <50, <40, and <80 mg/dL, respectively. Almost a third of reporting hospitals had no metric to track the quality of inpatient diabetes and hyperglycemia care. More than half (59%) indicated that they did not have an automated capability to extract and analyze glucose data. The most frequent barrier to implementing a glycemic control program was concern regarding hypoglycemia (61%). Hospitals are addressing the issue of inpatient diabetes and glycemic control but face obstacles to implementation of quality improvement programs and vary in their approach to management. Improving the consistency of glucose control practices within hospitals in the United States should help enhance patient care and safety. Future efforts to help hospitals overcome barriers to introducing glucose control programs could include developing standardized glycemic control metrics, improving data collection and reporting methods, and providing improved tools that enable clinicians to control glucose safely.


Current epidemiology and antenatal presentation of posterior urethral valves: Outcome of BAPS CASS National Audit.
Posterior urethral valves (PUVs) are the most common cause of congenital bladder outlet obstruction (BOO) in boys and end-stage renal failure (ESRF) in childhood. In the 1980s, 1 in 4000 boys had PUV. Presentation was 1/3 antenatal/neonatally, 1/3 postnatal, 1/3 late (>1 year). This study aimed to describe the current proportions in a contemporary cohort. A national audit (BAPS CASS) of referrals in the UK and Ireland of boys diagnosed with suspected or confirmed PUV in a year was conducted. National registration data provided the male birth-rate. Data were presented as number (%), analysed by Mann-Whitney U-test and Chi-square test, with P < 0.05 taken as significant. The study was approved by a national ethics committee (NRES Committee South Central Oxford A (12/SC/0416)). Data were collected from 1st October 2014 to 30th September 2015 from 25/26 centres on 121 cases of suspected bladder outlet obstruction (BOO), of which 113 (93%) were because of PUV. The male birth rate during the period was 432,806/year. The calculated incidence of BOO was 1/3580 and for PUV was 1/3800 per-annum. The proportion of PUV presenting according to age was: antenatally (n = 40, 35%), infancy (n = 47, 42%), and late (n = 26, 23%). Plasma creatinine was higher in antenatally-diagnosed BOO vs. postnatal, 54 (39.5-109.5) μmol/l vs. 34(21-47) μmol/l, P = 0.0005. Hydronephrosis and ureteric dilatation were significantly greater in antenatally diagnosed BOO vs. postnatal vs. late. Renal dysplasia (cortical thinning, poor corticomedullary differentiation, or renal cysts) was significantly more likely in antenatally diagnosed BOO. Neither the incidence (~1/4000) nor the proportion antenatally diagnosed (~1/3) of boys with PUV appears to have changed in the past 30 years. Those boys who were antenatally diagnosed have significantly higher postnatal plasma creatinine, more hydroureteronephrosis, and renal dysplasia than those diagnosed in infancy or later. It may be hypothesized that this is the reason they are detected antenatally. Prognosis study - Level I - prospective national cohort study.


Self-management in bipolar disorder: the story so far.
Research suggests that psychoeducation, relapse prevention and recovery are all the key aspects of psychological treatment for bipolar disorder and the common components of self-management programmes. This review traces the origins of self-management interventions as it appears in physical health research and evaluates the current evidence associated with self-management interventions for depression and more specifically for bipolar disorder. Literature review. Despite significant clinical and cost benefits associated with self-management programmes for physical and mental health problems, to date there has been less progress in the development of self-management interventions for bipolar disorder. Preliminary evidence indicates that people with bipolar disorder will engage with self-management support. The rapid development and evaluation of self-management programmes for bipolar disorder is an important research and clinical priority.


Interplay of choline metabolites and genes in patient-derived breast cancer xenografts.
Dysregulated choline metabolism is a well-known feature of breast cancer, but the underlying mechanisms are not fully understood. In this study, the metabolomic and transcriptomic characteristics of a large panel of human breast cancer xenograft models were mapped, with focus on choline metabolism. Tumor specimens from 34 patient-derived xenograft models were collected and divided in two. One part was examined using high-resolution magic angle spinning (HR-MAS) MR spectroscopy while another part was analyzed using gene expression microarrays. Expression data of genes encoding proteins in the choline metabolism pathway were analyzed and correlated to the levels of choline (Cho), phosphocholine (PCho) and glycerophosphocholine (GPC) using Pearson's correlation analysis. For comparison purposes, metabolic and gene expression data were collected from human breast tumors belonging to corresponding molecular subgroups. Most of the xenograft models were classified as basal-like (N = 19) or luminal B (N = 7). These two subgroups showed significantly different choline metabolic and gene expression profiles. The luminal B xenografts were characterized by a high PCho/GPC ratio while the basal-like xenografts were characterized by highly variable PCho/GPC ratio. Also, Cho, PCho and GPC levels were correlated to expression of several genes encoding proteins in the choline metabolism pathway, including choline kinase alpha (CHKA) and glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5). These characteristics were similar to those found in human tumor samples. The higher PCho/GPC ratio found in luminal B compared with most basal-like breast cancer xenograft models and human tissue samples do not correspond to results observed from in vitro studies. It is likely that microenvironmental factors play a role in the in vivo regulation of choline metabolism. Cho, PCho and GPC were correlated to different choline pathway-encoding genes in luminal B compared with basal-like xenografts, suggesting that regulation of choline metabolism may vary between different breast cancer subgroups. The concordance between the metabolic and gene expression profiles from xenograft models with breast cancer tissue samples from patients indicates that these xenografts are representative models of human breast cancer and represent relevant models to study tumor metabolism in vivo.


A sulfur-based transport pathway in Cu+-ATPases.
Cells regulate copper levels tightly to balance the biogenesis and integrity of copper centers in vital enzymes against toxic levels of copper. PIB -type Cu(+)-ATPases play a central role in copper homeostasis by catalyzing the selective translocation of Cu(+) across cellular membranes. Crystal structures of a copper-free Cu(+)-ATPase are available, but the mechanism of Cu(+) recognition, binding, and translocation remains elusive. Through X-ray absorption spectroscopy, ATPase activity assays, and charge transfer measurements on solid-supported membranes using wild-type and mutant forms of the Legionella pneumophila Cu(+)-ATPase (LpCopA), we identify a sulfur-lined metal transport pathway. Structural analysis indicates that Cu(+) is bound at a high-affinity transmembrane-binding site in a trigonal-planar coordination with the Cys residues of the conserved CPC motif of transmembrane segment 4 (C382 and C384) and the conserved Met residue of transmembrane segment 6 (M717 of the MXXXS motif). These residues are also essential for transport. Additionally, the studies indicate essential roles of other conserved intramembranous polar residues in facilitating copper binding to the high-affinity site and subsequent release through the exit pathway.


Sip1 regulates the generation of the inner nuclear layer retinal cell lineages in mammals.
The transcription factor Sip1 (Zeb2) plays multiple roles during CNS development from early acquisition of neural fate to cortical neurogenesis and gliogenesis. In humans, SIP1 (ZEB2) haploinsufficiency leads to Mowat-Wilson syndrome, a complex congenital anomaly including intellectual disability, epilepsy and Hirschsprung disease. Here we uncover the role of Sip1 in retinogenesis. Somatic deletion of Sip1 from mouse retinal progenitors primarily affects the generation of inner nuclear layer cell types, resulting in complete loss of horizontal cells and reduced numbers of amacrine and bipolar cells, while the number of Muller glia is increased. Molecular analysis places Sip1 downstream of the eye field transcription factor Pax6 and upstream of Ptf1a in the gene network required for generating the horizontal and amacrine lineages. Intriguingly, characterization of differentiation dynamics reveals that Sip1 has a role in promoting the timely differentiation of retinal interneurons, assuring generation of the proper number of the diverse neuronal and glial cell subtypes that constitute the functional retina in mammals.


Feeling unreal: a PET study of depersonalization disorder.
The goal of this study was to assess brain glucose metabolism and its relationship to dissociation measures and clinical symptoms in DSM-IV depersonalization disorder. Positron emission tomography scans coregistered with magnetic resonance images of eight subjects with depersonalization disorder were compared to those of 24 healthy comparison subjects. The two groups did not differ in age, sex, education, performance on a baseline neuropsychological battery, or performance on a verbal learning task administered during [(18)F]fluorodeoxyglucose uptake. A cortical analysis by individual Brodmann's areas was performed. Compared to the healthy subjects, subjects with depersonalization disorder showed significantly lower metabolic activity in right Brodmann's areas 22 and 21 of the superior and middle temporal gyri and had significantly higher metabolism in parietal Brodmann's areas 7B and 39 and left occipital Brodmann's area 19. Dissociation and depersonalization scores among the subjects with depersonalization disorder were significantly positively correlated with metabolic activity in area 7B. Depersonalization appears to be associated with functional abnormalities along sequential hierarchical areas, secondary and cross-modal, of the sensory cortex (visual, auditory, and somatosensory), as well as areas responsible for an integrated body schema. These findings are in good agreement with the phenomenological conceptualization of depersonalization as a dissociation of perceptions as well as with the subjective symptoms of depersonalization disorder.


The signal transducing photoreceptors of plants.
Light signals are amongst the most important environmental cues regulating plant development. In addition to light quantity, plants measure the quality, direction and periodicity of incident light and use the information to optimise growth and development to the prevailing environmental conditions. Red and far-red wavelengths are perceived by the photoreversible phytochrome family of photoreceptors, whilst the detection of blue and ultraviolet (UV)-A wavelengths is conferred by the cryptochromes and phototropins. Higher plants contain multiple discrete phytochromes, the apoproteins of which are encoded by a small divergent gene family. In Arabidopsis, two cryptochrome and two phototropin family members have been identified and characterized. Photoreceptor action regulates development throughout the lifecycle of plants, from seed germination through to architecture of the mature plant and the onset of reproduction. The roles of individual photoreceptors in mediating plant development have, however, often been confounded by redundant, synergistic and in some cases mutually antagonistic mechanisms of action. The isolation of mutants null for individual photoreceptors and the construction of mutants null for multiple photoreceptors have therefore been paramount in elucidating photoreceptor functions. Photoreceptor action does not, however, operate in isolation from other signalling systems. The integration of light signals with other environmental cues enables plants to adapt their physiology to changing seasonal environments. This paper summarises current understanding of photoreceptor families and their functions throughout the lifecycle of plants. The integration of light signals with other environmental stimuli is also discussed.


Spilocaea oleagina in Olive Groves of Southern Spain: Survival, Inoculum Production, and Dispersal.
Olive scab caused by the mitosporic fungus Spilocaea oleagina is the most important foliar disease of olive. Limited information is available on pathogen survival and disease epidemiology; however, this information is essential for development of new control strategies. Pathogen survival and inoculum production on infected olive leaves and conidial dispersal were evaluated during 4 years in an olive orchard of the susceptible 'Picual' in southern Spain. Infected leaves in the tree canopy were important for pathogen survival and conidia production. The number of conidia per square centimeter of scab lesion and their viability varied greatly throughout the seasons and between years; conidial density in lesions was highest (about 1 to 5 × 105 conidia cm-2) from November to February in favorable years. Conidial density declined sharply in other periods of the year (becoming zero in summer) or in less favorable years. The pathogen did not form new conidia in scab lesions, although some pseudothecia-like structures and chlamydospores were detected on fallen leaves. Under humid conditions, the pathogen could not be detected on fallen leaves after 3 months because the leaves were colonized by saprophytic fungi. The dispersal of conidia as a function of distance from infected leaves in the tree canopy was well described by an exponential model which, together with the lack of conidia in a Burkard spore trap, showed that conidia were mainly rain-splash dispersed. Some trapped conidia were attached to olive leaf trichomes, suggesting that detached trichomes might enhance wind dispersal of conidia.


Thoracic radiation therapy alone compared with combined chemoradiotherapy for locally unresectable non-small cell lung cancer. A randomized, phase III trial.
To compare the survival of patients with medically inoperable or unresectable stage III non-small cell lung cancer treated with thoracic radiotherapy alone or in combination with chemotherapy. Randomized, prospective phase III trial. Multi-institutional cooperative oncology group. A total of 121 patients were enrolled in the study, of whom 7 (5.8%) were ineligible. All patients were ambulatory and had measurable or evaluable disease. Before they were randomized, patients were stratified by ECOG performance score, histologic type, maximum tumor diameter, and NCCTG institution. Radiotherapy consisted of a total of 5000 cGy in 5 weeks with a 1000 cGy boost in 5 fractions to a small tumor field. Combined modality therapy was MACC which is intravenous methotrexate, intravenous doxorubicin, intravenous cyclophosphamide, and oral lomustine (CCNU), on day 1 and 28. Chemotherapy was followed by identical thoracic radiotherapy 4 weeks after the second cycle of chemotherapy. Four weeks after thoracic radiotherapy was completed, patients received another two cycles of identical chemotherapy. Patients who had progression of disease after chest irradiation only were treated with MACC chemotherapy. Major clinical responses were observed in 31 of 56 (55%; 95% Cl, 42% to 68%) patients treated with combination therapy and 37 of 58 (64%; Cl, 51% to 76%) treated with radiation only (P greater than 0.2). The median time to progression was 192 days with radiotherapy only compared with 199 days for combined modality therapy (P greater than 0.2). The median survival time was 313 days compared with 317 days, respectively (P greater than 0.2). The 1-, 2-, and 5-year survival rates after thoracic radiation only were 45% (Cl, 32% to 58%), 16% (Cl, 6% to 25%), and 7%. With chemoradiotherapy, the survival rates were 46% (Cl, 33% to 60%), 21% (Cl, 11% to 32%), and 5%, respectively. Myelosuppression was significantly greater for the combined modality therapy arm (P = 0.002). Chemotherapy with MACC, in combination with thoracic radiotherapy, did not result in significant survival advantage compared with radiation alone (P greater than 0.2) in patients with medically inoperable or unresectable stage III non-small cell lung cancer.


Impact of Increasing Dietary Calcium Levels on Calcium Excretion and Vitamin D Metabolites in the Blood of Healthy Adult Cats.
Dietary calcium (Ca) concentrations might affect regulatory pathways within the Ca and vitamin D metabolism and consequently excretory mechanisms. Considering large variations in Ca concentrations of feline diets, the physiological impact on Ca homeostasis has not been evaluated to date. In the present study, diets with increasing concentrations of dicalcium phosphate were offered to ten healthy adult cats (Ca/phosphorus (P): 6.23/6.02, 7.77/7.56, 15.0/12.7, 19.0/17.3, 22.2/19.9, 24.3/21.6 g/kg dry matter). Each feeding period was divided into a 10-day adaptation and an 8-day sampling period in order to collect urine and faeces. On the last day of each feeding period, blood samples were taken. Urinary Ca concentrations remained unaffected, but faecal Ca concentrations increased (P < 0.001) with increasing dietary Ca levels. No effect on whole and intact parathyroid hormone levels, fibroblast growth factor 23 and calcitriol concentrations in the blood of the cats were observed. However, the calcitriol precursors 25(OH)D2 and 25(OH)D3, which are considered the most useful indicators for the vitamin D status, decreased with higher dietary Ca levels (P = 0.013 and P = 0.033). Increasing dietary levels of dicalcium phosphate revealed an acidifying effect on urinary fasting pH (6.02) and postprandial pH (6.01) (P < 0.001), possibly mediated by an increase of urinary phosphorus (P) concentrations (P < 0.001). In conclusion, calcitriol precursors were linearly affected by increasing dietary Ca concentrations. The increase in faecal Ca excretion indicates that Ca homeostasis of cats is mainly regulated in the intestine and not by the kidneys. Long-term studies should investigate the physiological relevance of the acidifying effect observed when feeding diets high in Ca and P.


Single capillary permeability to proteins having similar size but different charge.
We investigated the hypothesis that solute charge modulates transcapillary exchange in microvessels with continuous endothelium. Two globular proteins, alpha-lactalbumin and ribonuclease, having approximately the same size (mol wt 14,176 and 13,683, respectively) but different net charge (-10 and +4, respectively) were test solutes. Each solute was labeled with the fluorescent probe tetramethylrhodamine isothiocyanate. Labeling did not significantly change solute size, but increased negative charge on each solute by one valency unit. An in vivo fluorescent microscope technique [Huxley et. al., Am. J. Physiol. 252 (Heart Circ. Physiol. 21): H188-H197, 1987] was used to measure solute permeability coefficients (P) in single microvessels of frog mesentery at 14-16 degrees C. The mean P for alpha-lactalbumin, measured when capillary pressure was 10 cmH2O, was 2.1 X 10(-6) cm/s and the mean P for ribonuclease was 4.3 X 10(-6) cm/s. Our results conform to the hypothesis that the transcapillary pathways of frog mesenteric microvessels are negatively charged. With the use of a Donnan-type model for electrostatic partitioning, charge density in the pathway is estimated as 11.4 meq/l. Comparison of measured Ps with those for small solutes in frog mesenteric microvessels indicates that molecular size is a proportionally more significant determinant of solute permeability in continuous capillaries than is solute charge.


Twenty-year Follow-up of Kangaroo Mother Care Versus Traditional Care.
Kangaroo mother care (KMC) is a multifaceted intervention for preterm and low birth weight infants and their parents. Short- and mid-term benefits of KMC on survival, neurodevelopment, breastfeeding, and the quality of mother-infant bonding were documented in a randomized controlled trial (RCT) conducted in Colombia from 1993 to 1996. The aim of the present study was to evaluate the persistence of these results in young adulthood. From 2012 to 2014, a total of 494 (69%) of the 716 participants of the original RCT known to be alive were identified; 441 (62% of the participants in the original RCT) were re-enrolled, and results for the 264 participants weighing ≤1800 g at birth were analyzed. The KMC and control groups were compared for health status and neurologic, cognitive, and social functioning with the use of neuroimaging, neurophysiological, and behavioral tests. The effects of KMC at 1 year on IQ and home environment were still present 20 years later in the most fragile individuals, and KMC parents were more protective and nurturing, reflected by reduced school absenteeism and reduced hyperactivity, aggressiveness, externalization, and socio-deviant conduct of young adults. Neuroimaging showed larger volume of the left caudate nucleus in the KMC group. This study indicates that KMC had significant, long-lasting social and behavioral protective effects 20 years after the intervention. Coverage with this efficient and scientifically based health care intervention should be extended to the 18 million infants born each year who are candidates for the method.


Neurodevelopmental outcome of nutritional intervention in newborn infants at risk of neurodevelopmental impairment: the Dolphin neonatal double-blind randomized controlled trial.
To investigate whether neonates at risk for neurodevelopmental impairment have improved neurodevelopment after docosahexaenoic acid, choline, and uridine-5-monophosphate supplementation versus controls. Recruitment was from UK neonatal units. Eligible for inclusion were infants born at less than 31 weeks' gestation with a weight less than the ninth centile; infants born at less than 31 weeks' gestation with a grade II or higher intraventricular haemorrhage/preterm white matter injury; infants born between 31 weeks' and 40 weeks' gestation plus 28 days with a grade II or higher intraventricular haemorrhage/preterm white matter injury, moderate or severe hypoxic-ischaemic encephalopathy, or defined neuroimaging abnormalities. Treatment/control supplementation was for 2 years (double-blind, randomized, controlled design). Infants were stratified according to sex, gestation, and brain injury severity. Primary outcome was cognitive composite score (CCS) of the Bayley Scales of Infant Development, Third Edition (Bayley-III at 24mo). Secondary outcomes were language composite score (LCS) of the Bayley-III, motor composite score (MCS) of the Bayley-III, and Vineland Adaptive Behaviour Scales, Second Edition (VABS-II) score. Sixty-two neonates were recruited, 59 were randomized (34 males, 25 females). Fifty-three started supplementation. Most families found supplementation acceptable. The treatment group CCS-Bayley-III scores were non-significantly higher than controls (mean score difference at 24mo: 9.0; 95% confidence interval -0.2 to 18.2). Language and VABS-II scores, but not motor score, were non-significantly higher in the treatment group. Most families found supplementation feasible. Improved neurodevelopmental outcomes in the treatment group were not statistically significant. A larger multicentre trial exploration is warranted. Dietary supplementation of neonates at risk of neurodevelopmental impairment is feasible. No statistically significant neurodevelopmental advantages were identified for the treatment group compared to controls. Treatment group cognitive and language advantage are of a clinically meaningful magnitude.


Diagnosis and management of genitofemoral neuralgia.
Genitofemoral neuralgia is a syndrome characterized by chronic pain and paresthesia in the region of genitofemoral nerve distribution. Genitofemoral nerve entrapment has been described after inguinal herniorrhaphy, appendectomy, and cesarean section. Failure to distinguish it from ilioinguinal nerve entrapment can result in unnecessary inguinal reexploration, or patients severely debilitated from chronic pain. We recommend that patients with persistent pain and paresthesia in the inguinal region following surgery should have a local ilioinguinal nerve block. If this is unsuccessful in affecting relief of symptoms, a paravertebral block of L-1 and L-2 should be considered. Using these two blocks, a rational decision can then be made to operate on either the ilioinguinal nerve or the genitofemoral nerve. We describe three cases of genitofemoral neuralgia treated by extraperitoneal excision of the genitofemoral nerve.


Cell density-dependent nuclear accumulation of ELK3 is involved in suppression of PAI-1 expression.
Cell-cell contact regulates the proliferation and differentiation of non-transformed cells, e.g., NIH/3T3 cells show growth arrest at high cell density. However, only a few reports described the dynamic behavior of transcription factors involved in this process. In this study, we showed that the mRNA levels of plasminogen activator inhibitor type 1 (PAI-1) decreased drastically at high cell density, and that ELK3, a member of the Ets transcription factor family, repressed PAI-1 expression. We also demonstrated that while ELK3 was distributed evenly throughout the cell at low cell density, it accumulated in the nucleus at high cell density, and that binding of DNA by ELK3 at the A domain facilitated its nuclear accumulation. Furthermore, we found that ETS1, a PAI-1 activator, occupied the ELK3-binding site within the PAI-1 promoter at low cell density, while it was released at high cell density. These results suggest that at high cell density, the switching of binding of transcription factors from ETS1 to ELK3 occurs at a specific binding site of the PAI-1 promoter, leading to the cell-density dependent suppression of PAI-1 expression.


Biology of the Greenland shark Somniosus microcephalus.
Greenland shark Somniosus microcephalus is a potentially important yet poorly studied cold-water species inhabiting the North Atlantic and Arctic Oceans. Broad-scale changes in the Arctic ecosystem as a consequence of climate change have led to increased attention on trophic dynamics and the role of potential apex predators such as S. microcephalus in the structure of Arctic marine food webs. Although Nordic and Inuit populations have caught S. microcephalus for centuries, the species is of limited commercial interest among modern industrial fisheries. Here, the limited historical information available on S. microcephalus occurrence and ecology is reviewed and new catch, biological and life-history information from the Arctic and North Atlantic Ocean region is provided. Given the considerable by-catch rates in high North Atlantic Ocean latitudes it is suggested that S. microcephalus is an abundant predator that plays an important, yet unrecognized, role in Arctic marine ecosystems. Slow growth and large pup sizes, however, may make S. microcephalus vulnerable to increased fishing pressure in a warming Arctic environment.


A possible role for the endocannabinoid system in the neurobiology of depression.
The present review synthetically describes the currently advanced hypotheses for a neurobiological basis of depression, ranging from the classical monoaminergic to the more recent neurotrophic hypothesis. Moreover, the Authors review the available preclinical and clinical evidence suggesting a possible role for the endocannabinoid system in the physiopathology of depression. Indeed, in spite of the reporting of conflicting results, the pharmacological enhancement of endocannabinoid activity at the CB1 cannabinoid receptor level appears to exert an antidepressant-like effect in some animal models of depression. On the contrary, a reduced activity of the endogenous cannabinoid system seems to be associated with the animal model of depression, namely the chronic mild stress model. Moreover, a few studies have reported an interaction of antidepressants with the endocannabinoid system. With regard to clinical studies, several authors have reported an alteration of endocannabinoid serum levels in depression, while post mortem studies have demonstrated increased levels of endocannabinoids associated to a concomitant hyperactivity of CB1 receptor in the prefrontal cortex of suicide victims. No clinical trials carried out using cannabinoids in the treatment of affective disorders have been published to date, although anecdotal reports have described both antidepressant and antimanic properties of cannabis as well as the ability of cannabis to induce mania that has also been documented. These findings are discussed, leading us to conclude that, although data available are sufficient to suggest a possible involvement of the endogenous cannabinoid system in the neurobiology of depression, additional studies should be performed in order to better elucidate the role of this system in the physiopathology of depression.


Are antifibrinolytic drugs equivalent in reducing blood loss and transfusion in cardiac surgery? A meta-analysis of randomized head-to-head trials.
Aprotinin has been shown to be effective in reducing peri-operative blood loss and the need for re-operation due to continued bleeding in cardiac surgery. The lysine analogues tranexamic acid (TXA) and epsilon aminocaproic acid (EACA) are cheaper, but it is not known if they are as effective as aprotinin. Studies were identified by searching electronic databases and bibliographies of published articles. Data from head-to-head trials were pooled using a conventional (Cochrane) meta-analytic approach and a Bayesian approach which estimated the posterior probability of TXA and EACA being equivalent to aprotinin; we used as a non-inferiority boundary a 20% increase in the rates of transfusion or re-operation because of bleeding. Peri-operative blood loss was significantly greater with TXA and EACA than with aprotinin: weighted mean differences were 106 mls (95% CI 37 to 227 mls) and 185 mls (95% CI 134 to 235 mls) respectively. The pooled relative risks (RR) of receiving an allogeneic red blood cell (RBC) transfusion with TXA and EACA, compared with aprotinin, were 1.08 (95% CI 0.88 to 1.32) and 1.14 (95% CI 0.84 to 1.55) respectively. The equivalent Bayesian posterior mean relative risks were 1.15 (95% Bayesian Credible Interval [BCI] 0.90 to 1.68) and 1.21 (95% BCI 0.79 to 1.82) respectively. For transfusion, using a 20% non-inferiority boundary, the posterior probabilities of TXA and EACA being non-inferior to aprotinin were 0.82 and 0.76 respectively. For re-operation the Cochrane RR for TXA vs. aprotinin was 0.98 (95% CI 0.51 to 1.88), compared with a posterior mean Bayesian RR of 0.63 (95% BCI 0.16 to 1.46). The posterior probability of TXA being non-inferior to aprotinin was 0.92, but this was sensitive to the inclusion of one small trial. The available data are conflicting regarding the equivalence of lysine analogues and aprotinin in reducing peri-operative bleeding, transfusion and the need for re-operation. Decisions are sensitive to the choice of clinical outcome and non-inferiority boundary. The data are an uncertain basis for replacing aprotinin with the cheaper lysine analogues in clinical practice. Progress has been hampered by small trials and failure to study clinically relevant outcomes.


Bones hold the key to DNA virus history and epidemiology.
DNA in human skeletal remains represents an important historical source of host genomic information and potentially of infecting viruses. However, little is known about viral persistence in bone. We searched ca. 70-year-old long bones of putative Finnish casualties from World War II for parvovirus B19 (B19V) DNA, and found a remarkable prevalence of 45%. The viral sequences were exclusively of genotypes 2 (n = 41), which disappeared from circulation in 1970´s, or genotype 3 (n = 2), which has never been reported in Northern Europe. Based on mitochondrial and Y-chromosome profiling, the two individuals carrying B19V genotype 3 were likely from the Soviet Red Army. The most recent common ancestor for all genotypes was estimated at early 1800s. This work demonstrates the forms of B19V that circulated in the first half of the 20(th) century and provides the first evidence of the suitability of bone for exploration of DNA viruses.


Are social judgements made by children in relation to orthodontic appliances?
There is evidence to suggest that social judgements are made on the basis of dental appearance. This study sought to determine how children view other children with fixed orthodontic appliances. Cross-sectional, self-completion questionnaire. Year 7 (aged 11-12 years) and year 10 (aged 14-15 years) school children (the participants) were invited to look at colour photographs of one girl and one boy (the subjects) and to make a social judgement about these children. Participants were randomly allocated either pictures of the two children without fixed orthodontic appliances or pictures of the same children with fixed orthodontic appliances. Using a previously validated child-centred questionnaire, participants rated subjects using a four-point Likert scale for three negative and six positive attributes. Multivariate analysis of variance was used to determine whether participant year group or gender and the presence of the orthodontic appliance had a significant effect on total attribute score. Three hundred and twenty-two children completed the questionnaires, giving a response rate of 69%. There was a significant effect of year group (P = 0.003) and gender of the participant (P = 0.031) on the attribute score. There was no effect according to the presence or absence of an orthodontic appliance (P = 0.791). Female participants gave more positive ratings than their male peers. This study has found that children do not make social judgements about other children purely on the basis of wearing a fixed orthodontic appliance, suggesting that they are viewed as part of a normal dental appearance in adolescence.


Staff expectations on implementing new electronic applications in a changing organization.
This study was undertaken to describe staff expectations prior to implementation of new electronic applications in a changing organization. Changes are a part of human existence; changes based on implementation of technology and information and communication technology are taking place in the health care sector globally. The Swedish public health care and social care sector is taking a similar path. A qualitative approach with group interviews of 23 staff divided in 5 groups was performed. Latent content analysis was used to analyze the transcribed interviews. The theme, taking standpoint today in relation to the past, emerged from 3 areas of discussion: "distance holding," "ruled by the organization," and "health care development in the future." New restraints on staff affect the caregiving process. Managers should consider whether a particular change is revolutionary or evolutionary and act in the change process according to the possible psychological impact of the change.


Assessment for Subclinical Kidney Damage in Workers Exposed to Low Concentrations of Hydrocarbons.
It has been suggested the risk of hydrocarbon-induced chronic nephropathy is negligible at low exposure levels. The first purpose of the study was to test this hypothesis by selecting a population slightly exposed to hydrocarbons. Moreover, as hypertension might be associated with an increased excretion of nephrotoxic mercapturates, the association between blood pressure and urinary concentration of S-phenylmercapturic acid (S-PMA) was also examined. Lifetime exposure assessment, main tests of subclinical kidney damage, and statistical approach were taken from a previous study that had included primarily moderately or heavily exposed workers and had found hydrocarbon-induced nephrotoxic effects. No nephrotoxic effect of exposure could be ascertained in the present study. S-PMA concentration was not increased in hypertensive workers. Thus, the risk of hydrocarbon-induced chronic nephropathy might be extremely low in workers slightly exposed to hydrocarbons. The negative results of some studies might be due to the low lifetime hydrocarbon exposures of the study populations.


Inefficiency of orientation averaging: Evidence for hybrid serial/parallel temporal integration.
Intuition suggests that increased viewing time should allow for the accumulation of more visual information, but scant support for this idea has been found in studies of voluntary averaging, where observers are asked to make decisions based on perceived average size. In this paper we examine the dynamics of information accrual in an orientation-averaging task. With orientation (unlike intensive dimensions such as size), it is relatively safe to use an item's physical value as an approximation for its average perceived value. We displayed arrays containing eight iso-eccentric Gabor patterns, and asked six trained psychophysical observers to compare their average orientation with that of probe stimuli that were visible before, during, or only after the presentation of the Gabor array. From the relationship between orientation variance and human performance, we obtained estimates of effective set size, i.e., the number of items that an ideal observer would need to assess in order to estimate average orientation as well as our human observers did. We found that display duration had only a modest influence on effective set size. It rose from an average of ∼2 for 0.1-s displays to an average of ∼3 for 3.3-s displays. These results suggest that the visual computation is neither purely serial nor purely parallel. Computations of this nature can be made with a hybrid process that takes a series of subsamples of a few elements at a time.


[Specific features of neurological complications developing in patients with type 2 diabetes mellitus and metabolic syndrome: possibility for correction and prevention].
The prevalence of type 2 diabetes mellitus (DM) and preceding metabolic disturbances has reached epidemic proportions. Oxidative stress plays a significant role in the development of micro- and macrovascular complications in patients with DM. The accumulation of free radicals is responsible for the development of systemic and vascular inflammation, endothelial dysfunction, and hypercoagulable and ischemic states. Since vascular and nervous system damages do not level off even under adequate glycemic control, there is a need for complex pathogenetic treatment strategies. Antioxidant therapy using mexidol is one of the compulsory components of combination therapy for complications of DM.


Exploring genetic influences on cognition: emerging strategies for target validation and treatment optimization.
Genomic research has produced an abundance of new candidate targets that remain to be validated as potential treatments for neuropsychiatric disorders. Functional neuroimaging, meanwhile, has provided detailed new insights into the neural circuits involved in emotional and cognitive control. At the growing interface between these independent lines of progress, new efforts are underway to unify our understanding of regional brain function with that of genetic and biochemical influences on behavior. Such a unified understanding of the mechanisms involved in cognitive and emotional control may open up new avenues for therapeutic intervention at the pharmacological and behavioral levels. In line with this, a new initiative sponsored by the National Institutes of Mental Health (NIMH) aims to bridge gaps between clinical diagnostics and the molecular processes that influence susceptibility to psychiatric disorders. A major goal of this initiative is to identify the neural and neurochemical substrates of basic cognitive processes that are disrupted in psychiatric disorders and to examine the influence of genetic factors at the cognitive level. This review describes some well-known findings that are at the forefront of this interface. The progress already made indicates that the goals of the new initiative are well founded and achievable.


Fear and Trembling of Cruise Ship Employees: Psychological Effects of the COVID-19 Pandemic.
The current COVID-19 pandemic has evolved to unprecedented proportions. This research aimed to gain a deeper understanding of the psychological effects of the COVID-19 pandemic on cruise ship employees stuck at sea. Using an inductive qualitative approach, a synchronous online focus group was conducted with nine cruise ship employees who were stuck at sea during COVID-19 pandemic. The findings revealed that COVID-19 pandemic has managed to erase the feeling of joy from cruise ship employees who were stuck at sea while exposing weakness of cruise line companies such as poor human resource management leadership. Moreover, COVID-19 pandemic demonstrated that it is of paramount importance that cruise line companies create a comprehensive strategy in assisting their employees who are experiencing an anxiety disorder and depression. The managerial implications are outlined.


Acanthamoeba and Dictyostelium as Cellular Models for Legionella Infection.
Environmental bacteria of the genus Legionella naturally parasitize free-living amoebae. Upon inhalation of bacteria-laden aerosols, the opportunistic pathogens grow intracellularly in alveolar macrophages and can cause a life-threatening pneumonia termed Legionnaires' disease. Intracellular replication in amoebae and macrophages takes place in a unique membrane-bound compartment, the Legionella-containing vacuole (LCV). LCV formation requires the bacterial Icm/Dot type IV secretion system, which translocates literally hundreds of "effector" proteins into host cells, where they modulate crucial cellular processes for the pathogen's benefit. The mechanism of LCV formation appears to be evolutionarily conserved, and therefore, amoebae are not only ecologically significant niches for Legionella spp., but also useful cellular models for eukaryotic phagocytes. In particular, Acanthamoeba castellanii and Dictyostelium discoideum emerged over the last years as versatile and powerful models. Using genetic, biochemical and cell biological approaches, molecular interactions between amoebae and Legionella pneumophila have recently been investigated in detail with a focus on the role of phosphoinositide lipids, small and large GTPases, autophagy components and the retromer complex, as well as on bacterial effectors targeting these host factors.


Miniature grating for spectrally-encoded endoscopy.
Spectrally-encoded endoscopy (SEE) is an ultraminiature endoscopy technology that acquires high-definition images of internal organs through a sub-mm endoscopic probe. In SEE, a grating at the tip of the imaging optics diffracts the broadband light into multiple beams, where each beam with a distinctive wavelength is illuminated on a unique transverse location of the tissue. By encoding one transverse coordinate with the wavelength, SEE can image a line of the tissue at a time without using any beam scanning devices. This feature of the SEE technology allows the SEE probe to be miniaturized to sub-mm dimensions. While previous studies have shown that SEE has the potential to be utilized for various clinical imaging applications, the translation of SEE for medicine has been hampered by challenges in fabricating the miniature grating inherent to SEE probes. This paper describes a new fabrication method for SEE probes. The new method uses a soft lithographic approach to pattern a high-aspect-ratio grating at the tip of the miniature imaging optics. Using this technique, we have constructed a 500 μm-diameter SEE probe. The miniature grating at the tip of the probe had a measured diffraction efficiency of 75%. The new SEE probe was used to image a human finger and formalin fixed mouse embryos, demonstrating the capability of this device to visualize key anatomic features of tissues with high image contrast. In addition to providing high quality imaging SEE optics, the soft lithography method allows cost-effective and reliable fabrication of these miniature endoscopes, which will facilitate the clinical translation of SEE technology.


Classification algorithm for the International Classification of Diseases-11 chronic pain classification: development and results from a preliminary pilot evaluation.
The International Classification of Diseases-11 (ICD-11) chronic pain classification includes about 100 chronic pain diagnoses on different diagnostic levels. Each of these diagnoses requires specific operationalized diagnostic criteria to be present. The classification comprises more than 200 diagnostic criteria. The aim of the Classification Algorithm for Chronic Pain in ICD-11 (CAL-CP) is to facilitate the use of the classification by guiding users through these diagnostic criteria. The diagnostic criteria were ordered hierarchically and visualized in accordance with the standards defined by the Society for Medical Decision Making Committee on Standardization of Clinical Algorithms. The resulting linear decision tree underwent several rounds of iterative checks and feedback by its developers, as well as other pain experts. A preliminary pilot evaluation was conducted in the context of an ecological implementation field study of the classification itself. The resulting algorithm consists of a linear decision tree, an introduction form, and an appendix. The initial decision trunk can be used as a standalone algorithm in primary care. Each diagnostic criterion is represented in a decision box. The user needs to decide for each criterion whether it is present or not, and then follow the respective yes or no arrows to arrive at the corresponding ICD-11 diagnosis. The results of the pilot evaluation showed good clinical utility of the algorithm. The CAL-CP can contribute to reliable diagnoses by structuring a way through the classification and by increasing adherence to the criteria. Future studies need to evaluate its utility further and analyze its impact on the accuracy of the assigned diagnoses.


Back to Acid Soil Fields: The Citrate Transporter SbMATE Is a Major Asset for Sustainable Grain Yield for Sorghum Cultivated on Acid Soils.
Aluminum (Al) toxicity damages plant roots and limits crop production on acid soils, which comprise up to 50% of the world's arable lands. A major Al tolerance locus on chromosome 3, AltSB, controls aluminum tolerance in sorghum [Sorghum bicolor (L.) Moench] via SbMATE, an Al-activated plasma membrane transporter that mediates Al exclusion from sensitive regions in the root apex. As is the case with other known Al tolerance genes, SbMATE was cloned based on studies conducted under controlled environmental conditions, in nutrient solution. Therefore, its impact on grain yield on acid soils remains undetermined. To determine the real world impact of SbMATE, multi-trait quantitative trait loci (QTL) mapping in hydroponics, and, in the field, revealed a large-effect QTL colocalized with the Al tolerance locus AltSB, where SbMATE lies, conferring a 0.6 ton ha(-1) grain yield increase on acid soils. A second QTL for Al tolerance in hydroponics, where the positive allele was also donated by the Al tolerant parent, SC283, was found on chromosome 9, indicating the presence of distinct Al tolerance genes in the sorghum genome, or genes acting in the SbMATE pathway leading to Al-activated citrate release. There was no yield penalty for AltSB, consistent with the highly localized Al regulated SbMATE expression in the root tip, and Al-dependent transport activity. A female effect of 0.5 ton ha(-1) independently demonstrated the effectiveness of AltSB in hybrids. Al tolerance conferred by AltSB is thus an indispensable asset for sorghum production and food security on acid soils, many of which are located in developing countries.


Primary aldosteronism due to unilateral adrenal hyperplasia: a case report.
Primary aldosteronism is one of the differential diagnosis of secondary hypertension. This is usually caused by an aldosterone producing adenoma or bilateral adrenal hyperplasia which comprise about 65% and 30% of the cases, respectively. However, less than 1% of primary aldosteronism is caused by unilateral adrenal hyperplasia which is a relatively rare subset of primary aldosteronism. The clinical and biochemical manifestations of the disorder are indistinguishable from aldosterone-producing tumor, and a definitive diagnosis can only be made by pathological finding. A 33-year-old male Chinese patient presented with hypertension, hypokalemia, metabolic alkalosis, and the hypersecretion of aldosterone associated with suppressed plasma renin activity which is a typical hallmark of primary aldosteronism. Image studies including both magnetic resonance imaging (MRI) and 131I NIP-59 scan as well as postural test suggested an aldosterone-producing tumor of the right adrenal gland. Unilateral adrenectomy and pathological examination of the right adrenal gland eventually proved a case of unilateral adrenal hyperplasia. Blood pressure, plasma potassium, aldosterone and renin activity levels returned to normal two weeks after operation and had remained normal at up to one year of follow up. In addition, a saline loading test showed normal suppression of plasma aldosterone level one year after the operation, suggesting that the function of the left adrenal gland remains normal. The etiology of unilateral adrenal hyperplasia is unclear and the future recurrence of the disease is possible. Long-term follow-up is necessary to ensure the cure of this disorder.


Preclinical evaluation of an mRNA HIV vaccine combining rationally selected antigenic sequences and adjuvant signals (HTI-TriMix).
The development of a prophylactic vaccine against HIV-1 has so far not been successful. Therefore, attention has shifted more and more toward the development of novel therapeutic vaccines. Here, we evaluated a new mRNA-based therapeutic vaccine against HIV-1-encoding activation signals (TriMix: CD40L + CD70 + caTLR4) combined with rationally selected antigenic sequences [HIVACAT T-cell immunogen (HTI)] sequence: comprises 16 joined fragments from Gag, Pol, Vif, and Nef). For this purpose, peripheral blood mononuclear cells from HIV-1-infected individuals on cART, lymph node explants from noninfected humans, and splenocytes from immunized mice were collected and several immune functions were measured. Electroporation of immature monocyte-derived dendritic cells from HIV-infected patients with mRNA encoding HTI + TriMix potently activated dendritic cells which resulted in upregulation of maturation markers and cytokine production and T-cell stimulation, as evidenced by enhanced proliferation and cytokine secretion (IFN-γ). Responses were HIV specific and were predominantly targeted against the sequences included in HTI. These findings were confirmed in human lymph node explants exposed to HTI + TriMix mRNA. Intranodal immunizations with HTI mRNA in a mouse model increased antigen-specific cytotoxic T-lymphocyte responses. The addition of TriMix further enhanced cytotoxic responses. Our results suggest that uptake of mRNA, encoding strong activation signals and a potent HIV antigen, confers a T-cell stimulatory capacity to dendritic cells and enhances their ability to stimulate antigen-specific immunity. These findings may pave the way for therapeutic HIV vaccine strategies based on antigen-encoding RNA to specifically target antigen-presenting cells.


The European NAFLD Registry: A real-world longitudinal cohort study of nonalcoholic fatty liver disease.
Non-Alcoholic Fatty Liver Disease (NAFLD), a progressive liver disease that is closely associated with obesity, type 2 diabetes, hypertension and dyslipidaemia, represents an increasing global public health challenge. There is significant variability in the disease course: the majority exhibit only fat accumulation in the liver but a significant minority develop a necroinflammatory form of the disease (non-alcoholic steatohepatitis, NASH) that may progress to cirrhosis and hepatocellular carcinoma. At present our understanding of pathogenesis, disease natural history and long-term outcomes remain incomplete. There is a need for large, well characterised patient cohorts that may be used to address these knowledge gaps and to support the development of better biomarkers and novel therapies. The European NAFLD Registry is an international, prospectively recruited observational cohort study that aims to establish a large, highly-phenotyped patient cohort and linked bioresource. Here we describe the infrastructure, data management and monitoring plans, and the standard operating procedures implemented to ensure the timely and systematic collection of high-quality data and samples. Already recruiting subjects at secondary/tertiary care centres across Europe, the Registry is supporting the European Union IMI2-funded LITMUS 'Liver Investigation: Testing Marker Utility in Steatohepatitis' consortium, which is a major international effort to robustly validate biomarkers that diagnose, risk stratify and/or monitor NAFLD progression and liver fibrosis stage. The European NAFLD Registry has the demonstrable capacity to support research and biomarker development at scale and pace.


Integrative oncology drug discovery accompanied by preclinical translational research as prerequisite for clinical development.
The molecular heterogeneity of cancer calls for individualized therapies to become the standard of care. It is now generally accepted that target-specific compounds require specific new development programs. But, even for new drugs with general mode of action (i.e., chemotherapy), tailored treatment approaches, such as specific schedules or combinations, have been shown to improve the therapeutic outcome. Therefore, the preclinical development of new therapeutic agents needs, next to the "classical pharmacodynamic studies", the implementation of integrative translational research (TR) as early as possible. New TR approaches, starting already at target identification and validation (TIV) will allow to defining the optimal patient population for clinical development, to tailor individual treatment of the tumor disease and to choose a rational basis among the manifold options for treatment combinations. We will discuss several examples from TR studies, which have initially been started to evaluate the molecular mode of action and to recognize mechanisms which can lead to resistance. Research was extended later to identify predictive response biomarkers and establish a rationale for combination with different therapies. A detailed gene expression analysis of lung cancer cells and apoptotic pathway interference studies in colon cancer cells provided insight in the molecular mechanisms of action. These new findings are correlated with results from other studies performed during the preclinical development program. We discuss pros and cons, successes and failures of our integrative preclinical development program and provide recommendations for future oncology projects.


Microbially Guided Discovery and Biosynthesis of Biologically Active Natural Products.
The design of small molecules that inhibit disease-relevant proteins represents a longstanding challenge of medicinal chemistry. Here, we describe an approach for encoding this challenge-the inhibition of a human drug target-into a microbial host and using it to guide the discovery and biosynthesis of targeted, biologically active natural products. This approach identified two previously unknown terpenoid inhibitors of protein tyrosine phosphatase 1B (PTP1B), an elusive therapeutic target for the treatment of diabetes and cancer. Both inhibitors appear to target an allosteric site, which confers selectivity, and can inhibit PTP1B in living cells. A screen of 24 uncharacterized terpene synthases from a pool of 4464 genes uncovered additional hits, demonstrating a scalable discovery approach, and the incorporation of different PTPs into the microbial host yielded alternative PTP-specific detection systems. Findings illustrate the potential for using microbes to discover and build natural products that exhibit precisely defined biochemical activities yet possess unanticipated structures and/or binding sites.


Rapid degradation of oseltamivir phosphate in clinical samples by plasma esterases.
The anti-influenza drug oseltamivir is an ester prodrug activated by hepatic carboxylesterases. Plasma esterases also convert up to 31.8% of the parent compound to the active metabolite after 4 h ex vivo, with wide interindividual variation. This source of error is removed by adding the esterase inhibitor dichlorvos to blood collection tubes.


Altered expressions of VEGF mRNA splice variants during progression of uterine-peritoneal adhesions in the rat.
Postoperative pelvic adhesions contribute to infertility, pelvic pain, bowel obstruction, and difficult reoperative procedures. In the present study, a rat uterine-peritoneal adhesion model was developed to study the progression of adhesion formation during a course of 7 days following pelvic surgery. The distal 1 cm of each uterine horn and its adjacent peritoneum was abraded by six scratches with a scalpel blade, producing punctate bleeding. The scratched portion of uterine horn and the peritoneum was then held with Vicryl 3-0 to promote adhesion. The uterine tissue and the portion of peritoneum, held with suture, were then excised from a group of four rats, each at 6, 12, 24, 48, 72 hr and 5 and 7 days following surgery. Total RNA was isolated from these tissues and the expression pattern of different splice variants of vascular endothelial growth factors (VEGF) was examined using relative abundance reverse transcriptase polymerase chain reaction (RA-RT-PCR) method. Three known splice variants of VEGF mRNA (VEGF120, VEGF164 and VEGF188), as well as an additional band (approximately 510 bp), were amplified from these tissues. The relative abundance of known VEGF isoforms demonstrated altered expression during adhesion progression. When compared with noninjured uterine tissues, VEGF120 and VEGF188 demonstrated up-regulation during early stages of adhesion formation, whereas VEGF164 rather demonstrated down-regulation 24 and 48 hr following surgery. The up-regulation of VEGF isoforms during the progression of uterine-peritoneal adhesion may be a compensatory mechanism regulating angiogenesis in order to provide nutrients and oxygen to the injured tissues.


Mitochondrial DNA perspective of Serbian genetic diversity.
Although south-Slavic populations have been studied to date from various aspects, the population of Serbia, occupying the central part of the Balkan Peninsula, is still genetically understudied at least at the level of mitochondrial DNA (mtDNA) variation. We analyzed polymorphisms of the first and the second mtDNA hypervariable segments (HVS-I and HVS-II) and informative coding-region markers in 139 Serbians to shed more light on their mtDNA variability, and used available data on other Slavic and neighboring non-Slavic populations to assess their interrelations in a broader European context. The contemporary Serbian mtDNA profile is consistent with the general European maternal landscape having a substantial proportion of shared haplotypes with eastern, central, and southern European populations. Serbian population was characterized as an important link between easternmost and westernmost south-Slavic populations due to the observed lack of genetic differentiation with all other south-Slavic populations and its geographical positioning within the Balkan Peninsula. An increased heterogeneity of south Slavs, most likely mirroring turbulent demographic events within the Balkan Peninsula over time (i.e., frequent admixture and differential introgression of various gene pools), and a marked geographical stratification of Slavs to south-, east-, and west-Slavic groups, were also found. A phylogeographic analyses of 20 completely sequenced Serbian mitochondrial genomes revealed not only the presence of mtDNA lineages predominantly found within the Slavic gene pool (U4a2a*, U4a2a1, U4a2c, U4a2g, HV10), supporting a common Slavic origin, but also lineages that may have originated within the southern Europe (H5*, H5e1, H5a1v) and the Balkan Peninsula in particular (H6a2b and L2a1k).


Smoothening of wrinkles in CVD-grown hexagonal boron nitride films.
Hexagonal boron nitride (h-BN) is an ideal substrate for two-dimensional (2D) materials because of its unique electrically insulating nature, atomic smoothness and low density of dangling bonds. Although mechanical exfoliation from bulk crystals produces the most pristine flakes, scalable fabrication of devices is still dependent on other more direct synthetic routes. To date, the most utilized method to synthesize large-area h-BN films is by chemical vapor deposition (CVD) using catalytic metal substrates. However, a major drawback for such synthetic films is the manifestation of thermally-induced wrinkles, which severely disrupt the smoothness of the h-BN films. Here, we provide a detailed characterization study of the microstructure of h-BN wrinkles and demonstrate an effective post-synthesis smoothening route by thermal annealing in air. The smoothened h-BN film showed an improved surface smoothness by up to 66% and resulted in a much cleaner surface due to the elimination of polymer residues with no substantial oxidative damage to the film. The unwrinkling effect is attributed to the hydroxylation of the h-BN film as well as the substrate surface, resulting in a reduction in adhesion energy at the interface. Dehydroxylation occurs over time under ambient conditions at room temperature and the smoothened film can be restored back with the intrinsic properties of h-BN. This work provides an efficient route to achieve smoother h-BN films, which are beneficial for high-performance 2D heterostructure devices.


Single nucleotide polymorphism discovery in elite North American potato germplasm.
Current breeding approaches in potato rely almost entirely on phenotypic evaluations; molecular markers, with the exception of a few linked to disease resistance traits, are not widely used. Large-scale sequence datasets generated primarily through Sanger Expressed Sequence Tag projects are available from a limited number of potato cultivars and access to next generation sequencing technologies permits rapid generation of sequence data for additional cultivars. When coupled with the advent of high throughput genotyping methods, an opportunity now exists for potato breeders to incorporate considerably more genotypic data into their decision-making. To identify a large number of Single Nucleotide Polymorphisms (SNPs) in elite potato germplasm, we sequenced normalized cDNA prepared from three commercial potato cultivars: 'Atlantic', 'Premier Russet' and 'Snowden'. For each cultivar, we generated 2 Gb of sequence which was assembled into a representative transcriptome of ~28-29 Mb for each cultivar. Using the Maq SNP filter that filters read depth, density, and quality, 575,340 SNPs were identified within these three cultivars. In parallel, 2,358 SNPs were identified within existing Sanger sequences for three additional cultivars, 'Bintje', 'Kennebec', and 'Shepody'. Using a stringent set of filters in conjunction with the potato reference genome, we identified 69,011 high confidence SNPs from these six cultivars for use in genotyping with the Infinium platform. Ninety-six of these SNPs were used with a BeadXpress assay to assess allelic diversity in a germplasm panel of 248 lines; 82 of the SNPs proved sufficiently informative for subsequent analyses. Within diverse North American germplasm, the chip processing market class was most distinct, clearly separated from all other market classes. The round white and russet market classes both include fresh market and processing cultivars. Nevertheless, the russet and round white market classes are more distant from each other than processing are from fresh market types within these two groups. The genotype data generated in this study, albeit limited in number, has revealed distinct relationships among the market classes of potato. The SNPs identified in this study will enable high-throughput genotyping of germplasm and populations, which in turn will enable more efficient marker-assisted breeding efforts in potato.


Low Temperature Affects Stem Cell Maintenance in Brassica oleracea Seedlings.
Most of the above ground tissues in higher plants originate from stem cells located in the shoot apical meristem (SAM). Several plant species can suffer from spontaneous stem cell arrest resulting in lack of further shoot development. In Brassica oleracea this SAM arrest is known as blindness and occurs in an unpredictable manner leading to considerable economic losses for plant raisers and farmers. Detailed analyses of seedlings showed that stem cell arrest is triggered by low temperatures during germination. To induce this arrest reproducibly and to study the effect of the environment, an assay was developed. The role of genetic variation on the susceptibility to develop blind seedlings was analyzed by a quantitative genetic mapping approach, using seeds from a double haploid population from a cross between broccoli and Chinese kale, produced at three locations. The analysis revealed, besides an effect of the seed production location, a region on linkage group C3 associated with blindness sensitivity. A subsequent dynamic genome-wide transcriptome analysis resulted in the identification of around 3000 differentially expressed genes early after blindness induction. A large number of cell cycle genes were en masse induced early during the development of blindness, whereas shortly after, all were down-regulated. This miss-regulation of core cell cycle genes is accompanied with a strong reduction of cells reaching the DNA replication phase. From the differentially expressed genes, 90 were located in the QTL region C3. Among them are two genes belonging to the MINICHROMOSOMAL MAINTENANCE gene family, known to be involved in DNA replication, a RETINOBLASTOMA-RELATED gene, a key regulator for cell cycle initiation, and several MutS homologs genes, involved in DNA repair. These genes are potential candidates for being involved in the development of blindness in Brassica oleracea sensitive genotypes.


Comparing low-pass sequencing and genotyping for trait mapping in pharmacogenetics.
Low pass sequencing has been proposed as a cost-effective alternative to genotyping arrays to identify genetic variants that influence multifactorial traits in humans. For common diseases this typically has required both large sample sizes and comprehensive variant discovery. Genotyping arrays are also routinely used to perform pharmacogenetic (PGx) experiments where sample sizes are likely to be significantly smaller, but clinically relevant effect sizes likely to be larger. To assess how low pass sequencing would compare to array based genotyping for PGx we compared a low-pass assay (in which 1x coverage or less of a target genome is sequenced) along with software for genotype imputation to standard approaches. We sequenced 79 individuals to 1x genome coverage and genotyped the same samples on the Affymetrix Axiom Biobank Precision Medicine Research Array (PMRA). We then down-sampled the sequencing data to 0.8x, 0.6x, and 0.4x coverage, and performed imputation. Both the genotype data and the sequencing data were further used to impute human leukocyte antigen (HLA) genotypes for all samples. We compared the sequencing data and the genotyping array data in terms of four metrics: overall concordance, concordance at single nucleotide polymorphisms in pharmacogenetics-related genes, concordance in imputed HLA genotypes, and imputation r2. Overall concordance between the two assays ranged from 98.2% (for 0.4x coverage sequencing) to 99.2% (for 1x coverage sequencing), with qualitatively similar numbers for the subsets of variants most important in pharmacogenetics. At common single nucleotide polymorphisms (SNPs), the mean imputation r2 from the genotyping array was 0.90, which was comparable to the imputation r2 from 0.4x coverage sequencing, while the mean imputation r2 from 1x sequencing data was 0.96. These results indicate that low-pass sequencing to a depth above 0.4x coverage attains higher power for association studies when compared to the PMRA and should be considered as a competitive alternative to genotyping arrays for trait mapping in pharmacogenetics.


Results with commercial radioassay kits compared with microbiological assay of folate in serum and whole-blood.
We compared results with three commercial folate radioassay kits [Bio-Rad, New England Nuclear (NEN), and RIA Products] with those by microbiological assay for more than 200 samples of human serum and whole blood. All but one kit (NEN) compared favorably with the microbiological assay for serum samples, although there were notable diagnostic discrepancies. Two kits (NEN and Bio-Rad) were tested on whole-blood samples; both yielded values significantly higher than those by microbiological assay. The frequency distributions of erythrocyte folate data differed strikingly between the two kits; the NEN method yielded a much narrower range of normal values than did either the Bio-Rad or the microbiological assay. Radioassay kits appear to be suitable diagnostic agents for serum folate, if the behavior of a particular kit is investigated thoroughly before its routine use. However, the diagnostic value of radioassays of erythrocyte folate needs to be validated.


Using BMI to determine cardiovascular risk in childhood: how do the BMI cutoffs fare?
Although adverse health outcomes are increased among children with BMI above the 85th (overweight) and 95th (obese) percentiles, previous studies have not clearly defined the BMI percentile at which adverse health outcomes begin to increase. We examined whether the existing BMI percentile cutoffs are optimal for defining increased risk for dyslipidemia, dysglycemia, and hypertension. This was a cross-sectional analysis of the National Health and Nutrition Examination Survey from 2001 to 2006. Studied were 8216 children aged 6 to 17 years, representative of the US population. BMI was calculated by using measured height and weight and converted to percentiles for age in months and gender. Outcome measures (dyslipidemia, dysglycemia, and hypertension) were based on laboratory and physical examination results; these were analyzed as both continuous and categorical outcomes. Significant increases for total cholesterol values and prevalence of abnormal cholesterol begin at the 80th percentile. Significant increases in glycohemoglobin values and prevalence of abnormal values begin at the 99th percentile. Consistent significant increases in the prevalence of high or borderline systolic blood pressure begin at the 90th percentile. Intervening for overweight children and their health requires clinical interventions that target the right children. On the basis of our data, a judicious approach to screening could include consideration of lipid screening for children beginning at the 80th percentile but for dysglycemia at the 99th percentile. Current definitions of overweight and obese may be more useful for general recognition of potential health problems and discussions with parents and children about the need to address childhood obesity.


Hypoxia-Inducible PIM Kinase Expression Promotes Resistance to Antiangiogenic Agents.
Purpose: Patients develop resistance to antiangiogenic drugs, secondary to changes in the tumor microenvironment, including hypoxia. PIM kinases are prosurvival kinases and their expression increases in hypoxia. The goal of this study was to determine whether targeting hypoxia-induced PIM kinase expression is effective in combination with VEGF-targeting agents. The rationale for this therapeutic approach is based on the fact that antiangiogenic drugs can make tumors hypoxic, and thus more sensitive to PIM inhibitors.Experimental Design: Xenograft and orthotopic models of prostate and colon cancer were used to assess the effect of PIM activation on the efficacy of VEGF-targeting agents. IHC and in vivo imaging were used to analyze angiogenesis, apoptosis, proliferation, and metastasis. Biochemical studies were performed to characterize the novel signaling pathway linking PIM and HIF1.Results: PIM was upregulated following treatment with anti-VEGF therapies, and PIM1 overexpression reduced the ability of these drugs to disrupt vasculature and block tumor growth. PIM inhibitors reduced HIF1 activity, opposing the shift to a pro-angiogenic gene signature associated with hypoxia. Combined inhibition of PIM and VEGF produced a synergistic antitumor response characterized by decreased proliferation, reduced tumor vasculature, and decreased metastasis.Conclusions: This study describes PIM kinase expression as a novel mechanism of resistance to antiangiogenic agents. Our data provide justification for combining PIM and VEGF inhibitors to treat solid tumors. The unique ability of PIM inhibitors to concomitantly target HIF1 and selectively kill hypoxic tumor cells addresses two major components of tumor progression and therapeutic resistance. Clin Cancer Res; 24(1); 169-80. ©2017 AACR.


Characterization of promoter elements required for cell-specific expression of the neurotensin/neuromedin N gene in a human endocrine cell line.
Expression of the gene encoding neurotensin/neuromedin N (NT/N) is mostly limited to the brain and specialized enteroendocrine cells (N cells) of the distal small intestine. We have analyzed the NT/N DNA sequences upstream of the RNA start site that direct cell-specific expression using a novel human endocrine cell line, BON, that resembles intestinal N cells in several important aspects, including NT/N precursor protein processing, ratios of different NT/N mRNA forms, and high levels of constitutive expression of the NT/N gene. Transient transfection assays with plasmids with progressive 5' deletions of the rat NT/N promoter identified the proximal 216 bp of 5' flanking sequences as essential for high-level constitutive NT/N expression in BON cells. In addition, a detailed mutational analysis defined multiple regions within the proximal 216 bp that contribute to cell-specific NT/N expression. These elements include a proximal cyclic AMP response element (CRE)/AP-1-like motif (TGACATCA) that binds c-Jun, JunD, CRE-binding (CREB), and ATF proteins, a near-consensus glucocorticoid response element, and a distal consensus AP-1 site that binds c-Fos, Fra-1, and JunD. In addition, elements contained within two 21-bp imperfect direct repeats play an important role in NT/N expression in BON cells and may bind novel factors that act as positive regulators of NT/N expression. DNase I footprinting and gel shift analyses demonstrate that the sites identified by mutational analysis, and at least one additional site, specifically bind BON cell nuclear proteins in vitro. We speculate that a complex pattern of regulation requiring interaction between a proximal CRE/AP-1-like motif and other upstream control elements play an important role in the high-level constitutive expression of NT/N in the human endocrine cell line BON. In addition, the BON cell line provides a unique model to further characterize the factors regulating cell-specific NT/N expression and to better understand the mechanisms responsible for the terminal differentiation of the N-cell lineage in the gut.


Bar code, good for industry and trade--how does it benefit the dentist?
Every dentist who attentively follows the change in product labelling can easily see that the HIBC bar code is on the increase. In fact, according to information from FIDE/VDDI and ADE/BVD, the dental industry and trade are firmly resolved to apply the HIBC bar code to all products used internationally in dental practices. Why? Indeed, at first it looks like extra expense to additionally print a bar code on the packages. Good reasons can only lie in advantages which manufacturers and the trade expect from the HIBC bar code, Indications in dental technician circles are that the HIBC bar code is coming. If there are advantages, what are these, and can the dentist also profit from them? What does HIBC bar code mean and what items of interest does it include? What does bar code cost and does only one code exist? This is explained briefly, concentrating on the benefits bar code can bring for different users.


Recombinant Protein-Based Nanoparticles: Elucidating their Inflammatory Effects In Vivo and their Potential as a New Therapeutic Format.
Bacterial inclusion bodies (IBs) are protein-based nanoparticles of a few hundred nanometers formed during recombinant protein production processes in different bacterial hosts. IBs contain active protein in a mechanically stable nanostructured format that has been broadly characterized, showing promising potential in different fields such as tissue engineering, protein replacement therapies, cancer, and biotechnology. For immunomodulatory purposes, however, the interference of the format immunogenic properties-intrinsic to IBs-with the specific effects of the therapeutic protein is still an uncovered gap. For that, active and inactive forms of the catalytic domain of a matrix metalloproteinase-9 (MMP-9 and mutMMP-9, respectively) have been produced as IBs and compared with the soluble form for dermal inflammatory effects in mmp9 knock-out mice. After protein injections in air-pouches in the mouse model, MMP-9 IBs induce local neutrophil recruitment and increase pro-inflammatory chemokine levels, lasting for at least two days, whereas the effects triggered by the soluble MMP-9 format fade out after 3 h. Interestingly, the IB intrinsic effects (mutMMP-9 IBs) do not last more than 24 h. Therefore, it may be concluded that IBs could be used for the delivery of therapeutic proteins, such as immunomodulating proteins while preserving their stability in the specific tissue and without triggering important unspecific inflammatory responses due to the protein format.


Nanoplasmonic biosensing for soft matter adsorption: kinetics of lipid vesicle attachment and shape deformation.
An indirect nanoplasmonic sensing platform is reported for investigating the kinetics of attachment and shape deformation associated with lipid vesicle adsorption onto a titanium oxide-coated substrate. The localized surface plasmon resonance (LSPR) originates from embedded gold nanodisks and is highly sensitive to the local lipid environment. To interpret the corresponding results, we have extended treatments of diffusion-limited adsorption kinetics and adsorbate-related LSPR physics, identified the expected scaling laws for the LSPR-tracked kinetics measured at different lipid concentrations and/or nanometer-scale vesicle sizes in the case when vesicle deformation is negligible, and scrutinized experimental deviations accordingly. After adsorption, the smallest 58 nm diameter vesicles were found to maintain shape on the time scale of adsorption at high lipid concentrations in solution, and shape deformation became more appreciable at lower lipid concentrations. Higher saturation coverage was observed with increasing lipid concentration, which is attributed to the difference in relative time scales of vesicle attachment and deformation. For larger vesicles between 80 and 160 nm diameter, deviations associated with their shape deformation and correlations with the location of gold nanodisks became more apparent at moderate and high coverages. Taken together, the results obtained support that the quantitative measurement capabilities of nanoplasmonic biosensing should be considered for applications demanding highly surface-sensitive characterization of soft matter adsorption and related phenomena at liquid-solid interfaces.


New insights into the radiolytic stability of metal(iv) phosphonate hybrid adsorbent materials.
Stable metal(iv) phosphonate hybrids are a promising class of materials for the critical issue of nuclear waste cleanup. However, to be of practical use, adsorbent materials must demonstrate radiolytic stability and this property remains poorly understood. Therefore, the radiolytic stabilities of post-functionalised mesoporous zirconium titanate and zirconium phosphonate coordination polymers were compared. For the first time, solid-state 31P MAS-NMR was used to probe the radiolytic degradation of metal(iv) phosphonates and provide mechanistic insight. Polyphosphonate-functionalized hybrids were more stable than monophosphonate hybrids, as the monophosphonate readily detached from the oxide surface. The zirconium phosphonate coordination polymer (Zr-ATMP) demonstrated the greatest radiolytic stability, attributed to its high ligand loading and intimately mixed structure. Zr-ATMP maintained highly efficient sorption from strongly acidic solutions even after receiving doses of gamma radiation up to 2.9 MGy.


Deinococcus deserti sp. nov., a gamma-radiation-tolerant bacterium isolated from the Sahara Desert.
Two gamma- and UV-radiation-tolerant, Gram-negative, rod-shaped bacterial strains, VCD115T and VCD117, were isolated from a mixture of sand samples collected in the Sahara Desert in Morocco and Tunisia, after exposure of the sand to 15 kGy gamma radiation. Phylogenetic analysis based on 16S rRNA gene sequences and DNA-DNA hybridizations showed that VCD115T and VCD117 are members of a novel species belonging to the genus Deinococcus, with Deinococcus grandis as its closest relative. The DNA G+C contents of VCD115T and VCD117 are 59.8 and 60.6 mol%, respectively. The major fatty acids (straight-chain 15 : 1, 16 : 1, 17 : 1 and 16 : 0), polar lipids (dominated by phosphoglycolipids and glycolipids) and quinone type (MK-8) support the affiliation to the genus Deinococcus. The strains did not grow on rich medium such as trypticase soy broth (TSB), but did grow as whitish colonies on tenfold-diluted TSB. The genotypic and phenotypic properties allowed differentiation of VCD115T and VCD117 from recognized Deinococcus species. Strains VCD115T and VCD117 are therefore identified as representing a novel species, for which the name Deinococcus deserti sp. nov. is proposed, with the type strain VCD115T (=DSM 17065T=LMG 22923T).