Immune cell repertoires in breast cancer patients after adjuvant chemotherapy.
Adjuvant chemotherapy in breast cancer patients causes immune cell depletion at an age when the regenerative capacity is compromised. Successful regeneration requires the recovery of both quantity and quality of immune cell subsets. Although immune cell numbers rebound within a year after treatment, it is unclear whether overall compositional diversity is recovered. We investigated the regeneration of immune cell complexity by comparing peripheral blood mononuclear cells from breast cancer patients ranging from 1-5 years after chemotherapy with those of age-matched healthy controls using mass cytometry and T cell receptor sequencing. These data reveal universal changes in patients' CD4+ T cells that persisted for years and consisted of expansion of Th17-like CD4 memory populations with incomplete recovery of CD4+ naive T cells. Conversely, CD8+ T cells fully recovered within a year. Mechanisms of T cell regeneration, however, were unbiased, as CD4+ and CD8+ T cell receptor diversity remained high. Likewise, terminal differentiated effector memory cells were not expanded, indicating that regeneration was not driven by recognition of latent viruses. These data suggest that, while CD8+ T cell immunity is successfully regenerated, the CD4 compartment may be irreversibly affected. Moreover, the bias of CD4 memory toward inflammatory effector cells may impact responses to vaccination and infection.


Hydration status of Arabic adolescents and young men: measurement, evaluation, and a school-based initiative to improve drinking behavior.
Despite the importance of hydration, limited research on the topic has been undertaken in Arabic populations. Study 1. Five sequential daily midmorning urine samples were provided by 88 adult military cadets and 32 school-based adolescents. Hydration thresholds were produced using percentiles of estimated urine osmolality (Uosm) and urine color (Ucol). Study 2. The authors assessed 1,077 midmorning urine samples from 120 military cadets and 52 adolescents for the Uosm:Ucol relationship using regression. Study 3. The authors conducted a 4-wk hydration campaign in which 21 adolescents participated, providing urine samples before (PreC), at the end of (EndC), and 2 wk after the campaign (PostC). Study 1. Euhydration (41-60th percentile) was 881-970 mOsmol/kg in adults and 821-900 mOsmol/kg in adolescents. Study 2. In both cohorts, Uosm and Ucol were associated (p < .01): adults R² = .33, adolescents R² = .59. Study 3. Urine osmolality was significantly higher PreC than at EndC and PostC. Urinary output of Arabic adolescents and military cadets was more concentrated than frequently recommended for euhydration. Further work in similar populations is required to determine if these values represent hypohydration or merely reflect dietary and cultural differences. In male Arabic adolescents and adults, Ucol was an adequate indicator of hydration status. Favorable hydration changes were made after a school-based health campaign.


Guidelines for Adolescent Depression in Primary Care (GLAD-PC): Part II. Treatment and Ongoing Management.
To update clinical practice guidelines to assist primary care (PC) in the screening and assessment of depression. In this second part of the updated guidelines, we address treatment and ongoing management of adolescent depression in the PC setting. By using a combination of evidence- and consensus-based methodologies, the guidelines were updated in 2 phases as informed by (1) current scientific evidence (published and unpublished) and (2) revision and iteration among the steering committee, including youth and families with lived experience. These updated guidelines are targeted for youth aged 10 to 21 years and offer recommendations for the management of adolescent depression in PC, including (1) active monitoring of mildly depressed youth, (2) treatment with evidence-based medication and psychotherapeutic approaches in cases of moderate and/or severe depression, (3) close monitoring of side effects, (4) consultation and comanagement of care with mental health specialists, (5) ongoing tracking of outcomes, and (6) specific steps to be taken in instances of partial or no improvement after an initial treatment has begun. The strength of each recommendation and the grade of its evidence base are summarized. The Guidelines for Adolescent Depression in Primary Care cannot replace clinical judgment, and they should not be the sole source of guidance for adolescent depression management. Nonetheless, the guidelines may assist PC clinicians in the management of depressed adolescents in an era of great clinical need and a shortage of mental health specialists. Additional research concerning the management of depressed youth in PC is needed, including the usability, feasibility, and sustainability of guidelines, and determination of the extent to which the guidelines actually improve outcomes of depressed youth.


Mendelian Randomization Study of ACLY and Cardiovascular Disease.
ATP citrate lyase is an enzyme in the cholesterol-biosynthesis pathway upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the target of statins. Whether the genetic inhibition of ATP citrate lyase is associated with deleterious outcomes and whether it has the same effect, per unit decrease in the low-density lipoprotein (LDL) cholesterol level, as the genetic inhibition of HMGCR is unclear. We constructed genetic scores composed of independently inherited variants in the genes encoding ATP citrate lyase (ACLY) and HMGCR to create instruments that mimic the effect of ATP citrate lyase inhibitors and HMGCR inhibitors (statins), respectively. We then compared the associations of these genetic scores with plasma lipid levels, lipoprotein levels, and the risk of cardiovascular events and cancer. A total of 654,783 participants, including 105,429 participants who had major cardiovascular events, were included in the study. The ACLY and HMGCR scores were associated with similar patterns of changes in plasma lipid and lipoprotein levels and with similar effects on the risk of cardiovascular events per decrease of 10 mg per deciliter in the LDL cholesterol level: odds ratio for cardiovascular events, 0.823 (95% confidence interval [CI], 0.78 to 0.87; P = 4.0×10-14) for the ACLY score and 0.836 (95% CI, 0.81 to 0.87; P = 3.9×10-19) for the HMGCR score. Neither lifelong genetic inhibition of ATP citrate lyase nor lifelong genetic inhibition of HMGCR was associated with an increased risk of cancer. Genetic variants that mimic the effect of ATP citrate lyase inhibitors and statins appeared to lower plasma LDL cholesterol levels by the same mechanism of action and were associated with similar effects on the risk of cardiovascular disease per unit decrease in the LDL cholesterol level. (Funded by Esperion Therapeutics and others.).


The NeST long ncRNA controls microbial susceptibility and epigenetic activation of the interferon-γ locus.
Long noncoding RNAs (lncRNAs) are increasingly appreciated as regulators of cell-specific gene expression. Here, an enhancer-like lncRNA termed NeST (nettoie Salmonella pas Theiler's [cleanup Salmonella not Theiler's]) is shown to be causal for all phenotypes conferred by murine viral susceptibility locus Tmevp3. This locus was defined by crosses between SJL/J and B10.S mice and contains several candidate genes, including NeST. The SJL/J-derived locus confers higher lncRNA expression, increased interferon-γ (IFN-γ) abundance in activated CD8(+) T cells, increased Theiler's virus persistence, and decreased Salmonella enterica pathogenesis. Transgenic expression of NeST lncRNA alone was sufficient to confer all phenotypes of the SJL/J locus. NeST RNA was found to bind WDR5, a component of the histone H3 lysine 4 methyltransferase complex, and to alter histone 3 methylation at the IFN-γ locus. Thus, this lncRNA regulates epigenetic marking of IFN-γ-encoding chromatin, expression of IFN-γ, and susceptibility to a viral and a bacterial pathogen.


Biological network border detection.
Complex networks have been widely used to model biological systems. The concept of accessibility has been proposed recently as a means to organize the nodes of complex networks as belonging to its border or center. Such an approach paves the way to investigating how the functional and structural properties of nodes vary with their respective position in the networks. In this work, we approach such a problem in a biological context applying border detection to Protein-Protein Interaction networks from four organisms of the Mycoplasma genus. We found evidence that the borderness of proteins bears a relation with their spatial organization and molecular function specificity.


Perturbation of TSG101 protein affects cell cycle progression.
tsg101 was recently identified as a tumor susceptibility gene by functional inactivation of allelic loci in mouse 3T3 fibroblasts. Although previous studies suggested that homozygous intragenic deletion of TSG101 is rare in breast cancer cells and specimens, the neoplastic phenotype caused by tsg101 inactivation implicated that tsg101 may play a significant role in cell growth control. Here, we characterize mouse polyclonal and monoclonal antibodies that specifically recognize the TSG101 protein (molecular mass, 46 kDa) in whole-cell lysates by straight Western blot analysis. By indirect immunofluorescence staining, TSG101 was found to be localized in the cytoplasm throughout the entire cell cycle. However, the nuclear staining increases from G1 to S phase and becomes dominant in late S phase. TSG101 is mainly distributed surrounding the chromosomes during M phase. The expression level of TSG101 is not cell cycle dependent. It is possible that the relocalization of TSG101 from the cytoplasm into the nucleus may be relevant to its function. Microinjection of both polyclonal and monoclonal antibodies specific to TSG101 into cells during G1 or S phase results in cell cycle arrest. Furthermore, overexpression of TSG101 leads to cell death, suggesting that the appropriate amount of TSG101 is critical for cell cycle progression. Taken together, these results suggest that neoplastic transformation caused by TSG101 deficiency may result from bypassing of the cell cycle checkpoints.


Phonological and visual distinctiveness effects in syllogistic reasoning: implications for mental models theory.
Two experiments are reported in which the representational distinctiveness of terms within categorical syllogisms was manipulated in order to examine the assumption of mental models theory that abstract, spatially based representations underpin deduction. In Experiment 1, participants evaluated conclusion validity for syllogisms containing either phonologically distinctive terms (e.g., harks, paps, and fids) or phonologically nondistinctive terms (e.g., fuds, fods, and feds). Logical performance was enhanced with the distinctive contents, suggesting that the phonological properties of syllogism terms can play an important role in deduction. In Experiment 2, participants received either the phonological materials from Experiment 1 or syllogisms involving distinctive or nondistinctive visual contents. Logical inference was again enhanced for the distinctive contents, whether phonological or visual in nature. Our findings suggest a broad involvement of multimodal information in syllogistic reasoning and question the assumed primacy of abstract, spatially organized representations in deduction, as is claimed by mental models theorists.


Multivariate General Linear Models (MGLM) on Riemannian Manifolds with Applications to Statistical Analysis of Diffusion Weighted Images.
Linear regression is a parametric model which is ubiquitous in scientific analysis. The classical setup where the observations and responses, i.e., (xi , yi ) pairs, are Euclidean is well studied. The setting where yi is manifold valued is a topic of much interest, motivated by applications in shape analysis, topic modeling, and medical imaging. Recent work gives strategies for max-margin classifiers, principal components analysis, and dictionary learning on certain types of manifolds. For parametric regression specifically, results within the last year provide mechanisms to regress one real-valued parameter, xi ∈ R, against a manifold-valued variable, yi ∈ . We seek to substantially extend the operating range of such methods by deriving schemes for multivariate multiple linear regression -a manifold-valued dependent variable against multiple independent variables, i.e., f : Rn → . Our variational algorithm efficiently solves for multiple geodesic bases on the manifold concurrently via gradient updates. This allows us to answer questions such as: what is the relationship of the measurement at voxel y to disease when conditioned on age and gender. We show applications to statistical analysis of diffusion weighted images, which give rise to regression tasks on the manifold GL(n)/O(n) for diffusion tensor images (DTI) and the Hilbert unit sphere for orientation distribution functions (ODF) from high angular resolution acquisition. The companion open-source code is available on nitrc.org/projects/riem_mglm.


Cartilaginous tissue formation using a mechano-active scaffold and dynamic compressive stimulation.
It is known that complex loading is involved in the development and maintenance of articular cartilage in the body. It means the compressive mechanical stimulation is a very important factor for formation of articular cartilage using a tissue-engineering technique. The objective of this study is to engineer cartilaginous constructs with mechano-active scaffolds and to evaluate the effect of dynamic compression for regeneration of cartilage. The mechano-active scaffolds were prepared from a very elastic poly(L-lactide-co-epsilon-caprolactone) (PLCL) with 85% porosity and 300-500 mum pore size using a gel-pressing method. The scaffold was seeded with 2 x 10(6) chondrocytes and the continuous compressive deformation of 5% strain was applied with 0.1 Hz for 10 days and 24 days, respectively. Then, the chondrocytes-seeded constructs were implanted subcutaneously into nude mice. Mechano-active scaffolds with complete rubber-like elasticity showed almost complete (over 97%) recovery at an applied strain of up to 500%. The amount of chondral extracellular matrix was increased significantly by mechanical stimulation on the highly elastic mechano-active scaffolds. Histological analysis showed the mechanically stimulated implants formed mature and well-developed cartilaginous tissue, as evidenced by the chondrocytes within lacunae and the abundant accumulation of sulfated GAGs. However, unhealthy lacunae shapes and hypertrophy forms were observed in the implants stimulated mechanically for 24 days, compared with those stimulated for 10 days. In conclusion, the proper periodical application of dynamic compression can encourage chondrocytes to maintain their phenotypes and enhance the production of GAGs, which would improve the quality of cartilaginous tissue formed both in vitro and in vivo.


A dynamic network model of temporal receptive fields in primary auditory cortex.
Auditory neurons encode stimulus history, which is often modelled using a span of time-delays in a spectro-temporal receptive field (STRF). We propose an alternative model for the encoding of stimulus history, which we apply to extracellular recordings of neurons in the primary auditory cortex of anaesthetized ferrets. For a linear-non-linear STRF model (LN model) to achieve a high level of performance in predicting single unit neural responses to natural sounds in the primary auditory cortex, we found that it is necessary to include time delays going back at least 200 ms in the past. This is an unrealistic time span for biological delay lines. We therefore asked how much of this dependence on stimulus history can instead be explained by dynamical aspects of neurons. We constructed a neural-network model whose output is the weighted sum of units whose responses are determined by a dynamic firing-rate equation. The dynamic aspect performs low-pass filtering on each unit's response, providing an exponentially decaying memory whose time constant is individual to each unit. We find that this dynamic network (DNet) model, when fitted to the neural data using STRFs of only 25 ms duration, can achieve prediction performance on a held-out dataset comparable to the best performing LN model with STRFs of 200 ms duration. These findings suggest that integration due to the membrane time constants or other exponentially-decaying memory processes may underlie linear temporal receptive fields of neurons beyond 25 ms.


Effects of glucocorticoid deficiency on renal medullary cyclic adenosine monophosphate of rats.
1. The effects of adrenalectomy on the adenylate cyclase--adenosine 3':5'-cyclic monophosphate (cyclic AMP) system of rat renal medulla were examined to evaluate the mechanism of the impaired water diuresis in glucocorticoid deficiency. 2. Concentrations of cyclic AMP in medullary tubules from adrenalectomized rats were significantly higher than in the tubules from control animals both in the presence and absence of antidiuretic hormone. 3. This abnormality was corrected by the treatment in vivo of the adrenalectomized rats with dexamethasone, but addition of this drug to the incubation medium did not abolish the differences in cyclic AMP between tubules from adrenalectomized and normal rats. 4. The activity of adenylate cyclase or cyclic AMP phosphodiesterase in vitro was not affected by adrenalectomy. 5. In glucocorticoid deficiency, the concentration of cyclic AMP in medullary tubules is increased both with and without antidiuretic hormone. This abnormality may render medullary tubules more permeable to water and may underlie the impaired water diuresis in glucocorticoid deficiency.


Mechanisms of Ly2 suppressor cell activity. Activation of an Ly1 I-J+ cell is required to transduce the suppressive signal.
A cell-free product secreted by Ly1-2+ T cells (Ly2 TsF) can suppress the in vitro response to sheep erythrocytes (SRBC) of spleen cells depleted of Ly2+ T cells. This suppressor factor expresses biological activity only when the acceptor cells share major histocompatibility complex (MHC)-linked polymorphic genes with the cells that made the Ly2 TsF. Removal of Ly1 I-J+ cells from the assay culture abrogates the ability of Ly2 TsF to suppress these cultures, but we can replace the need for the I-J+ cells in the assay culture with an I-J+ soluble factor derived from them. We investigated the cellular interactions involved in the activation of I-J+ cells by Ly2 TsF in vitro. We have been able to induce the production of an I-J+ molecule needed for Ly2 TsF activity in a 48-h intermediate culture of B cell-depleted Ly1 spleen cells, Ly2 TsF, and antigen. This molecule not only fails to bind antigen, but is also antigen nonspecific in that it can be induced by Ly2 TsF of irrelevant specificities. In order to replace the activity of the Ly1 I-J+ cell in the assay culture, the cell induced by Ly2 TsF to produce the I-J+ molecule in vitro must share genetic polymorphisms linked to the MHC with the Ly2 TsF, and genetic polymorphisms linked to the Igh-V gene complex with the target cell. In order for Ly2 TsF to induce cells of the primary culture to produce the I-J+ molecule, Ly2 TsF must share genetic polymorphisms linked to the IE region of the MHC with the Ly1 I-J+ cell producing the I-J+ molecule. These results indicate that the suppressive mechanism of Ly2 TsF involves the interaction with an Ly1 I-J+ molecule. This I-J+ molecule serves to focus the antigen-specific suppressor molecule on the target cell. The recognition event of this suppressive complex on the surface of the acceptor cell is controlled by Igh-V-linked genes restricted by the I-J+ molecule of the suppressor complex. This suppressor interaction is confined to the suppressor effector phase of the suppressor circuit since the I-J+ molecules needed for by Ly2 TsF activity do not substitute for the I-J+ molecules needed for the activity of Ly1 TsiF , a T cell factor that initiates the suppressor cell circuit.(ABSTRACT TRUNCATED AT 400 WORDS)


Pretreatment with Human Chorionic Gonadotropin Protects the Neonatal Brain against the Effects of Hypoxic-Ischemic Injury.
Though the human fetus is exposed to placentally derived human chorionic gonadotropin (hCG) throughout gestation, the role of hCG on the fetal brain is unknown. Review of the available literature appears to indicate that groups of women with higher mean levels of hCG during pregnancy tend to have offspring with lower cerebral palsy (CP) risk. Given that newborn cerebral injury often precedes the development of CP, we aimed to determine whether hCG may protect against the neurodegenerative effects of neonatal brain injury. We utilized the Rice-Vannucci model of neonatal cerebral hypoxia-ischemia (HI) in postnatal day 7 mice to examine whether intraperitoneal administration of hCG 15-18 h prior, 1 h after or immediately following HI decrease brain tissue loss 7 days after injury. We next studied whether hCG has pro-survival and trophic properties in neurons by exposing immature cortical and hippocampal neurons to hCG in vitro and examining neurite sprouting and neuronal survival prior and after glutamate receptor-mediated excitotoxic injury. We found that intraperitoneal injection of hCG 15 h prior to HI, but not at or 1 h after HI induction, resulted in a significant decrease in hippocampal and striatal tissue loss 7 days following brain injury. Furthermore, hCG reduced N-methyl-d-aspartate (NMDA)-mediated neuronal excitotoxicity in vitro when neurons were continuously exposed to this hormone for 10 days or when given at the time and following neuronal injury. In addition, continuous in vitro administration of hCG for 6-9 days increased neurite sprouting and basal neuronal survival as assessed by at least a 1-fold increase in MAP2 immunoreactivity and a 2.5-fold increase in NeuN + immunoreactivity. Our findings suggest that hCG can decrease HI-associated immature neural degeneration. The mechanism of action for this neuroprotective effect may partly involve inhibition of NMDA-dependent excitotoxic injury. This study supports the hypothesis that hCG during pregnancy has the potential for protecting the developing brain against HI, an important CP risk factor.


Bronchial asthma and air pollution at workplaces.
This case-referent study was performed to investigate the possibility of nonspecific air pollution at workplaces increasing the risk of bronchial asthma for formerly healthy adults. Seventy-nine cases of asthma, diagnosed at a lung clinic, among persons aged 20-65 years were compared with 304 referents drawn randomly from the population of the catchment area. Questionnaire information was obtained regarding occupation, exposure to suspect allergens, place of residence, smoking habits, and atopy. The subjects' occupations were categorized into four air pollution classes based on how the referents reported air pollution in their respective occupations. Three years or more of work in air-polluted occupations resulted in an odds ratio of 3.0 (OR) (95% confidence interval 1.5-6.1) in a comparison with work in occupations with slight or no air pollution. Stratification of the material for smoking habits or atopy did not alter the results. Nor did the exclusion of specific exposures to asthmatogenic agents such as ioscyanates, stainless steel welding, or aluminum salts change the effects of the nonspecific air pollution at workplaces. Smoking per se was associated with an almost doubled risk for asthma (OR 1.9, 95% confidence interval 1.1-3.4). The results of this study support an association between occupational exposure to nonspecific air pollution and the development of bronchial asthma.


Membrane filter method based on FC-5-bromo-4-chloro-3-indolyl-beta-D-glucuronide medium facilitates enumeration of Escherichia coli in foods and poultry carcass rinses.
Three enumeration methods for Escherichia coli in foods, the Health Protection Branch most-probable-number (MPN) method MFHPB-19, a hydrophobic grid membrane filter method MFHPB-26 (HGMF-indole), and a hydrophobic grid membrane filter method utilizing 5-bromo-4-chloro-3-indolyl-beta-D-glucuronide in a (modified) mFC agar (HGMF-FC-BCIG) were compared in 80 food samples that included naturally and artificially contaminated raw vegetables, mung bean and alfalfa sprouts, raw meats, and chicken carcass rinses. The number of samples confirmed as positive for E. coli were 44, 36, and 42 for the MPN, HGMF-indole, and HGMF-BCIG methods, respectively. By the MPN method, E. coli was detected in 3 samples at levels below the limits of detection of the HGMFs; but the MPN method was very time-consuming. With the HGMF-indole procedure E. coli was missed in 4 artificially contaminated samples. With the HGMF-FC-BCIG method E. coli was enumerated in 1 sample of bean sprouts missed by both the MPN and HGMF-indole procedures. High levels of indole-positive Klebsiella spp. in bean sprouts interfered with the HGMF-indole method, but the blue colonies of E. coli were easily observed in the HGMF-FC-BCIG method. Specificity of the HGMF-FC-BCIG method is high enough that routine confirmation should be unnecessary; however, confirmation of presumptive E. coli is easier since no lethal indole-staining step is involved. It appears to be a very simple method for quantifying E. coli in foods or carcass rinses.


[ANCA-associated vasculitis].
ANCA-associated vasculitis. The term "antineutrophil cytoplasm antibody (ANCA)- associated vasculitis" (AASV) ihighers generally used to include primary vasculitis syndromes in which circulating ANCA against proteinase 3 (PR3) and myeloperoxidase (MPO) are commonly found. AASV syndromes include Wegener's granulomatosis, microscopic polyangiitis, idiopathic pauci- immune necrotizing crescentic glomerulonephritis and Churg-Strauss syndrome (CSS). AASV syndromes share some general clinical-histological manifestations, such as rapidly progressive renal failure and focal necrotizing glomerulonephritis with extracapillary proliferation in the absence (or in the presence of modest) immunoglobulins deposits (pauci- immune). Untreated AASV follow a progressive course with a fatal outcome due to vital organ failure. The combination of cyclophosphamide and prednisone is now established as the treatment of choice for patients with AASV, but there is considerable debate over the duration of therapy and the best way to administer cyclophosphamide. Treatment of AASV can be divided into two phases: an induction of remission and a maintenance of remission phase. Patients with AASV and renal involvement (serum creatinine less than 500 ml/L or 5.6 mg/dl) should be treated with a combination of oral prednisone with gradual tapering and cyclophosphamide. Once remission is achieved, usually after 3-6 months, azathioprine should replace cyclophosphamide. It is not known for how long treatment should be continued but at least one year of treatment after remission is warranted. When serum creatinine is than 500 ml/L (5.6 mg/dl) and/or oliguria is present, the addition of methylprednisolone pulses and/or plasma exchange should be considered.


Chromosome aberrations induced in human lymphocytes after partial-body irradiation.
Chromosomal aberrations in peripheral blood lymphocytes obtained from two patients before and after they received one fraction of partial-body irradiation for palliative treatment were analyzed. Blood samples were taken 30 min and 24 h after radiation treatment. The yield of dicentrics obtained from case A 30 min after a partial-body (about 21%) treatment with 8 Gy was 0.066/cell, while the yield obtained 24 h after radiation treatment was 0.071/cell. The fraction of irradiated lymphocytes that reached metaphase at 52 h was 0.08 as evaluated by mixing cultures of in vitro irradiated and unirradiated blood. The yield of dicentrics for blood from case B 30 min after 6 Gy partial-body (about 24%) irradiation was 0.655/cell, while the yield 24 h after irradiation was 0.605/cell. The fraction of irradiated cells was 0.29. Estimation of doses and irradiated fractions for the two cases using the method proposed by Dolphin and the Qdr method is discussed. Although there was no significant difference between the mean yields of dicentrics per cell obtained 30 min and 24 h after radiation treatment, the data obtained at 24 h seemed more useful for the purpose of dose estimation. When a higher dose (8 Gy) was delivered to a smaller percentage of the body, underestimation of the dose was encountered.


High-energy x-ray nanotomography introducing an apodization Fresnel zone plate objective lens.
In this study, high-energy x-ray nanotomography (nano-computed tomography, nano-CT) based on full-field x-ray microscopy was developed. Fine two-dimensional and three-dimensional (3D) structures with linewidths of 75 nm-100 nm were successfully resolved in the x-ray energy range of 15 keV-37.7 keV. The effective field of view was ∼60 µm, and the typical measurement time for one tomographic scan was 30 min-60 min. The optical system was established at the 250-m-long beamline 20XU of SPring-8 to realize greater than 100× magnification images. An apodization Fresnel zone plate (A-FZP), specifically developed for high-energy x-ray imaging, was used as the objective lens. The design of the A-FZP for high-energy imaging is discussed, and its diffraction efficiency distribution is evaluated. The spatial resolutions of this system at energies of 15 keV, 20 keV, 30 keV, and 37.7 keV were examined using a test object, and the measured values are shown to be in good agreement with theoretical values. High-energy x-ray nano-CT in combination with x-ray micro-CT is applied for 3D multiscale imaging. The entire bodies of bulky samples, ∼1 mm in diameter, were measured with the micro-CT, and the nano-CT was used for nondestructive observation of regions of interest. Examples of multiscale CT measurements involving carbon steel, mouse bones, and a meteorite are discussed.


Effect of cholesterol depletion on the pore dilation of TRPV1.
The TRPV1 ion channel is expressed in nociceptors, where pharmacological modulation of its function may offer a means of alleviating pain and neurogenic inflammation processes in the human body. The aim of this study was to investigate the effects of cholesterol depletion of the cell on ion-permeability of the TRPV1 ion channel. The ion-permeability properties of TRPV1 were assessed using whole-cell patch-clamp and YO-PRO uptake rate studies on a Chinese hamster ovary (CHO) cell line expressing this ion channel. Prolonged capsaicin-induced activation of TRPV1 with N-methyl-D-glucamine (NMDG) as the sole extracellular cation, generated a biphasic current which included an initial outward current followed by an inward current. Similarly, prolonged proton-activation (pH 5.5) of TRPV1 under hypocalcemic conditions also generated a biphasic current including a fast initial current peak followed by a larger second one. Patch-clamp recordings of reversal potentials of TRPV1 revealed an increase of the ion-permeability for NMDG during prolonged activation of this ion channel under hypocalcemic conditions. Our findings show that cholesterol depletion inhibited both the second current, and the increase in ion-permeability of the TRPV1 channel, resulting from sustained agonist-activation with capsaicin and protons (pH 5.5). These results were confirmed with YO-PRO uptake rate studies using laser scanning confocal microscopy, where cholesterol depletion was found to decrease TRPV1 mediated uptake rates of YO-PRO. Hence, these results propose a novel mechanism by which cellular cholesterol depletion modulates the function of TRPV1, which may constitute a novel approach for treatment of neurogenic pain.


Performing cost-effectiveness analysis by integrating randomized trial data with a comprehensive decision model: application to treatment of acute ischemic stroke.
A recent national panel on cost-effectiveness in health and medicine has recommended that cost-effectiveness analysis (CEA) of randomized controlled trials (RCTs) should reflect the effect of treatments on long-term outcomes. Because the follow-up period of RCTs tends to be relatively short, long-term implications of treatments must be assessed using other sources. We used a comprehensive simulation model of the natural history of stroke to estimate long-term outcomes after a hypothetical RCT of an acute stroke treatment. The RCT generates estimates of short-term quality-adjusted survival and cost and also the pattern of disability at the conclusion of follow-up. The simulation model incorporates the effect of disability on long-term outcomes, thus supporting a comprehensive CEA. Treatments that produce relatively modest improvements in the pattern of outcomes after ischemic stroke are likely to be cost-effective. This conclusion was robust to modifying the assumptions underlying the analysis. More effective treatments in the acute phase immediately following stroke would generate significant public health benefits, even if these treatments have a high price and result in relatively small reductions in disability. Simulation-based modeling can provide the critical link between a treatment's short-term effects and its long-term implications and can thus support comprehensive CEA.


Human DNA polymerase alpha. Compensation for heat-labile mouse DNA polymerase alpha and its gene localization on the X chromosome.
The chromosomal location of human DNA polymerase alpha gene was determined by studies on somatic cell hybrids between a temperature-sensitive mutant cell line of mouse FM3A cells and normal human lymphocytes or a line of human diploid fibroblasts derived from a patient with the fragile X syndrome. A temperature-sensitive mutant, FT20-M6, a 6-thioguanine-resistant derivative of tsFT20, has heat-labile DNA polymerase alpha. Interspecific cell hybrids between FT20-M6 and human cells grew at the non-permissive temperature, indicating that some human chromosomes can compensate for the temperature-sensitive defect of tsFT20 in mouse-human cell hybrids. Three of these hybrid clones were examined further, and were shown to contain heat-stable DNA polymerase alpha that was neutralized with human DNA polymerase alpha-specific monoclonal antibody. Subcloning and segregation tests of these hybrid clones showed a positive correlation between the expression of human DNA polymerase alpha and the presence of the human X chromosome. Two subclones, however, did not conform to this relationship: they grew at the nonpermissive temperature but not in hypoxanthine/amethopterin/thymidine medium. Detailed examination of the human chromosomes in these subclones revealed that these clones had only one human chromosome, an X chromosome with a terminal deletion of the long arm including the locus of the gene for hypoxanthine phosphoribosyltransferase (EC 18.104.22.168). From these data, the functional DNA polymerase alpha gene was located on the human X chromosome.


Immunophilins and HIV-1 infection.
Peptides of the V3 loop of the HIV-1 envelope glycoprotein gp120 have been shown to bind with high affinity to the immunophilins cyclophilin (Cyp) A, CypB and the FK506-binding protein 12 (FKBP12) [10]. We investigated whether immunophilins affect HIV-1 infection by assuming they are able to bind to the V3 loop of gp120. T cells and peripheral blood mononuclear cells were infected with T-cell-tropic or macrophage-tropic HIV-1 strains, respectively, in the presence of different concentrations of immunophilins. P24 antigen ELISA and real-time PCR measurements demonstrated that exogenously added immunophilins do not influence HIV-1 infection. CypA is known to interact with the HIV-1 Gag polyprotein and to be incorporated into the virions. This incorporation can be prevented by cyclosporin A (CsA) resulting in a decreased yield of infectious virus, the mechanism of which is unknown. We measured a normal production of proviral DNA in the first round of infection in CsA treated cells but afterwards, infection was decreased if CsA was present. Pre-treatment of the HIV-1 inocula with CsA, blocking the function of virus-associated CypA, did not inhibit the ensuing yield of infection. We therefore may conclude that endogenous CypA exerts its action after reverse transcription but before virus maturation, probably during capsid formation. FK520, an immunosuppressor which binds to FKBP, had no effect on HIV-1 infection.


Tea4p links microtubule plus ends with the formin for3p in the establishment of cell polarity.
Microtubules regulate actin-based processes such as cell migration and cytokinesis, but molecular mechanisms are not understood. In the fission yeast Schizosaccharomyces pombe, microtubule plus ends regulate cell polarity in part by transporting the kelch repeat protein tea1p to cell ends. Here, we identify tea4p, a SH3 domain protein that binds directly to tea1p. Like tea1p, tea4p localizes to growing microtubule plus ends and to cortical sites at cell ends, and it is necessary for the establishment of bipolar growth. Tea4p binds directly to and recruits the formin for3p, which nucleates actin cable assembly. During "new end take off" (NETO), formation of a protein complex that includes tea1p, tea4p, and for3p is necessary and sufficient for the establishment of cell polarity and localized actin assembly at new cell ends. Our results suggest a molecular mechanism for how microtubule plus ends regulate the spatial distribution of actin assembly.


The eye of the beholder: inter-rater agreement among experts on psychogenic jerky movement disorders.
The current criteria for conversion disorder in the Diagnostic and Statistical Manual of Mental Disorders rely on the assumption that neurological disorders can be distinguished from conversion disorders through clinical assessment. This study aims to assess inter-rater agreement among clinicians with experience in the diagnosis of various hyperkinetic jerky movements, including psychogenic jerks. 60 patients with psychogenic jerks, myoclonus or tics were rated by international experts using a standardised survey resembling daily clinical practice. The survey included the following diagnostic steps: a short video offering a visual impression of the patients and their jerky movements, medical history, neurological examination (on video), additional investigations and the findings of a standardised psychiatric interview. The diagnosis and diagnostic certainty were scored after each step. After all clinical information was given, moderate inter-rater agreement was reached (κ=0.56±0.1) with absolute agreement (100%) of experts on the diagnosis in 12 (20%) patients and reasonable agreement (>75%) in 43 (72%) patients. Psychiatric evaluation did not contribute to inter-rater agreement or diagnostic certainty. Our findings illustrate the fact that experienced movement disorder specialists moderately agree on the clinical diagnosis of jerky movements. Clinical assessment, especially by a team of clinicians in challenging individual cases, might improve diagnostic agreement.


Complete life cycle of Myxobolus rotundus (Myxosporea: Myxobolidae), a gill myxozoan of common bream Abramis brama.
The life cycle of Myxobolus rotundus Nemeczek, 1911, a myxosporean parasite of the gills of common bream Abramis brama L., was studied under laboratory conditions. Mature Myxobolus spp. spores from plasmodia in the gills of wild bream were used to infect naïve oligochaete worms in a flow-through system of aquaria. Triactinomyxon-type actinospores were released from the oligochaetes 1 yr later and allowed to continually flow into a tank containing uninfected bream fry. The gills of the fry were checked for development of plasmodia in squash preparations 3 d postexposure, and then at weekly intervals for 8 wk. Tissue samples were fixed at each time point. Developing plasmodia were first observed 17 d post-exposure (Day 17). Mature spores were collected from plasmodia on Day 56 and were added to plastic dishes containing parasite-free Tubifex tubifex oligochaetes. Second-generation actinospores were released from these worms 8 mo post-exposure, and were morphologically identical to first-generation spores. Myxospores obtained from the bream fry were morphologically identical to those identified in wild bream as M. rotundus. Small subunit ribosomal RNA gene sequences obtained from first- and second-generation actinospores and the bream fry myxospores were 100% similar to M. rotundus spores from the original wild fish.


Genetic dissection of maize phenology using an intraspecific introgression library.
Collections of nearly isogenic lines where each line carries a delimited portion of a donor source genome into a common recipient genetic background are known as introgression libraries and have already shown to be instrumental for the dissection of quantitative traits. By means of marker-assisted backcrossing, we have produced an introgression library using the extremely early-flowering maize (Zea mays L.) variety Gaspé Flint and the elite line B73 as donor and recipient genotypes, respectively, and utilized this collection to investigate the genetic basis of flowering time and related traits of adaptive and agronomic importance in maize. The collection includes 75 lines with an average Gaspé Flint introgression length of 43.1 cM. The collection was evaluated for flowering time, internode length, number of ears, number of nodes (phytomeres), number of nodes above the ear, number and proportion of nodes below the ear and plant height. Five QTLs for flowering time were mapped, all corresponding to major QTLs for number of nodes. Three additional QTLs for number of nodes were mapped. Besides flowering time, the QTLs for number of nodes drove phenotypic variation for plant height and number of nodes below and above the top ear, but not for internode length. A number of apparently Mendelian-inherited phenotypes were also observed. While the inheritance of flowering time was dominated by the well-known QTL Vgt1, a number of other important flowering time QTLs were identified and, thanks to the type of plant material here utilized, immediately isogenized and made available for fine mapping. At each flowering time QTL, early flowering correlated with fewer vegetative phytomeres, indicating the latter as a key developmental strategy to adapt the maize crop from the original tropical environment to the northern border of the temperate zone (southern Canada), where Gaspé Flint was originally cultivated. Because of the trait differences between the two parental genotypes, this collection will serve as a permanent source of nearly isogenic materials for multiple studies of QTL analysis and cloning.


Optical path-length spectroscopy of incipient caries lesions in relation to quantitative light-induced fluorescence and lesion characteristics.
A basic understanding of the light-scattering processes that take place inside the dental tissue (either sound or carious) is obtained both with measurements of the photon path-length distribution of light inside such media and with Monte Carlo simulations. Furthermore, the following is investigated: the correlations between different momenta of the photon path-length distribution of light inside caries lesions, the fluorescence loss determined with quantitative light-induced fluorescence, and/or the demineralization and depth of caries lesions determined with transversal microradiography. It is concluded that (i) the light paths inside both carious and sound enamel are considerably influenced by the refractive-index contrast at the tooth surface; (ii) contrary to a previous hypothesis, the fluorescence loss is larger in lesions in which the average photon path length is longer; (iii) very good correlations are obtained between the optical characteristics and the physical parameters of lesions when the optical measurements are performed such that there is high refractive contrast at the tooth surface.


Bioavailability, antipsoriatic efficacy and tolerability of a new light cream with mometasone furoate 0.1%.
Mometasone furoate, a potent glucocorticoid (class III) with a favorable benefit/risk ratio, has emerged as a standard medication for the treatment of inflammatory skin disorders. The purpose of the investigation presented here was to determine the noninferiority of a topical mometasone formulation, a light cream (O/W 60/40 emulsion) with mometasone furoate 0.1% (water content of 33%) versus marketed comparators. Using the vasoconstrictor assay, a strong blanching effect of the new cream (called Mometasone cream) comparable to that of a mometasone comparator, a fatty cream with mometasone furoate 0.1%, could be demonstrated. Thus, the topical bioavailability of the active ingredient mometasone furoate (0.1%) was regarded to be similar for Mometasone cream and the mometasone comparator. Using the psoriasis plaque test, a strong antipsoriatic effect comparable to that of the mometasone comparator was found for Mometasone cream after 12 days of occlusive treatment. A nearly identical reduction in the mean infiltrate thickness and similar mean AUC values were noted with both formulations confirmed by clinical assessment data. The noninferiority of Mometasone cream to its active comparator with respect to the AUC of change to baseline in infiltrate thickness was demonstrated. Both medications were well tolerated. Overall, Mometasone cream and the mometasone comparator showed similar efficacy and tolerability. Mometasone cream, in addition to its high potency and good tolerability, provides the properties of a light cream, which might make this new medication particularly suitable for application on acutely inflamed and sensitive skin.


Cost-effectiveness of genotypic antiretroviral resistance testing in HIV-infected patients with treatment failure.
Genotypic antiretroviral resistance testing (GRT) in HIV infection with drug resistant virus is recommended to optimize antiretroviral therapy, in particular in patients with virological failure. We estimated the clinical effect, cost and cost-effectiveness of using GRT as compared to expert opinion in patients with antiretroviral treatment failure. We developed a mathematical model of HIV disease to describe disease progression in HIV-infected patients with treatment failure and compared the incremental impact of GRT versus expert opinion to guide antiretroviral therapy. The analysis was conducted from the health care (discount rate 4%) and societal (discount rate 2%) perspective. Outcome measures included life-expectancy, quality-adjusted life-expectancy, health care costs, productivity costs and cost-effectiveness in US Dollars per quality-adjusted life-year (QALY) gained. Clinical and economic data were extracted from the large Swiss HIV Cohort Study and clinical trials. Patients whose treatment was optimized with GRT versus expert opinion had an increase in discounted life-expectancy and quality-adjusted life-expectancy of three and two weeks, respectively. Health care costs with and without GRT were $US 421,000 and $US 419,000, leading to an incremental cost-effectiveness ratio of $US 35,000 per QALY gained. In the analysis from the societal perspective, GRT versus expert opinion led to an increase in discounted life-expectancy and quality-adjusted life-expectancy of three and four weeks, respectively. Health care costs with and without GRT were $US 551,000 and $US 549,000, respectively. When productivity changes were included in the analysis, GRT was cost-saving. GRT for treatment optimization in HIV-infected patients with treatment failure is a cost-effective use of scarce health care resources and beneficial to the society at large.


Barriers and facilitators to antenatal and delivery care in western Kenya: a qualitative study.
In western Kenya, maternal mortality is a major public health problem estimated at 730/100,000 live births, higher than the Kenyan national average of 488/100,000 women. Many women do not attend antenatal care (ANC) in the first trimester, half do not receive 4 ANC visits. A high proportion use traditional birth attendants (TBA) for delivery and 1 in five deliver unassisted. The present study was carried out to ascertain why women do not fully utilise health facility ANC and delivery services. A qualitative study using 8 focus group discussions each consisting of 8-10 women, aged 15-49 years. Thematic analysis identified the main barriers and facilitators to health facility based ANC and delivery. Attending health facility for ANC was viewed positively. Three elements of care were important; testing for disease including HIV, checking the position of the foetus, and receiving injections and / or medications. Receiving a bed net and obtaining a registration card were also valuable. Four barriers to attending a health facility for ANC were evident; attitudes of clinic staff, long clinic waiting times, HIV testing and cost, although not all women felt the cost was prohibitive being worth it for the health of the child. Most women preferred to deliver in a health facility due to better management of complications. However cost was a barrier, and a reason to visit a TBA because of flexible payment. Other barriers were unpredictable labour and transport, staff attitudes and husbands' preference. Our findings suggest that women in western Kenya are amenable to ANC and would be willing and even prefer to deliver in a healthcare facility, if it were affordable and accessible to them. However for this to happen there needs to be investment in health promotion, and transport, as well as reducing or removing all fees associated with antenatal and delivery care. Yet creating demand for service will need to go alongside investment in antenatal services at organisational, staffing and facility level in order to meet both current and future increase in demand.


Correlation of Superior Canal Dehiscence Surface Area With Vestibular Evoked Myogenic Potentials, Audiometric Thresholds, and Dizziness Handicap.
To correlate objective measures of vestibular and audiometric function as well as subjective measures of dizziness handicap with the surface area of the superior canal dehiscence (SCD). Retrospective chart review and radiological analysis. Single tertiary academic referral center. Preoperative computed tomography imaging, patient survey, audiometric thresholds, and vestibular evoked myogenic potential (VEMP) testing in patients with confirmed SCD. Image analysis techniques were developed to measure the surface area of each SCD in computed tomography imaging. Preoperative ocular and cervical VEMPs, air and bone conduction thresholds, air-bone gap, dizziness handicap inventory scores, and surface area of the SCD. Fifty-three patients (mean age 52.7 yr) with 84 SCD were analyzed. The median surface area of dehiscence was 1.44 mm (0.068-8.23 mm). Ocular VEMP amplitudes (r = 0.61, p <0.0001), cervical VEMP amplitudes (r = 0.62, p <0.0001), air conduction thresholds at 250 Hz (r = 0.25, p = 0.043), and air-bone gap at 500 Hz (r = 0.27, p = 0.01) positively correlated with increasing size of dehiscence. An inverse relationship between cervical VEMP thresholds (r = -0.56, p < 0.0001) and surface area of the dehiscence was observed. No association between dizziness handicap and surface area was identified. Among patients with confirmed SCD, ocular and cervical VEMP amplitudes, cervical VEMP thresholds, and air conduction thresholds at 250 Hz are significantly correlated with the surface area of the dehiscence.


The double-time protein kinase regulates the subcellular localization of the Drosophila clock protein period.
The Period (PER), Timeless (TIM), and Double-Time (DBT) proteins are essential components of one feedback loop in the Drosophila circadian molecular clock. PER and TIM physically interact. Coexpression of PER and TIM promotes their nuclear accumulation and influences the activity of DBT: although DBT phosphorylates and destabilizes PER, this is suppressed by TIM. Experiments using Drosophila cells in culture have indicated that PER can translocate to the nucleus without TIM and will repress transcription in a DBT-potentiated manner. In this study, we examined the control of PER subcellular localization in Drosophila clock cells in vivo. We found that PER can translocate to the nucleus in tim(01) null mutants but only if DBT kinase activity is inhibited. We also found that nuclear PER is a potent transcriptional repressor in dbt mutants in vivo without TIM. Thus, in vivo, DBT regulates PER subcellular localization, in addition to its previously documented role as a mediator of PER stability. However, DBT does not seem essential for transcriptional repression by PER. It was reported previously that overexpression of a second kinase, Shaggy (SGG)/Glycogen Synthase Kinase 3, accelerates PER nuclear accumulation. Here, we show that these effects of SGG on PER nuclear accumulation require TIM. We propose a revised clock model that incorporates this tight kinase regulation of PER and TIM nuclear entry.


Adaptive intertidal seed-based seagrass restoration in the Dutch Wadden Sea.
Seagrasses form the foundation of many coastal ecosystems but are rapidly declining on a global scale. The Dutch Wadden Sea once supported extensive subtidal seagrass meadows that have all disappeared. Here, we report on the setbacks and successes of intertidal seed-based restoration experiments in the Dutch Wadden Sea between 2014-2017. Our main goals were to 1) optimize plant densities, and 2) reduce seed losses. To achieve our goals, we conducted research-based, adaptive seagrass (Zostera marina) restoration, adjusting methods yearly based on previous results. We applied various seeding methods in three subsequent years-from Buoy Deployed Seeding (BuDS), and 'BuDS-in-frame' in fall, to a newly developed 'Dispenser Injection Seeding' (DIS) method. Our adaptive experimental approach revealed high seed losses between seeding and seedling establishment of the BuDS methods (>99.9%), which we mitigated by controlled harvest and storage of seeds throughout fall and winter, followed by DIS-seeding in spring. These iterative innovations resulted in 83 times higher plant densities in the field (0.012 to 1.00 plants m-2) and a small reduction in seed loss (99.94 to 99.75%) between 2015-2017. Although these developments have not yet resulted in self-sustaining seagrass populations, we are one step closer towards upscaling seagrass restoration in the Dutch Wadden Sea. Our outcomes suggest that an iterative, research-based restoration approach that focuses on technological advancement of precision-seeding may result in advancing knowledge and improved seed-based seagrass restoration successes.


Periodically Arranged Arrays of Dendritic Pt Nanospheres Using Cage-Type Mesoporous Silica as a Hard Template.
Dendritic Pt nanospheres of 20 nm diameter are synthesized by using a highly concentrated surfactant assembly within the large-sized cage-type mesopores of mesoporous silica (LP-FDU-12). After diluting the surfactant solution with ethanol, the lower viscosity leads to an improved penetration inside the mesopores. After Pt deposition followed by template removal, the arrangement of the Pt nanospheres is a replication from that of the mesopores in the original LP-FDU-12 template. Although it is well known that ordered LLCs can form on flat substrates, the confined space inside the mesopores hinders surfactant self-organization. Therefore, the Pt nanospheres possess a dendritic porous structure over the entire area. The distortion observed in some nanospheres is attributed to the close proximity existing between neighboring cage-type mesopores. This new type of nanoporous metal with a hierarchical architecture holds potential to enhance substance diffusivity/accessibility for further improvement of catalytic activity.


Plasma Extracellular Vesicle α-Synuclein Level in Patients with Parkinson's Disease.
The most established pathognomonic protein of Parkinson's disease (PD), α-synuclein, is extensively investigated for disease diagnosis and prognosis; however, investigations into whether the free form of α-synuclein in the blood functions as a PD biomarker have not been fruitful. Extracellular vesicles (EVs) secreted from cells and present in blood transport molecules are novel platforms for biomarker identification. In blood EVs, α-synuclein originates predominantly from the brain without the interference of the blood-brain barrier. The present study investigated the role of plasma EV-borne α-synuclein as a biomarker of PD. Patients with mild to moderate stages of PD (n = 116) and individuals without PD (n = 46) were recruited to serve as the PD study group and the control group, respectively. Plasma EVs were isolated, and immunomagnetic reduction-based immunoassay was used to assess EV α-synuclein levels. Conventional statistical analysis was performed using SPSS 25.0, and p < 0.05 was considered significant. Compared with controls, we observed significantly lower plasma EV α-synuclein levels in the patients with PD (PD: 56.0 ± 3.7 fg/mL vs. control: 74.5 ± 4.3 fg/mL, p = 0.009), and the significance remained after adjustment for age and sex. Plasma EV α-synuclein levels in the patients with PD did not correlate with age, disease duration, Part I and II scores of the Unified Parkinson's Disease Rating Scale (UPDRS), or the Mini-Mental State Examination scores. However, such levels were significantly correlated with UPDRS Part III score, which assesses motor dysfunction. Furthermore, the severity of akinetic-rigidity symptoms, but not tremor, was inversely associated with plasma EV α-synuclein level. Plasma EV α-synuclein was significantly different between the control and PD group and was associated with akinetic-rigidity symptom severity in patients with PD. This study corroborates the possible diagnostic and subtyping roles of plasma EV α-synuclein in patients with PD, and it further provides a basis for this protein's clinical relevance and feasibility as a PD biomarker.


Promise and performance of agricultural nutrient management policy: Lessons from the Baltic Sea.
Following decades of international collaboration to restore the Baltic Sea, we provide an assessment of the domestic implementation of measures agreed to limit diffuse agricultural pollution and the patterns of policy instruments applied. Despite the Helsinki Convention being unusually specific in detailing what measures countries should introduce, we find many shortcomings. These are most pronounced in the larger countries (Poland, Germany and Russia), while smaller countries perform better, notably Sweden and Estonia. The patterns of policy instruments applied differ, influenced by domestic politics. The limited use of complementary policy instruments suggests that other priorities overrule full and effective implementation, with engagement mirroring the advantages that a restored Baltic Sea can bring to countries. Using the European Agricultural Fund for Rural Development to support farmers in managing nutrients, particularly advisory services and investments in modern manure management technologies, represents a significant opportunity for reducing agricultural pollution in most countries.


Pseudomonas fluorescens bacteremia from blood transfusion.
In October 1980, two units of blood contaminated with Pseudomonas fluorescens caused septic transfusion reactions in two recipients at a Chicago hospital; one patient died. Both units had been purchased from the same blood center. Investigation at the blood center and at other hospitals it supplied revealed another fatal case of P. fluorescens sepsis that had occurred one year earlier. Despite extensive environmental culturing at the blood center, the source of P. fluorescens was not identified. However, comparison of the interval between collection and administration of contaminated and non-contaminated units indicated that prolonged storage was a risk factor that may have caused clustering of cases in one hospital. Laboratory studies showed that small inocula of P. fluorescens proliferated in refrigerated fresh whole blood and reached 10(6) to 10(7) colony-forming units per milliliter seven days after incubation. These data suggest that prolonged storage of blood may be an important risk factor for the development of transfusion-related sepsis.


The autonomous axon: a model based on local synthesis of proteins.
In the current understanding of axons, axoplasmic synthesis of proteins is negated, and it is asserted that proteins are transported from perikarya to axons. This 'transport model' in which axons are fully dependent of perikarya is seriously flawed. The 'autonomous axon' proposed here negates in turn transport of proteins, and asserts (i) local synthesis of axoplasmic proteins, corner stone of this model, (ii) existence of internal programs in axon and terminals, (iii) external control of programs resulting in local regulation of phenotype of axons and terminals, hence they are autonomous from perikarya; (iv) participation of perikarya through the fast transport in setting up the axonal programs but not in their immediate regulation. The word merotrophism (meros meaning part) denotes post-transcriptional regulation of phenotype of restricted regions of a cell. We surmise that merotrophism is at the base of many plastic phenomena.


Predicting species distribution: offering more than simple habitat models.
In the last two decades, interest in species distribution models (SDMs) of plants and animals has grown dramatically. Recent advances in SDMs allow us to potentially forecast anthropogenic effects on patterns of biodiversity at different spatial scales. However, some limitations still preclude the use of SDMs in many theoretical and practical applications. Here, we provide an overview of recent advances in this field, discuss the ecological principles and assumptions underpinning SDMs, and highlight critical limitations and decisions inherent in the construction and evaluation of SDMs. Particular emphasis is given to the use of SDMs for the assessment of climate change impacts and conservation management issues. We suggest new avenues for incorporating species migration, population dynamics, biotic interactions and community ecology into SDMs at multiple spatial scales. Addressing all these issues requires a better integration of SDMs with ecological theory.


Likelihood of missed and recurrent adenomas in the proximal versus the distal colon.
Colonoscopy may be less efficacious in reducing colorectal cancer mortality in the proximal compared with the distal colon. A greater likelihood for missed and recurrent adenomas in the proximal colon may contribute to this phenomenon. To examine whether a proximal adenoma is associated with the risk and location of missed and recurrent adenomas. Prospective. Polyp Prevention Trial. A total of 1864 patients with an adenoma at baseline underwent a follow-up colonoscopy 4 years later (adenoma recurrence). Of these, 1731 underwent a clearing colonoscopy 1 year after the baseline examination (missed adenoma). Association of baseline adenoma location with the risk and location of adenomas found at colonoscopy performed 1 year and 4 years later. At the year 1 colonoscopy, 598 patients (34.6%) had an adenoma (missed adenoma). Compared with those with a distal-only adenoma at baseline, patients with a proximal-only adenoma at baseline were more likely to have any missed adenomas (relative risk [RR] 1.28; 95% CI, 1.09-1.49) and a proximal-only missed adenoma (RR 2.05; 95% CI, 1.49-2.80). At the year 4 colonoscopy, 733 patients (39.3%) had adenoma recurrence. Patients with a baseline proximal-only adenoma were more likely to have any adenoma recurrence (RR 1.14; 95% CI, 1.00-1.31) and a proximal-only adenoma recurrence (RR 1.52; 95% CI, 1.15-2.02). Sensitivity analyses involving missed adenomas did not materially affect the risk or location of recurrent adenomas at year 4 colonoscopy. Lesions may still be missed on repeated colonoscopies. Missed and recurrent adenomas are more likely to be in the proximal colon.


Limb Position Change Affects Tourniquet Pressure.
Limb position changes are likely during transport from injury location to definitive care. This study investigated passive limb position change effects on tourniquet pressure and occlusion. Triplicate buddy-applied OMNA® Marine Tourniquet applications to Doppler-based occlusion were done to sitting and laying supine mid-thigh (n=5) and sitting mid-arm (n=3). Tourniqueted limb positions were bent/straight/bent and straight/bent/straight (randomized first position order, 5 seconds/position, pressure every 0.1 second, two-way repeated measures ANOVA). Sitting thigh occlusion pressures leg bent were higher than straight (median, minimum-maximum; 328, 307-403mmHg versus 312, 295-387mmHg, p = .013). In each recipient, the pressure change for each position change for each limb had p < .003. In each recipient, when sitting, leg bent to straight increased pressure (326, 276-415mmHg to 371, 308-427mmHg bent first and 275, 233-354mmHg to 311, 241-353mmHg straight first), and straight to bent decreased pressure (371, 308-427mmHg to 301, 262-388mmHg bent first and 312, 265-395mmHg to 275, 233-354mmHg straight first). When laying, position changes from leg bent first resulted in pressure changes in each recipient but not in the same directions in each recipient. From laying leg straight first, in each recipient changing to bent increased the pressure (295, 210-366mmHg to 328, 255-376mmHg) and to straight decreased the pressure (328, 255-376 mmHg to 259, 210-333 mmHg). Sitting arm bent occlusion pressures were lower than straight (230, 228-252mmHg versus 256, 250-287mmHg, p = .026). Arm position changes resulted in pressure changes in each recipient but not in the same directions in each recipient. Changes in pressure trace character (presence or absence of rhythmically pulsatile traces) and Doppler-based occlusion were consistent with limb position-induced changes in tourniquet pressure (each p ≤ .001 leg, p = .071 arm traces, and p = .188 arm occlusion). Passive limb position changes can cause significant changes in tourniquet pressure. Therefore, tourniquet adequacy should be reassessed after any limb position change.


A novel scoring system as a preoperative predictor for pain-free survival after microsurgery for trigeminal neuralgia.
OBJECTIVEPain relief following microvascular decompression (MVD) for trigeminal neuralgia (TN) may be related to pain type, degree of neurovascular conflict, arterial compression, and location of compression. The objective of this study was to construct a predictive pain-free scoring system based on clinical and radiographic factors that can be used to preoperatively prognosticate long-term outcomes for TN patients following surgical intervention (MVD or internal neurolysis [IN]). It was hypothesized that contributing factors would include pain type, presence of an artery or vein, neurovascular conflict severity, and compression location (root entry zone).METHODSAt the authors' institution 275 patients with type 1 or type 2 TN (TN1 or TN2) underwent MVD or IN following preoperative high-resolution brain MRI studies. Outcome data were obtained retrospectively by chart review and/or phone follow-up. Characteristics of neurovascular conflict were obtained from preoperative MRI studies. Factors that resulted in a probability value of < 0.05 on univariate logistic regression analyses were entered into a multivariate Cox regression analysis in a backward stepwise fashion. For the multivariate analysis, significance at the 0.15 level was used. A prognostic system was then devised with 4 possible scores (0, 1, 2, or 3) and pain-free survival analyses conducted.RESULTSUnivariate predictors of pain-free survival were pain type (p = 0.013), presence of any vessel (p = 0.042), and neurovascular compression severity (p = 0.038). Scores of 0, 1, 2, and 3 were found to be significantly different in regard to pain-free survival (log rank, p = 0.005). At 5 and 10 years there were 36%, 43%, 61%, and 69%, and 36%, 43%, 56%, and 67% pain-free survival rates in groups 0, 1, 2, and 3, respectively. While TN2 patients had worse outcomes regardless of score, a subgroup analysis of TN1 patients with higher neurovascular conflict (score of 3) had significantly better outcomes than TN1 patients without severe neurovascular conflict (score of 1) (log rank, p = 0.005). Regardless of pain type, those patients with severe neurovascular conflict were more likely to have arterial compression (99%) compared to those with low neurovascular conflict (p < 0.001).CONCLUSIONSPain-free survival was predicted by a scoring system based on preoperative clinical and radiographic findings. Higher scores predicted significantly better pain relief than lower scores. TN1 patients with severe neurovascular conflict had the best long-term pain-free outcome.


Human gut Bacteroidetes can utilize yeast mannan through a selfish mechanism.
Yeasts, which have been a component of the human diet for at least 7,000 years, possess an elaborate cell wall α-mannan. The influence of yeast mannan on the ecology of the human microbiota is unknown. Here we show that yeast α-mannan is a viable food source for the Gram-negative bacterium Bacteroides thetaiotaomicron, a dominant member of the microbiota. Detailed biochemical analysis and targeted gene disruption studies support a model whereby limited cleavage of α-mannan on the surface generates large oligosaccharides that are subsequently depolymerized to mannose by the action of periplasmic enzymes. Co-culturing studies showed that metabolism of yeast mannan by B. thetaiotaomicron presents a 'selfish' model for the catabolism of this difficult to breakdown polysaccharide. Genomic comparison with B. thetaiotaomicron in conjunction with cell culture studies show that a cohort of highly successful members of the microbiota has evolved to consume sterically-restricted yeast glycans, an adaptation that may reflect the incorporation of eukaryotic microorganisms into the human diet.


Chaotic itinerancy within the coupled dynamics between a physical body and neural oscillator networks.
Chaotic itinerancy is a phenomenon in which the state of a nonlinear dynamical system spontaneously explores and attracts certain states in a state space. From this perspective, the diverse behavior of animals and its spontaneous transitions lead to a complex coupled dynamical system, including a physical body and a brain. Herein, a series of simulations using different types of non-linear oscillator networks (i.e., regular, small-world, scale-free, random) with a musculoskeletal model (i.e., a snake-like robot) as a physical body are conducted to understand how the chaotic itinerancy of bodily behavior emerges from the coupled dynamics between the body and the brain. A behavior analysis (behavior clustering) and network analysis for the classified behavior are then applied. The former consists of feature vector extraction from the motions and classification of the movement patterns that emerged from the coupled dynamics. The network structures behind the classified movement patterns are revealed by estimating the "information networks" different from the given non-linear oscillator networks based on the transfer entropy which finds the information flow among neurons. The experimental results show that: (1) the number of movement patterns and their duration depend on the sensor ratio to control the balance of strength between the body and the brain dynamics and on the type of the given non-linear oscillator networks; and (2) two kinds of information networks are found behind two kinds movement patterns with different durations by utilizing the complex network measures, clustering coefficient and the shortest path length with a negative and a positive relationship with the duration periods of movement patterns. The current results seem promising for a future extension of the method to a more complicated body and environment. Several requirements are also discussed.


The (re)-introduction of semiotics into medical education: on the works of Thure von Uexküll.
Thure von Uexküll's reputation as a pioneer in biosemiotics and also in psychosomatic medicine is well documented. It is easy to see these disciplines reflected in his notable publications, both in English and in German. However, if one spares the time to filter through all of his articles, monographs, conference papers and editorials in English and in German, a notable gap arises in his English language publications: that of clinical education. This gap in the English language literature may seem unimportant in and of itself, but it speaks volumes when we consider the total absence of medical semiotics in the curriculum of medical schools in the English speaking world. This runs in stark contrast to the strong traditions of psychosomatic medicine in Germany, which Thure von Uexküll largely helped to instil. Do the works of Thure von Uexküll offer a possible step towards a resurrection of medical semiotics in clinical education? This chapter attempts to explore the lesser known German literature on clinical education that Thure von Uexküll produced, and explore the role semiotics can play in Medical Education in the English speaking world. While also seeking to contrast this literature with other existing approaches in British and American medical schools who have attempted to reintroduce medical humanities and reflexive thinking into clinical education.


Decision processes in temporal discrimination.
The processing dynamics underlying temporal decisions and the response times they generate have received little attention in the study of interval timing. In contrast, models of other simple forms of decision making have been extensively investigated using response times, leading to a substantial disconnect between temporal and non-temporal decision theories. An overarching decision-theoretic framework that encompasses existing, non-temporal decision models may, however, account both for interval timing itself and for time-based decision-making. We sought evidence for this framework in the temporal discrimination performance of humans tested on the temporal bisection task. In this task, participants retrospectively categorized experienced stimulus durations as short or long based on their perceived similarity to two, remembered reference durations and were rewarded only for correct categorization of these references. Our analysis of choice proportions and response times suggests that a two-stage, sequential diffusion process, parameterized to maximize earned rewards, can account for salient patterns of bisection performance. The first diffusion stage times intervals by accumulating an endogenously noisy clock signal; the second stage makes decisions about the first-stage temporal representation by accumulating first-stage evidence corrupted by endogenous noise. Reward-maximization requires that the second-stage accumulation rate and starting point be based on the state of the first-stage timer at the end of the stimulus duration, and that estimates of non-decision-related delays should decrease as a function of stimulus duration. Results are in accord with these predictions and thus support an extension of the drift-diffusion model of static decision making to the domain of interval timing and temporal decisions.


Development of rotational movements, hand shaping, and accuracy in advance and withdrawal for the reach-to-eat movement in human infants aged 6-12 months.
The reach-to-eat movement, transport of a hand to grasp an object that is withdrawn and placed in the mouth, is amongst the earliest developing functional movements of human infants. The present longitudinal study is the first description of the maturation of hand-rotation, hand shaping, and accuracy associated with the advance and withdrawal phases of the movement. Eight infants, aged 6-12 months, and eight adults, were video recorded as they reached for familiar objects or food items. Hand, arm, and trunk movements were assessed frame-by-frame with the Skilled Reaching Rating Scale, previously developed for the assessment of adult reaching, and supplementary kinematic analysis. Reach-to-eat maturation was characterized by three changes. First, for advance, a simple open hand transport gradually matured to a movement associated with pronation and hand shaping of the digits for precision grasping. Second, for withdrawal to the mouth, a direct withdrawal movement gradually became associated with hand supination that oriented the target object to the mouth. Third, associated with the maturation of rotational movements, inaccurate and fragmented hand transport and withdrawal movements developed into precise targeting of the hand-to-object and object-to-mouth. Across the age range, there was a decrease in bimanual reaching and an increase in right handed reaching. The results are discussed in relation to the idea that the maturation of the reach-to-eat movement involves the development of rotational and shaping movements of the hand and visual and somatosensory guidance of a preferred hand.


Systematic Review and Meta-Analysis of Hard Tissue Outcomes of Alveolar Ridge Preservation.
Alveolar ridge preservation procedures have been advocated to minimize postextraction dimensional loss. There is a need for systematic analyses of clinical factors affecting the outcomes of these procedures in order to improve their clinical outcomes. This systematic review and meta-analysis aimed to assess the efficacy of alveolar ridge preservation procedures in terms of hard tissue dimensional changes and to determine clinical factors affecting outcomes of these procedures. Studies comparing alveolar ridge preservation procedures with tooth extraction alone that reported quantitative outcomes for hard tissue dimensional changes were included. The primary outcome variable was horizontal dimensional changes of alveolar bone. Subgroup analyses evaluated effects of wound closure, flap elevation, type of grafting materials, use of barrier membranes, use of growth factors, socket morphology, and the position of teeth on outcomes of alveolar ridge preservation procedures. Twenty-one studies were included, and quantitative analyses were performed for seven outcome variables. Significant differences between alveolar ridge preservation and control sites were found for six outcome variables, all favoring alveolar ridge preservation procedures. The magnitude of effect for the primary outcome variable (horizontal dimensional changes of alveolar bone) was 1.86 mm (95% CI = 1.44, 2.28; P < .001). This magnitude of effect for the primary variable (as determined by subgroup analysis) was also significantly affected by type of wound closure (P = .033), type of grafting materials (P = .001), use of barrier membranes (P = .006), use of growth factors (P = .003), and socket morphology (P < .001). Alveolar ridge preservation procedures are effective in minimizing postextraction hard tissue dimensional loss. The outcomes of these procedures are affected by morphology of extraction sockets, type of wound closure, type of grafting materials, use of barrier membranes, and use of growth factors.


Mitochondrial biology: From molecules to diseases.
As an integral part of the cell, mitochondria play a pivotal role in the regulation of energy metabolism, signaling pathways, cell differentiation, cell proliferation and cell death. Mitochondrion with its own genetic material has characteristics distinct from those of the nuclear counterpart and its dysregulation is associated with a myriad of diseases. The discovery of interplay between the nuclear and mitochondrial genes, and various post-transcriptional modifications associated with their products has added excitement in the field. This has led to a better understanding of the basic mitochondrial function in normal and disease states, and is important for diagnosis and prognosis of a large number of disorders. The Fourth Annual Conference of Society for Mitochondrial Research and Medicine - India (SMRM) was titled "Mitochondrial Biology: from Molecules to Disease". The conference was organized by K. Satyamoorthy and K. Thangaraj at School of Life Sciences, Manipal University, Manipal, India, during 8-9 December, 2014. The aim of the conference was to bring researchers and clinicians to a common platform; create an opportunity for networking between laboratories; and to discuss about the recent development in mitochondrial biology, diagnosis, and therapy. This review summarizes the key outcomes of the conference.


Effects of hypercarbic acidotic reperfusion on recovery of myocardial function after cardioplegic ischemia in neonatal lambs.
There is continued controversy over the management of pH during ischemia and reperfusion. Calcium overload is an integral feature of the injury resulting from ischemia and reperfusion, and hydrogen ions are known to blunt Ca2+ influx into cells because H+ inhibits the Na(+)-Ca2+ exchange and the slow calcium channels. Hypercarbia is one source of H+, but elevated CO2 level is also known to be a potent coronary vasodilator, which may be beneficial during early reperfusion. This study was designed to explore the effect of respiratory and metabolic acidosis during the initial phases of reperfusion after hypothermic cardioplegic ischemia in the neonatal lamb. Forty isolated, blood-perfused neonatal lamb hearts underwent 2 hours of cold cardioplegic ischemia followed by reperfusion with blood with various pH values. pH was controlled either by altering the FICO2 in the ventilating gas to the oxygenator (groups A through D) or by adding HCl to the reperfusate (group E). pH of the initial reperfusate was 6.8 in group A, 7.1 in group B, 7.5 in group C, and 7.8 in group D. In these groups, pH values were maintained for the initial 5 minutes of reperfusion and then corrected to 7.4 over 20 minutes by changing the FICO2 to the oxygenator. In group E, HCl was added to the reperfusate to give pH 6.8 (metabolic acidosis). pH was corrected after 5 minutes of reperfusion by administration of NaHCO3 and THAM over the next 15 minutes. At 30 and 60 minutes of reperfusion, left ventricular maximum developed pressure, dP/dt, -dP/dt, maximum developed pressure at V10 (volume that gave left ventricular end-diastolic pressure of 10 mm Hg during baseline measurements), and dP/dt at V10 were measured. Coronary blood flow and oxygen consumption (MVO2) were also measured to evaluate the metabolic recovery. Group A showed better functional recovery than groups B, C, or D (maximum dP/dt V10: group A, 88.3 +/- 7.7%; group B, 69.3 +/- 10.8%; group C, 74.6 +/- 10.3%; group D, 66.1 +/- 9.4%; and group E, 73.7 +/- 13.8% at 30 minutes [P < .05]; group A, 76.1 +/- 13.6%; group B, 61.9 +/- 8.6%; group C, 63.8 +/- 5.4%; group D, 57.9 +/- 9.4%; and group E, 62.6 +/- 12.7% at 60 minutes [P < .05]). Coronary blood flow was higher in group A than in other groups (A, 177.2 +/- 29.6%; B, 144.1 +/- 18.1%; C, 127.3 +/- 18.5%; D, 150.4 +/- 24.3%; and E, 106.0 +/- 20.0% [P < .05]). There were no significant differences in MVO2. These data indicate that hypercarbic reperfusion (pH 6.8) for a short period after ischemia improved functional recovery after cold cardioplegic ischemia in neonatal lamb hearts but that metabolic acidosis to an equivalent pH did not improve postischemic function. Possible mechanisms for this effect include reduction of calcium loading to the myocardium through H+ inhibition of calcium uptake or the induction of coronary vasodilation by hypercarbia.


SHBG gene polymorphism (rs1799941) associates with metabolic syndrome in children and adolescents.
Metabolic syndrome (MetS) is a complex disorder characterized by coexistence of several cardiometabolic (CM) factors, i.e. hyperlipidemia, obesity, high blood pressure and insulin resistance. The presence of MetS is strongly associated with increased risk of cardiovascular disease (CVD). The syndrome was originally defined as an adult disorder, but MetS has become increasingly recognized in children and adolescents. Genetic variants influence biological components common to the CM factors that comprise MetS. We investigated single locus associations between six single nucleotide polymorphisms (SNPs), previously shown to modulate lipid or sex hormone binding globulin (SHBG) levels, with MetS in a Turkish pediatric cohort (37 cases, 323 controls). Logistic regression analysis revealed a significant association between rs1799941, located in SHBG, and MetS (OR = 3.09, p-value = 0.006). The association with MetS remained after sequential adjustment for each CM factor included in the syndrome definition, indicating that the identified association is not being driven by any single trait. A relationship between rs1799941 and SHBG levels, was also discovered, but it was dependent on MetS status. In control subjects, the A allele of rs1799941 associated with a significant increase in SHBG levels (p = 0.012), while in cases there was no association between rs1799941 and SHBG levels (p = 0.963). The significant association between rs1799941 and MetS in children is not contingent on any single CM trait. Additionally, the presence of MetS may abrogate effect of rs1799941 polymorphism on SHBG levels in children.


The evolution of prefrontal inputs to the cortico-pontine system: diffusion imaging evidence from Macaque monkeys and humans.
The cortico-ponto-cerebellar system is one of the largest projection systems in the primate brain, but in the human brain the nature of the information processing in this system remains elusive. Determining the areas of the cerebral cortex which contribute projections to this system will allow us to better understand information processing within it. Information from the cerebral cortex is conveyed to the cerebellum by topographically arranged fibres in the cerebral peduncle - an important fibre system in which all cortical outputs spatially converge on their way to the cerebellum via the pontine nuclei. Little is known of their anatomical organization in the human brain. New in vivo diffusion imaging and probabilistic tractography methods now offer a way in which input tracts in the cerebral peduncle can be characterized in detail. Here we use these methods to contrast their organization in humans and macaque monkeys. We confirm the dominant contribution of the cortical motor areas to the macaque monkey cerebral peduncle. However, we also present novel anatomical evidence for a relatively large prefrontal contribution to the human cortico-ponto-cerebellar system in the cerebral peduncle. These findings suggest the selective evolution of prefrontal inputs to the human cortico-ponto-cerebellar system.


Correlation between cystoscopic biopsy results and hypoamylasuria in bladder-drained pancreas transplants.
Urinary amylase (UA) remains the most common biochemical parameter to detect rejection in bladder-drained pancreas allografts. With the development of the cystoscopic transduodenal pancreas transplant biopsy technique, tissue samples of the pancreas graft are now frequently obtained. A definitive correlative analysis between UA activity and biopsy results has not been done in the three different pancreas transplant categories (simultaneous pancreas-kidney, pancreas transplant alone, and pancreas after kidney). We studied 66 pancreaticoduodenal biopsy specimens obtained for hypoamylasuria. Rejection was defined as a greater than 25% decrease from stable posttransplantation baseline on two consecutive measurements at least 12 hours apart. To perform biopsies we used our newly developed 14- and 16-gauge core-cut needles (50 cm long). Biopsy specimens were considered positive if either pancreatic or duodenal rejection was found. To assess the quality of UA activity we studied 13 biopsy specimens from patients with stable UA levels; these 13 specimens were negative for rejection. Acute rejection was diagnosed in 36 biopsy specimens (55%). The mean decrease in UA levels was 67% +/- 8% (range, 28% to 99%) for the positive biopsy results, and 57% +/- 16% (range, 22% to 92%) for the negative biopsy results (p = 0.147). Within 1 month, UA levels returned to baseline in 19% of our patients with positive biopsy results versus 97% with negative results; postbiopsy 1-year graft survival was 64% versus 97% (p < or = 0.05). In assessing the test quality of our biopsy specimens (including 13 obtained for reasons other than hypoamylasuria), we found a sensitivity of 100% (stable UA levels mean no rejection) and a specificity of 30%. The predictive value of a positive test was 53%; of a negative test it was 100%. By performing biopsies we avoided antirejection treatment in 47% of the patients studied. We found no biopsy-related complications. Stable UA levels reliably rule out rejection; a decrease is a marker for acute rejection but is unspecific. Performing biopsy is currently the only way to reliably diagnose rejection in solitary pancreas recipients (pancreas transplant alone and pancreas after kidney) and in simultaneous pancreas-kidney recipients with isolated hypoamylasuria. The procedure is safe and should always be attempted to avoid unnecessary rejection treatment.


Faster ticking rate of the epigenetic clock is associated with faster pubertal development in girls.
Epigenetic age is an indicator of biological aging, capturing the impact of environmental and behavioral influences across time on cellular function. Deviance between epigenetic age and chronological age (AgeAccel) is a predictor of health. Pubertal timing has similarly been associated with cancer risk and mortality rate among females. We examined the association between AgeAccel and pubertal timing and adolescent breast composition in the longitudinal Growth and Obesity Cohort Study. AgeAccel was estimated in whole blood using the Horvath method at breast Tanner 2 (B2) and 4 (B4). Total breast volume, absolute fibro-glandular volume (FGV), and %FGV were evaluated at B4 using dual X-ray absorptiometry. The impact of AgeAccel (mean: 0; SD: 3.78) across puberty on the time to breast development (thelarche), menarche, and pubertal tempo (thelarche to menarche) was estimated using accelerated failure time models; generalized estimating equations were used to evaluate associations with breast density. A five-year increase in average adolescent AgeAccel was associated with a significant decrease in time to menarche [hazard ratio (HR): 1.37; 95% confidence interval (CI): 1.04, 1.80] adjusting for birth weight, maternal pre-pregnancy body mass index, maternal height, maternal education, B2 height, fat percentage, and cell composition. AgeAccel displayed a stronger inverse association with pubertal tempo (HR: 1.48; 95% CI: 1.10, 1.99). A five-year increase in AgeAccel was associated with 5% greater %FGV, adjusting for B4 percent body fat, and maternal traits (95% CI: 1.01, 1.10). Our study provides unique insight into the influence of AgeAccel on pubertal development in girls, which may have implications for adult health.


The Wnt signaling mediator tcf1 is required for expression of foxd3 during Xenopus gastrulation.
TCF1 belongs to the family of LEF1/TCF transcription factors that regulate gene expression downstream of Wnt/β-catenin signaling, which is crucial for embryonic development and is involved in adult stem cell regulation and tumor growth. In early Xenopus embryos, tcf1 plays an important role in mesoderm induction and patterning. Foxd3 emerged as a potential tcf1 target gene in a microarray analysis of gastrula stage embryos. Because foxd3 and tcf1 are coexpressed during gastrulation, we investigated whether foxd3 is regulated by tcf1. By using morpholino-mediated knockdown, we show that during gastrulation foxd3 expression is dependent on tcf1. By chromatin immunoprecipitation, we also demonstrate direct interaction of β-catenin/tcf complexes with the foxd3 gene locus. Hence, our results indicate that tcf1 acts as an essential activator of foxd3, which is critical for dorsal mesoderm formation in early embryos.


Recruitment of childhood leukaemia patients to clinical trials in Great Britain during 1980-2007: variation by birth weight, congenital malformation, socioeconomic status and ethnicity.
To assess recruitment of children to national clinical trials for acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) in Great Britain during 1980-2007 and describe variation by some factors that might influence trial entry. Records of leukaemia patients aged 0-14 years at diagnosis were identified in the National Registry of Childhood Tumours and linked to birth registrations, Children's Cancer and Leukaemia Group records, Hospital Episode Statistics and Medical Research Council clinical trial registers. Trial entry rates were compared between categories of birth weight, congenital malformation, socioeconomic status and ethnicity. 9147 ALL and 1466 AML patients were eligible for national clinical trials during 1980-2007. Overall recruitment rates were 81% and 60% respectively. For ALL, rates varied significantly with congenital malformation (Down syndrome 61%, other malformations 80%, none 82%; p<0.001) and ethnicity (South Asian 78%, other minority groups 80%, white 85%; p<0.001). For AML, rates varied with birth weight (< 2500 g 48%, 2500-4000 g 69%, >4000 g 67%; p=0.001) and congenital malformation (Down syndrome 28%, other malformations 56%, none 63%; p<0.001). Although recruitment rates to clinical trials for childhood leukaemia are high, future trials should monitor possible variation by birth weight, ethnicity and presence of congenital malformations.


Evidence for a navigational map stretching across the continental U.S. in a migratory songbird.
Billions of songbirds migrate several thousand kilometers from breeding to wintering grounds and are challenged with crossing ecological barriers and facing displacement by winds along the route. A satisfactory explanation of long-distance animal navigation is still lacking, partly because of limitations on field-based study. The navigational tasks faced by adults and juveniles differ fundamentally, because only adults migrate toward wintering grounds known from the previous year. Here, we show by radio tracking from small aircraft that only adult, and not juvenile, long-distance migrating white-crowned sparrows rapidly recognize and correct for a continent-wide displacement of 3,700 km from the west coast of North America to previously unvisited areas on the east coast. These results show that the learned navigational map used by adult long-distance migratory songbirds extends at least on a continental scale. The juveniles with less experience rely on their innate program to find their distant wintering areas and continue to migrate in the innate direction without correcting for displacement.


Iron deficiency anemia in Helicobacter pylori infection: meta-analysis of randomized controlled trials.
Helicobacter pylori (H. pylori) infection and iron deficiency anemia are prevalent in disadvantaged populations worldwide. The benefit of H. pylori eradiation for iron deficiency anemia has been extensively studied, but data are still equivocal. A search in The Cochrane Library, PUBMED, EMBASE, EBM Review databases, Science Citation Index Expanded, and CMB (Chinese Biomedical Literature Database) was performed. Randomized controlled trials (RCTs) comparing anti-H. pylori plus oral iron to oral iron alone for the iron deficiency patients in whom H. pylori was positive were selected for meta-analysis. Reviev Manager 5.0 software was used for the performance of meta-analysis. Sixteen randomized controlled trials totaling 956 patients were included. The meta-analysis showed that the difference from baseline to endpoint of hemoglobin (Hb), serum iron (SI), and serum ferritin (SF) was statistically significantly different between anti-H. pylori treatment plus oral iron and oral iron alone (SMD, Hb 1.48; 95% CI, 0.96, 2.00; p < 0.00001; SI 1.15; 95% CI, 0.87, 1.43; p < 0.00001; SF 1.84; 95% CI, 1.20, 2.48; p < 0.00001, respectively). Our study suggests that treatment of H. pylori infection could be effective in improving anemia and iron statue in IDA patients infected by H. pylori, particularly in patients with moderate or severe anemia.


Diagnostic agreement and interobserver concordance with teledermoscopy referrals.
Malignant melanoma and non-melanoma skin cancers are among the fastest increasing malignancies in many countries. With the help of new tools, such as teledermoscopy referrals between primary health care and dermatology clinics, the management of these patients could be made more efficient. To evaluate the diagnostic agreement and interobserver concordance achieved when assessing referrals sent through a mobile teledermoscopic referral system as compared to referrals sent via the current paper-based system without images. The referral information from 80 teledermoscopy referrals and 77 paper referrals were evaluated by six Swedish dermatologists. They were asked to answer questions about the probable diagnosis, the priority, and a management decision. Teledermoscopy generally resulted in higher diagnostic agreement, better triaging and more malignant tumours being booked directly to surgery. The largest difference between the referral methods was seen for invasive melanomas. Referrals for benign lesions were significantly more often correctly resent to primary health care with teledermoscopy. However, referrals for cases of melanoma in situ were also incorrectly resent five times. The interobserver concordance was moderate with both methods. By adding clinical and dermoscopic images to referrals, the triage process for both benign and dangerous skin tumours can be improved. With teledermoscopy, patients with melanoma especially can receive treatment more swiftly.