Energy-Transfer Schemes To Probe Fluorescent Nanocarriers and Their Emissive Cargo.
A strategy to probe supramolecular nanocarriers and their cargo in the intracellular space was developed on the basis of fluorescence measurements and energy transfer. It relies on the covalent attachment of an energy donor, or acceptor, to the macromolecular backbone of amphiphilic polymers and the noncovalent encapsulation of a complementary acceptor, or donor, in the resulting micelles. In aqueous environments, these macromolecules self-assemble into nanostructured constructs and bring the complementary chromophores in close proximity to enable efficient energy transfer. These supramolecular assemblies travel from the extracellular to the intracellular space and retain their integrity in the process. Indeed, donors and acceptors remain close to each other after internalization, and excitation of the former chromophores translates into significant intracellular emission from the latter. Furthermore, these supramolecular assemblies exchange their components with fast kinetics in aqueous dispersions because of the reversible character of the noncovalent contacts holding them together. As a result, micelles incorporating exclusively the donors and nanocarriers containing only the acceptors scramble their chromophoric building blocks, upon mixing, to allow the transfer of energy. These dynamic processes can be reproduced in the intracellular environment with the sequential incubation of cells with the two sets of complementary nanostructured assemblies. Thus, these operating principles and choice of supramolecular synthons are particularly valuable to monitor self-assembling nanocarriers and their cargo inside living cells and can facilitate the elucidation of the behavior of these promising delivery vehicles in a diversity of biological specimens.


A reappraisal of the morphology and systematic position of the theropod dinosaur Sigilmassasaurus from the "middle" Cretaceous of Morocco.
Sigilmassasaurus brevicollis is an enigmatic theropod dinosaur from the early Late Cretaceous (Cenomanian) of Morocco, originally based on a few isolated cervical vertebrae. Ever since its original description, both its taxonomic validity and systematic affinities were contentious. Originally considered to represent its own family, Sigilmassasauridae, the genus has variously been suggested to represent a carcharodontosaurid, an ornithischian, and, more recently, a spinosaurid. Here we describe new remains referrable to this taxon and re-evaluate its taxonomic status and systematic affinities. Based on the new remains, a re-evaluation of the original materials, and comparisons with other spinosaurids, the holotype of Sigilmassasaurus brevicollis is identified as an anterior dorsal, rather than a cervical vertebra, and differences between elements referred to this taxon can be explained by different positions of the elements in question within the vertebral column. Many characters used previously to diagnose the genus and species are found to be more widespread among basal tetanurans, and specifically spinosaurids. However, the taxon shows several autapomorphies that support its validity, including the presence of a strongly rugose, ventrally offset triangular platform that is confluent with a ventral keel anteriorly in the mid-cervical vertebral centra and a strongly reduced lateral neural arch lamination, with no or an incomplete distinction between anterior and posterior centrodiapophyseal laminae in the posterior cervical and anterior dorsal vertebrae. We argue furthermore that Spinosaurus maroccanus, also described on the basis of isolated cervical vertebrae from the same stratigraphic unit and in the same paper as Sigilmassasaurus brevicollis, is a subjective synonym of the latter. Both a detailed comparison of this taxon with other theropods and a formal phylogenetic analysis support spinosaurid affintities for Sigilmassasaurus. However, we reject the recently proposed synonymy of both Spinosaurus maroccanus and Sigilmassasurus brevicollis with Spinosaurus aegyptiacus from the Cenomanian of Egypt, as there are clear differences between the vertebrae of these taxa, and they do not share any derived character that is not found in other spinosaurids. Together with a comparison with other spinosaurid vertebral material from the Kem Kem, this suggests that more than one taxon of spinosaurid was present in the Kem Kem assemblage of Morocco, so the referral of non-overlapping material from this unit to a single taxon should be regarded with caution.


Investigation of TNF-alpha release as a measure of skin irritancy.
Contact dermatitis is by far the most frequently reported occupational disease, with irritant dermatitis accounting for up to 80% of all cases. A wide variety of materials are capable of causing skin inflammation including soaps, cosmetics, pesticides, organic dyes, solvents and industrial chemicals and wastes. Skin irritation results from a complex series of events involving the development of an inflammatory response at the site of exposure. Cytokines are a family of proteins and glycoproteins that regulate immune and inflammatory responses; many are produced by epidermal cells. The present study examines the response of mouse epidermal strips to the cutaneous irritant sodium dodecyl sulphate (SDS). A time-dependent relationship was established for the release of the cytokine tumour necrosis factor-alpha, from epidermal keratinocytes after treatment with 20% SDS. The potential value of this methodology for the detection of cutaneous irritants has been established. The utility of the approach for the identification in vitro of other materials of known in vivo irritant potential will be investigated.


Liver transcriptome response to hyperthermic stress in three distinct chicken lines.
High ambient temperatures cause stress in poultry, especially for broiler lines, which are genetically selected for rapid muscle growth. RNA-seq technology provides powerful insights into environmental response from a highly metabolic tissue, the liver. We investigated the effects of acute (3 h, 35 °C) and chronic (7d of 35 °C for 7 h/d) heat stress on the liver transcriptome of 3-week-old chicks of a heat-susceptible broiler line, a heat-resistant Fayoumi line, and their advanced intercross line (AIL). Transcriptome sequencing of 48 male chickens using Illumina HiSeq 2500 technology yielded an average of 33.9 million, 100 base-pair, single-end reads per sample. There were 8 times more differentially expressed genes (DEGs) (FDR < 0.05) in broilers (n = 627) than Fayoumis (n = 78) when comparing the acute-heat samples to the control (25 °C) samples. Contrasting genetic lines under similar heat treatments, the highest number of DEGs appeared between Fayoumi and broiler lines. Principal component analysis of gene expression and analysis of the number of DEGs suggested that the AIL had a transcriptomic response more similar to the Fayoumi than the broiler line during acute heat stress. The number of DEGs also suggested that acute heat stress had greater impact on the broiler liver transcriptome than chronic heat stress. The angiopoietin-like 4 (ANGPTL4) gene was identified as differentially expressed among all 6 contrasts. Ingenuity Pathway Analysis (IPA) created a novel network that combines the heat shock protein family with immune response genes. This study extends our understanding of the liver transcriptome response to different heat exposure treatments in distinct genetic chicken lines and provides information necessary for breeding birds to be more resilient to the negative impacts of heat. The data strongly suggest ANGPTL4 as a candidate gene for improvement of heat tolerance in chickens.


Utility of SOX6 and DAB2 for the Diagnosis of Malignant Mesothelioma.
The separation of malignant mesothelioma from non-small cell lung carcinomas can be a difficult problem. Sex-determining region Y box 6 (SOX6) and disabled homolog 2 (DAB2) have recently been proposed as sensitive/specific markers of mesothelial lineage, but have not yet been independently tested for utility in mesothelioma diagnosis. Using tissue microarrays containing mesotheliomas (epithelioid: n=40, sarcomatoid: n=23) and non-small cell lung carcinomas (adenocarcinoma: n=52, squamous cell carcinoma: n=57, large cell carcinoma: n=12) we evaluated the performance of SOX6 and DAB2 by themselves, in conjunction with other established mesothelioma markers (calretinin, WT1, D2-40, CK5/6, HEG1) and combined with 3 broad-spectrum established carcinoma markers: claudin-4, MOC31, and BerEP4. For epithelioid mesothelioma, SOX6 and DAB2 had sensitivities of 85% and 98%, respectively. For sarcomatoid mesothelioma, SOX6 had a sensitivity of 13% and DAB2 could not be assessed due to background stromal staining. For SOX6 alone, specificity for mesothelioma versus adenocarcinoma, squamous cell carcinoma, and large cell carcinoma was 94%, 79%, and 92%, respectively, while for DAB2 specificity was 77%, 86%, and 67%. Combinations of SOX6 and established mesothelioma markers produced sensitivities of 95% or greater. A combination of SOX6 positive/claudin-4 negative staining was 95% to 100% specific for mesothelioma versus carcinoma with a sensitivity of 85%. SOX6 is a promising marker for the diagnosis of mesothelioma and potentially could be combined with other mesothelial markers or a broad-spectrum carcinoma marker to reach an accurate diagnosis with relatively few immunostains, The relatively low specificity and difficulty of interpreting DAB2 staining limits its utility for mesothelioma diagnosis.


A combination of the tree-code and IPS method to simulate large scale systems by molecular dynamics.
An IPS/Tree method which is a combination of the isotropic periodic sum (IPS) method and tree-based method was developed for large-scale molecular dynamics simulations, such as biological and polymer systems, that need hundreds of thousands of molecules. The tree-based method uses a hierarchical tree structure to reduce the calculation cost of long-range interactions. IPS/Tree is an efficient method like IPS/DFFT, which is a combination of the IPS method and FFT in calculating large-scale systems that require massively parallel computers. The IPS method has two different versions: IPSn and IPSp. The basic idea is the same expect for the fact that the IPSn method is applied to calculations for point charges, while the IPSp method is used to calculate polar molecules. The concept of the IPS/Tree method is available for both IPSn and IPSp as IPSn/Tree and IPSp/Tree. Even though the accuracy of the Coulomb forces with tree-based method is well known, the accuracy for the combination of the IPS and tree-based methods is unclear. Therefore, in order to evaluate the accuracy of the IPS/Tree method, we performed molecular dynamics simulations for 32,000 bulk water molecules, which contains around 10(5) point charges. IPSn/Tree and IPSp/Tree were both applied to study the interaction calculations of Coulombic forces. The accuracy of the Coulombic forces and other physical properties of bulk water systems were evaluated. The IPSp/Tree method not only has reasonably small error in estimating Coulombic forces but the error was almost the same as the theoretical error of the ordinary tree-based method. These facts show that the algorithm of the tree-based method can be successfully applied to the IPSp method. On the other hand, the IPSn/Tree has a relatively large error, which seems to have been derived from the interaction treatment of the original IPSn method. The self-diffusion and radial distribution functions of water were calculated each by both the IPSn/Tree and IPSp/Tree methods, where both methods showed reasonable agreement with the Ewald method. In conclusion, the IPSp/Tree method is a potentially fast and sufficiently accurate technique for predicting transport coefficients and liquid structures of water in a homogeneous system.


The diffusion-simulated connectivity (DiSCo) dataset.
The methodological development in the mapping of the brain structural connectome from diffusion-weighted magnetic resonance imaging (DW-MRI) has raised many hopes in the neuroscientific community. Indeed, the knowledge of the connections between different brain regions is fundamental to study brain anatomy and function. The reliability of the structural connectome is therefore of paramount importance. In the search for accuracy, researchers have given particular attention to linking white matter tractography methods - used for estimating the connectome - with information about the microstructure of the nervous tissue. The creation and validation of methods in this context were hampered by a lack of practical numerical phantoms. To achieve this, we created a numerical phantom that mimics complex anatomical fibre pathway trajectories while also accounting for microstructural features such as axonal diameter distribution, myelin presence, and variable packing densities. The substrate has a micrometric resolution and an unprecedented size of 1 cubic millimetre to mimic an image acquisition matrix of 40 × 40 × 40 voxels. DW-MRI images were obtained from Monte Carlo simulations of spin dynamics to enable the validation of quantitative tractography. The phantom is composed of 12,196 synthetic tubular fibres with diameters ranging from 1.4 µm to 4.2 µm, interconnecting sixteen regions of interest. The simulated images capture the microscopic properties of the tissue (e.g. fibre diameter, water diffusing within and around fibres, free water compartment), while also having desirable macroscopic properties resembling the anatomy, such as the smoothness of the fibre trajectories. While previous phantoms were used to validate either tractography or microstructure, this phantom can enable a better assessment of the connectome estimation's reliability on the one side, and its adherence to the actual microstructure of the nervous tissue on the other.


Efficacy of benfotiamine versus thiamine on function and glycation products of peripheral nerves in diabetic rats.
In rats with streptozotocin (STZ) induced diabetes the effect of (watersoluble) thiamine nitrate and of (lipidsoluble) benfotiamine on peripheral nerve function (motor nerve conduction velocity) as well as on the formation of advanced glycation end-products in peripheral nerve tissue was studied. In one group of animals drug administration was started immediately after diabetes induction (prevention study) and in another group two months after diabetes induction (treatment study). Motor nerve conduction velocity (NCV) dropped by 10.5% in diabetic animals, carboxymethyl-lysine (CML) rose to a 3.5fold concentration, deoxyglucosone (3DG)-type AGE formation was increased 5.1fold compared with controls. After three months preventive administration of both vitamin B(1) preparations NCV had increased substantially compared with results in diabetic controls. It was nearly normal after six months with benfotiamine, while the administration of thiamine nitrate resulted in no further amelioration. NCV was nearly normalized after six months of benfotiamine application but not with thiamine. Furthermore, benfotiamine induced a major inhibition of neural imidazole-type AGE formation and completely prevented diabetes induced glycoxidation products (CML). Treatment with thiamine did not significantly affect AGE or cmL levels. Unlike treatment with water-soluble thiamine nitrate timely administration of liposoluble prodrug benfotiamine was effective in the prevention of functional damage and of AGE and cmL formation in nerves of diabetic rats.


Effect of variation of charged and uncharged tRNA(Trp) levels on ppGpp synthesis in Escherichia coli.
We introduced into a stringent Escherichia coli tryptophan auxotroph a plasmid bearing the tRNA(Trp) gene under the control of an inducible promoter. This allows us to manipulate the total concentration of tRNA(Trp) in the cell according to whether and when inducer is added to the culture. We also manipulated the concentration of Trp-tRNA(Trp) in vivo since the strain used bears a mutation in the Trp-tRNA synthetase affecting the Km for tryptophan, such that varying the exogenous concentration of tryptophan led to variation in the level of Trp-tRNA(Trp) in the cell. With this system, we found that the signal eliciting ppGpp synthesis during a stringent response triggered by tryptophan limitation did not depend on the absolute concentration of either charged or uncharged tRNA(Trp) but rather depended on a decline in the ratio of charged/uncharged tRNA(Trp). In addition, we found that the amplitude of the response, once triggered by tryptophan limitation, was determined by the total concentration of tRNA(Trp) present in the cell (which is mostly uncharged at that point in time). However, excess uncharged tRNA(Trp) did not amplify ppGpp synthesis triggered by limitation of a different amino acid. These data provide in vivo support for the in vitro-derived model of ppGpp synthesis on ribosomes.


Dentatorubral pallidoluysian atrophy in South Wales.
Dentatorubral pallidoluysian atrophy (DRPLA) is a rare, autosomal dominant, clinically heterogeneous neurodegenerative disorder characterised clinically by progressive dementia, ataxia, chorea, myoclonic epilepsy and psychiatric disturbance and pathologically by combined degeneration of the dentatorubral and pallidoluysian systems. DRPLA has a marked ethnic predilection, most commonly reported in Japan and thought to be rare in Caucasian populations. We describe the clinical and genetic characteristics of 17 patients with DRPLA segregating in four families in South Wales. There was marked clinical heterogeneity with considerable overlap of symptoms and signs between and within families. The age of onset ranged from 34 to 60 years with an earlier onset associated with myoclonic epilepsy and a later onset associated with a Huntington disease-like presentation. We identified a distinct haplotype within one family not present within the other three families, suggesting that the expansion in at least one family did not arise from an immediate common ancestor. Analysis of repeat length polymorphisms in 306 Welsh control patients identified 14 (4.6%) with repeat lengths in the high-normal range, compared with 0% and 7.4% in previously reported north American Caucasian and Japanese control populations, respectively. DRPLA may not be as geographically or ethnically restricted as previously thought and the diagnosis should be considered in non-Asian patients presenting with a wide spectrum of neurological disease, especially if there is a dominant family history of dementia or movement disorder. The prevalence of high-normal length alleles may account for the relatively high prevalence of DRPLA in Wales.


[Validation of National College Health Risk Behavior Survey to be use with Brazilian college students].
The objective of this article is to translate, to adapt and to validate the National College Health Risk Behavior Survey to apply at Brazilian college students. 208 college students from the Federal University of Pernambuco (UFPE) and University of Pernambuco (UPE) participated in the study. The validation was carried through in five stages: (1) translation; (2) retrotranslation; (3) correction and semantic adaptation (cultural adaptation); (4) face validation; (5) test-retest. Adaptations were done to deal with any semantic disagreements found between translation and retrotranslation. After face validation, the questionnaire was reduced from 96 to 52 questions. From the 11 items analyzed, the majority presented good and perfect Kappa: security and violence (Kappa=0.89); suicide (Kappa=1.00); use of the tobacco (Kappa=0.90); drinking consumption (Kappa=0.78); cocaine and other drugs consumption (Kappa=0.70); sexual behavior (Kappa=0,88) and corporal weight (Kappa=0.89). Only the item about feeding presented weak Inter-examiner Kappa (Kappa = 0.26) and the topic on health information presented moderate Kappa (Kappa=0.56). The average Kappa for all items was good (0.76). The instrument may be considered validated in the Portuguese language in Brazil with acceptable reproducibility.


Multiple isoforms of CDC25 oppose ATM activity to maintain cell proliferation during vertebrate development.
The early development of vertebrate embryos is characterized by rapid cell proliferation necessary to support the embryo's growth. During this period, the embryo must maintain a balance between ongoing cell proliferation and mechanisms that arrest or delay the cell cycle to repair oxidative damage and other genotoxic stresses. The ataxia-telangiectasia mutated (ATM) kinase is a critical regulator of the response to DNA damage, acting through downstream effectors, such as p53 and checkpoint kinases (CHK) to mediate cell-cycle checkpoints in the presence of DNA damage. Mice and humans with inactivating mutations in ATM are viable but have increased susceptibility to cancers. The possible role of ATM in limiting cell proliferation in early embryos has not been fully defined. One target of ATM and CHKs is the Cdc25 phosphatase, which facilitates cell-cycle progression by removing inhibitory phosphates from cyclin-dependent kinases (CDK). We have identified a zebrafish mutant, standstill, with an inactivating mutation in cdc25a. Loss of cdc25a in the zebrafish leads to accumulation of cells in late G(2) phase. We find that the novel family member cdc25d is essential for early development in the absence of cdc25a, establishing for the first time that cdc25d is active in vivo in zebrafish. Surprisingly, we find that cell-cycle progression in cdc25a mutants can be rescued by chemical or genetic inhibition of ATM. Checkpoint activation in cdc25a mutants occurs despite the absence of increased DNA damage, highlighting the role of Cdc25 proteins to balance constitutive ATM activity during early embryonic development.


Molecular pathogenesis of disease progression in MLL-rearranged AML.
Leukemic relapse is frequently accompanied by progressively aggressive clinical course. To understand the molecular mechanism of leukemic relapse, MLL/AF9-transformed mouse leukemia cells were serially transplanted in C57BL/6 mice (N = 96) by mimicking repeated recurrences, where mutations were monitored by exome sequencing (N = 42). The onset of leukemia was progressively promoted with advanced transplants, during which increasing numbers of somatic mutations were acquired (P < 0.005). Among these, mutations in Ptpn11 (p.G60R) and Braf (p.V637E) corresponded to those identified in human MLL-AML, while recurrent mutations affecting Msn (p.R295C) were observed only in mouse but not in human MLL-AML. Another mutated gene of interest was Gnb2 which was reported to be recurrently mutated in various hematological neoplasms. Gnb2 mutations (p.G77R) were significantly increased in clone size (P = 0.007) and associated with earlier leukemia onset (P = 0.011). GNB2 transcripts were significantly upregulated in human MLL-AML compared to MLL-negative AML (P < 0.05), which was supported by significantly increased Gnb2 transcript induced by MLL/AF9 overexpression (P < 0.001). In in vivo model, both mutation and overexpression of GNB2 caused leukemogenesis, and downregulation of GNB2 expression reduced proliferative potential and survival benefit, suggesting a driver role of GNB2. In conclusion, alterations of driver genes over time may play an important role in the progression of MLL-AML.


Longitudinal associations between negative urgency, symptoms of depression, cannabis and alcohol use in veterans.
There is a high comorbidity between symptoms of depression and cannabis and alcohol use in civilian and veteran populations. Prospective studies attempting to clarify the directionality of these comorbidities have yielded mixed results. Further, the relations between these constructs and impulsive personality, particularly negative urgency (NU, the tendency to act rashly when experiencing emotional distress) warrants further attention, as NU relates to symptoms of depression and alcohol and cannabis use. Importantly, NU partially accounts for the association between symptoms of depression and cannabis and alcohol problems in cross-sectional studies. This study examined alternative theories of directionality in order to better understand the longitudinal associations between symptoms of depression, NU, and cannabis or alcohol use. Three semiannual waves of data (baseline, 6-month, and 12-month) were collected in parallel assessments from a sample of Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn veterans (N = 361). Autoregressive cross-lagged panel models were used to test four alternative theory-driven models about the longitudinal associations between the interaction of symptoms of depression and NU and cannabis or alcohol use. Models revealed unique direction of effects specific to each substance, such that the interaction between symptoms of depression and NU at 6 months postbaseline predicted more alcohol use at 12 months postbaseline, whereas more cannabis use at 6 months postbaseline predicted more severe symptoms of depression at 12 months postbaseline. Results suggests alternate directions of effect for cannabis and alcohol use. Future research should examine these patterns over wider assessment periods in order to see more variability and change over time. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Impact of morphology on polaron delocalization in a semicrystalline conjugated polymer.
We investigate the delocalization of holes in the semicrystalline conjugated polymer poly(2,5-bis(3-alkylthiophene-2-yl)thieno[3,2-b]thiophene) (PBTTT) by directly measuring the hyperfine coupling between photogenerated polarons and bound nuclear spins using electron nuclear double resonance spectroscopy. An extrapolation of the corresponding oligomer spectra reveals that charges tend to delocalize over 4.0-4.8 nm with delocalization strongly dependent on molecular order and crystallinity of the PBTTT polymer thin films. Density functional theory calculations of hyperfine couplings confirm that long-range corrected functionals appropriately describe the change in coupling strength with increasing oligomer size and agree well with the experimentally measured polymer limit. Our discussion presents general guidelines illustrating the various pitfalls and opportunities when deducing polaron localization lengths from hyperfine coupling spectra of conjugated polymers.


Effect of adhesive agent and fissure morphology on the in vitro microleakage and penetrability of pit and fissure sealants.
To evaluate the effect of adhesive agents and fissure morphology on the microleakage and penetrability of pit and fissure sealants. Sealants used in this study included Aegis (Bosworth), conseal f (Southern Dental Industries), and Admira Seal (Voco). Adhesive agents included Optibond Solo Plus (sds/Kerr) and Clearfil S3Bond (Kuraray). Ninety extracted permanent molars were randomly assigned to 9 groups combining sealant and adhesive agent materials. A sealant and control group (phosphoric acid etch only) was also included. Dye penetration (microleakage), penetrability, and fissure morphology assessment was performed for the treatment groups through microscopic evaluation. Significant (P = .003) differences in microleakage were exhibited, with the Aegis + control and Aegis + Optibond Solo Plus groups displaying less leakage, while significant (P = .03) differences were also noted between groups regarding penetrability. Fissure morphology was not a significant (P = .82) factor affecting microleakage; however, fissure type did significantly (P < .001) impact penetrability. No correlation was found between the extent of microleakage and penetrability. Application of sealants using phosphoric acid as a conditioning agent revealed superior results, while the use of adhesives was found to be unnecessary.


Immunomodulatory effects of adipose-derived stem cells: fact or fiction?
Adipose-derived stromal cells (ASCs) are often referred to as adipose-derived stem cells due to their potential to undergo multilineage differentiation. Their promising role in tissue engineering and ability to modulate the immune system are the focus of extensive research. A number of clinical trials using ASCs are currently underway to better understand the role of such cell niche in enhancing or suppressing the immune response. If governable, such immunoregulatory role would find application in several conditions in which an immune response is present (i.e., autoimmune conditions) or feared (i.e., solid organ or reconstructive transplantation). Although allogeneic ASCs have been shown to prevent acute GvHD in both preclinical and clinical studies, their potential warrants further investigation. Well-designed and standardized clinical trials are necessary to prove the role of ASCs in the treatment of immune disorders or prevention of tissue rejection. In this paper we analyze the current literature on the role of ASCs in immunomodulation in vitro and in vivo and discuss their potential in regulating the immune system in the context of transplantation.


Strength and power capabilities predict weighted parameter ranking of saut de chat leaping performance in dancers.
Limited research exists on the relationship between aesthetic saut de chat performance and muscle-tendon unit (MTU) characteristics of dancers. We developed a weighted parameter ranking (WPR) tool to incorporate aesthetic leaping aspects (i.e., height, peak split angle, average trunk angle and trunk angle range) for correlation with MTU properties. The purpose was to identify the relationship of saut de chat WPR and leap height with maximal plantarflexion strength, medial gastrocnemius (MG) stiffness, Achilles tendon (AT) stiffness and relative peak power (PP). Dancers (n = 18) performed maximal plantarflexion, short-range stretches and isometric ramping contractions on a dynamometer equipped with ultrasound to determine strength, MG stiffness and AT stiffness, respectively. Subjects then performed saut de chat leaps atop force platforms surrounded by motion capture cameras. A principal component analysis (PCA) was performed to compare WPR variable weightings with PCA results and rankings. Moderate-strong relationships were identified among WPR, maximal plantarflexion strength, MG stiffness and PP. Strong-very strong relationships were also identified between leap height and maximal plantarflexion strength, MG stiffness, AT stiffness, peak split angle and PP. A very strong correlation existed between PCA rankings and WPRs. Practitioners may consider developing strength and power capabilities in dancers to improve leaping.


Social, economic, and resource predictors of variability in household air pollution from cookstove emissions.
We examine if social and economic factors, fuelwood availability, market and media access are associated with owning a modified stove and variation in household emissions from biomass combustion, a significant environmental and health concern in rural India. We analyze cross-sectional household socio-economic data, and PM(2.5) and particulate surface area concentration in household emissions from cookstoves (n=100). This data set combines household social and economic variables with particle emissions indexes associated with the household stove. The data are from the Foundation for Ecological Society, India, from a field study of household emissions. In our analysis, we find that less access to ready and free fuelwood and higher wealth are associated with owning a replacement/modified stove. We also find that additional kitchen ventilation is associated with a 12% reduction in particulate emissions concentration (p<0.05), after we account for the type of stove used. We did not find a significant association between replacement/modified stove on household emissions when controlling for additional ventilation. Higher wealth and education are associated with having additional ventilation. Social caste, market and media access did not have any effect on the presence of replacement or modified stoves or additional ventilation. While the data available to us does not allow an examination of direct health outcomes from emissions variations, adverse environmental and health impacts of toxic household emissions are well established elsewhere in the literature. The value of this study is in its further examination of the role of social and economic factors and available fuelwood from commons in type of stove use, and additional ventilation, and their effect on household emissions. These associations are important since the two direct routes to improving household air quality among the poor are stove type and better ventilation.


Femtosecond laser irradiation stress induced in pure silica.
We reveal stress fields induced by femtosecond laser irradiation by investigating the topography of surface relaxation of a cleavage of silica plates in which irradiation was performed, varying intensity, laser polarization and displacement of the writing beam. The stress field appears to depend on the writing parameters differently according to the laser intensity. For pulse intensity larger than 0.1 microJ, a first shear stress developed. Above 0.25 microJ, another shear stress appears that is dependent on the direction of writing and coupling with a phase matching condition between the pump wave and the third harmonic.


Animal Models of the Neuromuscular Junction, Vitally Informative for Understanding Function and the Molecular Mechanisms of Congenital Myasthenic Syndromes.
The neuromuscular junction is the point of contact between motor nerve and skeletal muscle, its vital role in muscle function is reliant on the precise location and function of many proteins. Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders of neuromuscular transmission with 30 or more implicated proteins. The use of animal models has been instrumental in determining the specific role of many CMS-related proteins. The mouse neuromuscular junction (NMJ) has been extensively studied in animal models of CMS due to its amenability for detailed electrophysiological and histological investigations and relative similarity to human NMJ. As well as their use to determine the precise molecular mechanisms of CMS variants, where an animal model accurately reflects the human phenotype they become useful tools for study of therapeutic interventions. Many of the animal models that have been important in deconvolving the complexities of neuromuscular transmission and revealing the molecular mechanisms of disease are highlighted.


Association of resting heart rate with carotid and aortic arterial stiffness: multi-ethnic study of atherosclerosis.
Resting heart rate is an easily measured, noninvasive vital sign that is associated with cardiovascular disease events. The pathophysiology of this association is not known. We investigated the relationship between resting heart rate and stiffness of the carotid (a peripheral artery) and the aorta (a central artery) in an asymptomatic multi-ethnic population. Resting heart rate was recorded at baseline in the Multi-Ethnic Study of Atherosclerosis (MESA). Distensibility was used as a measure of arterial elasticity, with a lower distensibility indicating an increase in arterial stiffness. Carotid distensibility was measured in 6484 participants (98% of participants) using B-mode ultrasound, and aortic distensibility was measured in 3512 participants (53% of participants) using cardiac MRI. Heart rate was divided into quintiles and we used progressively adjusted models that included terms for physical activity and atrioventricular nodal blocking agents. Mean resting heart rate of participants (mean age, 62 years; 47% men) was 63 bpm (SD, 9.6 bpm). In unadjusted and fully adjusted models, carotid distensibility and aortic distensibility decreased monotonically with increasing resting heart rate (P for trend <0.001 and 0.009, respectively). The relationship was stronger for carotid versus aortic distensibility. Similar results were seen using the resting heart rate taken at the time of MRI scanning. Our results suggest that a higher resting heart rate is associated with an increased arterial stiffness independent of atrioventricular nodal blocker use and physical activity level, with a stronger association for a peripheral (carotid) compared with a central (aorta) artery.


Undernutrition, the acute phase response to infection, and its effects on micronutrient status indicators.
Infection and undernutrition are prevalent in developing countries and demonstrate a synergistic relation. Undernutrition increases infection-related morbidity and mortality. The acute phase response (APR) is an innate, systemic inflammatory reaction to a wide array of disruptions in a host's homeostasis, including infection. Released from immune cells in response to deleterious stimuli, proinflammatory cytokines act on distant tissues to induce behavioral (e.g., anorexia, weakness, and fatigue) and systemic effects of the APR. Cytokines act to increase energy and protein requirements to manifest fever and support hepatic acute phase protein (APP) production. Blood concentrations of glucose and lipid are augmented to provide energy to immune cells in response to cytokines. Additionally, infection decreases intestinal absorption of nutrients and can cause direct loss of micronutrients. Traditional indicators of iron, zinc, and vitamin A status are altered during the APR, leading to inaccurate estimations of deficiency in populations with a high or unknown prevalence of infection. Blood concentrations of APPs can be measured in nutrition interventions to assess the time stage and severity of infection and correct for the APR; however, standardized cutoffs for nutrition applications are needed. Protein-energy malnutrition leads to increased gut permeability to pathogens, abnormal immune cell populations, and impaired APP response. Micronutrient deficiencies cause specific immune impairments that affect both innate and adaptive responses. This review describes the antagonistic interaction between the APR and nutritional status and emphasizes the need for integrated interventions to address undernutrition and to reduce disease burden in developing countries.


"LRRK2: Autophagy and Lysosomal Activity".
It has been 15 years since the Leucine-rich repeat kinase 2 (LRRK2) gene was identified as the most common genetic cause for Parkinson's disease (PD). The two most common mutations are the LRRK2-G2019S, located in the kinase domain, and the LRRK2-R1441C, located in the ROC-COR domain. While the LRRK2-G2019S mutation is associated with increased kinase activity, the LRRK2-R1441C exhibits a decreased GTPase activity and altered kinase activity. Multiple lines of evidence have linked the LRRK2 protein with a role in the autophagy pathway and with lysosomal activity in neurons. Neurons rely heavily on autophagy to recycle proteins and process cellular waste due to their post-mitotic state. Additionally, lysosomal activity decreases with age which can potentiate the accumulation of α-synuclein, the pathological hallmark of PD, and subsequently lead to the build-up of Lewy bodies (LBs) observed in this disorder. This review provides an up to date summary of the LRRK2 field to understand its physiological role in the autophagy pathway in neurons and related cells. Careful assessment of how LRRK2 participates in the regulation of phagophore and autophagosome formation, autophagosome and lysosome fusion, lysosomal maturation, maintenance of lysosomal pH and calcium levels, and lysosomal protein degradation are addressed. The autophagy pathway is a complex cellular process and due to the variety of LRRK2 models studied in the field, associated phenotypes have been reported to be seemingly conflicting. This review provides an in-depth discussion of different models to assess the normal and disease-associated role of the LRRK2 protein on autophagic function. Given the importance of the autophagy pathway in Parkinson's pathogenesis it is particularly relevant to focus on the role of LRRK2 to discover novel therapeutic approaches that restore lysosomal protein degradation homeostasis.


Receptor activator of nuclear factor kB ligand, osteoprotegerin, and risk of death following a breast cancer diagnosis: results from the EPIC cohort.
Receptor activator of nuclear factor kappa-B (RANK)-signaling is involved in tumor growth and spread in experimental models. Binding of RANK ligand (RANKL) to RANK activates signaling, which is inhibited by osteoprotegerin (OPG). We have previously shown that circulating soluble RANKL (sRANKL) and OPG are associated with breast cancer risk. Here we extend these findings to provide the first data on pre-diagnosis concentrations of sRANKL and OPG and risk of breast cancer-specific and overall mortality after a breast cancer diagnosis. Two thousand six pre- and postmenopausal women with incident invasive breast cancer (1620 (81%) with ER+ disease) participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort were followed-up for mortality. Pre-diagnosis concentrations of sRANKL and OPG were quantified in baseline serum samples using an enzyme-linked immunosorbent assay and electrochemiluminescent assay, respectively. Hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer-specific and overall mortality were calculated using Cox proportional hazards regression models. Especially in women with ER+ disease, higher circulating OPG concentrations were associated with higher risk of breast cancer-specific (quintile 5 vs 1 HR 1.77 [CI 1.03, 3.04]; ptrend 0.10) and overall mortality (q5 vs 1 HR 1.39 [CI 0.94, 2.05]; ptrend 0.02). sRANKL and the sRANKL/OPG ratio were not associated with mortality following a breast cancer diagnosis. High pre-diagnosis endogenous concentrations of OPG, the decoy receptor for RANKL, were associated with increased risk of death after a breast cancer diagnosis, especially in those with ER+ disease. These results need to be confirmed in well-characterized patient cohorts.


Gut microbiome composition and metabolomic profiles of wild western lowland gorillas (Gorilla gorilla gorilla) reflect host ecology.
The metabolic activities of gut microbes significantly influence host physiology; thus, characterizing the forces that modulate this micro-ecosystem is key to understanding mammalian biology and fitness. To investigate the gut microbiome of wild primates and determine how these microbial communities respond to the host's external environment, we characterized faecal bacterial communities and, for the first time, gut metabolomes of four wild lowland gorilla groups in the Dzanga-Sangha Protected Areas, Central African Republic. Results show that geographical range may be an important modulator of the gut microbiomes and metabolomes of these gorilla groups. Distinctions seemed to relate to feeding behaviour, implying energy harvest through increased fruit consumption or fermentation of highly fibrous foods. These observations were supported by differential abundance of metabolites and bacterial taxa associated with the metabolism of cellulose, phenolics, organic acids, simple sugars, lipids and sterols between gorillas occupying different geographical ranges. Additionally, the gut microbiomes of a gorilla group under increased anthropogenic pressure could always be distinguished from that of all other groups. By characterizing the interplay between environment, behaviour, diet and symbiotic gut microbes, we present an alternative perspective on primate ecology and on the forces that shape the gut microbiomes of wild primates from an evolutionary context.


Epidemiological and clinical aspects will guide the neuroimaging research in bipolar disorder.
Although neurobiological mechanisms of bipolar disorder (BD) are still unclear, neural models of the disease have recently been conceptualised thanks to neuroimaging. Indeed, magnetic resonance imaging (MRI) studies investigating structural and functional connectivity between different areas of the brain suggest an altered prefrontal-limbic coupling leading to disrupted emotional processing in BD, including uncinate fasciculus, amygdala, parahippocampal cortex, cingulate cortex as well corpus callosum. Specifically, these models assume an altered prefrontal control over a hyperactivity of the subcortical limbic structures implicated in automatic emotional processing. This impaired mechanism may finally trigger emotional hyper-reactivity and mood episodes. In this review, we first summarised some key neuroimaging studies on BD. In the second part of the work, we focused on the heterogeneity of the available studies. This variability is partly due to methodological factors (i.e., small sample size) and differences among studies (i.e., MRI acquisition and post-processing analyses) and partly to the clinical heterogeneity of BD. We finally outlined how epidemiological studies should indicate which risk factors and clinical dimensions of BD are relevant to be studied with neuroimaging in order to reduce heterogeneity and go beyond diagnostic categories.


Development of fluorescent probes based on protection-deprotection of the key functional groups for biological imaging.
Recently, the strategy of protection-deprotection of functional groups has been widely employed to design fluorescent probes, as the protection-deprotection of functional groups often induces a marked change in electronic properties. Significant advances have been made in the development of analyte-responsive fluorescent probes based on the protection-deprotection strategy. In this tutorial review, we highlight the representative examples of small-molecule based fluorescent probes for bioimaging, which are operated via the protection-deprotection of key functional groups such as aldehyde, hydroxyl, and amino functional groups reported from 2010 to 2014. The discussion includes the general protection-deprotection methods for aldehyde, hydroxyl, or amino groups, as well as the design strategies, sensing mechanisms, and deprotection modes of the representative fluorescent imaging probes applied to bio-imaging.


ImageJ for Partially and Fully Automated Analysis of Trypanosome Micrographs.
Trypanosomes and related parasites such as Leishmania are unicellular parasites with a precise internal structure. This makes light microscopy a powerful tool for interrogating their biology-whether considering advance techniques for visualizing the precise localization of proteins within the cell or simply measuring parasite cell shape. Methods to partially or fully automate analysis and interpretation are extremely powerful and provide easier access to microscope images as a source of quantitative data. This chapter provides an introduction to these methods using ImageJ/FIJI, free and open source software for scientific image analysis. It provides an overview of how ImageJ handles images and introduces the ImageJ macro/scripting language for automated images, starting at a basic level and assuming no previous programming/scripting experience. It then outlines three methods using ImageJ for automated analysis of trypanosome micrographs: Semiautomated cropping and setting image contrast for presentation, automated analysis of cell properties from a light micrograph field of view, and example semiautomated tools for quantitative analysis of protein localization. These are not presented as strict methods, but are instead described in detail with the intention of furnishing the reader with the ability to "hack" the scripts for their own needs or write their own scripts for partially and fully automated quantitation of trypanosomes from light micrographs. Most of the methods described here are transferrable to other types of microscope image and other cell types.


Genetic association analyses of atopic illness and proinflammatory cytokine genes with type 1 diabetes.
The genetic basis of the autoimmune disease type 1 diabetes (T1D) has now been largely determined, so now we can compare these findings with emerging genetic knowledge of disorders and phenotypes that have been negatively or positively associated with T1D historically. Here, we assessed the role in T1D of variants previously reported to be associated with atopic diseases and epithelial barrier function, profilaggrin (FLG), and those that affect the expression levels of the proinflammatory cytokines tumour necrosis factor (TNF)-α, interleukin (IL)-1β, interferon (IFN)γ and IL-18. We genotyped single nucleotide polymorphisms (SNPs): -105/rs28665122 in SELS or SEPS1 (selenoprotein), three single nucleotide polymorphisms in IL18 (-105/rs360717, +183/rs5744292 and +1467/rs574456) and R501X/rs61816761 in FLG, the major locus associated with atopic dermatitis and predisposing to asthma, in a minimum of 6743 T1D cases and 7864 controls. No evidence of T1D association was found for any of the SNPs we genotyped at FLG, SELS or IL18 (p≥0.03), nor with haplotypes of IL18 (p=0.82). Review of previous T1D genome-wide association results revealed that four (human leucocyte antigen (HLA), gasdermin B/ORM1 (Saccharomyces cerevisiae)-like/gasdermin B/, GSDMB/ORMDL3/GSDMA and IL2RB) of ten loci recently reported to be associated with asthma were associated with T1D (p≤0.005). These results show that there are shared genetic associations for atopy-related traits and T1D, and this might help in the future to understand the mechanisms, pathways and environmental factors that underpin the rapid rise in incidence of both disorders in children.


A new approach to determine vapour pressures and hygroscopicities of aqueous aerosols containing semi-volatile organic compounds.
We present a new approach to study the equilibrium gas-particle partitioning of volatile and semi-volatile organic components in aqueous aerosol, deriving a correlational analysis method that examines and interprets simultaneous and correlated fluctuations in particle size and composition. From this approach, changes in particle size driven by organic component evaporation can be clearly resolved from size changes driven by hygroscopicity and fluctuations in environmental conditions. The approach is used to interpret measurements of the evaporation of semi-volatile organic components from binary aqueous/organic aerosol and the hygroscopic growth of involatile inorganic aerosol. The measurements have been made by the aerosol optical tweezers technique, which allows the simultaneous retrieval of particle size and refractive index with high accuracy. We suggest that this approach will be particularly valuable for investigating the thermodynamic behaviour of mixed component aqueous aerosol and will allow the accurate derivation of solution phase equilibrium properties that are prone to large uncertainties when measurements are made simply of the change in particle size with gas phase relative humidity.


Co-Flocculation of Yeast Species, a New Mechanism to Govern Population Dynamics in Microbial Ecosystems.
Flocculation has primarily been studied as an important technological property of Saccharomyces cerevisiae yeast strains in fermentation processes such as brewing and winemaking. These studies have led to the identification of a group of closely related genes, referred to as the FLO gene family, which controls the flocculation phenotype. All naturally occurring S. cerevisiae strains assessed thus far possess at least four independent copies of structurally similar FLO genes, namely FLO1, FLO5, FLO9 and FLO10. The genes appear to differ primarily by the degree of flocculation induced by their expression. However, the reason for the existence of a large family of very similar genes, all involved in the same phenotype, has remained unclear. In natural ecosystems, and in wine production, S. cerevisiae growth together and competes with a large number of other Saccharomyces and many more non-Saccharomyces yeast species. Our data show that many strains of such wine-related non-Saccharomyces species, some of which have recently attracted significant biotechnological interest as they contribute positively to fermentation and wine character, were able to flocculate efficiently. The data also show that both flocculent and non-flocculent S. cerevisiae strains formed mixed species flocs (a process hereafter referred to as co-flocculation) with some of these non-Saccharomyces yeasts. This ability of yeast strains to impact flocculation behaviour of other species in mixed inocula has not been described previously. Further investigation into the genetic regulation of co-flocculation revealed that different FLO genes impact differently on such adhesion phenotypes, favouring adhesion with some species while excluding other species from such mixed flocs. The data therefore strongly suggest that FLO genes govern the selective association of S. cerevisiae with specific species of non-Saccharomyces yeasts, and may therefore be drivers of ecosystem organisational patterns. Our data provide, for the first time, insights into the role of the FLO gene family beyond intraspecies cellular association, and suggest a wider evolutionary role for the FLO genes. Such a role would explain the evolutionary persistence of a large multigene family of genes with apparently similar function.


Trends in, and transitions to, institutional residence among older people in England and Wales, 1971-91.
To compare transitions from private households to institutions between 1971-81 and 1981-91 among elderly people and see whether (1) differentials in the risk of institutionalisation changed and (2) whether the risk was higher in the second period. Cross sequential analysis of data from the Office of National Statistics longitudinal study, a record linkage study which included individual level data from three national censuses, (1971, 1981, and 1991) and linked vital registration data. Altogether 26,400 people aged 65 and over in 1971-81 and 32,500 persons aged 65 and over in 1981-91. These samples represent 1% of the population of England and Wales. In both periods models including age, housing tenure, and marital status or household/family type terms fitted the data reasonably well. The effect of age was stronger in the second decade, while that of marital status was reduced. The risk of transition to an institution was nearly 33-52% higher in the second decade after controlling for these factors. During the 1980s the availability of state financed institutional care increased substantially; a growth which the 1990 NHS and Community Care Act was designed to reverse. Increased access to institutional care undoubtedly is one factor underlying the higher transition rate to institutions observed in 1981-91 than for the previous decade. During 1981-91, transitions to live with relatives also declined substantially. It is not clear whether this simply represents the continuation of a previous trend or whether the increased availability of institutional care led to some substitution for family care. Either interpretation has worrying implications for policy makers keen to promote care in the community.


MicroRNAs and regeneration: Let-7 members as potential regulators of dedifferentiation in lens and inner ear hair cell regeneration of the adult newt.
MicroRNAs are known to regulate the expression of many mRNAs by binding to complementary target sequences at the 3'UTRs. Because of such properties, miRNAs may regulate tissue-specific mRNAs as a cell undergoes transdifferentiation during regeneration. We have tested this hypothesis during lens and hair cell regeneration in newts using microarray analysis. We found that distinct sets of miRNAs are associated with lens and hair cell regeneration. Members of the let-7 family are expressed in both events and they are regulated in a similar fashion. All the let-7 members are down regulated during the initiation of regeneration, which is characterized by dedifferentiation of terminally differentiated cells. This is the first report to correlate expression of miRNAs as novel regulators of vertebrate regeneration, alluding to a novel mechanism whereby transdifferentiation occurs.


Anti-tumor effects of PC-SPES, an herbal formulation in prostate cancer.
Prostate cancer is the most common cancer amongst males in developed countries. Surgical removal of the prostate effectively cures the primary disease but the metastatic disease is refractory to most forms of chemotherapy. There is a clinical need to develop novel treatment strategies that exploit the mode of action of both conventional and alternative drugs/medicinal plants. We have been investigating the anti-proliferative and anti-tumor effects of an herbal preparation termed PC-SPES (patent pending, US serial number 08/697, 920) which is a refined powder of eight different medicinal plants. PC-SPES administered as a food supplement caused a dramatic decrease in prostate specific antigen levels in some prostate cancer patients with advanced disease. These preliminary clinical findings laid the foundation for a program to examine the in vitro and in vivo effects of PC-SPES, and identify the active component in this mixture so that a standardized treatment regimen can be formulated. In this communication, we report the anti-tumor effects of PC-SPES incorporated in the diet utilizing a well studied Dunning R3327 rat prostate cancer model. Dietary PC-SPES at levels of 0.05% and 0.025% did not exhibit any toxicity and no significant difference in food intake was noted at the end of six weeks. Dose dependent inhibitory effect of dietary PC-SPES was observed on both tumor incidence (P=0. 01) and rate of tumor growth when tumors were induced in syngeneic Copenhagen rats by intradermal injections of MAT-LyLu cells that are known to metastasize in the lung and lymph nodes. The number of pulmonary metastases in animals on PC-SPES that showed no primary tumor growth had no metastatic lesions in the lung, however, in animals that did not respond to PC-SPES, the number of pulmonary metastases was not significantly different from the non-treated controls. The significant anti-tumor effects of PC-SPES on MAT-LyLu induced tumorigenesis and metastasis in Copenhagen rats, in general refractory to most conventional therapy, suggests a therapeutic benefit of this herbal food supplement and may be a useful adjuvant to conventional therapeutic modalities.


[Novel physiological and therapeutic implications of leptin].
The adipose tissue is an endocrine organ that produces a variety of protein hormones. One of them is leptin, which regulates several critical functions at the central nervous system such as caloric intake, basal energy expenditure, reproduction, glucose and lipid metabolism and osteogenesis. Acting at a local level, leptin modulates the immune system and promotes liver fibrogenesis. The most promising therapeutic implications of leptin will possibly be in type 1 diabetes mellitus (DM1). Its supplementation in animal models of DM1 prevents hyperglycemia and ketoacidosis. These actions depend on the activation of leptin receptors in the central nervous system and the suppression of glucagon signaling in the liver.


Recent origin and cultural reversion of a hunter-gatherer group.
Contemporary hunter-gatherer groups are often thought to serve as models of an ancient lifestyle that was typical of human populations prior to the development of agriculture. Patterns of genetic variation in hunter-gatherer groups such as the Kung and African Pygmies are consistent with this view, as they exhibit low genetic diversity coupled with high frequencies of divergent mtDNA types not found in surrounding agricultural groups, suggesting long-term isolation and small population sizes. We report here genetic evidence concerning the origins of the Mlabri, an enigmatic hunter-gatherer group from northern Thailand. The Mlabri have no mtDNA diversity, and the genetic diversity at Y-chromosome and autosomal loci are also extraordinarily reduced in the Mlabri. Genetic, linguistic, and cultural data all suggest that the Mlabri were recently founded, 500-800 y ago, from a very small number of individuals. Moreover, the Mlabri appear to have originated from an agricultural group and then adopted a hunting-gathering subsistence mode. This example of cultural reversion from agriculture to a hunting-gathering lifestyle indicates that contemporary hunter-gatherer groups do not necessarily reflect a pre-agricultural lifestyle.


Interaction of calcium and microtubules in the action of cyclic AMP on the toad urinary bladder.
Involvement of microtubules in the cellular action of vasopressin was studied by physiological and biochemical procedures. The inhibitory effect of 10(-4) M colchicine on the hydro-osmotic response of the toad bladder to 2 mM cyclic AMP was completely blocked by an increase in the concentration of calcium in the serosal bathing medium from 1 to 8 mM. Most of the colchicine-binding activity of extracts of the bladder epithelial cells was recovered by DEAE-Sephadex chromatography in a procedure similar to that used to isolate tubulin of bovine brain. Sodium dodecyl sulfate urea and urea gel electrophoresis of the DEAE-Sephadex fraction from the bladder epithelial cells yielded bands that corresponded to those of bovine brain tubulin. When 8 mM CaCl2 was present in an incubation mixture, the binding of colchicine to tubulin from the bladder epithelial cells and bovine brain was significantly inhibited. However, 1 mM CaCl2 did not affect the binding of colchicine to tubulin. Although the present study supports the concept that microtubules and calcium play an important role in the cellular action of vasopressin on the toad urinary bladder, the mechanism by which calcium blocks the inhibitory effect of colchicine on the hydro-osmotic response to cyclic AMP could not be elucidated.


Segregation and pathfinding of callosal axons through EphA3 signaling.
The corpus callosum, composed of callosal axons, is the largest structure among commissural connections in eutherian animals. Axon pathfinding of callosal neurons has been shown to be guided by intermediate targets, such as midline glial structures. However, it has not yet been understood completely how axon-axon interactions, another major mechanism for axon pathfinding, are involved in the pathfinding of callosal neurons. Here, we show that callosal axons from the medial and lateral regions of the mouse cerebral cortex pass through the dorsal and ventral parts, respectively, of the corpus callosum. Using an explant culture system, we observed that the axons from the medial and lateral cortices were segregated from each other in vitro, and that this segregation was attenuated by inhibition of EphA3 signaling. We also found that knockdown of EphA3, which is preferentially expressed in the lateral cortex, resulted in disorganized segregation of the callosal axons and disrupted axon pathfinding in vivo. These results together suggest the role of axonal segregation in the corpus callosum, mediated at least in part by EphA3, in correct pathfinding of callosal neurons.


BAFF-R, a newly identified TNF receptor that specifically interacts with BAFF.
B cell homeostasis has been shown to critically depend on BAFF, the B cell activation factor from the tumor necrosis factor (TNF) family. Although BAFF is already known to bind two receptors, BCMA and TACI, we have identified a third receptor for BAFF that we have termed BAFF-R. BAFF-R binding appears to be highly specific for BAFF, suggesting a unique role for this ligand-receptor interaction. Consistent with this, the BAFF-R locus is disrupted in A/WySnJ mice, which display a B cell phenotype qualitatively similar to that of the BAFF-deficient mice. Thus, BAFF-R appears to be the principal receptor for BAFF-mediated mature B cell survival.


Serotonin mediated changes in corticotropin releasing factor mRNA expression and feeding behavior isolated to the hypothalamic paraventricular nuclei.
Fenfluramine reduces hunger and promotes body weight loss by increasing central serotonin (5-HT) signaling. More recently, neuropeptides have been linked to the regulation of feeding behavior, metabolism and body weight. To examine possible interactions between 5-HT and neuropeptides in appetite control, fenfluramine (200 nmol/0.5 μl/side) was administered directly into the hypothalamic paraventricular nuclei (PVN) of male rats. Bilateral fenfluramine produced significant hypophagia and increased expression of PVN corticotropin releasing factor (CRF) mRNA and neuropeptide Y (NPY) mRNA in the arcuate nucleus within the first hour after drug administration. Fenfluramine's effects on feeding behavior and mRNA expression were blocked by PVN injections of a 5-HT(1-2) receptor antagonist, metergoline (15 nmol/0.5 μl/side). These data suggest that 5-HT neurons targeting hypothalamic paraventricular CRF neurons may participate in an appetite control circuit for reducing food intake.


Interventions for prevention of drug use by young people delivered in non-school settings.
Interventions intended to prevent or reduce use of drugs by young people may be delivered in schools or in other settings. This review aims to summarise the current literature about the effectiveness of interventions delivered in non schools settings. (1) - To summarise the current evidence about the effectiveness of interventions delivered in non-school settings intended to prevent or reduce drug use by young people under 25;(2) - To investigate whether interventions' effects are modified by the type and setting of the intervention, and the age of young people targeted;(3) - To identify areas where more research is needed. We searched Cochrane Central Register of Controlled Trials (CENTRAL - The Cochrane Library Issue 4, 2004), MEDLINE (1966-2004), EMBASE (1980-2004), PsycInfo (1972-2004), SIGLE (1980-2004), CINAHL (1982-2004) and ASSIA (1987-2004). We searched also reference lists of review articles and retrieved studies. Randomised trials that evaluated an intervention targeting drug use by young people under 25 years of age, delivered in a non-school setting, compared with no intervention or another intervention, that reported substantive outcomes relevant to the review. Two authors independently assessed trial quality and extracted data. Results were tabulated, as studies were considered too dissimilar to combine using meta-analysis. Seventeen studies, 9 cluster randomised studies, with 253 clusters, 8 individually randomised studies with 1230 participants, evaluating four types of intervention: motivational interviewing or brief intervention, education or skills training, family interventions and multi-component community interventions. Many studies had methodological drawbacks, especially high levels of loss to follow-up. There were too few studies for firm conclusions. One study of motivational interviewing suggested that this intervention was beneficial on cannabis use. Three family interventions (Focus on Families, Iowa Strengthening Families Program and Preparing for the Drug-Free Years), each evaluated in only one study, suggested that they may be beneficial in preventing cannabis use. The studies of multi component community interventions did not find any strong effects on drug use outcomes, and the two studies of education and skills training did not find any differences between the intervention and control groups. There is a lack of evidence of effectiveness of the included interventions. Motivational interviewing and some family interventions may have some benefit. Cost-effectiveness has not yet been addressed in any studies, and further research is needed to determine whether any of these interventions can be recommended.


Key Points to Facilitate the Adoption of Computer-Based Assessments.
There are strong pedagogical arguments in favor of adopting computer-based assessment. The risks of technical failure can be managed and are offset by improvements in cost-effectiveness and quality assurance capability. Academic, administrative, and technical leads at an appropriately senior level within an institution need to be identified, so that they can act as effective advocates. All stakeholder groups need to be represented in undertaking a detailed appraisal of requirements and shortlisting software based on core functionality, summative assessment life cycle needs, external compatibility, security, and usability. Any software that is a candidate for adoption should be trialed under simulated summative conditions, with all stakeholders having a voice in agreeing the optimum solution. Transfer to a new system should be carefully planned and communicated, with a programme of training established to maximize the success of adoption.


The spanish connection: transcription and mRNA processing get even closer.
The synthesis of mRNA by RNA polymerase II appears coupled to numerous RNA-processing events, based on physical or functional connections revealed by biochemical or genetic tests. New findings were presented at a recent meeting in Spain that begin to illuminate the mechanisms underlying the connections between mRNA processing and specific steps in transcription (initiation, elongation, and termination) as well as recombination.


Establishment of HRAS(G12V) transgenic medaka as a stable tumor model for in vivo screening of anticancer drugs.
Most targeted anticancer drugs have been identified by screening at the molecular or cellular level in vitro. However, many compounds selected by such costly and time-consuming screening do not prove effective against tumors in vivo. The development of anticancer drugs would thus be facilitated by the availability of an in vivo screening system based on a multicellular organism. We have now established a transgenic line of the freshwater fish medaka in which melanophores (melanocytes) proliferate in a manner dependent on heat shock-induced signaling by a human RAS oncoprotein. The human HRAS(G12V) oncogene was expressed under the control of a melanophore-specific gene promoter in order to allow visualization of tumor growth in live fish maintained in a water tank. The expression of HRAS(G12V) was induced as a result of Cre-mediated recombination by exposure of the fish to a temperature of 37°C for 30 min, given that the Cre gene was placed under the control of a medaka heat shock promoter. One of the stable transgenic lines developed abnormal pigment cell proliferation in the eyes and epidermis with 100% penetrance by 6 months postfertilization. Sorafenib, an inhibitor of RAS signaling, was administered to the transgenic fish and was found both to reduce the extent of melanophore proliferation and to improve survival. The transgenic medaka established here thus represents a promising in vivo system with which to screen potential anticancer drugs that target RAS signaling, and this system can readily be adapted for the screening of agents that target other oncogenes.


Validated HPLC method for quantitative determination of talinolol in rat plasma and application to a preclinical pharmacokinetic study.
A simple HPLC-UV method with a high reproducibility and sensitivity for the determination of talinolol in rat plasma was developed in this study. After liquid-liquid extraction, the compounds were separated on a Vydac(®) C18 monomeric column (250 × 4.6 mm inner diameter × 5-µm particle size) using a mobile phase composed of acetonitrile and potassium dihydrogen phosphate buffer (34:66 v/v), delivered isocratically at a flow rate of 1.0 ml min(-1). Escitalopram was used as an internal standard. The chromatographic peak-area ratio, based on UV absorbency at 245 nm, was used for quantitative analysis. Calibration standards with concentrations over the range of 10-1000 ng ml(-1) were validated for routine sample analysis to support pharmacokinetic studies with talinolol in rats. The intra- and inter-day precision studies showed good reproducibility with coefficients of variation of less than 11.49%. The developed method is simpler and more sensitive than previously reported methods. The analytical sensitivity and accuracy of this assay were adequate for characterization of talinolol in rat plasma and the assay has been applied successfully to the in vivo kinetic study of talinolol in rats. After talinolol (10 mg kg(-1)) was given orally, the maximum concentration and the AUC(0-∞) were 341.8 ± 99.4 ng ml(-1) and 976.26 ± 173.37 ng h ml(-1), respectively. The oral bioavailability was approximately 52.14 ± 9.26%. The advantages of our method are a small sample volume (200 µl), short analysis time (13.5 min) and a simple sample extraction and clean-up compared with multiple extraction and washing steps and a longer analysis time in previously published methods.


Beyond expressive writing: evolving models of developmental creative writing.
Pennebaker's expressive writing paradigm has helped to introduce the benefits of writing to health care. However, research in expressive writing has been largely dominated by an experimental and quantitative approach that does not take into account critical methodologies and approaches in health psychology, the increasingly complex ways in which creative writing is now being used in health care settings or recent research in the broader field of creative writing and personal development, health and well-being (developmental creative writing). This article contrasts expressive writing theories and methodologies with those evolving in the relatively new field of developmental creative writing. It investigates a number of theoretical and methodological problems with the expressive writing model and argues for a more critical approach to future research.


Orienting Auditory Attention through Vision: the Impact of Monaural Listening.
The understanding of linguistic messages can be made extremely complex by the simultaneous presence of interfering sounds, especially when they are also linguistic in nature. In two experiments, we tested if visual cues directing attention to spatial or temporal components of speech in noise can improve its identification. The hearing-in-noise task required identification of a five-digit sequence (target) embedded in a stream of time-reversed speech. Using a custom-built device located in front of the participant, we delivered visual cues to orient attention to the location of target sounds and/or their temporal window. In Exp. 1 ( n = 14), we validated this visual-to-auditory cueing method in normal-hearing listeners, tested under typical binaural listening conditions. In Exp. 2 ( n = 13), we assessed the efficacy of the same visual cues in normal-hearing listeners wearing a monaural ear plug, to study the effects of simulated monaural and conductive hearing loss on visual-to-auditory attention orienting. While Exp. 1 revealed a benefit of both spatial and temporal visual cues for hearing in noise, Exp. 2 showed that only the temporal visual cues remained effective during monaural listening. These findings indicate that when the acoustic experience is altered, visual-to-auditory attention orienting is more robust for temporal compared to spatial attributes of the auditory stimuli. These findings have implications for the relation between spatial and temporal attributes of sound objects, and when planning devices to orient audiovisual attention for subjects suffering from hearing loss.


Epithelial cell-intrinsic Notch signaling plays an essential role in the maintenance of gut immune homeostasis.
Intestinal epithelial cells (IECs) have important functions as the first line of defense against diverse microorganisms on the luminal surface. Impaired integrity of IEC has been implicated in increasing the risk for inflammatory disorders in the gut. Notch signaling plays a critical role in the maintenance of epithelial integrity by regulating the balance of secretory and absorptive cell lineages, and also by facilitating epithelial cell proliferation. We show in this article that mice harboring IEC-specific deletion of Rbpj (RBP-J(ΔIEC)), a transcription factor that mediates signaling through Notch receptors, spontaneously develop chronic colitis characterized by the accumulation of Th17 cells in colonic lamina propria. Intestinal bacteria are responsible for the development of colitis, because their depletion with antibiotics prevented the development of colitis in RBP-J(ΔIEC) mice. Furthermore, bacterial translocation was evident in the colonic mucosa of RBP-J(ΔIEC) mice before the onset of colitis, suggesting attenuated epithelial barrier functions in these mice. Indeed, RBP-J(ΔIEC) mice displayed increase in intestinal permeability after rectal administration of FITC-dextran. In addition to the defect in physical barrier, loss of Notch signaling led to arrest of epithelial cell turnover caused by downregulation of Hes1, a transcriptional repressor of p27(Kip1) and p57(Kip2). Thus, epithelial cell-intrinsic Notch signaling ensures integrity and homeostasis of IEC, and this mechanism is required for containment of intestinal inflammation.


Tumour-targeting photosensitisers for one- and two-photon activated photodynamic therapy.
Despite the advantages of photodynamic therapy (PDT) over chemotherapy or radiotherapy such as low side effects, lack of treatment resistance and spatial selectivity inherent to light activation of the drug, several limitations especially related to the photosensitiser (PS) prevent PDT from becoming widespread in oncology. Herein, new folic acid- and biotin-conjugated PSs for tumour-targeting PDT are reported, with promising properties related to PDT such as intense absorption following one-photon excitation in the red or two-photon excitation in the near-infrared, and also high singlet oxygen quantum yield (close to 70% in DMSO). Cellular studies demonstrated that both targeted PSs induced phototoxicity, the folate-targeted PS being the most effective one with 80% of cell death following 30 min of irradiation and a phototoxicity four times higher than that of the non-targeted PS. This result is in accordance with the uptake of the folate-targeted PS in HeLa cells, mediated by the folate receptors. Moreover, this folate-targeted PS was also phototoxic following two-photon excitation at 920 nm, opening new perspectives for highly selective PDT treatment of small and deep tumours.


[Effect of electroacupuncture on Quchi (LI 11) and Taichong (LR 3) on blood pressure variability in young patients with hypertension].
To compare the therapeutic effect of electroacupuncture and western medication on blood pressure variability in young patients with hypertension. Sixty cases of hypertension in young patients were randomized into an electroacupuncture group and a western medication group, 30 cases in each one. In electroacupuncture group, electroacupuncture was applied on Quchi (LI 11) and Taichong (LR 3). In western medication group, Captopril was taken orally. Twenty-four hour dynamic blood pressure, blood pressure variability and day-night rhythm were observed after 14 days treatment in two groups. Electroacupuncture on Quchi (LI 11) and Taichong (LR 3) reduced systolic pressure and diastolic pressure at different time phases in young patients with hypertension (all P < 0.01), which did not present significant statistical difference as compared with western medication group (all P > 0.05). Electroacupuncture on Quchi (Li, 11) and Taichong (LR 3) reduced apparently the standard deviations of systolic pressure and diastolic pressure at different time phases in young patients with hypertension, indicating significant statistical differences as compared with the deviations before the treatment (P < 0.01, P < 0.05). The statistical significance presented in 24 h systolic standard deviation (24 h SSD), 24 h diastolic standard deviation (24 h DSD), daytime SSD (dSSD), nighttime SSD (nSSD) and nighttime DSD (nDSD) between two groups (P < 0.01, P < 0.05). In comparison of the numbers of Dippers and non-Dippers in two groups, the significant statistical difference presented between two groups after treatment (P < 0.05). Electroacupuncture on Quchi (LI 11) and Taichong (LR 3) has long-term antihypertensive effect and improves effectively day-night rhythm variation in young patients with hypertension. Quchi (LI 11) and Taichong (LR 3) are the effective pair points for hypertension treated with acupuncture.


Well-child care clinical practice redesign for serving low-income children.
Our objective was to conduct a rigorous, structured process to create a new model of well-child care (WCC) in collaboration with a multisite community health center and 2 small, independent practices serving predominantly Medicaid-insured children. Working groups of clinicians, staff, and parents (called "Community Advisory Boards" [CABs]) used (1) perspectives of WCC stakeholders and (2) a literature review of WCC practice redesign to create 4 comprehensive WCC models for children ages 0 to 3 years. An expert panel, following a modified version of the Rand/UCLA Appropriateness Method, rated each model for potential effectiveness on 4 domains: (1) receipt of recommended services, (2) family-centeredness, (3) timely and appropriate follow-up, and (4) feasibility and efficiency. Results were provided to the CABs for selection of a final model to implement. The newly developed models rely heavily on a health educator for anticipatory guidance and developmental, behavioral, and psychosocial surveillance and screening. Each model allots a small amount of time with the pediatrician to perform a brief physical examination and to address parents' physical health concerns. A secure Web-based tool customizes the visit to parents' needs and facilitates previsit screening. Scheduled, non-face-to-face methods (text, phone) for parent communication with the health care team are also critical to these new models of care. A structured process that engages small community practices and community health centers in clinical practice redesign can produce comprehensive, site-specific, and innovative models for delivery of WCC. This process, as well as the models developed, may be applicable to other small practices and clinics interested in practice redesign.


Generation of auxotrophic mutants of Enterococcus faecalis.
A 22-kb segment of chromosomal DNA from Enterococcus faecalis OG1RF containing the pyrimidine biosynthesis genes pyrC and pyrD was previously detected as complementing Escherichia coli pyrC and pyrD mutations. In the present study, it was found that the E. faecalis pyrimidine biosynthetic genes in this clone (designated pKV48) are part of a larger cluster resembling that seen in Bacillus spp. Transposon insertions were isolated at a number of sites throughout the cluster and resulted in loss of the ability to complement E. coli auxotrophs. The DNA sequences of the entire pyrD gene of E. faecalis and selected parts of the rest of the cluster were determined, and computer analyses found these to be similar to genes from Bacillus subtilis and Bacillus caldolyticus pyrimidine biosynthesis operons. Five of the transposon insertions were introduced back into the E. faecalis chromosome, and all except insertions in pyrD resulted in pyrimidine auxotrophy. The prototrophy of pyrD knockouts was observed for two different insertions and suggests that E. faecalis is similar to Lactococcus lactis, which has been shown to possess two pyrD genes. A similar analysis was performed with the purL gene from E. faecalis, contained in another cosmid clone, and purine auxotrophs were isolated. In addition, a pool of random transposon insertions in pKV48, isolated in E. coli, was introduced into the E. faecalis chromosome en masse, and an auxotroph was obtained. These results demonstrate a new methodology for constructing defined knockout mutations in E. faecalis.


Genetic insights into disease mechanisms of autoimmunity.
Educating the immune system to distinguish between self and non-self is critical to ensure that an immune response is mounted against foreign antigens and not against self. A breakdown in these mechanisms can lead to the onset of autoimmune disease. Clinical and molecular data suggest that shared immunogenetic mechanisms lead to the autoimmune process. The most studied genes and molecules are the human leukocyte antigen (HLA) region and the cytotoxic T-lymphocyte-associated 4 molecule (CTLA-4). Recently progress has been achieved in narrowing down the primary variants within both gene regions, but further work is needed to determine the function and extent of the aetiological variant(s) present. Recent exciting results also suggest a role for the newly discovered lymphoid-specific phosphatase (LYP) protein. As well as these general mechanisms, disease-specific mechanisms are beginning to be elucidated, for example the role of autoimmune regulatory element 1 (AIRE1) in autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy (APECED). Taken together, these data suggest that both general and disease-specific mechanisms lead to the clinical outcome of autoimmune disease and that increased understanding of these mechanisms will improve our knowledge of how autoimmune disease occurs, eventually leading to the development of novel therapeutic agents.


Preventive effects of soy meal (+/- isoflavone) on spatial cognitive deficiency and body weight in an ovariectomized animal model of Parkinson's disease.
The aim of the present study was to investigate the preventive effect of 4 weeks soy meal (+/- isoflavone) on post-menopausal cognitive deficiency and body weight alteration in ovariectomized (OVX)-6-hydroxy dopamine (6-OHDA)-induced animal model of Parkinson's Disease (PD) which mimics status in menopause women. Female Wistar rats (250-300 g, 5-6 months old) were divided into 2 main groups. (1) Control; (2) OVX; included 5 subgroups that were pre-treated with 10 or 20 g soy with isoflavone in 30 g daily diet (10 and 20 groups, respectively), 10 or 20 g soy without isoflavone in 30 g daily diet (-10 and -20 groups, respectively) and 0 g soy (sham treated group) during 4 weeks after OVX. To induce animal model ofPD in main second group (OVX rats) the substantia nigra pars compacta (SNpc) was lesioned by 6-hydroxydopamine (6-OHDA) (8 microg kg(-1) 4 microL(-1) normal saline contains 0.1% ascorbate). All animals were trained in Morris water maze for evaluating the spatial learning and memory. The results indicated that pre-treatment of Parkinsonian rats with different doses of dietary soy meal (+/- isoflavone) improved the spatial learning and memory and prevents increasing the body weight after menopause significantly. Our data show that, long-duration dietary soy meal may have the potential neuroprotective effect against post-menopausal cognitive deficiency induced by degeneration of nigrostriatal dopaminergic system and constant body weight during post-menopausal life cycle.


Workplace risk factors for cancer in the German rubber industry: Part 1. Mortality from respiratory cancers.
To determine the cancer specific mortality by work area among active and retired male workers in the German rubber industry. A cohort of 11,663 male German workers was followed up for mortality from 1 January 1981 to 31 December 1991. Cohort members were classified as active (n = 7536) or retired (n = 4127) as of 1 January 1981 and had been employed for at least one year in one of five study plants producing tyres or technical rubber goods. Work histories were reconstructed with routinely documented "cost centre codes" which were classified into six categories: I preparation of materials; II production of technical rubber goods; III production of tyres; IV storage and dispatch; V maintenance; and VI others. Standardised mortality ratios (SMRs) adjusted for age and calendar year and 95% confidence intervals (95% CIs), stratified by work area (employment in respective work area for at least one year) and time related variables (year of hire, lagged years of employment in work area), were calculated from national reference rates. SMRs for laryngeal cancer were highest in work area I (SMR 253; 95% CI 93 to 551) and were significant among workers who were employed for > 10 years in this work area (SMR 330; 95% CI 107 to 779). Increased mortality rates from lung cancer were identified in work areas I (SMR 162; 95% CI 129 to 202), II (SMR 134; 95% CI 109 to 163), and V (SMR 131; 95% CI 102 to 167). Mortality from pleural cancer was increased in all six work areas, and significant excesses were found in work areas I (SMR 448; 95% CI 122 to 1146), II (SMR 505; 95% CI 202 to 1040), and V (SMR 554; 95% CI 179 to 1290). A causal relation between the excess of pleural cancer and exposure to asbestos among rubber workers is plausible and likely. In this study, the pattern of excess of lung cancer parallels the pattern of excess of pleural cancer. This points to asbestos as one risk factor for the excess deaths from lung cancer among rubber workers. The study provides further evidence for an increased mortality from laryngeal cancer among workers in the rubber industry, particularly in work area I.


Opposing, spatially-determined epigenetic forces impose restrictions on stochastic olfactory receptor choice.
Olfactory receptor (OR) choice represents an example of genetically hardwired stochasticity, where every olfactory neuron expresses one out of ~2000 OR alleles in a probabilistic, yet stereotypic fashion. Here, we propose that topographic restrictions in OR expression are established in neuronal progenitors by two opposing forces: polygenic transcription and genomic silencing, both of which are influenced by dorsoventral gradients of transcription factors NFIA, B, and X. Polygenic transcription of OR genes may define spatially constrained OR repertoires, among which one OR allele is selected for singular expression later in development. Heterochromatin assembly and genomic compartmentalization of OR alleles also vary across the axes of the olfactory epithelium and may preferentially eliminate ectopically expressed ORs with more dorsal expression destinations from this "privileged" repertoire. Our experiments identify early transcription as a potential "epigenetic" contributor to future developmental patterning and reveal how two spatially responsive probabilistic processes may act in concert to establish deterministic, precise, and reproducible territories of stochastic gene expression.


Volition as narrative: understanding motivation in chronic illness.
This paper expands the current concept of volition in the Model of Human Occupation. The present version views personal causation, values, and interests as traits that determine choices to engage in occupations. Through a detailed investigation of the life histories of two persons with psychiatric disorders, this paper illustrates how volition is embedded in a personal narrative. Two features of narratively organized volition are highlighted: (a) how narrative places decisions and actions within a plot, thus giving them meaning in the context of a whole life, and (b) how the personal narrative motivates the person by serving as a context for choosing and action. Thus, the paper illustrates how persons seek to narrate their lives and live their life narratives.


Brief Report: Association Between Menopause and Unprotected Sex in High-Risk HIV-Positive Women in Mombasa, Kenya.
Many HIV-positive women now live well beyond menopause. Postmenopausal women are no longer at risk for pregnancy, and some studies suggest that they may use condoms less often than premenopausal women. This study tests the hypothesis that, in HIV-positive women who report trading sex for cash or in-kind payment, unprotected sex is more common at postmenopausal visits compared with premenopausal visits. Prospective cohort study of HIV-positive women ≥16 years old in Mombasa, Kenya. At enrollment and monthly follow-up visits, participants completed a standardized interview. Study clinicians collected genital samples at enrollment and quarterly visits. Menopausal status was assessed annually. The primary outcome of unprotected sex was determined by detection of prostate specific antigen (PSA) in vaginal secretions. This study followed 404 HIV-positive women who contributed 2753 quarterly examination visits. Detection of PSA was less frequent at postmenopausal visits compared with premenopausal visits [55/554, 10.5% versus 394/2199, 17.9%; relative risk (RR) 0.58, 95% confidence interval (CI): 0.39 to 0.87]. Adjusting for age diminished the association between menopause and PSA detection (adjusted RR 0.73, 95% CI: 0.47 to 1.14). At visits where women reported sexual activity in the past week, they reported similar rates of 100% condom use at postmenopausal and premenopausal visits (RR 0.99, 95% CI: 0.87 to 1.13). In this population of high-risk HIV-positive Kenyan women, postmenopausal status was not associated with a greater risk of unprotected sex. The relationship between menopause and unprotected sex is likely context specific and may differ with varying risk groups, regions, and levels of exposure to sexual health education.


Current and future economic burden of osteoporosis in New Zealand.
Osteoporosis is recognized as a serious health condition in developed as well as developing countries. There are no accurate estimates of the extent of the burden of osteoporosis in New Zealand. The purpose of this study was to estimate the economic burden of osteoporosis in New Zealand using data from international studies and population and health services information from New Zealand. To estimate the number of osteoporotic fractures and cost of treatment and management of osteoporosis and osteoporotic fractures to the health system in New Zealand in 2007 and to project the future burden in 2013 and 2020. Hospitalizations for hip fractures were combined with New Zealand census data and estimates from previous studies to estimate the expected number of osteoporotic vertebral, humeral, pelvic and other sites fractures in 2007. Health services usage and costs were estimated by combining data from New Zealand hospitals, the New Zealand Health Survey on the number of people diagnosed with osteoporosis, and the New Zealand Health Information Service (NZHIS) on pharmaceutical treatments. All prices are in New Zealand dollars ($NZ), year 2007 values. Losses in QALYs resulting from osteoporotic fractures were used to indicate the impact on morbidity and mortality. The lost QALYs and economic cost associated with osteoporosis were projected to 2013 and 2020 using population projections from the New Zealand census. There were an estimated 84 354 osteoporotic fractures in New Zealand in 2007, including 3803 hip and 27 994 vertebral fractures. Osteoporosis resulted in a loss of 11 249 QALYs. The total direct cost of osteoporosis was$NZ330 million, including $NZ212 million to treat the fractures, $NZ85 million for care after fractures and $NZ34 million for treatment and management of the estimated 70 631 people diagnosed with osteoporosis. Sensitivity analysis suggested the results were robust to assumptions regarding the number of fractures receiving medical treatment. Hospitalization costs represented a significant component of total costs. The cost of treatment and management of osteoporosis is expected to increase to over $NZ391 million in 2013 and $NZ458 million in 2020, with the number of QALYs lost increasing to 13 205 in 2013 and 15 176 in 2020. Osteoporosis and osteoporotic fractures create a significant burden on the health system in New Zealand. This study highlights the significant scope of the burden of osteoporosis and the potential gains that might be made from introducing interventions to mitigate the burden.


Oxytocin and pain: a systematic review and synthesis of findings.
A review of the literature was conducted to assess the association between oxytocin (OT) and pain. PsychInfo, PubMed, and Medline (EBSCO) research databases were searched for peer-reviewed articles written between 1950 and 2012. Of a total of 1166 articles returned, 50 (9 human, 33 animal, and 8 spinal cord samples) met full inclusion criteria and were included in the review. OT had a reliable effect as defined by increasing pain tolerance in 29 of 33 animal studies reviewed. This effect persisted across central and peripheral modes of administration and type of noxious stimulus used (eg, heat, electric). The results suggest that OT acts as an analgesic for acute pain in animals. Preliminary research with humans offers consistent evidence to suggest that OT decreases pain sensitivity, though the reliability and stability of such effects cannot yet be determined. Although the findings are encouraging, there is a need for methodologically rigorous work in humans where OT is administered centrally. Further research seems to be warranted as the existence of biologically and psychologically plausible mechanisms linking OT and pain have been well supported using animal models with limited but encouraging human research. Implications and recommendations are discussed. Findings from this research may inform therapeutic methods for the management of pain.


Combining collective and artificial intelligence for global health diseases diagnosis using crowdsourced annotated medical images.
Visual inspection of microscopic samples is still the gold standard diagnostic methodology for many global health diseases. Soil-transmitted helminth infection affects 1.5 billion people worldwide, and is the most prevalent disease among the Neglected Tropical Diseases. It is diagnosed by manual examination of stool samples by microscopy, which is a time-consuming task and requires trained personnel and high specialization. Artificial intelligence could automate this task making the diagnosis more accessible. Still, it needs a large amount of annotated training data coming from experts.In this work, we proposed the use of crowdsourced annotated medical images to train AI models (neural networks) for the detection of soil-transmitted helminthiasis in microscopy images from stool samples leveraging non-expert knowledge collected through playing a video game. We collected annotations made by both school-age children and adults, and we showed that, although the quality of crowdsourced annotations made by school-age children are sightly inferior than the ones made by adults, AI models trained on these crowdsourced annotations perform similarly (AUC of 0.928 and 0.939 respectively), and reach similar performance to the AI model trained on expert annotations (AUC of 0.932). We also showed the impact of the training sample size and continuous training on the performance of the AI models.In conclusion, the workflow proposed in this work combined collective and artificial intelligence for detecting soil-transmitted helminthiasis. Embedded within a digital health platform can be applied to any other medical image analysis task and contribute to reduce the burden of disease.