Prevalence of physical activity and obesity in US counties, 2001-2011: a road map for action.
Obesity and physical inactivity are associated with several chronic conditions, increased medical care costs, and premature death. We used the Behavioral Risk Factor Surveillance System (BRFSS), a state-based random-digit telephone survey that covers the majority of United States counties, and the National Health and Nutrition Examination Survey (NHANES), a nationally representative sample of the US civilian noninstitutionalized population. About 3.7 million adults aged 20 years or older participated in the BRFSS from 2000 to 2011, and 30,000 adults aged 20 or older participated in NHANES from 1999 to 2010. We calculated body mass index (BMI) from self-reported weight and height in the BRFSS and adjusted for self-reporting bias using NHANES. We calculated self-reported physical activity-both any physical activity and physical activity meeting recommended levels-from self-reported data in the BRFSS. We used validated small area estimation methods to generate estimates of obesity and physical activity prevalence for each county annually for 2001 to 2011. Our results showed an increase in the prevalence of sufficient physical activity from 2001 to 2009. Levels were generally higher in men than in women, but increases were greater in women than men. Counties in Kentucky, Florida, Georgia, and California reported the largest gains. This increase in level of activity was matched by an increase in obesity in almost all counties during the same time period. There was a low correlation between level of physical activity and obesity in US counties. From 2001 to 2009, controlling for changes in poverty, unemployment, number of doctors per 100,000 population, percent rural, and baseline levels of obesity, for every 1 percentage point increase in physical activity prevalence, obesity prevalence was 0.11 percentage points lower. Our study showed that increased physical activity alone has a small impact on obesity prevalence at the county level in the US. Indeed, the rise in physical activity levels will have a positive independent impact on the health of Americans as it will reduce the burden of cardiovascular diseases and diabetes. Other changes such as reduction in caloric intake are likely needed to curb the obesity epidemic and its burden.


TREM-like transcript-1 protects against inflammation-associated hemorrhage by facilitating platelet aggregation in mice and humans.
Triggering receptor expressed on myeloid cells-like (TREM-like) transcript-1 (TLT-1), a type 1 single Ig domain orphan receptor specific to platelet and megakaryocyte alpha-granules, relocates to the platelet surface upon platelet stimulation. We found here that patients diagnosed with sepsis, in contrast to healthy individuals, had substantial levels of soluble TLT-1 (sTLT-1) in their plasma that correlated with the presence of disseminated intravascular coagulation. sTLT-1 bound to fibrinogen and augmented platelet aggregation in vitro. Furthermore, the cytoplasmic domain of TLT-1 could also bind ezrin/radixin/moesin family proteins, suggesting its ability to link fibrinogen to the platelet cytoskeleton. Accordingly, platelets of Treml1-/- mice failed to aggregate efficiently, extending tail-bleeding times. Lipopolysaccharide-treated Treml1-/- mice developed higher plasma levels of TNF and D-dimers than wild-type mice and were more likely to succumb during challenge. Finally, Treml1-/- mice were predisposed to hemorrhage associated with localized inflammatory lesions. Taken together, our findings suggest that TLT-1 plays a protective role during inflammation by dampening the inflammatory response and facilitating platelet aggregation at sites of vascular injury. Therefore, therapeutic modulation of TLT-1-mediated effects may provide clinical benefit to patients with hypercoagulatory conditions, including those associated with inflammation.


Alcohol consumption and high risk sexual behaviour among female sex workers in Uganda.
Alcohol consumption has been associated with high risk sexual behaviour among key populations such as female sex workers. We explored the drivers of alcohol consumption and its relationship to high risk sexual behaviour. Participants were drawn from a cohort of 1027 women selected from 'hot spots' in the suburbs of Kampala city. We conducted 3 in-depth interviews with 40 female sex workers between 2010 and 2011. Data were analysed thematically, focusing on alcohol use within the context of sex work. Alcohol consumption was very high with only seven women reporting that they did not drink. Alcohol consumption was driven by the emotional and economic needs of the participants, but also promoted by clients who encouraged consumption. Many sex workers only started drinking alcohol when they joined sex work on the advice of more experienced peers, as a way to cope with the job. Alcohol was blamed for unsafe sex, acts of violence and poor decision making which increased sexual and physical violence. Alcohol was reported to affect medication adherence for HIV-positive women who forgot to take medicine. The findings suggest that the drivers of alcohol consumption are multifaceted in this group and require both individual and structural interventions. Alcohol reduction counselling can be supportive at the individual level and should be an integral part of HIV prevention programmes for female sex workers and others such as patrons in bars. The counselling should be addressed in a sensitive manner to bar owners and managers.


Orbital complications of sinusitis.
Despite the modern antibiotherapies applied in the practice of otorhinolaryngology, the orbital complications of sinusitis are still considered a serious threat to essential functions of the eye, including loss of vision, and at worst, life threatening symptoms. The goal of this study is to consider and analyse patients who were treated for these complications in the last decade in our hospital, which is the only tertiary hospital in our country. Retrospective analysis of cases. In our practice, cases treated in the hospital are rhinosinusitis cases where surgical intervention is necessary, or those with a suspicion of complications. Between the years 1999 and 2009 there were 177 cases, the clinical charts of which were reviewed. The cases that are omitted from this study are those involving soft tissues, bone, and intracranial complications. The diagnoses were determined based on anamnesis, anterior rhinoscopy, x-rays of the sinuses with the Water's projection or where there was a suspicion of a complication, and CT scans with coronal and axial projections. In all cases, intensive treatment was initiated with a combination of cefalosporines, aminoglycosides and Proetz manoeuvre. When an improvement in the conditions did not occur within 24-48 hours, we intervened with a surgical procedure, preferably the Lynch-Patterson external frontoethmoidectomy. In our study, we encountered 35 cases (19.8%) of orbital complications with an average age of 25 (range: 3-75); Palpebral inflammatory oedema (15), orbital cellulitis (10), subperiosteal abscess (6), orbital abscess (3), and cavernous sinus thrombosis (1 patient). The average time that patients remained in hospital was 4.6 days; for those with orbital complications this was 7 days. Orbital complications of sinusitis are considered to be severe pathologies. The appearance of oedema in the corner of the eye should be evaluated immediately and the means to exclude acute sinusitis should be taken under serious consideration. Early diagnosis and aggressive treatment are key to the reduction of these unwanted manifestations.


Multilocus half-tetrad analysis and centromere mapping in citrus: evidence of SDR mechanism for 2n megagametophyte production and partial chiasma interference in mandarin cv 'Fortune'.
The genetic structure of 2n gametes and, particularly, the parental heterozygosity restitution at each locus depends on the meiotic process by which they originated, with first-division restitution and second-division restitution (SDR) being the two major mechanisms. The origin of 2n gametes in citrus is still controversial, although sexual polyploidisation is widely used for triploid seedless cultivar development. In this study, we report the analysis of 2n gametes of mandarin cv 'Fortune' by genotyping 171 triploid hybrids with 35 simple sequence repeat markers. The microsatellite DNA allele counting-peak ratios method for allele-dosage evaluation proved highly efficient in segregating triploid progenies and allowed half-tetrad analysis (HTA) by inferring the 2n gamete allelic configuration. All 2n gametes arose from the female genitor. The observed maternal heterozygosity restitution varied between 10 and 82%, depending on the locus, thus SDR appears to be the mechanism underlying 2n gamete production in mandarin cv 'Fortune'. A new method to locate the centromere, based on the best fit between observed heterozygosity restitution within a linkage group and theoretical functions under either partial or no chiasmata interference hypotheses was successfully applied to linkage group II. The maximum value of heterozygosity restitution and the pattern of restitution along this linkage group would suggest there is partial chiasma interference. The implications of such a restitution mechanism for citrus breeding are discussed.


Comparison of proteomic profiles of serum, plasma, and modified media supplements used for cell culture and expansion.
The culture and expansion of human cells for clinical use requires the presence of human serum or plasma in culture media. Although these supplements have been extensively characterized in their chemical composition, only recently it has been possible to provide by high throughput protein analysis, a comprehensive profile of the soluble factors contributing to cell survival. This study analyzed and compared the presence of 100 proteins including chemokines, cytokines and soluble factors in six different types of media supplements: serum, plasma, recalcified plasma, heat inactivated serum, heat inactivated plasma and heat inactivated recalcified plasma. Serum, plasma, recalcified plasma, and heat inactivated supplements were prepared from ten healthy subjects. The levels of 100 soluble factors were measured in each sample using a multiplexed ELISA assay and compared by Eisen hierarchical clustering analysis. A comparison of serum and plasma levels of soluble factors found that 2 were greater in plasma but 18 factors were greater in serum including 11 chemokines. The levels of only four factors differed between recalcified plasma and plasma. Heat inactivation had the greatest effect on soluble factors. Supervised Eisen hierarchical clustering indicated that the differences between heat inactivated supplements and those that were not were greater than the differences within these two groups. The levels of 36 factors differed between heat inactivated plasma and plasma. Thirty one of these factors had a lower concentration in heat inactivated plasma including 12 chemokines, 4 growth factors, 4 matrix metalloproteases, and 3 adhesion molecules. Heat inactivated decalcified plasma is often used in place of heat inactivated serum and the levels of 19 soluble factors differed between these two supplements. Our report provides a comprehensive protein profile of serum, plasma recalcified plasma, and heat inactivated supplements. This profile represents a qualitative and quantitative database that can aid in the selection of the appropriate blood derived supplement for human cell cultures with special requirements.


Chemical and pharmacological investigation of micropropagated Hygrophila pogonocalyx produced from leaf explants.
An optimized method for indirect shoot organogenesis from the leaf explants of Hygrophila pogonocalyx, a rare and endemic species in Taiwan, was developed to supply enough quantity of plant materials for the first chemical and pharmacological investigation. Incubation of the young leaves on Murashige and Skoog (MS) medium supplemented with 6-benzylaminopurine (0.5 mg/l) and indole-3-acetic acid (0.1 mg/l) resulted in the best multiplication rate for organogenesis. The average number of adventitious buds per leaf was 22.8 ± 1.9 after 8-week culture. The adventitious buds rooted and developed into plantlets when cultured simply on MS medium. Using this protocol, up to 37,600 plants were produced from a single leaf explant in one year. From the ethanol extract of the leaves of this micropropagated plant, 13 compounds were isolated and identified, including two flavones (1, 11), four flavonols (9, 10, 12, and 13), three phenylethanoid glycosides (6-8), two alkylated glycosides (2-3), and two steroids (4-5). Of these, acteoside (7) exhibited anti-tyrosinase activity in human epidermal melanocytes and luteolin 7-O-β-D-glucopyranoside (11) exhibited the greatest neurocytoprotective activity. The method, indirect shoot organogenesis from leaf explants of H. pogonocalyx, could be developed to supply enough quantity of plant materials for the chemical and pharmacological investigation. In the present study, the isolated active compounds may develop for whitening agents or treating neurodegenerative diseases in the future.


Purification and characterization of a DNA-binding recombinant PREP1:PBX1 complex.
Human PREP1 and PBX1 are homeodomain transcriptional factors, whose biochemical and structural characterization has not yet been fully described. Expression of full-length recombinant PREP1 (47.6 kDa) and PBX1 (46.6 kDa) in E. coli is difficult because of poor yield, high instability and insufficient purity, in particular for structural studies. We cloned the cDNA of both proteins into a dicistronic vector containing an N-terminal glutathione S-transferase (GST) tag and co-expressed and co-purified a stable PBX1:PREP1 complex. For structural studies, we produced two C-terminally truncated complexes that retain their ability to bind DNA and are more stable than the full-length proteins through various purification steps. Here we report the production of large amounts of soluble and pure recombinant human PBX1:PREP1 complex in an active form capable of binding DNA.


[Identification of surface antigens of Trichomonas vaginalis].
Surface proteins of Trichomonas vaginalis (T. vaginalis) were analyzed to study the antigenic variation. The surface proteins of protozoa were labelled by N-hydroxysuccinimide-biotin (NHS-biotin), the NHS-biotin-labelled proteins were immunoprecipitated with rabbit antiserum to purify the antigenic fractions and analysed by SDS-PAGE plus electroblotting. The results obtained in this study were as follows; Biotinylated T. vaginalis-proteins obtained from intact cell and cells disrupted prior to labelling were detected by anti-biotin-peroxidase in Western blots. Labelled proteins were immunoprecipitated by T. vaginalis-immunized rabbit serum and the six bands with the molecular weights of 46, 60, 68, 90, 130 and 220 kDa were identified as having antigenicity. T. vaginalis HY-1, HY-15 and ATCC 50148 were immunoprecipitated by immune rabbit serum after biotinylation and there were no difference from antigenic bands among these strains by this technique. In conclusion with the results obtained in the present study, it was assumed that surface proteins of T. vaginalis were labelled by biotinylation and the six labelled bands at 46, 60, 68, 90, 130 and 220 kDa in their molecular weight were identified as having antigenicity by immunoprecipitation (IP) and this biotinylation-IP technique may be used for further study of surface antigen of T. vaginalis.


Ancient ubiquitous protein-1 mediates sterol-induced ubiquitination of 3-hydroxy-3-methylglutaryl CoA reductase in lipid droplet-associated endoplasmic reticulum membranes.
Sterol-induced binding to Insigs in endoplasmic reticulum (ER) membranes triggers ubiquitination of the cholesterol biosynthetic enzyme 3-hydroxy-3-methylglutaryl CoA reductase. This ubiquitination, which is mediated by Insig-associated ubiquitin ligases gp78 and Trc8, is obligatory for extraction of reductase from lipid droplet-associated ER membranes into the cytosol for proteasome-mediated, ER-associated degradation (ERAD). In this study, we identify lipid droplet-associated, ancient, ubiquitous protein-1 (Aup1) as one of several proteins that copurify with gp78. RNA interference (RNAi) studies show that Aup1 recruits the ubiquitin-conjugating enzyme Ubc7 to lipid droplets and facilitates its binding to both gp78 and Trc8. The functional significance of these interactions is revealed by the observation that RNAi-mediated knockdown of Aup1 blunts sterol-accelerated ubiquitination of reductase, which appears to occur in lipid droplet-associated membranes and subsequent ERAD of the enzyme. In addition, Aup1 knockdown inhibits ERAD of Insig-1, another substrate for gp78, as well as that of membrane-bound precursor forms of sterol-regulatory, element-binding protein-1 and -2, transcription factors that modulate expression of genes encoding enzymes required for cholesterol synthesis. Considered together, these findings not only implicate a role for Aup1 in maintenance of intracellular cholesterol homeostasis, but they also highlight the close connections among ERAD, lipid droplets, and lipid droplet-associated proteins.


Topography of the motion aftereffect with and without eye movements.
Although a lot is known about various properties of the motion aftereffect (MAE), there is no systematic study of the topographic organization of MAE. In the current study, first we provided a topographic map of the MAE to investigate its spatial properties in detail. To provide a fine topographic map, we measured MAE with small test stimuli presented at different loci after adaptation to motion in a large region within the visual field. We found that strength of MAE is highest on the internal edge of the adapted area. Our results show a sharper aftereffect boundary for the shearing motion compared to compression and expansion boundaries. In the second experiment, using a similar paradigm, we investigated topographic deformation of the MAE area after a single saccadic eye movement. Surprisingly, we found that topographic map of MAE splits into two separate regions after the saccade: one corresponds to the retinal location of the adapted stimulus and the other matches the spatial location of the adapted region on the display screen. The effect was stronger at the retinotopic location. The third experiment is basically replication of the second experiment in a smaller zone that confirms the results of previous experiments in individual subjects. The eccentricity of spatiotopic area is different from retinotopic area in the second experiment; Experiment 3 controls the effect of eccentricity and confirms the major results of the second experiment.


Membrane sweeping for induction of labour.
Sweeping of the membranes, also named stripping of the membranes, is a relatively simple technique usually performed without admission to hospital. During vaginal examination, the clinician's finger is introduced into the cervical os. Then, the inferior pole of the membranes is detached from the lower uterine segment by a circular movement of the examining finger. This intervention has the potential to initiate labour by increasing local production of prostaglandins and, thus, reduce pregnancy duration or pre-empt formal induction of labour with either oxytocin, prostaglandins or amniotomy. This is one of a series of reviews of methods of cervical ripening and labour induction using standardised methodology. To determine the effects of membrane sweeping for third trimester induction of labour. We searched the Cochrane Pregnancy and Childbirth Group trials register (6 July 2004) and bibliographies of relevant papers. Clinical trials comparing membrane sweeping used for third trimester cervical ripening or labour induction with placebo/no treatment or other methods listed above it on a predefined list of labour induction methods. A strategy was developed to deal with the large volume and complexity of trial data relating to labour induction. This involved a two-stage method of data extraction. Twenty-two trials (2797 women) were included, 20 comparing sweeping of membranes with no treatment, three comparing sweeping with prostaglandins and one comparing sweeping with oxytocin (two studies reported more than one comparison). Risk of caesarean section was similar between groups (relative risk (RR) 0.90, 95% confidence interval (CI) 0.70 to 1.15). Sweeping of the membranes, performed as a general policy in women at term, was associated with reduced duration of pregnancy and reduced frequency of pregnancy continuing beyond 41 weeks (RR 0.59, 95% CI 0.46 to 0.74) and 42 weeks (RR 0.28, 95% CI 0.15 to 0.50). To avoid one formal induction of labour, sweeping of membranes must be performed in eight women (NNT = 8). There was no evidence of a difference in the risk of maternal or neonatal infection. Discomfort during vaginal examination and other adverse effects (bleeding, irregular contractions) were more frequently reported by women allocated to sweeping. Studies comparing sweeping with prostaglandin administration are of limited sample size and do not provide evidence of benefit. Routine use of sweeping of membranes from 38 weeks of pregnancy onwards does not seem to produce clinically important benefits. When used as a means for induction of labour, the reduction in the use of more formal methods of induction needs to be balanced against women's discomfort and other adverse effects.


Interaction of apolipoprotein J-amyloid beta-peptide complex with low density lipoprotein receptor-related protein-2/megalin. A mechanism to prevent pathological accumulation of amyloid beta-peptide.
Apolipoprotein J (apoJ) has been shown to be the predominant amyloid beta-peptide (Abeta)-binding protein in cerebrospinal fluid. We have previously demonstrated that the endocytic receptor low density lipoprotein receptor-related protein-2/megalin (LRP-2), which is expressed by choroid plexus epithelium and ependymal cells lining the brain ventricles and neural tube, binds and mediates cellular uptake of apoJ (Kounnas, M. Z., Loukinova, E. B., Stefansson, S., Harmony, J. A., Brewer, B., Strickland, D. K., and Argraves, W. S. (1995) J. Biol. Chem. 270, 13070-13075). In the present study, we evaluated the ability of apoJ to mediate binding of Abeta1-40-apoJ complex to LRP-2 in vitro. Immunoblot analysis showed that incubation of apoJ with Abeta1-40 resulted in the formation of Abeta1-40-apoJ complex and the inhibition of the formation of Abeta1-40 aggregates. Using an enzyme-linked immunosorbent assay, an estimated dissociation constant (Kd) of 4.8 nM was derived for the interaction between Abeta1-40 and apoJ. Enzyme-linked immunosorbent assay was also used to study the interaction of the Abeta1-40-apoJ complex with LRP-2. The results showed that Abeta alone did not bind directly to LRP-2; however, when Abeta1-40 was combined with apoJ to form a complex, binding to LRP-2 took place. The binding interaction could be blocked by inclusion of the receptor-associated protein, an antagonist of apoJ binding to LRP-2. When LRP-2-expressing cells were given 125I-Abeta1-40, cellular uptake of the radiolabeled peptide was promoted by co-incubation with apoJ. When the cells were provided purified 125I-Abeta1-40-apoJ complex, the complex was internalized and degraded, and both processes were inhibited with polyclonal LRP-2 antibodies. Furthermore, chloroquine treatment inhibited the cellular degradation of the complex. The data indicate that apoJ facilitates Abeta1-40 binding to LRP-2 and that the receptor mediates cellular clearance of Abeta1-40-apoJ complex leading to lysosomal degradation of Abeta1-40. The findings support the possibility that LRP-2 can act in vivo to mediate clearance of the complex from biological fluids such as cerebrospinal fluid and thereby play a role in the regulation of Abeta accumulation.


Mechanisms of Wnt signaling in development.
Wnt genes encode a large family of secreted, cysteine-rich proteins that play key roles as intercellular signaling molecules in development. Genetic studies in Drosophila and Caenorhabditis elegans, ectopic gene expression in Xenopus, and gene knockouts in the mouse have demonstrated the involvement of Wnts in processes as diverse as segmentation, CNS patterning, and control of asymmetric cell divisions. The transduction of Wnt signals between cells proceeds in a complex series of events including post-translational modification and secretion of Wnts, binding to transmembrane receptors, activation of cytoplasmic effectors, and, finally, transcriptional regulation of target genes. Over the past two years our understanding of Wnt signaling has been substantially improved by the identification of Frizzled proteins as cell surface receptors for Wnts and by the finding that beta-catenin, a component downstream of the receptor, can translocate to the nucleus and function as a transcriptional activator. Here we review recent data that have started to unravel the mechanisms of Wnt signaling.


Meteorite Kr in Earth's mantle suggests a late accretionary source for the atmosphere.
Noble gas isotopes are key tracers of both the origin of volatiles found within planets and the processes that control their eventual distribution between planetary interiors and atmospheres. Here, we report the discovery of primordial Kr in samples derived from Earth's mantle and show it to be consistent with a meteorite or fractionated solar nebula source. The high-precision Kr and Xe isotope data together suggest that Earth's interior acquired its volatiles from accretionary material similar to average carbonaceous chondrites and that the noble gases in Earth's atmosphere and oceans are dominantly derived from later volatile capture rather than impact degassing or outgassing of the solid Earth during its main accretionary stage.


Regulated expression of human globin genes and flanking DNA in mouse erythroleukemia--human cell hybrids.
The expression of human globin genes and intergenic DNA is being investigated in MEL-human hybrids containing intact human chromosomes derived from nonerythroid cells. The studies indicate that a factor(s) present in MEL cells can cause activation of both beta- and gamma-globin genes that can be further stimulated by treatment with DMSO, an inducer of MEL cell differentiation. MEL-lymphoblast and MEL-fibroblast hybrids express an adult-like program in which much larger amounts of beta-globin mRNA than gamma-globin mRNA are produced; human beta-globin is at least as efficient as mouse beta-globin gene expression. The expression of both beta- and gamma-globin genes appears to be normal, as their mRNAs were found in polyribosomes and human beta-globin chains were readily detected. These results suggest that the MEL cells may be exploited as recipients of human globin genes for studies of molecular mechanisms controlling their expression. Comparison of intergenic DNA transcription patterns in hybrids and other cells not expressing human beta-globin has led to the identification of two regions flanking the delta-beta-globin locus whose transcription is correlated with beta-globin. One region 3' to the beta gene may define the site where its transcription terminates. Transcription of the other region, which is 5' to the delta gene, may be involved in some unknown way in hemoglobin switching.


N-Heterocyclic carbene-stabilized gold nanoparticles with tunable sizes.
A simple and straightforward synthesis of N-heterocyclic carbene (NHC)-protected gold nanoparticles is derived from (benz)imidazolium-AuX4 complexes and NaBH4 only. The proposed method allows size tuning, from 3 to 6 nm, by adding (benz)imidazolium bromide. Changing the reducing agent to tBuNH2BH3 shifts the size range to ca. 6-12 nm. A one pot protocol is also reported from AuCl, (benz)imidazolium bromides and NaBH4, thereby providing an even more straightforward way of producing NHC-capped gold nanoparticles. In addition, X-ray photoelectron spectroscopy (XPS) is used to unambiguously evidence, on the nanoparticles, the covalent bond formed between the NHC and the surface gold atoms.


Reduced expression of the growth hormone and type 1 insulin-like growth factor receptors in human somatotroph tumours and an analysis of possible mutations of the growth hormone receptor.
Clinical acromegaly is characterized by elevated GH secretion in the presence of high circulating IGF-I levels. We hypothesized that the physiological IGF-I/GH negative feedback loop may be reset in somatotroph adenomas, specifically in terms of the level of expression of these receptors or mutations of the GH receptor (GH-R) in such tumours. We therefore investigated the full coding sequence of the GH-R in a series of somatotroph and other pituitary adenomas. We also investigated the mRNA expression of these putative feedback receptors in a series of pituitary adenomas and normal pituitary tissue, and their protein expression by immunostaining. Real-time RT-PCR assay was used for the quantification of the type 1 IGF receptor (IGF-R) and GH receptor (GH-R) mRNA, and sequence analysis was performed on the coding region of the GH-R gene. No somatic mutations of the GH-R mRNA were detected in 18 GH-secreting tumours or two nonfunctioning pituitary adenomas (NFPAs). However, the levels of GH-R mRNA were significantly lower in both somatotroph tumours and NFPAs compared to the normal pituitary (P < 0.05 for both). Immunostaining for GH-R also showed significantly less GH-R expression in somatotroph adenomas compared to normal pituitary tissue (P < 0.0001). IGF-R mRNA levels were significantly lower in somatotroph tumours compared to normal pituitary (P = 0.005), and trended lower in corticotroph tumours (P = 0.07), while the other tumour types showed no significant difference from normal pituitary. Immunostaining for IGF-R also showed less IGF-R protein in the somatotroph adenomas compared to the normal pituitary tissue (P < 0.01). Our findings suggest that decreased feedback inhibition of GH because of somatic mutations of the coding region of the GH-R are unlikely to be a common factor in the pathogenesis of these tumours. Nevertheless, decreased expression of the GH-R and of IGF-R in somatotroph tumours (both at the mRNA and protein level) may, at least in part, help explain the continuous secretion of GH from the tumour despite the high circulating levels of IGF-I and GH.


Multirate method for co-simulation of electrical-chemical systems in multiscale modeling.
Multiscale modeling by means of co-simulation is a powerful tool to address many vital questions in neuroscience. It can for example be applied in the study of the process of learning and memory formation in the brain. At the same time the co-simulation technique makes it possible to take advantage of interoperability between existing tools and multi-physics models as well as distributed computing. However, the theoretical basis for multiscale modeling is not sufficiently understood. There is, for example, a need of efficient and accurate numerical methods for time integration. When time constants of model components are different by several orders of magnitude, individual dynamics and mathematical definitions of each component all together impose stability, accuracy and efficiency challenges for the time integrator. Following our numerical investigations in Brocke et al. (Frontiers in Computational Neuroscience, 10, 97, 2016), we present a new multirate algorithm that allows us to handle each component of a large system with a step size appropriate to its time scale. We take care of error estimates in a recursive manner allowing individual components to follow their discretization time course while keeping numerical error within acceptable bounds. The method is developed with an ultimate goal of minimizing the communication between the components. Thus it is especially suitable for co-simulations. Our preliminary results support our confidence that the multirate approach can be used in the class of problems we are interested in. We show that the dynamics ofa communication signal as well as an appropriate choice of the discretization order between system components may have a significant impact on the accuracy of the coupled simulation. Although, the ideas presented in the paper have only been tested on a single model, it is likely that they can be applied to other problems without loss of generality. We believe that this work may significantly contribute to the establishment of a firm theoretical basis and to the development of an efficient computational framework for multiscale modeling and simulations.


Occurrence of retained placenta is preceded by an inflammatory state and alterations of energy metabolism in transition dairy cows.
Failure to expel fetal membranes within 24 h of calving is a pathological condition defined as retained placenta (RP). The objective of this investigation was to evaluate whether there are alterations in several selected serum variables related to innate immunity and carbohydrate and lipid metabolism that precede occurrence of RP in transition Holstein dairy cows. One hundred multiparous Holstein dairy cows were involved in the study. Blood samples were collected from the coccygeal vein during the -8 to +4 wks around parturition, once per week before the morning feeding. Six healthy control cows (CON) and 6 cows with RP were selected and serum samples at -8, -4, time of diagnosis of disease, and +4 wks relative to parturition were used for analyses. All samples were analyzed for lactate, non-esterified fatty acids (NEFA), β-hydroxybutyrate (BHBA), interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor (TNF), haptoglobin (Hp), and serum amyloid A (SAA). Cows with RP had greater concentrations of serum lactate, IL-1, IL-6, TNF, and SAA in comparison with CON cows. Intriguingly, elevated concentrations of all five variables were observed at -8 and -4 wks before the occurrence of RP compared to healthy cows. Cows with RP also had lower DMI and milk production vs CON animals; however milk composition was not affected by RP. Cows with RP showed an activated innate immunity 8 wks prior to diagnosis of disease. Overall results suggest that serum IL-1, IL- 6, and TNF, and lactate can be used as screening biomarkers to indicate cows that might have health issues during the transition period.


Magnetic resonance angiography at 3.0 Tesla: initial clinical experience.
Magnetic resonance (MR) angiography has undergone significant development over the past decade. It has gone from being a novelty application of MR with limited clinical use to replacing catheter angiography in some clinical applications. One of the principal limitations inherent to all MR angiographic techniques is that they remain signal limited when pushed to the limits of higher resolution and short acquisition time. Developments in magnetic gradient hardware, coil design, and pulse sequences now are well optimized for MR angiography obtained at 1.5-T main magnetic field (B-field) strength, with acquisition times and imaging matrix size near their optimal limits, respectively. Recently, the United States Food and Drug Administration (FDA) approved use of clinical magnetic resonance imaging with main magnetic field strengths of up to 4 T. Before FDA approval, use of MR with magnetic field strengths much greater than 1.5 T was essentially reserved for investigational or research applications. The main advantage of high B-field imaging is a significant improvement in the signal-to-noise ratio (SNR), which increases in an approximately linear fashion with field strength in the range of 1.5 to 3.0 T. This increased SNR is directly available when performing MR angiographic acquisitions at higher magnetic field strengths, allowing for better resolution and conspicuity of vessels with similar acquisition times. Little has been reported on the benefits of performing MR angiography at magnetic field strengths >1.5 T. The purpose of this article is to summarize our current experience with intracranial and cervical MR angiographic techniques at 3.0 T.


Effectiveness of Mindfulness-based Therapy for Reducing Anxiety and Depression in Patients With Cancer: A Meta-analysis.
Anxiety and depression are common among patients with cancer, and are often treated with psychological interventions including mindfulness-based therapy.The aim of the study was to perform a meta-analysis of the effectiveness of mindfulness-based interventions for improving anxiety and depression in patients with cancer.Medline, the Cochrane Library, EMBASE, and Google Scholar were searched. The randomized controlled trials designed for patients diagnosed with cancer were included. Mindfulness-based interventions were provided.The outcomes assessed were the changes in anxiety and depression scores from before to after the intervention. The treatment response was determined by calculating the standardized mean difference (SMD) for individual studies and for pooled study results. Subgroup analyses by cancer type, type of therapy, and length of follow-up were performed.Seven studies, involving 469 participants who received mindfulness-based interventions and 419 participants in a control group, were included in the meta-analysis. Mindfulness-based stress reduction and art therapy were the most common interventions (5/7 studies). All studies reported anxiety and depression scores. The pooled SMD of the change in anxiety significantly favored mindfulness-based therapy over control treatment (-0.75, 95% confidence interval -1.28, -0.22, P = 0.005). Likewise, the pooled SMD of the change in depression also significantly favored mindfulness-based therapy over control (-0.90, 95% confidence interval -1.53, -0.26, P = 0.006). During the length of follow-ups less than 12 weeks, mindfulness-based therapy significantly improved anxiety for follow-up ≤12 weeks after the start of therapy, but not >12 weeks after the start of therapy.There was a lack of consistency between the studies in the type of mindfulness-based/control intervention implemented. Patients had different forms of cancer. Subgroup analyses included a relatively small number of studies and did not account for factors such as the severity of anxiety and/or depression, the time since diagnosis, and cancer stage.Mindfulness-based interventions effectively relieved anxiety and depression among patients with cancer. However, additional research is still warranted to determine how long the beneficial effects of mindfulness-based therapy persist.


HIV status disclosure to families for social support in South Africa (NIMH Project Accept/HPTN 043).
Literature on HIV status disclosure among persons living with HIV/AIDS (PLWHA) is dominated by research on the rates, barriers and consequences of disclosure to sexual partners, because of the assumed preventive health benefits of partner disclosure. Disclosure of HIV status can lead to an increase in social support and other positive psychosocial outcomes for PLWHA, but disclosure can also be associated with negative social outcomes including stigma, discrimination, and violence. The purpose of this article is to describe the HIV status disclosure narratives of PLWHA living in South Africa. Thirty in-depth interviews were conducted with 13 PLWHA (11 women, 2 men) over a three-year period. We explored disclosure narratives of the PLWHA through questions about who they chose to disclose to, how they disclosed to these individuals, and how these individuals reacted. Narratives focused on disclosure to family members and contained relatively little discussion of disclosure to sexual partners. Participants often disclosed first to one trusted family member, and news of the diagnosis remained with this person for a long period of time, prior to sharing with others. This family member helped the PLWHA cope with the news of their diagnosis and prepared them to disclose to others. Disclosure to one's partner was motivated primarily by a desire to encourage partners to test for HIV. Two participants described overtly negative reactions from a partner upon disclosure, and none of the PLWHA in this sample described very supportive relationships with their partners after disclosure. The critical role that family members played in the narratives of these PLWHA emphasizes the need for a greater focus on disclosure to families for social support in HIV counseling protocols.


An evolutionary perspective on the kinome of malaria parasites.
Malaria parasites belong to an ancient lineage that diverged very early from the main branch of eukaryotes. The approximately 90-member plasmodial kinome includes a majority of eukaryotic protein kinases that clearly cluster within the AGC, CMGC, TKL, CaMK and CK1 groups found in yeast, plants and mammals, testifying to the ancient ancestry of these families. However, several hundred millions years of independent evolution, and the specific pressures brought about by first a photosynthetic and then a parasitic lifestyle, led to the emergence of unique features in the plasmodial kinome. These include taxon-restricted kinase families, and unique peculiarities of individual enzymes even when they have homologues in other eukaryotes. Here, we merge essential aspects of all three malaria-related communications that were presented at the Evolution of Protein Phosphorylation meeting, and propose an integrated discussion of the specific features of the parasite's kinome and phosphoproteome.


Hepatotoxin-induced changes in the adult murine liver promote MYC-induced tumorigenesis.
Overexpression of the human c-MYC (MYC) oncogene is one of the most frequently implicated events in the pathogenesis of hepatocellular carcinoma (HCC). Previously, we have shown in a conditional transgenic mouse model that MYC overexpression is restrained from inducing mitotic cellular division and tumorigenesis in the adult liver; whereas, in marked contrast, MYC induces robust proliferation associated with the very rapid onset of tumorigenesis in embryonic and neonatal mice. Here, we show that non-genotoxic hepatotoxins induce changes in the liver cellular context associated with increased cellular proliferation and enhanced tumorigenesis. Both 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and carbon tetrachloride (CCl(4)) cooperate with MYC to greatly accelerate the onset of liver cancer in an adult host to less than 7 days versus a mean latency of onset of over 35 weeks for MYC alone. These hepatotoxin-enhanced liver tumors grossly and histologically resemble embryonic and neonatal liver tumors. Importantly, we found that MYC overexpression is only capable of inducing expression of the mitotic Cyclin B1 in embryonic/neonatal hosts or adult hosts that were treated with either carcinogen. Our results suggest a model whereby oncogenes can remain latently activated, but exposure of the adult liver to hepatotoxins that promote hepatocyte proliferation can rapidly uncover their malignant potential.


Computational investigation of the binding mode of bis(hydroxylphenyl)arenes in 17β-HSD1: molecular dynamics simulations, MM-PBSA free energy calculations, and molecular electrostatic potential maps.
17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyzes the last step of the estrogen biosynthesis, namely the reduction of estrone to the biologically potent estradiol. As such it is a potentially attractive drug target for the treatment of estrogen-dependent diseases like breast cancer and endometriosis. 17β-HSD1 belongs to the bisubstrate enzymes and exists as an ensemble of conformations. These principally differ in the region of the βFαG'-loop, suggesting a prominent role in substrate and inhibitor binding. Although several classes of potent non-steroidal 17β-HSD1 inhibitors currently exist, their binding mode is still unclear. We aimed to elucidate the binding mode of bis(hydroxyphenyl)arenes, a highly potent class of 17β-HSD1 inhibitors, and to rank these compounds correctly with respect to their inhibitory potency, two essential aspects in drug design. Ensemble docking experiments resulted in a steroidal binding mode for the closed enzyme conformations and in an alternative mode for the opened and occluded conformers with the inhibitors placed below the NADPH interacting with it synergically via π-π stacking and H-bond formation. Both binding modes were investigated by MD simulations and MM-PBSA binding free energy estimations using as representative member for this class compound 1 (50 nM). Notably, only the alternative binding mode proved stable and was energetically more favorable, while when simulated in the steroidal binding mode compound 1 was displaced from the active site. In parallel, ab initio studies of small NADPH-inhibitor complexes were performed, which supported the importance of the synergistic interaction between inhibitors and cofactor.


Long-Term Oral Toxicity and Anti-osteoporotic Effect of Sintered Dicalcium Pyrophosphate in Rat Model of Postmenopausal Osteoporosis.
Sintered dicalcium pyrophosphate (SDCP), a synthetic pyrophosphate analog, has shown potential for the management of osteoporosis. The long-term oral toxicity and anti-osteoporotic effect of SDCP in a postmenopausal osteoporosis rat model were evaluated in this study. SDCP was orally administered to bilateral ovariectomized (OVX) Wistar rats at a dose of 0.75 mg/kg daily for 24 weeks following by 2 weeks of observation. There were no abnormal findings in clinical signs of toxicity, food consumption, body weight, blood examination, necropsy, and histological inspection attributable to the ingestion of SDCP. The serum level of type I collagen fragments, a bone resorption marker, decreased in SDCP-treated rats, and the bone formation markers alkaline phosphatase, osteocalcin, and osteopontin significantly decreased. These findings indicate that the bone turnover rate decreased in SDCP-treated animals. Relative to OVX rats, the increase in serum tartrate-resistant acid phosphatase 5b level represents an increase in bony tissues in the SDCP-treated rats. Histological examinations of distal femoral metaphyses further revealed that the ingestion of SDCP improved the trabecular bone architecture and decreased bone porosity. Analysis of limb bone ashes showed a significant increase in bone mineral content. Our results show that SDCP inhibits bone resorption to restore bone mass in OVX rats without deleterious effects, and therefore that SDCP has potential in the management of osteoporosis.


Moral Distress in Clinicians Caring for Critically Ill Patients Who Require Mechanical Circulatory Support.
Although use of mechanical circulatory support is increasing, it is unclear how providing such care affects clinicians' moral distress. To measure moral distress among intensive care unit clinicians who commonly care for patients receiving mechanical circulatory support. In this prospective study, the Moral Distress Scale-Revised was administered to physicians, nurses, and advanced practice providers from 2 intensive care units in an academic medical center. Linear regression was used to assess whether moral distress was associated with clinician type, burnout, or desire to leave one's job. Clinicians' likelihood of reporting frequent moral distress when caring for patients receiving mechanical circulatory support vs other critically ill patients also was assessed. The sample comprised 102 clinicians who had a mean (SD) score of 100.5 (51.6) on the Moral Distress Scale- Revised. After adjustment for clinician characteristics, moral distress was significantly higher in registered nurses than physicians/advanced practice providers (115.9 vs 71.0, P < .001), clinicians reporting burnout vs those who did not (114.7 vs 83.1, P = .003), and those considering leaving vs those who were not (121.1 vs 89.2, P = .001). Clinicians were more likely to report experiencing frequent moral distress when caring for patients receiving mechanical circulatory support (26.5%) than when caring for patients needing routine care (10.8%; P = .004), but less likely than when caring for patients with either chronic critical illness (57.8%) or multisystem organ failure (56.9%; both P < .001). Moral distress was high among clinicians who commonly care for patients receiving mechanical circulatory support, suggesting that use of this therapy may affect well-being among intensive care unit clinicians.


Disparities in Surgical Treatment of Early-Stage Breast Cancer Among Female Residents of Texas: The Role of Racial Residential Segregation.
Early-stage breast cancer can be surgically treated by using mastectomy or breast-conserving surgery and adjuvant radiotherapy, also known as breast-conserving therapy (BCT). Little is known about the association between racial residential segregation, year of diagnosis, and surgical treatment of early-stage breast cancer, and whether racial residential segregation influences the association between other demographic characteristics and disparities in surgical treatment. This was a retrospective study using data from the Texas Cancer Registry composed of individuals diagnosed with breast cancer between 1995 and 2012. The dependent variable was treatment using mastectomy or BCT (M/BCT) and the independent variables of interest (IVs) were racial residential segregation and year of diagnosis. The covariates were race, residence, ethnicity, tumor grade, census tract (CT) poverty level, age at diagnosis, stage at diagnosis, and year of diagnosis. Bivariate and multivariable multilevel logistic regression models were estimated. The final sample size was 69,824 individuals nested within 4335 CTs. Adjusting for the IVs and all covariates, there were significantly decreased odds of treatment using M/BCT, as racial residential segregation increased from 0 to 1 (odds ratio [OR] 0.47; 95% confidence interval [CI], 0.41-0.54). There was also an increased likelihood of treatment using M/BCT with increasing year of diagnosis (OR 1.14; 95% CI, 1.13-1.16). A positive interaction effect between racial residential segregation and race was observed (OR 0.56; 95% CI, 0.36-0.88). Residents of areas with high indices of racial residential segregation were less likely to be treated with M/BCT. Racial disparities in treatment using M/BCT increased with increasing racial residential segregation.


Visible light-switched cytosol release of siRNA by amphiphilic fullerene derivative to enhance RNAi efficacy in vitro and in vivo.
Cationic macromolecules are attractive for use as small interfering RNA (siRNA) carriers due to their performance in non-immunological reactions, customization during synthesis, and low costs compared to viral carriers. However, their low transfection efficiency substantially hinders their application in both clinical practices and academic research, which is mostly attributable to the low capacity of siRNA/cationic macromolecule complexes to escape lysosomes. To address this challenge, we designed an amphiphilic fullerene derivative (C60-Dex-NH2) for efficient and controllable siRNA delivery. To synthesize C60-Dex-NH2, terminally aminated dextran was conjugated to C60. The conjugate was further cationized by covalently introducing ethylenediamine to the dextran. The physicochemical characteristics of C60-Dex-NH2 was examined with elemental analyses, gel permeation chromatography, solid-state nuclear magnetic resonance (13C, HPDEC), agarose gel electrophoresis, and dynamic light scattering. The cytotoxicity, cellular uptake, intracellular distribution, and in vitro RNA interference (RNAi) of siRNA/C60-Dex-NH2 complex was evaluated in the human breast cancer cell line MDA-MB-231. The RNAi efficiencies mediated by C60-Dex-NH2in vivo was evaluated in subcutaneous tumor-bearing mice. The results showed that C60-Dex-NH2 has a specific amphiphilic skeleton and could form micelle-like aggregate structures in water, which could prevent siRNA from destroying by reactive oxygen species (ROS). When exposed to visible light, C60-Dex-NH2 could trigger controllable ROS generation which could destroy the lysosome membrane, promote the lysosomal escape, and enhance the gene silencing efficiency of siRNA in vitro and in vivo. The gene silencing efficiency could reach a maximum of 53% in the MDA-MB-231-EGFP cells and 69% in the 4T1-GFP-Luc2 tumor-bearing mice. We designed a novel photosensitive amphiphilic carrier (C60-Dex-NH2) for efficient and controllable siRNA delivery, which can be used in gene therapy. We showed that C60-Dex-NH2 could destroy lysosome membrane via controllable generation of ROS when exposed to light, which can help siRNA to escape from lysosome before degradation. This can enhance the gene silencing efficiency significantly and provides a useful way to regulate RNAi efficiency by light. One advantage for C60-Dex-NH2 system is C60 has broad absorbance spectrum and can be activated by weak visible light; Furthermore, C60-Dex-NH2 has a specific amphiphilic structure, which may prevent siRNA from degrading and allows C60-Dex-NH2 to embed into the lipid membrane of lysosome to improve the ROS induced lysosomal disturbance after internalization.


Urban teens and young adults describe drama, disrespect, dating violence and help-seeking preferences.
Adolescent dating violence is increasingly recognized as a public health problem. Our qualitative investigation sought input from urban, African-American adolescents at risk for dating violence concerning (Tjaden and Thoennes in Full report of the prevelance, incidence, and consequences of violence against women: findings from the national violence against women survey. US Department of Justice, Washington, DC, 2000) dating violence descriptions, (WHO multi-country study on women's health and domestic violence against women: Summary report of initial results on prevalence, health outcomes and women's responses. World Health Organization, Geneva, 2005) preferences for help-seeking for dating violence, and (Intimate partner violence in the United States. Bureau of Justice Statistics, US Department of Justice, Office of Justice Programs, Washington, DC, 2007) recommendations for a teen dating violence resource center. Four focus groups were conducted with urban, African American adolescents (n = 32) aged 13-24 recruited from an urban adolescent clinic's community outreach partners. Qualitative analysis was conducted. Participants assigned a wide range of meanings for the term "relationship drama", and used dating violence using language not typically heard among adults, e.g., "disrespect". Participants described preferences for turning to family or friends before seeking formal services for dating violence, but reported barriers to their ability to rely on these informal sources. When asked to consider formal services, they described their preferred resource center as confidential and safe, with empathetic, non-judgmental staff. Teens also gave insight into preferred ways to outreach and publicize dating violence resources. Findings inform recommendations for youth-specific tailoring of violence screening and intervention efforts. Current evidence that slang terms, i.e., "drama", lack specificity suggests that they should not be integrated within screening protocols. These data highlight the value of formative research in understanding terminology and help-seeking priorities so as to develop and refine dating violence prevention and intervention efforts for those most affected.


Mapping the caregiving process in paediatric asthma: Parental burden, acceptance and denial coping strategies and quality of life.
Based on a multidimensional model of the caregiving process, the main goal of this study was to examine the direct and indirect links, via acceptance and denial coping, between the caregiving burden and the quality of life (QoL) in parents of children with asthma. The sample was composed of 182 parents of a child/adolescent between 8 and 18 years of age with a clinical diagnosis of asthma. Data were obtained via self-report questionnaires assessing the caregiving burden, acceptance and denial coping strategies and QoL. Results from structural equation modelling indicated a good fit for the mediation model, which explained 30% of the variability of the parents' QoL. Higher levels of caregiving burden were negatively and indirectly associated with the parents' QoL, via less use of acceptance and greater use of denial coping strategies. Multigroup analyses ascertained the invariance of these links across the children's asthma severity, age and socio-economic groups. These findings emphasise acceptance and denial as important coping mechanisms in the caregiving process. Thus, broad-spectrum family-centred interventions in paediatric asthma settings can target the development of the parents' coping tendencies characterised by greater acceptance and less denial as a way of reappraising caregiving demands as less burdensome and improving their QoL.


DNA-RNA hybrid duplexes with decreasing pyrimidine content in the DNA strand provide structural snapshots for the A- to B-form conformational transition of nucleic acids.
DNA-RNA hybrids are heterogeneous nucleic acid duplexes consisting of a DNA strand and a RNA strand, and are formed as key intermediates in many important biological processes. They serve as substrates for the RNase H enzymatic activity, which has been exploited for several biomedical technologies such as antiviral and antisense therapies. To understand the relation of structural properties with the base composition in DNA-RNA hybrids, molecular dynamics (MD) simulations were performed on selected model systems by systematically varying the deoxypyrimidine (dPy) content from 0 to 100% in the DNA strand. The results suggest that the hybrid duplex properties are highly dependent on their deoxypyrimidine content of the DNA strand. However, such variations are not seen in their corresponding pure DNA and RNA duplex counterparts. It is also noticed that the systematic variation in deoxypyrimidine content of hybrids leads to gradual transformation between B- and A-form nucleic acid structures. Binding free energy calculations explain the previous experimental findings that the hybrids with high deoxypyrimidine content (>50%) are more stable than their respective pure counterparts. Pseudorotation angles, minor groove widths, phosphodiester angles, and glycosidic dihedral angles exhibit gradual A- to A/B-like conformation with decreasing deoxypyrimidine content. Based on extensive analysis, possible factors that affect RNase H enzymatic activity on hybrid duplexes with high dPy composition are proposed.


Clinical experience of volumetric modulated arc therapy for malignant pleural mesothelioma after extrapleural pneumonectomy.
The purpose of this study was to evaluate the efficacy and safety of volumetric modulated arc therapy (VMAT) after extrapleural pneumonectomy (EPP) in patients with malignant pleural mesothelioma (MPM). A total of 15 patients who received VMAT after EPP were enrolled. All patients were males, and the median age was 67 years (Stage IB in two, II in six, and III in seven patients). The clinical target volume (CTV) included the entire preoperative ipsilateral hemithorax and involved nodal stations. The CTV was generally expanded by 10-15 mm beyond the planning target volume (PTV). The dose prescription was designed to cover 95% of the PTV with 54 Gy in 30 fractions. The median follow-up period was 11 months. Treatment-related toxicities were evaluated by Common Terminology Criteria for Adverse Events (CTCAE) ver. 4. One-year local control, disease-free survival, and overall survival rates were 55.7% [95% confidence interval (CI): 25.6-85.8%], 29.3% (95% CI: 5.3-53.3%), and 43.1% (95% CI: 17.1-69.0%), respectively. According to the histological analysis, the one-year LC rate was significantly worse in patients with non-epithelial type (biphasic and sarcomatoid types) than in patients with epithelial type [epithelial type: 83.3% (95% CI, 53.5-100%), non-epithelial type: 0% (95% CI, 0%), P = 0.0011]. Grade 3 pneumonitis after VMAT was observed in three patients (20.0%); however, no patients died of pulmonary toxicity. VMAT appears to be relatively safe for patients with MPM after EPP because of the low pulmonary dose.


Plastic and the nest entanglement of urban and agricultural crows.
Much attention has been paid to the impacts of plastics and other debris on marine organisms, but the effects of plastic on terrestrial organisms have been largely ignored. Detrimental effects of terrestrial plastic could be most pronounced in intensively human-modified landscapes (e.g., urban and agricultural areas), which are a source of much anthropogenic debris. Here, we examine the occurrence, types, landscape associations, and consequences of anthropogenic nest material in the American crow (Corvus brachyrhynchos), a North American species that breeds in both urban and agricultural landscapes. We monitored 195 nestlings in 106 nests across an urban and agricultural gradient in the Sacramento Valley, California, USA. We found that 85.2% of crow nests contained anthropogenic material, and 11 of 195 nestlings (5.6%) were entangled in their nests. The length of the material was greater in nests in agricultural territories than in urban territories, and the odds of entanglement increased 7.55 times for each meter of anthropogenic material in the nest. Fledging success was significantly lower for entangled than for unentangled nestlings. In all environments, particularly urban, agricultural, and marine, careful disposal of potential hazards (string, packing and hay bale twine, balloon ribbon, wire, fishing line) could reduce the occurrence of entanglement of nestling birds.


Resource utilization in clubfoot management.
Both private and socialized healthcare systems require treatments to be not only effective, but also cost-efficient. Although the Ponseti method of clubfoot treatment is effective, its cost-effectiveness has not been demonstrated. We compared the difference in resource use between two prospective cohorts treated for clubfoot by either the Ponseti method or below-knee casting followed by primary surgical release in the socialized healthcare system of New Zealand. Using these cohorts and US billing data, costs of treating these cohorts in the US healthcare system were also calculated. Treatment of initial deformity, recurrences, and complications in both cohorts were included in the final assessment. Twenty-six patients (40 feet) were enrolled in the Ponseti cohort and 29 (46 feet) in the primary surgical cohort. For most patients, the Ponseti method was more cost-effective than the primary surgical treatment in both healthcare systems. The cost of treating both cohorts was lower in the socialized system than in the US healthcare system. Level II, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence.


Bioinspired Theranostic Coordination Polymer Nanoparticles for Intranasal Dopamine Replacement in Parkinson's Disease.
Dopamine (DA) is one of the main neurotransmitters found in the central nervous system and has a vital role in the function of dopaminergic (DArgic) neurons. A progressive loss of this specific subset of cells is one of the hallmarks of age-related neurodegenerative disorders such as Parkinson's disease (PD). Symptomatic therapy for PD has been centered in the precursor l-DOPA administration, an amino acid precursor of DA that crosses the blood-brain barrier (BBB) while DA does not, although this approach presents medium- to long-term side effects. To overcome this limitation, DA-nanoencapsulation therapies are actively being searched as an alternative for DA replacement. However, overcoming the low yield of encapsulation and/or poor biodistribution/bioavailability of DA is still a current challenge. Herein, we report the synthesis of a family of neuromelanin bioinspired polymeric nanoparticles. Our system is based on the encapsulation of DA within nanoparticles through its reversible coordination complexation to iron metal nodes polymerized with a bis-imidazol ligand. Our methodology, in addition to being simple and inexpensive, results in DA loading efficiencies of up to 60%. In vitro, DA nanoscale coordination polymers (DA-NCPs) exhibited lower toxicity, degradation kinetics, and enhanced uptake by BE(2)-M17 DArgic cells compared to free DA. Direct infusion of the particles in the ventricle of rats in vivo showed a rapid distribution within the brain of healthy rats, leading to an increase in striatal DA levels. More importantly, after 4 days of nasal administrations with DA-NCPs equivalent to 200 μg of the free drug per day, the number and duration of apomorphine-induced rotations was significantly lower from that in either vehicle or DA-treated rats performed for comparison purposes. Overall, this study demonstrates the advantages of using nanostructured DA for DA-replacement therapy.


Directional statistics-based reflectance model for isotropic bidirectional reflectance distribution functions.
We introduce a novel parametric bidirectional reflectance distribution function (BRDF) model that can accurately encode a wide variety of real-world isotropic BRDFs with a small number of parameters. The key observation we make is that a BRDF may be viewed as a statistical distribution on a unit hemisphere. We derive a novel directional statistics distribution, which we refer to as the hemispherical exponential power distribution, and model real-world isotropic BRDFs as mixtures of it. We derive a canonical probabilistic method for estimating the parameters, including the number of components, of this novel directional statistics BRDF model. We show that the model captures the full spectrum of real-world isotropic BRDFs with high accuracy, but a small footprint. We also demonstrate the advantages of the novel BRDF model by showing its use for reflection component separation and for exploring the space of isotropic BRDFs.


Systolic blood pressure, chronic obstructive pulmonary disease and cardiovascular risk.
In individuals with complex underlying health problems, the association between systolic blood pressure (SBP) and cardiovascular disease is less well recognised. The association between SBP and risk of cardiovascular events in patients with chronic obstructive pulmonary disease (COPD) was investigated. In this cohort study, 39 602 individuals with a diagnosis of COPD aged 55-90 years between 1990 and 2009 were identified from validated electronic health records (EHR) in the UK. The association between SBP and risk of cardiovascular end points (composite of ischaemic heart disease, heart failure, stroke and cardiovascular death) was analysed using a deep learning approach. In the selected cohort (46.5% women, median age 69 years), 10 987 cardiovascular events were observed over a median follow-up period of 3.9 years. The association between SBP and risk of cardiovascular end points was found to be monotonic; the lowest SBP exposure group of <120 mm Hg presented nadir of risk. With respect to reference SBP (between 120 and 129 mm Hg), adjusted risk ratios for the primary outcome were 0.99 (95% CI 0.93 to 1.05) for SBP of <120 mm Hg, 1.02 (0.97 to 1.07) for SBP between 130 and 139 mm Hg, 1.07 (1.01 to 1.12) for SBP between 140 and 149 mm Hg, 1.11 (1.05 to 1.17) for SBP between 150 and 159 mm Hg and 1.16 (1.10 to 1.22) for SBP ≥160 mm Hg. Using deep learning for modelling EHR, we identified a monotonic association between SBP and risk of cardiovascular events in patients with COPD.


Genome-Wide Profiling of Prognostic Alternative Splicing Pattern in Pancreatic Cancer.
Alternative splicing (AS) has a critical role in tumor progression and prognosis. Our study aimed to investigate pancreatic cancer-specific AS events using RNA-seq data, gaining systematic insights into potential prognostic predictors. We downloaded 10,623 genes with 45,313 pancreatic cancer-specific AS events from the Cancer Genome Atlas (TCGA) and SpliceSeq database. Cox univariate analyses of overall survival suggested there was a remarkable association between 6,711 AS events and overall survival in pancreatic cancer patients (P < 0.05). The area under the curves (AUC) of the receiver operator characteristic curves (ROC) of risk score was 0.89 for final prognostic predictor. Results indicated that AS events of DAZAP1, RBM4, ESRP1, QKI, and SF1 were significantly associated with overall survival. The results of FunRich showed that transcription factors KLF7, GABPA, and SP1 were the most highly related to survival-associated AS genes. Furthermore, using DriverDBv2, we identified 13 driver genes associated with survival-associated AS events, including TP53 and CDC27. Thus, we concluded that the aberrant AS patterns in pancreatic cancer patients might serve as prognostic predictors.


Conditional Knock-out of mGluR5 from Astrocytes during Epilepsy Development Impairs High-Frequency Glutamate Uptake.
Astrocyte expression of metabotropic glutamate receptor 5 (mGluR5) is consistently observed in resected tissue from patients with epilepsy and is equally prevalent in animal models of epilepsy. However, little is known about the functional signaling properties or downstream consequences of astrocyte mGluR5 activation during epilepsy development. In the rodent brain, astrocyte mGluR5 expression is developmentally regulated and confined in expression/function to the first weeks of life, with similar observations made in human control tissue. Herein, we demonstrate that mGluR5 expression and function dramatically increase in a mouse model of temporal lobe epilepsy. Interestingly, in both male and female mice, mGluR5 function persists in the astrocyte throughout the process of epileptogenesis following status epilepticus. However, mGluR5 expression and function are transient in animals that do not develop epilepsy over an equivalent time period, suggesting that patterns of mGluR5 expression may signify continuing epilepsy development or its resolution. We demonstrate that, during epileptogenesis, astrocytes reacquire mGluR5-dependent calcium transients following agonist application or synaptic glutamate release, a feature of astrocyte-neuron communication absent since early development. Finally, we find that the selective and conditional knock-out of mGluR5 signaling from astrocytes during epilepsy development slows the rate of glutamate clearance through astrocyte glutamate transporters under high-frequency stimulation conditions, a feature that suggests astrocyte mGluR5 expression during epileptogenesis may recapitulate earlier developmental roles in regulating glutamate transporter function.SIGNIFICANCE STATEMENT In development, astrocyte mGluR5 signaling plays a critical role in regulating structural and functional interactions between astrocytes and neurons at the tripartite synapse. Notably, mGluR5 signaling is a positive regulator of astrocyte glutamate transporter expression and function, an essential component of excitatory signaling regulation in hippocampus. After early development, astrocyte mGluR5 expression is downregulated, but reemerges in animal models of temporal lobe epilepsy (TLE) development and patient epilepsy samples. We explored the hypothesis that astrocyte mGluR5 reemergence recapitulates earlier developmental roles during TLE acquisition. Our work demonstrates that astrocytes with mGluR5 signaling during TLE development perform faster glutamate uptake in hippocampus, revealing a previously unexplored role for astrocyte mGluR5 signaling in hypersynchronous pathology.


An Ophthalmic Targeted Exome Sequencing Panel as a Powerful Tool to Identify Causative Mutations in Patients Suspected of Hereditary Eye Diseases.
We evaluate the power of a next-generation sequencing-based ophthalmic targeted sequencing panel (NGS-based OTSP) as a genetics-testing tool for patients suspected of a wide range of hereditary eye diseases. NGS-based OTSP encompasses 126 genes with identified mutations that account for the majority of Chinese families with hereditary eye diseases. A total of 568 probands suspected of having hereditary eye diseases underwent genetic testing by OTSP with targeted phenotype-driven analysis. NGS-based OTSP detected 329 potential pathogenic variants in 62 genes. These mutations might represent the genetic cause in 52% (293/568) of probands suspected of having hereditary eye diseases. Within the disease subgroups, the detection rates were 61% (124/202) for retinal degeneration disease, 53% (35/66) for eye tumors, 49% (53/108) for retinal vessel disease, 46% (13/28) for retinal detachment, 33% (19/58) for significant refractive error, 35% (16/46) for optic atrophy, 48% (11/23) for anterior segment dysgenesis, and 59% (22/37) for other hereditary eye diseases. These detection rates are comparable to those obtained in our previous study performed with whole exome sequencing. Mutations in the same gene were detected in different forms of hereditary eye diseases. The average turnaround time for OTSP is 30 days, and the average cost is 139 USD per patient. NGS-based OTSP is a powerful tool for routine clinical genetic diagnostic testing in patients suspected of having hereditary eye diseases. NGS-based OTSP can be used as a routine clinical test to improve the genetic counseling and medical care of patients suspected of having hereditary eye diseases.


Parkin mutations and susceptibility alleles in late-onset Parkinson's disease.
Parkin, an E2-dependent ubiquitin protein ligase, carries pathogenic mutations in patients with autosomal recessive juvenile parkinsonism, but its role in the late-onset form of Parkinson's disease (PD) is not firmly established. Previously, we detected linkage of idiopathic PD to the region on chromosome 6 containing the Parkin gene (D6S305, logarithm of odds score, 5.47) in families with at least one subject with age at onset (AAO) younger than 40 years. Mutation analysis of the Parkin gene in the 174 multiplex families from the genomic screen and 133 additional PD families identified mutations in 18% of early-onset and 2% of late-onset families (5% of total families screened). The AAO of patients with Parkin mutations ranged from 12 to 71 years. Excluding exon 7 mutations, the mean AAO of patients with Parkin mutations was 31.5 years. However, mutations in exon 7, the first RING finger (Cys253Trp, Arg256Cys, Arg275Trp, and Asp280Asn) were observed primarily in heterozygous PD patients with a much later AAO (mean AAO, 49.2 years) but were not found in controls in this study or several previous reports (920 chromosomes). These findings suggest that mutations in Parkin contribute to the common form of PD and that heterozygous mutations, especially those lying in exon 7, act as susceptibility alleles for late-onset form of Parkinson disease.


Chemotaxis of Rhizobium meliloti towards Nodulation Gene-Inducing Compounds from Alfalfa Roots.
Luteolin, a flavone present in seed exudates of alfalfa, induces nodulation genes (nod) in Rhizobium meliloti and also serves as a biochemically specific chemoattractant for the bacterium. The present work shows that R. meliloti RCR2011 is capable of very similar chemotactic responses towards 4',7-dihydroxyflavone, 4',7-Dihydroxyflavanone, and 4,4'-dihydroxy-2-methoxychalcone, the three principal nod gene inducers secreted by alfalfa roots. Chemotactic responses to the root-secreted nod inducers in capillary assays were usually two- to four-fold above background and, for the flavone and flavonone, occurred at concentrations lower than those required for half-maximal induction of the nodABC genes. Complementation experiments indicated that the lack of chemotactic responsiveness to luteolin seen in nodD1 and nodA mutants of R. meliloti was not due to mutations in the nod genes, as previously thought. Thus, while nod gene induction and flavonoid chemotaxis have the same biochemical specificity, these two functions appear to have independent receptors or transduction pathways. The wild-type strain was found to suffer selective, spontaneous loss of chemotaxis towards flavonoids during laboratory subculture.


Integrated morbidity management for lymphatic filariasis and podoconiosis, Ethiopia.
Lymphatic filariasis and podoconiosis are the major causes of tropical lymphoedema in Ethiopia. The diseases require a similar provision of care, but until recently the Ethiopian health system did not integrate the morbidity management. To establish health-care services for integrated lymphoedema morbidity management, the health ministry and partners used existing governmental structures. Integrated disease mapping was done in 659 out of the 817 districts, to identify endemic districts. To inform resource allocation, trained health extension workers carried out integrated disease burden assessments in 56 districts with a high clinical burden. To ensure standard provision of care, the health ministry developed an integrated lymphatic filariasis and podoconiosis morbidity management guideline, containing a treatment algorithm and a defined package of care. Experienced professionals on lymphoedema management trained government-employed health workers on integrated morbidity management. To monitor the integration, an indicator on the number of lymphoedema-treated patients was included in the national health management information system. In 2014, only 24% (87) of the 363 health facilities surveyed provided lymphatic filariasis services, while 12% (44) provided podoconiosis services. To date, 542 health workers from 53 health centres in 24 districts have been trained on integrated morbidity management. Between July 2013 and June 2016, the national health management information system has recorded 46 487 treated patients from 189 districts. In Ethiopia, an integrated approach for lymphatic filariasis and podoconiosis morbidity management was feasible. The processes used could be applicable in other settings where these diseases are co-endemic.


Multimodal monitoring of human cortical organoids implanted in mice reveal functional connection with visual cortex.
Human cortical organoids, three-dimensional neuronal cultures, are emerging as powerful tools to study brain development and dysfunction. However, whether organoids can functionally connect to a sensory network in vivo has yet to be demonstrated. Here, we combine transparent microelectrode arrays and two-photon imaging for longitudinal, multimodal monitoring of human cortical organoids transplanted into the retrosplenial cortex of adult mice. Two-photon imaging shows vascularization of the transplanted organoid. Visual stimuli evoke electrophysiological responses in the organoid, matching the responses from the surrounding cortex. Increases in multi-unit activity (MUA) and gamma power and phase locking of stimulus-evoked MUA with slow oscillations indicate functional integration between the organoid and the host brain. Immunostaining confirms the presence of human-mouse synapses. Implantation of transparent microelectrodes with organoids serves as a versatile in vivo platform for comprehensive evaluation of the development, maturation, and functional integration of human neuronal networks within the mouse brain.


A new high affinity binding site for suppressor of cytokine signaling-3 on the erythropoietin receptor.
Erythropoietin (Epo) is a hematopoietic cytokine that is crucial for the differentiation and proliferation of erythroid progenitor cells. Epo acts on its target cells by inducing homodimerization of the erythropoietin receptor (EpoR), thereby triggering intracellular signaling cascades. The EpoR encompasses eight tyrosine motifs on its cytoplasmic tail that have been shown to recruit a number of regulatory proteins. Recently, the feedback inhibitor suppressor of cytokine signaling-3 (SOCS-3), also referred to as cytokine-inducible SH2-containing protein 3 (CIS-3), has been shown to act on Epo signaling by both binding to the EpoR and the EpoR-associated Janus kinase 2 (Jak2) [Sasaki, A., Yasukawa, H., Shouda, T., Kitamura, T., Dikic, I. & Yoshimura, A. (2000) J. Biol. Chem 275, 29338-29347]. In this study tyrosine 401 was identified as a binding site for SOCS-3 on the EpoR. Here we show that human SOCS-3 binds to pY401 with a Kd of 9.5 microm while another EpoR tyrosine motif, pY429pY431, can also interact with SOCS-3 but with a ninefold higher affinity than we found for the previously reported motif pY401. In addition, SOCS-3 binds the double phosphorylated motif pY429pY431 more potently than the respective singly phosphorylated tyrosines indicating a synergistic effect of these two tyrosine residues with respect to SOCS-3 binding. Surface plasmon resonance analysis, together with peptide precipitation assays and model structures of the SH2 domain of SOCS-3 complexed with EpoR peptides, provide evidence for pY429pY431 being a new high affinity binding site for SOCS-3 on the EpoR.


An infant with poor weight gain and hypochloremic metabolic alkalosis: a case report.
Bartter syndrome is an autosomal recessive disease manifested by a defect in chloride transport in the thick loop of Henle, with different genetic origins and molecular pathophysiology. Children with Bartter syndrome generally present in early infancy with persistent polyuria and associated dehydration, electrolyte imbalance, and failure to thrive. Although early diagnosis and appropriate treatment of Bartter syndrome may improve the outcome, some children will progress to renal failure. We report a case of an 8-week-old infant who was admitted for electrolyte imbalance and failure to thrive. Laboratory studies revealed hypochloremic metabolic alkalosis with severe hypokalemia. Health care providers should consider Bartter syndrome when excessive chloride losses appear to be renal in origin and the patient has normal blood pressure and high levels of serum renin and aldosterone. Treatments, including indomethacin, spironolactone, and aggressive fluid and electrolyte replacement, may prevent renal failure in children with Bartter syndrome. Molecular genetics studies are indicated to identify the primary genetic defect.


Estimating confidence intervals for the difference in diagnostic accuracy with three ordinal diagnostic categories without a gold standard.
With three ordinal diagnostic categories, the most commonly used measures for the overall diagnostic accuracy are the volume under the ROC surface (VUS) and partial volume under the ROC surface (PVUS), which are the extensions of the area under the ROC curve (AUC) and partial area under the ROC curve (PAUC), respectively. A gold standard (GS) test on the true disease status is required to estimate the VUS and PVUS. However, oftentimes it may be difficult, inappropriate, or impossible to have a GS because of misclassification error, risk to the subjects or ethical concerns. Therefore, in many medical research studies, the true disease status may remain unobservable. Under the normality assumption, a maximum likelihood (ML) based approach using the expectation-maximization (EM) algorithm for parameter estimation is proposed. Three methods using the concepts of generalized pivot and parametric/nonparametric bootstrap for confidence interval estimation of the difference in paired VUSs and PVUSs without a GS are compared. The coverage probabilities of the investigated approaches are numerically studied. The proposed approaches are then applied to a real data set of 118 subjects from a cohort study in early stage Alzheimer's disease (AD) from the Washington University Knight Alzheimer's Disease Research Center to compare the overall diagnostic accuracy of early stage AD between two different pairs of neuropsychological tests.


Staying afloat: community perspectives on health system resilience in the management of pregnancy and childbirth care during floods in Cambodia.
Resilient health systems have the capacity to continue providing health services to meet the community's diverse health needs following floods. This capacity is related to how the community manages its own health needs and the community and health system's joined capacities for resilience. Yet little is known about how community participation influences health systems resilience. The purpose of this study was to understand how community management of pregnancy and childbirth care during floods is contributing to the system's capacity to absorb, adapt or transform as viewed through a framework on health systems resilience. Eight focus group discussions and 17 semi-structured interviews were conducted with community members and leaders who experienced pregnancy or childbirth during recent flooding in rural Cambodia. The data were analysed by thematic analysis and discussed in relation to the resilience framework. The theme 'Responsible for the status quo' reflected the community's responsibility to find ways to manage pregnancy and childbirth care, when neither the expectations of the health system nor the available benefits changed during floods. The theme was informed by notions on: i) developmental changes, the unpredictable nature of floods and limited support for managing care, ii) how information promoted by the public health system led to a limited decision-making space for pregnancy and childbirth care, iii) a desire for security during floods that outweighed mistrust in the public health system and iv) the limits to the coping strategies that the community prepared in case of flooding. The community mainly employed absorptive strategies to manage their care during floods, relieving the burden on the health system, yet restricted support and decision-making may risk their capacity. Further involvement in decision-making for care could help improve the health system's resilience by creating room for the community to adapt and transform when experiencing floods.


Temperature and malaria trends in highland East Africa.
There has been considerable debate on the existence of trends in climate in the highlands of East Africa and hypotheses about their potential effect on the trends in malaria in the region. We apply a new robust trend test to mean temperature time series data from three editions of the University of East Anglia's Climatic Research Unit database (CRU TS) for several relevant locations. We find significant trends in the data extracted from newer editions of the database but not in the older version for periods ending in 1996. The trends in the newer data are even more significant when post-1996 data are added to the samples. We also test for trends in the data from the Kericho meteorological station prepared by Omumbo et al. We find no significant trend in the 1979-1995 period but a highly significant trend in the full 1979-2009 sample. However, although the malaria cases observed at Kericho, Kenya rose during a period of resurgent epidemics (1994-2002) they have since returned to a low level. A large assembly of parasite rate surveys from the region, stratified by altitude, show that this decrease in malaria prevalence is not limited to Kericho.


Staphylococcus epidermidis strains isolated from breast milk of women suffering infectious mastitis: potential virulence traits and resistance to antibiotics.
Although Staphylococcus aureus is considered the main etiological agent of infectious mastitis, recent studies have suggested that coagulase-negative staphylococci (CNS) may also play an important role in such infections. The aims of this work were to isolate staphylococci from milk of women with lactational mastitis, to select and characterize the CNS isolates, and to compare such properties with those displayed by CNS strains isolated from milk of healthy women. The milk of 30 women was collected and bacterial growth was noted in 27 of them, of which Staphylococcus epidermidis was isolated from 26 patients and S. aureus from 8. Among the 270 staphylococcal isolates recovered from milk of women with mastitis, 200 were identified as Staphylococcus epidermidis by phenotypic assays, species-specific PCR and PCR sequencing. They were typified by pulsed field gel electrophoresis (PFGE) genotyping. The PFGE profiles of the S. epidermidis strains were compared with those of 105 isolates from milk of healthy women. A representative of the 76 different PFGE profiles was selected to study the incidence of virulence factors and antibiotic resistance. The number of strains that contained the biofilm-related icaD gene and that showed resistance to oxacillin, erythromycin, clindamycin and mupirocin was significantly higher among the strains isolated from mastitic milk. S. epidermidis may be a frequent but largely underrated cause of infectious mastitis in lactating women. The resistance to diverse antibiotics and a higher ability to form biofilms found among the strains isolated from milk of women suffering mastitis may explain the chronic and/or recurrent nature of this infectious condition.


Porous silicon Bloch surface and sub-surface wave structure for simultaneous detection of small and large molecules.
A porous silicon (PSi) Bloch surface wave (BSW) and Bloch sub-surface wave (BSSW) composite biosensor is designed and used for the size-selective detection of both small and large molecules. The BSW/BSSW structure consists of a periodic stack of high and low refractive index PSi layers and a reduced optical thickness surface layer that gives rise to a BSW with an evanescent tail that extends above the surface to enable the detection of large surface-bound molecules. Small molecules were detected in the sensor by the BSSW, which is a large electric field intensity spatially localized to a desired region of the Bragg mirror and is generated by the implementation of a step or gradient refractive index profile within the Bragg mirror. The step and gradient BSW/BSSW sensors are designed to maximize both resonance reflectance intensity and sensitivity to large molecules. Size-selective detection of large molecules including latex nanospheres and the M13KO7 bacteriophage as well as small chemical linker molecules is reported.


Vegetarian diet, change in dietary patterns, and diabetes risk: a prospective study.
Vegetarian diets are inversely associated with diabetes in Westerners but their impact on Asians-whose pathophysiology differ from Westerners-is unknown. We aim to investigate the association between a vegetarian diet, change in dietary patterns and diabetes risk in a Taiwanese Buddhist population. We prospectively followed 2918 non-smoking, non-alcohol drinking Buddhists free of diabetes, cancer, and cardiovascular diseases at baseline, for a median of 5 years, with 183 incident diabetes cases confirmed. Diet was assessed through a validated food frequency questionnaire at baseline and a simple questionnaire during follow-ups. Incident cases of diabetes were ascertained through follow-up questionnaires, fasting glucose and HbA1C. Stratified Cox Proportional Hazards Regression was used to assess the effect of diets on risk of diabetes. Consistent vegetarian diet was associated with 35% lower hazards (HR: 0.65, 95% CI: 0.46, 0.92), while converting from a nonvegetarian to a vegetarian pattern was associated with 53% lower hazards (HR: 0.47, 95% CI: 0.30, 0.71) for diabetes, comparing with nonvegetarians while adjusting for age, gender, education, physical activity, family history of diabetes, follow-up methods, use of lipid-lowering medications, and baseline BMI. Vegetarian diet and converting to vegetarian diet may protect against diabetes independent of BMI among Taiwanese.


Perspectives and experiences of new migrants on health screening in Sweden.
In Sweden, migrants from countries considered to have a high burden of certain infectious diseases are offered health screening to prevent the spread of these diseases, but also identify their health needs. However, very little is known about their experiences and perceptions about the screening process. This study aimed at exploring these perceptions and experiences in order to inform policy and clinical practice. Using an interpretive description framework, 26 new migrants were interviewed between April and June 2013 in four Swedish counties. Thematic analysis was used to analyze data. The three themes developed include: new country, new practices; new requirements in the new country; and unmet needs and expectations. Participants described what it meant for them to come to a new country with a foreign language, new ways of communicating with caregivers/authorities and being offered health screening without clarification. Participants perceived health screening as a requirement from the authorities to be fulfilled by all newcomers but conceded that it benefits equally the host society and themselves. However, they also expressed concern over the involvement of the Migration Board staff and feared possible collaboration with health service to their detriment. They further stated that the screening program fell short of their expectations as it mainly focused on identifying infectious diseases and overlooked their actual health needs. Finally, they expressed frustration over delay in screening, poor living conditions in reception centers and the restrictive entitlement to care. Migrants are aware of their vulnerability and the need to undergo health screening though they view it as an official requirement. Thus, those who underwent the screening were more concerned about residency rather than the actual benefits of screening. The issues highlighted in this study may limit access to and uptake of the screening service, and compromise its effectiveness. To maximize the uptake: (1) linguistically and culturally adapted information is needed, (2) other screening approaches should be tried, (3) trained medical interpreters should be used, (4) a holistic and human right approach should be applied, (5) the involvement of migration staff should be reconsidered to avoid confusion and worries. Finally, to improve the effectiveness, (6) all migrants from targeted countries should be offered screening and efforts should be taken to improve the health literacy of migrants and the living conditions in reception centers.


Expression of the neural cell adhesion molecule in endocrine cells of the ovary.
In the adult mammalian ovary morphogenesis and differentiation processes are under hormonal control and, thus, occur in a highly regulated way during the sexual cycle. Cell-cell interactions, such as cell adhesion and cell separation, are crucial during these events. Here we show that the ovarian endocrine cells, which are prototypes of steroid-producing cells, express neural cell adhesion molecules (NCAMs). The combined use of in situ hybridization histochemistry, immunocytochemistry at the light and electron microscope levels, S1 nuclease protection assays, and Western blotting revealed that in the ovary of the adult rat during the estrus cycle and pregnancy, NCAM mRNA and the 140-kDa isoform of this protein are expressed mainly in granulosa cells of growing preantral and antral follicles and in corpora lutea. Since the granulosa cells lining the forming antrum and the antral fluid were strongly immunoreactive, a role for NCAM in the formation of the follicular antrum is proposed. The expression of NCAM was also associated with luteal cells of the active corpus luteum, indicating a role for NCAM in the morphogenesis of this endocrine compartment. Moreover, thecal cells of large follicles and hypertrophic thecal cells of atretic follicles expressed NCAM, as did interstitial cells, which are derived from thecal cells of atretic follicles. We propose that the adhesion molecule, NCAM, is an important factor involved in the recognition and intercellular interaction of ovarian endocrine cells and, thus, participates in the regulation of the cyclic remodeling processes of the ovarian endocrine compartments.


Development of the Children's Communication Checklist (CCC): a method for assessing qualitative aspects of communicative impairment in children.
The Children's Communication Checklist (CCC) was developed to assess aspects of communicative impairment that are not adequately evaluated by contemporary standardised language tests. These are predominantly pragmatic abnormalities seen in social communication, although other qualitative aspects of speech and language were also included. Some items covering social relationships and restricted interests were incorporated, so that the relationship between pragmatic difficulties and other characteristics of pervasive developmental disorders could be explored. Checklist ratings were obtained for 76 children aged 7 to 9 years, all of whom had received special education for language impairment. In 71 cases, 2 raters (usually a teacher and speech-language therapist) independently completed the checklist, making it possible to establish inter-rater reliability. From an initial pool of 93 items, 70 items, grouped into 9 scales, were retained. Five of the subscales were concerned with pragmatic aspects of communication. A composite pragmatic impairment scale formed from these subscales had inter-rater reliability and internal consistency of around .80. This composite discriminated between children with a school diagnosis of semantic-pragmatic disorder and those with other types of specific language impairment (SLI). The majority of children with pragmatic language impairments did not have any evidence of restricted interests or significant difficulties in the domains of social relationships.