Molecular functions of the PP2A regulatory subunit Tap46 in plants.
Tap42/α4 is a regulatory subunit of the protein phosphatase 2A (PP2A) family of phosphatases and plays a role in the target of rapamycin (TOR) pathway that regulates cell growth, ribosome biogenesis, translation and cell cycle progression in both yeast and mammals. We determined the cellular functions of Tap46, the plant homolog of Tap42/α4, in both Arabidopsis thaliana and Nicotiana benthamiana. Tap46 associated with the catalytic subunits of PP2A and the PP2A-like phosphatases PP4 and PP6 in vivo. Tap46 was phosphorylated by TOR in vitro, indicating that Tap46 is a direct substrate of TOR kinase. Tap46 deficiency caused cellular phenotypes that are similar to TOR-depletion phenotypes, including repression of global translation and activation of both autophagy and nitrogen recycling. Furthermore, Tap46 depletion regulated total PP2A activity in a time-dependent manner similar to TOR deficiency. These results suggest that Tap46 acts as a positive effector of the TOR signaling pathway in controlling diverse metabolic processes in plants. However, Tap46 silencing caused acute cell death, while TOR silencing only hastened senescence. Furthermore, mitotic cells with reduced Tap46 levels exhibited chromatin bridges at anaphase, while TOR depletion did not cause a similar defect. These findings suggest that Tap46 may have TOR-independent functions as well as functions related to TOR signaling in plants.


Survival estimates and outcome predictors for shelter cats with feline panleukopenia virus infection.
OBJECTIVE To determine survival estimates and outcome predictors for shelter cats with feline panleukopenia virus (FPV) infection. DESIGN Retrospective cohort study. ANIMALS 177 shelter cats with FPV infection. PROCEDURES Medical records of cats treated for FPV infection from 2011 through 2013 were reviewed to collect information pertaining to signalment; history; results of physical examination, CBC, serum biochemical analysis, and blood gas analysis; and treatments (antimicrobials, antiparasitics, antivirals, antiemetics, analgesics, crystalloid or colloid solutions, and blood products). Survival time and outcome predictors were determined by means of Kaplan-Meier estimation, logistic regression, and mixed-model ANOVA. RESULTS Median survival time after hospital admission was 3 days; 20.3% (36/177) of cats survived to discharge from the hospital. Risk of nonsurvival was greater in cats with (vs without) signs of lethargy, rectal temperature < 37.9°C (I00.2°F), or low body weight at hospital admission. Lower (vs higher) leukocyte count on days 3,4, and 7 of hospitalization, but not at admission, was associated with nonsurvival. Amoxicillin-clavulanic acid, antiparasitics, and maropitant but not interferon-ω were associated with survival, whereas glucose infusion was associated with nonsurvival. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that FPV infection carried a poor prognosis for shelter cats. Several variables measured at admission or during hospitalization were associated with outcome. Remarkably and contrary to the existing literature, leukopenia at admission had no association with outcome, possibly owing to early prevention of complications.


Novel Parvoviruses from Wild and Domestic Animals in Brazil Provide New Insights into Parvovirus Distribution and Diversity.
Parvoviruses (family Parvoviridae) are small, single-stranded DNA viruses. Many parvoviral pathogens of medical, veterinary and ecological importance have been identified. In this study, we used high-throughput sequencing (HTS) to investigate the diversity of parvoviruses infecting wild and domestic animals in Brazil. We identified 21 parvovirus sequences (including twelve nearly complete genomes and nine partial genomes) in samples derived from rodents, bats, opossums, birds and cattle in Pernambuco, São Paulo, Paraná and Rio Grande do Sul states. These sequences were investigated using phylogenetic and distance-based approaches and were thereby classified into eight parvovirus species (six of which have not been described previously), representing six distinct genera in the subfamily Parvovirinae. Our findings extend the known biogeographic range of previously characterized parvovirus species and the known host range of three parvovirus genera (Dependovirus, Aveparvovirus and Tetraparvovirus). Moreover, our investigation provides a window into the ecological dynamics of parvovirus infections in vertebrates, revealing that many parvovirus genera contain well-defined sub-lineages that circulate widely throughout the world within particular taxonomic groups of hosts.


CD16-expressing CD8alpha alpha+ T lymphocytes in the intestinal epithelium: possible precursors of Fc gammaR-CD8alpha alpha+ T cells.
T lymphocytes normally express their Ag receptors in association with the CD3 proteins, which include CD3zeta. In CD3zeta eta(null) mice thymic and peripheral T lymphocytes do not express the TCR/CD3 complex on their surface due to retention in the endoplasmic reticulum of the remaining polypeptide chains. However, intestinal intraepithelial lymphocytes (iIEL) of CD3zeta eta(null) mice do express surface TCR, because the Fc epsilonRI gamma chain replaced the CD3zeta chain in the TCR/CD3 complex. Here we report that in a subset of CD8alpha alpha+ iIEL the presence of the Fc epsilonRI gamma chain could be accounted for by the surface expression of the Fc gammaRIII(CD16) complex. Because in wild-type (wt) mice only CD16+ iIEL coexpressed Fc epsilonRI gamma and CD3zeta, we concluded that the presence of Fc epsilonRI gamma was dictated by its required participation of CD16 complex. CD8alpha alpha+ iIEL bearing CD16 and B220 were also detected in the intestinal mucosa of RAG-2(null) mice from 12 days after birth onward. Two independent experimental settings were used in an attempt to demonstrate that CD16+ iIEL matured into CD16- T cells. First, in the RAG-2(null) mice, iIEL responded to in vivo administration of an anti-CD3epsilon mAb by progression to a more mature stage of development, characterized by a loss of CD16 and B220. Secondly, a conversion to CD16- iIEL occurred upon transfer of wt CD16+ iIEL into RAG-2(null) mice. We conclude from these experiments that in both RAG-2(null) and wt mice, a precursor/progeny relationship may exists between CD16+ B220+ CD8alpha alpha+ and CD16- B220- CD8alpha alpha+ iIEL.


Integrated semi-physiological pharmacokinetic model for both sunitinib and its active metabolite SU12662.
Previously published pharmacokinetic (PK) models for sunitinib and its active metabolite SU12662 were based on a limited dataset or lacked important elements such as correlations between sunitinib and its metabolite. The current study aimed to develop an improved PK model that circumvented these limitations and to prove the utility of the PK model in treatment optimization in clinical practice. One thousand two hundred and five plasma samples from 70 cancer patients were collected from three PK studies with sunitinib and SU12662. A semi-physiological PK model for sunitinib and SU12662 was developed incorporating pre-systemic metabolism using non-linear mixed effects modelling (nonmem). Allometric scaling based on body weight was applied. The final model was used for simulation of the PK of different treatment regimens. Sunitinib and SU12662 PK were best described by a one and two compartment model, respectively. Introduction of pre-systemic formation of SU12662 strongly improved model fit, compared with solely systemic metabolism. The clearance of sunitinib and SU12662 was estimated at 35.7 (relative standard error (RSE) 5.7%) l h(-1) and 17.1 (RSE 7.4%) l h(-1), respectively for 70 kg patients. Correlation coefficients were estimated between inter-individual variability of both clearances, both volumes of distribution and between clearance and volume of distribution of SU12662 as 0.53, 0.48 and 0.45, respectively. Simulation of the PK model predicted correctly the ratio of patients who did not reach proposed PK targets for efficacy. A semi-physiological PK model for sunitinib and SU12662 in cancer patients was presented including pre-systemic metabolism. The model was superior to previous PK models in many aspects.


Error consideration in contrast-enhanced three-dimensional optical tomography.
We present three-dimensional tomographic images of the absorption coefficient that is due to the presence of a fluorophore reconstructed from frequency domain fluence measurements of a tissue phantom containing a single, fluorescence contrast-enhanced inclusion. We show that such a reconstruction may be improved when the importance of measurement error correlations between relative phase shift and amplitude is assessed and when measurements are preprocessed to reduce the magnitude and the bias of system error.


Role of pyruvate dehydrogenase inhibition in the development of hypertrophy in the hyperthyroid rat heart: a combined magnetic resonance imaging and hyperpolarized magnetic resonance spectroscopy study.
Hyperthyroidism increases heart rate, contractility, cardiac output, and metabolic rate. It is also accompanied by alterations in the regulation of cardiac substrate use. Specifically, hyperthyroidism increases the ex vivo activity of pyruvate dehydrogenase kinase, thereby inhibiting glucose oxidation via pyruvate dehydrogenase. Cardiac hypertrophy is another effect of hyperthyroidism, with an increase in the abundance of mitochondria. Although the hypertrophy is initially beneficial, it can eventually lead to heart failure. The aim of this study was to use hyperpolarized magnetic resonance spectroscopy to investigate the rate and regulation of in vivo pyruvate dehydrogenase flux in the hyperthyroid heart and to establish whether modulation of flux through pyruvate dehydrogenase would alter cardiac hypertrophy. Hyperthyroidism was induced in 18 male Wistar rats with 7 daily intraperitoneal injections of freshly prepared triiodothyronine (0.2 mg x kg(-1) x d(-1)). In vivo pyruvate dehydrogenase flux, assessed with hyperpolarized magnetic resonance spectroscopy, was reduced by 59% in hyperthyroid animals (0.0022 ± 0.0002 versus 0.0055 ± 0.0005 second(-1); P=0.0003), and this reduction was completely reversed by both short- and long-term delivery of dichloroacetic acid, a pyruvate dehydrogenase kinase inhibitor. Hyperpolarized [2-(13)C]pyruvate was also used to evaluate Krebs cycle metabolism and demonstrated a unique marker of anaplerosis, the level of which was significantly increased in the hyperthyroid heart. Cine magnetic resonance imaging showed that long-term dichloroacetic acid treatment significantly reduced the hypertrophy observed in hyperthyroid animals (100 ± 20 versus 200 ± 30 mg; P=0.04) despite no change in the increase observed in cardiac output. This work has demonstrated that inhibition of glucose oxidation in the hyperthyroid heart in vivo is mediated by pyruvate dehydrogenase kinase. Relieving this inhibition can increase the metabolic flexibility of the hyperthyroid heart and reduce the level of hypertrophy that develops while maintaining the increased cardiac output required to meet the higher systemic metabolic demand.


Non-Hodgkin lymphoma incidence in the Swiss HIV Cohort Study before and after highly active antiretroviral therapy.
To assess the long-term effect of HAART on non-Hodgkin lymphoma (NHL) incidence in people with HIV (PHIV). Follow-up of the Swiss HIV Cohort Study (SHCS). Between 1984 and 2006, 12 959 PHIV contributed a total of 75 222 person-years (py), of which 36 787 were spent under HAART. Among these PHIV, 429 NHL cases were identified from the SHCS dataset and/or by record linkage with Swiss Cantonal Cancer Registries. Age- and gender-standardized incidence was calculated and Cox regression was used to estimate hazard ratios (HR). NHL incidence reached 13.6 per 1000 py in 1993-1995 and declined to 1.8 in 2002-2006. HAART use was associated with a decline in NHL incidence [HR = 0.26; 95% confidence interval (CI), 0.20-0.33], and this decline was greater for primary brain lymphomas than other NHL. Among non-HAART users, being a man having sex with men, being 35 years of age or older, or, most notably, having low CD4 cell counts at study enrollment (HR = 12.26 for < 50 versus >or= 350 cells/microl; 95% CI, 8.31-18.07) were significant predictors of NHL onset. Among HAART users, only age was significantly associated with NHL risk. The HR for NHL declined steeply in the first months after HAART initiation (HR = 0.46; 95% CI, 0.27-0.77) and was 0.12 (95% CI, 0.05-0.25) 7 to10 years afterwards. HAART greatly reduced the incidence of NHL in PHIV, and the influence of CD4 cell count on NHL risk. The beneficial effect remained strong up to 10 years after HAART initiation.


Age-Dependent Impact of Medication Underuse and Strategies for Improvement.
Medication underuse is common in aging populations and, because of the growing risk for competing deaths, the benefit of preventive medicines gradually vanishes with advancing age, thus limiting their success. To estimate the optimum time of initiation of the secondary prevention of cardiovascular events, we examined the impact of appropriate pharmacotherapy for different starting ages at which it is implemented. In the competing risk framework, we obtained the population's life course from life tables, combined it with effect estimates quantifying the real-world effectiveness of secondary prevention, and compared the outcome of patients not receiving appropriate treatment (underuse) with those receiving preventive medicines that have demonstrated a reduction in the transition to serious cardiovascular events (START criteria). Starting at the age of 55 years, the population proportions of the distinct states of the framework were calculated for each year of chronological age in subgroups of appropriate treatment and underuse. These proportions were used over a follow-up period to estimate measures of treatment effectiveness and risks of underuse. Despite increasing relative effectiveness with advancing age, benefits measured by patient-relevant endpoints, such as life years gained (LYG) or gained quality-adjusted life years (QALYs), markedly dropped after the starting age of 75 years, but even at an initiation age of 85 years, QALYs gained exceeded 1 year. Interventions targeting medication underuse may achieve considerable benefits at any stage of later life, while the benefit is probably largest if appropriate treatment is started before 75 years.


Postcranial robusticity in Homo. III: Ontogeny.
The influence of developmental factors on long-bone cross-sectional geometry and articular size in modern humans is investigated using two approaches: (1) an analysis of the effects of increased mechanical loading on long-bone structure when applied during different developmental periods, using data collected for a study of upper limb bone bilateral asymmetry in professional tennis players; and (2) an analysis of the relative timing of age changes in femoral dimensions among juveniles from the Pecos Pueblo Amerindian archaeological sample. Results of these analyses are used to interpret the femoral morphology of three pre-Recent Homo juveniles--the H. erectus KNM-WT 15000 and the archaic H. sapiens La Ferrassie 6 and Teshik-Tash 1--as well as observed differences in postcranial morphology between adult Recent and earlier Homo (Ruff et al., 1993). Our findings indicate the following: (1) There are age-related changes in long-bone diaphyseal envelope sensitivity to increased mechanical loading, with the periosteal envelope more responsive prior to mid-adolescence, and the endosteal envelope more responsive thereafter. The periosteal expansion and endosteal contraction of the diaphysis documented earlier for adult pre-Recent Homo relative to Recent humans (Ruff et al., 1993) is thus consistent with a developmental response to increased mechanical loading applied throughout life. The relatively large medullary cavity in the 11-12-year-old KNM-WT 15000 femur is also consistent with this model. However, the two archaic H. sapiens juveniles show relatively small medullary cavities, possibly indicating a modified developmental pattern in this group. (2) Articulations follow a growth pattern similar to that of long-bone length (and stature), while cross-sectional diaphyseal dimensions (cortical area, second moments of area) show a contrasting growth pattern, with slower initial growth from childhood through mid-adolescence, followed by a "catch-up" period that continues through early adulthood. This latter pattern is more similar to the growth curve for body weight, and may in fact partially reflect adaptation of the diaphysis to increased weight bearing. Because of these different growth patterns, articulations appear relatively large, and diaphyseal breadths relatively small during late childhood to mid-adolescence (i.e., about 9-13 years), when compared to adults from the same population. KNM-WT 15000 shows this same proportional difference from adult early Homo specimens, which is therefore interpreted as simply a developmental consequence of his age at death.(ABSTRACT TRUNCATED AT 400 WORDS)


A low-voltage activated, transient calcium current is responsible for the time-dependent depolarizing inward rectification of rat neocortical neurons in vitro.
Intracellular recordings were obtained from rat neocortical neurons in vitro. The current-voltage-relationship of the neuronal membrane was investigated using current- and single-electrode-voltage-clamp techniques. Within the potential range up to 25 mV positive to the resting membrane potential (RMP: -75 to -80 mV) the steady state slope resistance increased with depolarization (i.e. steady state inward rectification in depolarizing direction). Replacement of extracellular NaCl with an equimolar amount of choline chloride resulted in the conversion of the steady state inward rectification to an outward rectification, suggesting the presence of a voltage-dependent, persistent sodium current which generated the steady state inward rectification of these neurons. Intracellularly injected outward current pulses with just subthreshold intensities elicited a transient depolarizing potential which invariably triggered the first action potential upon an increase in current strength. Single-electrode-voltage-clamp measurements revealed that this depolarizing potential was produced by a transient calcium current activated at membrane potentials 15-20 mV positive to the RMP and that this current was responsible for the time-dependent increase in the magnitude of the inward rectification in depolarizing direction in rat neocortical neurons. It may be that, together with the persistent sodium current, this calcium current regulates the excitability of these neurons via the adjustment of the action potential threshold.


A voxel-based morphometric magnetic resonance imaging study of the brain detects age-related gray matter volume changes in healthy subjects of 21-45 years old.
Previous and more recent work of analyzing structural changes in the brain suggest that certain brain regions such as the frontal lobe are among the brain regions profoundly affected by the aging process across males and females. Also, a unified model of structural changes in a normally aging brain is still lacking. The present study investigated age-related structural brain changes in gray matter from young to early middle-age adulthood for males and females. Magnetic resonance images of 215 normal and healthy participants between the ages of 21-45 years were acquired. Changes in gray matter were assessed using voxel-based morphometry and gray matter volumetric analysis. The results showed significant decrease in gray matter volume between the youngest and oldest groups in the following brain regions: frontal, temporal, and parietal lobes. Grey matter loss in the frontal lobe was among the most widespread of all brain regions across the comparison groups that showed significant age-related changes in grey matter for both males and females. This work provides a unique pattern of age-related decline of normal and healthy adult males and females that can aid in the future development of a unified model of normal brain aging.


Intrapartum Fetal Heart Rate Tracing Among Small-for-Gestational Age Compared With Appropriate-for-Gestational-Age Neonates.
To compare fetal heart rate (FHR) patterns during the last hour of labor between small-for-gestational-age (SGA; birth weight less than the 10th percentile for gestational age) and appropriate-for-gestational-age (AGA; birth weight at the 10-90th percentile) neonates at 36 weeks of gestation or greater. We also compared the rate of cesarean delivery and composite neonatal morbidity among SGA and AGA newborns. This is a secondary analysis of a randomized trial of intrapartum fetal electrocardiographic ST-segment analysis. We excluded women with chorioamnionitis, insufficient duration of FHR tracing in the hour before delivery, and anomalous newborns. Fetal heart rate patterns were categorized by computerized pattern recognition software (PeriCALM Patterns). Composite neonatal morbidity was defined as any of the following: intrapartum fetal death, Apgar score 3 or less at 5 minutes, cord artery pH 7.05 or less, base deficit 12 mmol/L or greater, neonatal seizure, intubation at delivery, neonatal encephalopathy, and neonatal death. Logistic regression was used to evaluate the association between FHR patterns and SGA adjusted for magnesium sulfate exposure and stage of labor. Of the 11,108 women randomized, 85% (n=9,402) met inclusion criteria, of whom 9% were SGA. In the last hour, the likelihood of accelerations was significantly lower among SGA than AGA neonates (72.4% vs 66.8%; P=.001). Variable decelerations lasting greater than 60 seconds, with depth greater than 60 beats per minute (bpm) or nadir less than 60 bpm, were significantly more common with SGA than AGA (all P<.001). The rate of late decelerations, prolonged decelerations, or bradycardia were similar between SGA and AGA (all P>.05). Cesarean delivery for fetal indications was significantly more common with SGA (7.0%) than AGA (4.0%; P<.001). The composite neonatal morbidity was 1.4% among SGA and 1.0% among AGA (odds ratio 1.40, 95% CI 0.74-2.64). Although the FHR patterns in the last hour of labor differ among SGA and AGA neonates, as does the rate of cesarean delivery, the composite neonatal morbidity was similar.


Developing the family of picolinate ligands for Mn2+ complexation.
We have reported here a series of ligands containing pentadentate 6,6'-(azanediylbis(methylene))dipicolinic acid units that differ in the substituent present at the amine nitrogen atom (acetate: H3DPAAA; phenyl: H2DPAPhA; dodecyl: H2DPAC12A; 4-hexylphenyl: H2DPAC6PhA). The protonation constants of the hexadentate DPAAA3- and pentadentate DPAPhA2- ligands and the stability constants of their Mn2+ complexes were determined using pH-potentiometry (25 °C, 0.15 M NaCl). The mono-hydrated [Mn(DPAAA)]- complex (log KMnL = 13.19(5)) was found to be considerably more stable than the bis-hydrated [Mn(DPAPhA)] analogue (log KMnL = 9.55(1)). A detailed 1H and 17O NMR relaxometric study was carried out to determine the parameters that govern the proton relaxivities of these complexes. The [Mn(DPAC12A)] complex, which contains a dodecyl lipophilic chain, forms micelles in solution characterized by a critical micellar concentration (cmc) of 96(9) μM. The lipophilic [Mn(DPAC6PhA)] and [Mn(DPAC12A)] derivatives form rather strong adducts with Human Serum Albumin (HSA) with association constants of 7.1 ± 0.1 × 103 and 1.3 ± 0.4 × 105 M-1, respectively. The X-ray structure of the complex {K(H2O)4}{[Mn(DPAAA)(H2O)]}2 shows that the Mn2+ ion in [Mn(DPAAA)]- is coordinated to the six donor atoms of the ligand, a coordinated water molecule completing the pentagonal bipyramidal coordination environment.


Free energy profiles of amino acid side chain analogs near water-vapor interface obtained via MD simulations.
Solvation of 13 neutral amino acid side chain analogs at water-vapor interface was studied by computing high precision free energy profiles of the molecules across the interface using molecular dynamics (MD) simulations. The SPC water model (Berendsen, H. J. C., Postma, J. P. M., van Gunsteren, W. F., Hermans, P. A. K. J., Dixon, R., Cornell, W., Fox, T., Chipot, C., Pohorille, A. In: Wilkinson, A., Weiner, P. and van Gunsteren, W. F. editors. Intermolecular Forces, 1981, 3, 331) and OPLS-AA (Jorgensen et al., J Am Chem Soc, 1996, 118, 11225) potential parameter sets were used. A rigorous approach for the computation of high precision free energy profiles at water-vapor interface using constraint force technique is implemented. Methodology of obtaining high precision potential of mean force (PMF) profiles free of simulation artifacts in MD simulations is outlined and discussed. The accuracy of the calculations is examined by comparing the hydration free energies of studied solutes obtained from PMF calculations and separately using Bennett acceptance ratio technique by decoupling solvent-solute interactions in the bulk. All molecules exhibit a free energy minimum at interface. No significant desolvation barrier is observed for any of the studied species. Adsorption energies for studied molecules at water-vapor interface are estimated and compared with experimental observations. We find that for modeled neutral compounds pronounced surface influence on solute solvation vanishes already at 6-7 A behind the water surface as the solvation free energy approaches the bulk value. The possibility of force field refinement using adsorption free energies is outlined.


Translaminar lumbar epidural endoscopy: technique and clinical results.
To provide baseline outcome data for a new lumbar microinvasive diskectomy done with standard arthroscopic instrumentation, we retrospectively reviewed the cases of 190 patients. All patients were assessed by a modified MacNab outcome classification with a minimum of a 2-year follow-up. All complications of this procedure were reported as well. No previous outcome data are available for this procedure, since it has been done primarily at one center, by the same surgeon, using his previously reported techniques. Results were good or excellent in 175 patients and fair or poor in 15. Complications were not severe and were easily remedied. This success rate is comparable to rates reported for other minimally invasive operations on the lumbar spine. This new technique of minimally invasive lumbar spine surgery provides minimal morbidity and a long-term outcome comparable to that of other standard procedures. The added benefits of using standard arthroscopic instrumentation are discussed.


Network Analysis Indicates That Avolition Is the Most Central Domain for the Successful Treatment of Negative Symptoms: Evidence From the Roluperidone Randomized Clinical Trial.
A recent conceptual development in schizophrenia is to view its manifestations as interactive networks rather than individual symptoms. Negative symptoms, which are associated with poor functional outcome and reduced rates of recovery, represent a critical need in schizophrenia therapeutics. MIN101 (roluperidone), a compound in development, demonstrated efficacy in the treatment of negative symptoms in schizophrenia. However, it is unclear how the drug achieved its effect from a network perspective. The current study evaluated the efficacy of roluperidone from a network perspective. In this randomized clinical trial, participants with schizophrenia and moderate to severe negative symptoms were randomly assigned to roluperidone 32 mg (n = 78), 64 mg (n = 83), or placebo (N = 83). Macroscopic network properties were evaluated to determine whether roluperidone altered the overall density of the interconnections among symptoms. Microscopic properties were evaluated to examine which individual symptoms were most influential (ie, interconnected) on other symptoms in the network and are responsible for successful treatment effects. Participants receiving roluperidone did not differ from those randomized to placebo on macroscopic properties. However, microscopic properties (degree and closeness centrality) indicated that avolition was highly central in patients receiving placebo and that roluperidone reduced this level of centrality. These findings suggest that decoupling the influence of motivational processes from other negative symptom domains is essential for producing global improvements. The search for pathophysiological mechanisms and targeted treatment development should be focused on avolition, with the expectation of improvement in the entire constellation of negative symptoms if avolition is effectively treated.


Norovirus disease in the United States.
Although recognized as the leading cause of epidemic acute gastroenteritis across all age groups, norovirus has remained poorly characterized with respect to its endemic disease incidence. Use of different methods, including attributable proportion extrapolation, population-based surveillance, and indirect modeling, in several recent studies has considerably improved norovirus disease incidence estimates for the United States. Norovirus causes an average of 570-800 deaths, 56,000-71,000 hospitalizations, 400,000 emergency department visits, 1.7-1.9 million outpatient visits, and 19-21 million total illnesses per year. Persons >65 years of age are at greatest risk for norovirus-associated death, and children <5 years of age have the highest rates of norovirus-associated medical care visits. Endemic norovirus disease occurs year round but exhibits a pronounced winter peak and increases by ≤ 50% during years in which pandemic strains emerge. These findings support continued development and targeting of appropriate interventions, including vaccines, for norovirus disease.


Viral-associated trichodysplasia in a patient with lymphoma: a case report and review.
Viral-associated trichodysplasia is a recently described entity associated with immunosuppression. We describe a 68-year-old man with a history of treated lymphoma who developed numerous, disfiguring, papular and spiny lesions involving most of the central face. Both facial and body alopecia was noted. Histopathologic findings of a facial papule showed dramatic alterations of the hair bulbs, including bulbar distention, lack of hair shaft formation and a marked expansion of inner root sheath type epithelium. These findings were identical to those of previously described cases, so electron microscopy was performed. Numerous intranuclear virus particles were identified. Shortly after the diagnosis of trichodysplasia was made, the patient was found to have a relapse of his lymphoma, which may represent the source of his immunosuppression. Based on his skin biopsy findings, successful antiviral therapy was initiated. This case and a review of previously reported cases are discussed in this study.


Differentiation of the brain vasculature: the answer came blowing by the Wnt.
Vascularization of the vertebrate brain takes place during embryonic development from a preformed perineural vascular plexus. As a consequence of the intimate contact with neuroectodermal cells the vessels, which are entering the brain exclusively via sprouting angiogenesis, acquire and maintain unique barrier properties known as the blood-brain barrier (BBB). The endothelial BBB depends upon the close association of endothelial cells with pericytes, astrocytes, neurons and microglia, which are summarized in the term neuro-vascular unit. Although it is known since decades that the CNS tissue provides the cues for BBB induction and differentiation in endothelial cells, the molecular mechanism remained obscure.Only recently, the canonical Wnt/beta-catenin pathway and the Wnt7a/7b growth factors have been implicated in brain angiogenesis on the one hand and in BBB induction on the other. This breakthrough in understanding the differentiation of the brain vasculature prompted us to review these findings embedded in the emerging concepts of Wnt signaling in the vasculature. In particular, interactions with other pathways that are crucial for vascular development such as VEGF, Notch, angiopoietins and Sonic hedgehog are discussed. Finally, we considered the potential role of the Wnt pathway in vascular brain pathologies in which BBB function is hampered, as for example in glioma, stroke and Alzheimer's disease.


Analysis of microsatellite variation in Drosophila melanogaster with population-scale genome sequencing.
Genome sequencing technologies promise to revolutionize our understanding of genetics, evolution, and disease by making it feasible to survey a broad spectrum of sequence variation on a population scale. However, this potential can only be realized to the extent that methods for extracting and interpreting distinct forms of variation can be established. The error profiles and read length limitations of early versions of next-generation sequencing technologies rendered them ineffective for some sequence variant types, particularly microsatellites and other tandem repeats, and fostered the general misconception that such variants are inherently inaccessible to these platforms. At the same time, tandem repeats have emerged as important sources of functional variation. Tandem repeats are often located in and around genes, and frequent mutations in their lengths exert quantitative effects on gene function and phenotype, rapidly degrading linkage disequilibrium between markers and traits. Sensitive identification of these variants in large-scale next-gen sequencing efforts will enable more comprehensive association studies capable of revealing previously invisible associations. We present a population-scale analysis of microsatellite repeats using whole-genome data from 158 inbred isolates from the Drosophila Genetics Reference Panel, a collection of over 200 extensively phenotypically characterized isolates from a single natural population, to uncover processes underlying repeat mutation and to enable associations with behavioral, morphological, and life-history traits. Analysis of repeat variation from next-generation sequence data will also enhance studies of genome stability and neurodegenerative diseases.


Increased prevalence of prior malignancies and autoimmune diseases in patients diagnosed with chronic myeloid leukemia.
We recently reported an increased incidence of second malignancies in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKI). To elucidate whether this increase may be linked, not to TKI but rather to a hereditary or acquired susceptibility to develop cancer, we estimated the prevalence of malignancies, autoimmune disease (AD) and chronic inflammatory disease (CID) in CML patients prior to their CML diagnosis. Nationwide population-based registers were used to identify patients diagnosed with CML in Sweden 2002-2012 and to estimate the prevalence of other malignancies, AD and CID prior to their CML diagnosis. For each patient with CML, five matched controls were selected from the general population. Conditional logistic regression was used to calculate odds ratios (OR). Nine hundred and eighty-four CML patients were assessed, representing more than 45 000 person-years of follow-up. Compared with matched controls, the prevalence of prior malignancies and AD was elevated in CML patients: OR 1.47 (95% confidence interval (CI) 1.20-1.82) and 1.55 (95% CI 1.21-1.98), respectively. No associations were detected between CML and previous CID. An increased prevalence of other malignancies and AD prior to the diagnosis of CML suggest that a hereditary or acquired predisposition to cancer and/or autoimmunity is involved in the pathogenesis of CML.


Quantification of social behavior in D. discoideum reveals complex fixed and facultative strategies.
Understanding the maintenance of cooperation requires an understanding of the nature of cheaters and the strategies used to mitigate their effects. However, it is often difficult to determine how cheating or differential social success has arisen. For example, cheaters may employ different strategies (e.g., fixed and facultative), whereas other causes of unequal fitness in social situations can result in winners and losers without cheating. To address these problems, we quantified the social success of naturally occurring genotypes of Dictyostelium discoideum during the formation of chimeric fruiting bodies, consisting of dead stalk cells and viable spores. We demonstrate that an apparent competitive dominance hierarchy of spore formation in chimera is partly due to a fixed strategy where genotypes exhibit dramatically different spore allocations. However, we also find complex, variable facultative strategies, where genotypes change their allocation in chimera. By determining the magnitude and direction of these changes, we partition facultative cheating into two forms: (1) promotion of individual fitness through selfish behaviour ("self-promotion") and (2) coercion of other genotypes to act cooperatively. Our results demonstrate and define social interactions between D. discoideum isolates, thus providing a conceptual framework for the study of the genetic mechanisms that underpin social evolution.


Prevalence of dental anomalies in deciduous dentition and its association with succedaneous dentition: A cross-sectional study of 4180 South Indian children.
The objective of this study was to estimate the prevalence of dental anomalies in primary dentition of Indian population. This cross-sectional study was conducted on 4180 children in the age of 2-6 years. Anomalies were classified based on Kreiborg criteria. The term "double tooth" was used to avoid misinterpretation between gemination. and fusion. Patients having radiographs were also examined for associated dental anomalies in permanent dentition. The occurrence and gender prevalence were evaluated using descriptive statistics. About 95. (2.27%) children exhibited at least one dental anomaly. Thirty.seven children showed 51 missing teeth. (0.88%), mostly in lower right incisors with a statistically significant difference between arches. (P = 0.0056) Nine children. (0.21%) had supernumerary teeth commonly in the right maxilla. Two cases of oligodontia. (0.04%) and talon cusps. (0.04%) and one case of triple tooth. (0.02%) were observed. Forty children. (0.95%) had 43 double teeth mostly in the right mandible with a statistically significant difference between the arches. (P = 0.0105). No significant difference was observed based on gender and arch, but they were statistically significant between the right and left sides. (P = 0.018). Among the children with radiographs available, 45% showed anomalies in the succedaneous dentition. The prevalence rates of children with double tooth, hypodontia, and hyperdontia in our study are 0.95%, 0.88%, and 0.21%, respectively. The overall prevalence rate of anomalies among boys was higher than girls.


Have We Learned to Explain?: How Interpretability Methods Can Learn to Encode Predictions in their Interpretations.
While the need for interpretable machine learning has been established, many common approaches are slow, lack fidelity, or hard to evaluate. Amortized explanation methods reduce the cost of providing interpretations by learning a global selector model that returns feature importances for a single instance of data. The selector model is trained to optimize the fidelity of the interpretations, as evaluated by a predictor model for the target. Popular methods learn the selector and predictor model in concert, which we show allows predictions to be encoded within interpretations. We introduce EVAL-X as a method to quantitatively evaluate interpretations and REAL-X as an amortized explanation method, which learn a predictor model that approximates the true data generating distribution given any subset of the input. We show EVAL-X can detect when predictions are encoded in interpretations and show the advantages of REAL-X through quantitative and radiologist evaluation.


Why faces are and are not special: an effect of expertise.
Recognition memory for faces is hampered much more by inverted presentation than is memory for any other material so far examined. The present study demonstrates that faces are not unique with regard to this vulnerability to inversion. The experiments also attempt to isolate the source of the inversion effect. In one experiment, use of stimuli (landscapes) in which spatial relations among elements are potentially important distinguishing features is shown not to guarantee a large inversion effect. Two additional experiments show that for dog experts sufficiently knowledgeable to individuate dogs of the same breed, memory for photographs of dogs of that breed is as disrupted by inversion as is face recognition. A final experiment indicates that the effect of orientation on memory for faces does not depend on inability to identify single features of these stimuli upside down. These experiments are consistent with the view that experts represent items in memory in terms of distinguishing features of a different kind than do novices. Speculations as to the type of feature used and neuropsychological and developmental implications of this accomplishment are offered.


The effect of tissue expansion on the random flap viability and wound tensile strength of previously irradiated rabbit skin.
Tissue expansion facilitates coverage of cutaneous defects both through the generation of additional skin surface area and by increasing random flap length/width viability factors. The opportunity to apply tissue expansion techniques to head and neck defects within previously irradiated skin fields continues to increase. To study the effect of tissue expansion on the cutaneous perfusion and wound-healing capacity of irradiation-damaged skin, rabbit scalps were subjected to 5 weeks of fractionated radiation followed at 4 months by prolonged tissue expansion. Standardized random flaps were then created and reset within the expanded skin and analyzed in parallel with nonirradiated and nonexpanded control animals. Flap viability as expressed by area and mean maximum length was determined at 10 days postwounding followed by determination of wound-breaking strength. Irradiated tissues demonstrated a significantly reduced flap viability that was significantly increased by expansion. However, tissue expansion-related increases in flap length exceeded those expressed as percent of total area surviving for irradiated animals. Tissue expansion resulted in significant increases in wound tensile strength only in nonirradiated animals. These findings suggest that, compared with controls, several of the benefits of tissue expansion are less appreciable in radiation-damaged skin.


Interferon-β Modulates the Innate Immune Response against Glioblastoma Initiating Cells.
Immunotherapy targeting glioblastoma initiating cells (GIC) is considered a promising strategy. However, GIC are prone to evade immune response and there is a need for potent adjuvants. IFN-β might enhance the immune response and here we define its net effect on the innate immunogenicity of GIC. The transcriptomes of GIC treated with IFN-β and controls were assessed by microarray-based expression profiling for altered expression of immune regulatory genes. Several genes involved in adaptive and innate immune responses were regulated by IFN-β. We validated these results using reverse transcription (RT)-PCR and flow cytometry for corresponding protein levels. The up-regulation of the NK cell inhibitory molecules HLA-E and MHC class I was balanced by immune stimulating effects including the up-regulation of nectin-2. In 3 out of 5 GIC lines tested we found a net immune stimulating effect of IFN-β in cytotoxicity assays using NKL cells as effectors. IFN-β therefore warrants further investigation as an adjuvant for immunotherapy targeting GIC.


High-purity discrete PEG-oligomer crystals allow structural insight.
To great (monodisperse) lengths: An improved synthesis of purer ethylene glycol (EG) oligomers allows access to 16- and 32-mers pure enough for multiple incorporation, and also to the longest (48-mer) discrete EG oligomer yet reported. The high purity enables the first crystallizations and hence the first glimpses of secondary 3(10)-helical PEG structures.


Early experience with diverse foods increases intake of nonfamiliar flavors and feeds in sheep.
This study determined whether early experiences by sheep with monotonous or diverse diets influence intake of unfamiliar flavors and feeds later in life. Thirty 2-mo-old lambs were randomly assigned to 3 treatment diets (n = 10): diverse (DIV), diverse with plant toxins (DIV+T), and monotonous (MON). Lambs in DIV received in 9 successive periods of exposure 4-way choice combinations of 2 foods high in energy and 2 foods high in protein from an array of 6 foods: 3 high in energy [beet pulp, oat grain, and a mix of milo:grape pomace (60:40)] and 3 high in digestible protein (DP) (soybean meal, alfalfa, corn gluten meal). Lambs in DIV+T received the same exposure as DIV, but 2 plant toxins, oxalic acid (1.5%) and quebracho tannins (10%), were randomly added to 2 of the feeds in each of the choice combinations. Lambs in MON received a monotonous balanced diet, made with a mixture of all 6 feeds detailed before. All treatments received their feed in 4 separate buckets. During exposure, treatments did not differ in total daily DMI (P = 0.31), but daily intake of ME was less (P < 0.02) and daily intake of DP was greater (P < 0.03) for lambs in DIV and DIV+T than for lambs in MON. Treatments did not differ in ADG or G:F (P > 0.05). After exposure, lambs were offered a familiar feed (wheat bran) containing novel flavors (maple, garlic, or bitter) and 2-way choices of novel feeds (fescue hay vs. corn distillers grains, rice vs. calf manna, and green peas vs. rolled oats). Intake of maple-flavored wheat bran tended (P = 0.08) to be greater for lambs in DIV than for lambs in DIV+T and MON. Intake of bitter-flavored and garlic-flavored wheat bran were greater (P = 0.03 and P = 0.04, respectively) for lambs in DIV and DIV+T than for lambs in MON. During 2-way choice trials, lambs in DIV, but not in DIV+T, showed greater intakes of fescue hay (P = 0.05) and rice (P = 0.04) than lambs in MON. Intake of green peas was greater (P = 0.03) for lambs in DIV and DIV+T than for lambs in MON. At the end of testing, lambs in DIV but not in DIV+T showed greater ADG than lambs in MON (P = 0.05). Thus, early exposure to diverse foods enhanced acceptance of novel flavors relative to early exposure to a monotonous ration. Early experience with diverse feeds plus plant toxins led to a less diverse diet than early experience with diverse feeds. Early exposure to diverse feeds may be beneficial in production systems that require rapid acceptance and high intake of unfamiliar feeds.


Cycle progression and division of viable and nonviable Chinese hamster ovary cells following acute hyperthermia and their relationship to thermal tolerance decay.
Cell cycle progression delays and subsequent growth kinetics of viable and nonviable Chinese hamster cells following acute (45.5 degrees) hyperthermia were documented in an attempt to correlate these changes with the decay of thermal tolerance. Following heating for various lengths of time, cells exhibited a delay in subsequent division which was related to cell survival by a power function relationship. A cell was considered to be viable if it retained the ability to divide to form a colony of 50 or more cells. The components of the delay in cycle transit for viable cells heated in G1 for a treatment of 20 min at 45.5 degrees were approximately 28 hr in G1 and 20 hr in S and G2-M. This represents a 7-fold decrease in the rate progression through G1 and a 2-fold decrease through S and G2-M relative to control rates. The doubling times of viable cells, in subsequent generations, were significantly decreased to a rate 61% of that of control up to 120 hr after heating. This reduction was in part due to lethal sectoring, i.e., a division which produces only one daughter that is capable of forming a viable subclone, within the viable progeny. Within a viable subclone, up to 30% of the cells that divided from 48 to 91 hr after a heat treatment of 20 min at 45.5 degrees were found to be nonclonogenic. Following resumption of division, nonviable cells slowly lost their capacity for proliferation. Nearly all thermal tolerance development induced by a 20-min pretreatment occurred while the viable cells remained in G1. Subsequent progression into heat-sensitive S and G2-M phases modulated thermal tolerance only slightly. Finally, maximal loss of thermal tolerance was exhibited at the time corresponding to the resumption of viable cell division.


Systems biology of stored blood cells: can it help to extend the expiration date?
With increasingly stringent regulations regarding deferral and elimination of blood donors it will become increasingly important to extend the expiration date of blood components beyond the current allowed storage periods. One reason for the storage time limit for blood components is that platelets and red blood cells develop a condition called storage lesions during their storage in plastic blood containers. Systems biology provides comprehensive bio-chemical descriptions of organisms through quantitative measurements and data integration in mathematical models. The biological knowledge for a target organism can be translated in a mathematical format and used to compute physiological properties. The use of systems biology represents a concrete solution in the study of blood cell storage lesions, and it may open up new avenues towards developing better storage methods and better storage media, thereby extending the storage period of blood components. This article is part of a Special Issue entitled: Integrated omics.


GhJAZ2 negatively regulates cotton fiber initiation by interacting with the R2R3-MYB transcription factor GhMYB25-like.
Jasmonic acid (JA) signaling has been well studied in Arabidopsis. Most reports focus on the role of JA in biological pathways, such as stress resistance, trichome initiation and anthocyanin accumulation. The JASMONATE ZIM-DOMAIN (JAZ) protein is one of the important repressors in the JA signaling pathway. Previous studies showed that JA functions in fiber initiation and elongation, but little is known about how JAZ genes function in fiber development. In this study, a cotton JAZ protein (GhJAZ2) containing a highly conserved TIFY motif and a C-terminal Jas domain was identified, and its function during cotton fiber development was analysed. Gene expression analysis showed that GhJAZ2 was preferentially expressed in the root, hypocotyl, flower and ovule 1 day before anthesis. Overexpression of GhJAZ2 inhibited both lint and fuzz fiber initiation, and reduced the fiber length. Yeast two-hybrid assays showed that GhJAZ2 interacted with the R2R3-MYB transcription factors GhMYB25-like and GhGL1, the bHLH transcription factor GhMYC2, the WD repeat protein GhWD40 and the unknown protein GhJI1. Among these transcription factors, previous studies showed that downregulation of GhMYB25-like leads to a fiberless phenotype in cotton seeds. Molecular and genetic evidence showed that the GhJAZ2 protein suppresses fiber initiation in the overexpressing lines by interacting with GhMYB25-like and suppressing GhMYB25-like activity. Our results suggested that GhJAZ2 functions as a primary transcription repressor during lint and fuzz fiber initiation by interacting with GhMYB25-like, GhGL1, GhMYC2, GhWD40 and GhJI1 to regulate the JA signaling pathway.


Prevalence of traumatic dental injuries among 12- to 15-year-old schoolchildren in Ambala district, Haryana, India.
To assess the prevalence of traumatic dental injuries (TDIs) among 12- to 15-year-old schoolchildren in the Ambala district of Haryana state, India. A study was carried out on 963 schoolchildren of 15 government schools in the Ambala district. The examiner was calibrated and a pilot study was conducted. Maxillary as well as mandibular anterior teeth were taken into consideration to assess the traumatic dental injuries. The teeth involved, place of and reason for injury and other demographic details were recorded in a structured format. Data were analysed using SPSS version 13.0. Out of 963 subjects, 14.4% (139) had at least one tooth with TDI. Of these subjects, males and females accounted for 16.2% (77) and 12.7% (62), respectively. Permanent maxillary central incisors were the most commonly affected teeth. Enamel fracture was the most common (80% [111]) followed by enamel-dentin fracture (17.2% [24]). A higher number of children with incisal overjet greater than 3 mm had TDI than those with less than 3 mm, although this difference was not statistically significant. Subjects with Class III and Class II Div II malocclusion were more likely to have TDI, 16.2% and 17.7% respectively. Lip-closure incompetence was found to be more common in subjects having a TDI. Amongst the subjects having a TDI, only 83.4% (116) were aware of their injury, and falling was the reason most commonly reported. Traumatic dental injuries are highly prevalent among schoolchildren. Most of the TDIs involve only tooth enamel. Incompetent lip closure was significantly associated with TDIs and a fall was the major cause for TDIs in this age group.


Impact of antiretroviral therapy and changes in virus load on human immunodeficiency virus (HIV)-specific T cell responses in primary HIV infection.
Human immunodeficiency virus (HIV)-specific CD4(+) and CD8(+) T cell responses were evaluated prospectively in a large cohort of subjects with HIV primary infection via long-term follow-up examining different virological profiles related to different treatment interventions. No correlation was observed between baseline virus load and HIV-specific CD4(+) and CD8(+) T cell responses. Highly active antiretroviral therapy (HAART)-induced suppression of viremia was associated with an increase in CD4(+) T cell proliferative responses. The HIV-specific proliferative response also increased, at least in the first 18 months, in subjects with detectable viremia, either treated or untreated. The magnitude of the HIV-specific CD8(+) T cell response decreased with suppression of viremia. In subjects with detectable viremia, the breadth and magnitude of the HIV-specific CD8(+) T cell responses increased progressively. Finally, whether HAART was initiated before or after seroconversion had little effect on HIV-specific CD4(+) and CD8(+) T cell responses.


Hedgehog signaling activation in the development of squamous cell carcinoma and adenocarcinoma of esophagus.
Hedgehog (Hh) signaling is frequently activated in human cancer, including esophageal cancer. Most esophageal cancers are diagnosed in the advanced stages, therefore, identifying the very alterations that drive esophageal carcinogenesis may help designing novel strategies to diagnose and treat the disease. Analysis of Hh signaling in precancerous lesions is a critical first step in determining the significance of this pathway for carcinogenesis. Here we report our data on Hh target gene expression in 174 human esophageal specimens [28 esophageal adenocarcinomas (EAC), 19 Barrett's esophagus, 103 cases of esophageal squamous cell carcinoma (ESCC), and 24 of squamous dysplastic lesions], and in two rat models of esophageal cancer. We found that 96% of human EAC express Hh target genes. We showed that PTCH1 expression is the most reliable biomarker. In contrast to EAC, only 38% of ESCC express Hh target genes. We found activation of Hh signaling in precancerous lesions of ESCCs and EACs in different degrees (21% and 58% respectively). Expression of Hh target genes is frequently detected in severe squamous dysplasia/ carcinoma in situ (p=0.04) and Barrett's esophagus (p=0.01). Unlike EAC, sonic hedgehog (Shh) expression was rare in ESCCs. Consistent with the human specimen data, we found a high percentage of Hh signaling activation in precancerous lesions in rat models. These data indicate that Hh signaling activation is an early molecular event in the development of esophageal cancer, particularly EAC.


Cone beam computed tomography in pre-surgical assessment of mandibular third molars.
DesignMulticentre, randomised controlled clinical trial.InterventionPatients referred for third molar removal received a digital panoramic radiograph(PR). Adults with one or more lower third molars in a close relationship with the mandibular canal were eligible for the study. Patients randomised to the cone beam computed tomography (CBCT) group received a high resolution CBCT scan in addition to the PR. All lower third molar extractions were performed under local anaesthesia without sedation and without antibiotic prophylaxis. Information on variables such as experience of the surgeon, duration of surgery and technique for third molar removal were recorded.Outcome measureThe primary outcome measure was the number of patient-reported altered sensations one week after surgery. Secondary outcomes included the number of patients with an objective IAN injury; permanent IAN injury (>6 months); occurrence of other postoperative complications (wound infection, alveolar osteitis); Oral Health Related Quality of Life-14, questionnaire responses; pain (VAS score); duration of surgery; number of emergency visits; and number of missed days of work or study.ResultsThree hundred and forty-one patients with 477 lower third molars were randomised from three centres. Two hundred and sixty-eight patients with 320 mandibular third molars were analysed according to the intention-to-treat principle for the primary and secondary outcomes. The overall incidence of patient-reported altered sensations one week after surgery was 6.3%. At one week there was no difference in subjective IAN injury between the CBCT and PR group. No significant differences were noted between the two groups for any of the secondary outcomes recorded.ConclusionsAlthough CBCT is a valuable diagnostic adjunct for identification of an increased risk for IAN injury, the use of CBCT does not translate into a reduction of IAN injury and other postoperative complications, after removal of the complete mandibular third molar. In these selected cases with a high risk for IAN injury, an alternative strategy, such as monitoring or a coronectomy, might be more appropriate.


The ubiquitin proteasome system acutely regulates presynaptic protein turnover and synaptic efficacy.
The ubiquitin proteasome system (UPS) mediates regulated protein degradation and provides a mechanism for closely controlling protein abundance in spatially restricted domains within cells. We hypothesized that the UPS may acutely determine the local concentration of key regulatory proteins at neuronal synapses as a means for locally modulating synaptic efficacy and the strength of neurotransmission communication. We investigated this hypothesis at the Drosophila neuromuscular synapse by using an array of genetic and pharmacological tools. This study demonstrates that UPS components are present in presynaptic boutons and that the UPS functions locally in the presynaptic compartment to rapidly eliminate a conditional transgenic reporter of proteasome activity. We assayed a panel of synaptic proteins to determine whether the UPS acutely regulates the local abundance of native synaptic targets. Both acute pharmacological inhibition of the proteasome (<1 hr) and targeted genetic perturbation of proteasome function in the presynaptic neuron cause the specific accumulation of the essential synaptic vesicle-priming protein DUNC-13. Most importantly, acute pharmacological inhibition of the proteasome (<1 hr) causes a rapid strengthening of neurotransmission (an approximately 50% increase in evoked amplitude) because of increased presynaptic efficacy. The proteasome-dependent regulation of presynaptic protein abundance, both of the exogenous reporter and native DUNC-13, and the modulation of presynaptic neurotransmitter release occur on an intermediate, rapid (tens of minutes) timescale. Taken together, these studies demonstrate that the UPS functions locally within synaptic boutons to acutely control levels of presynaptic protein and that the rate of UPS-dependent protein degradation is a primary determinant of neurotransmission strength.


High-dose intravenous immunoglobulin therapy in neonatal immune haemolytic jaundice.
A controlled study was conducted to assess the role of high-dose i.v. immunoglobulin (HDIVIG) therapy in neonatal immune haemolytic jaundice. Patients with ABO and/or Rh incompatibilities proved by significant hyperbilirubinaemia (>204 mmol l(-1)), positive direct antiglobulin test and high reticulocyte count (> or =10%) were randomly assigned to receive either conventional phototherapy alone or phototherapy with high-dose i.v. immunoglobulin (1 g kg(-1), over 4 h) as soon as the diagnosis was established. Exchange transfusions were performed if serum bilirubin concentrations exceeded 290 mmol l(-1) and increased by more than 17 mmol l(-1) per h despite both treatment manoeuvres. Eight of 58 patients in the HDIVIG group required exchange transfusions, whereas it became necessary in 22 of 58 patients in the control group (p<0.001). The durations of phototherapy and hospitalization in terms of hours were significantly shorter in the HDIVIG group (p<0.05). No side effects of HDIVIG therapy were observed. In conclusion, HDIVIG therapy in newborns with ABO or Rh haemolytic diseases reduces haemolysis, serum bilirubin levels and the need for blood exchange transfusion, a procedure which has potential complications and carries a risk of mortality.


Outcomes of women with metachronous breast and ovarian carcinomas.
Women with a history of breast cancer have a significantly increased risk of developing a second primary ovarian cancer and vice versa. We proposed to determine the characteristics and outcomes of women diagnosed with metachronous breast and ovarian cancer. Patients were identified from the Surveillance, Epidemiology, and End Results program database between 1988 and 2001. Kaplan-Meier and Cox proportional hazards regression tests were used to determine survival outcomes. Of 704 women, 526 developed breast cancer then ovarian cancer (B-O) and 178 developed ovarian cancer then breast cancer (O-B). The mean age at diagnosis of the first cancer in the B-O versus O-B group was 60.3 versus 58.9 years, respectively (P = 0.23). Twenty-five percent of women in the B-O group had stage I-II ovarian cancer versus 63% in the O-B group (P < 0.001). The percentage of those with stage I-II breast cancer was 94% and 91% in the B-O versus O-B group, respectively (P = 0.13). Women in the B-O group had more high grade of ovarian cancer compared to those in the O-B group (P < 0.001). The mean time interval between diagnoses of breast then ovarian versus ovarian then breast cancer was 58 versus 56 months, respectively (P = 0.42). In the largest series to date, we found that women diagnosed with ovarian cancer first had significantly more early stage and lower grade ovarian cancers with better survival compared to those with breast cancer followed by ovarian cancer. Since half of the women had their second cancer beyond 5 years, continued surveillance of these high risk patients is recommended.


Origins and demonstrations of electrons with orbital angular momentum.
The surprising message of Allen et al. (Allen et al. 1992 Phys. Rev. A 45, 8185 (doi:10.1103/PhysRevA.45.8185)) was that photons could possess orbital angular momentum in free space, which subsequently launched advancements in optical manipulation, microscopy, quantum optics, communications, many more fields. It has recently been shown that this result also applies to quantum mechanical wave functions describing massive particles (matter waves). This article discusses how electron wave functions can be imprinted with quantized phase vortices in analogous ways to twisted light, demonstrating that charged particles with non-zero rest mass can possess orbital angular momentum in free space. With Allen et al. as a bridge, connections are made between this recent work in electron vortex wave functions and much earlier works, extending a 175 year old tradition in matter wave vortices.This article is part of the themed issue 'Optical orbital angular momentum'.


Challenges of radiotherapy: report on the 4D treatment planning workshop 2013.
This report, compiled by experts on the treatment of mobile targets with advanced radiotherapy, summarizes the main conclusions and innovations achieved during the 4D treatment planning workshop 2013. This annual workshop focuses on research aiming to advance 4D radiotherapy treatments, including all critical aspects of time resolved delivery, such as in-room imaging, motion detection, motion managing, beam application, and quality assurance techniques. The report aims to revise achievements in the field and to discuss remaining challenges and potential solutions. As main achievements advances in the development of a standardized 4D phantom and in the area of 4D-treatment plan optimization were identified. Furthermore, it was noticed that MR imaging gains importance and high interest for sequential 4DCT/MR data sets was expressed, which represents a general trend of the field towards data covering a longer time period of motion. A new point of attention was work related to dose reconstructions, which may play a major role in verification of 4D treatment deliveries. The experimental validation of results achieved by 4D treatment planning and the systematic evaluation of different deformable image registration methods especially for inter-modality fusions were identified as major remaining challenges. A challenge that was also suggested as focus for future 4D workshops was the adaptation of image guidance approaches from conventional radiotherapy into particle therapy. Besides summarizing the last workshop, the authors also want to point out new evolving demands and give an outlook on the focus of the next workshop.


SU-F-BRCD-09: Total Variation (TV) Based Fast Convergent Iterative CBCT Reconstruction with GPU Acceleration.
To improve image quality and reduce imaging dose in CBCT for radiation therapy applications and to realize near real-time image reconstruction based on use of a fast convergence iterative algorithm and acceleration by multi-GPUs. An iterative image reconstruction that sought to minimize a weighted least squares cost function that employed total variation (TV) regularization was employed to mitigate projection data incompleteness and noise. To achieve rapid 3D image reconstruction (< 1 min), a highly optimized multiple-GPU implementation of the algorithm was developed. The convergence rate and reconstruction accuracy were evaluated using a modified 3D Shepp-Logan digital phantom and a Catphan-600 physical phantom. The reconstructed images were compared with the clinical FDK reconstruction results. Digital phantom studies showed that only 15 iterations and 60 iterations are needed to achieve algorithm convergence for 360-view and 60-view cases, respectively. The RMSE was reduced to 10-4 and 10-2, respectively, by using 15 iterations for each case. Our algorithm required 5.4s to complete one iteration for the 60-view case using one Tesla C2075 GPU. The few-view study indicated that our iterative algorithm has great potential to reduce the imaging dose and preserve good image quality. For the physical Catphan studies, the images obtained from the iterative algorithm possessed better spatial resolution and higher SNRs than those obtained from by use of a clinical FDK reconstruction algorithm. We have developed a fast convergence iterative algorithm for CBCT image reconstruction. The developed algorithm yielded images with better spatial resolution and higher SNR than those produced by a commercial FDK tool. In addition, from the few-view study, the iterative algorithm has shown great potential for significantly reducing imaging dose. We expect that the developed reconstruction approach will facilitate applications including IGART and patient daily CBCT-based treatment localization.


Remaining missed opportunities of child survival in Peru: modelling mortality impact of universal and equitable coverage of proven interventions.
Peru has made great improvements in reducing stunting and child mortality in the past decade, and has reached the Millennium Development Goals 1 and 4. The remaining challenges or missed opportunities for child survival needs to be identified and quantified, in order to guide the next steps to further improve child survival in Peru. We used the Lives Saved Tool (LiST) to project the mortality impact of proven interventions reaching every women and child in need, and the mortality impact of eliminating inequalities in coverage distribution between wealth quintiles and urban-rural residence. Our analyses quantified the remaining missed opportunities in Peru, where prioritizing scale-up of facility-based case management for all small and sick babies will be most effective in mortality reduction, compared to other evidenced-based interventions that prevent maternal and child deaths. Eliminating coverage disparities between the poorest quintiles and the richest will reduce under-five and neonatal mortality by 22.0 and 40.6 %, while eliminating coverage disparities between those living in rural and urban areas will reduce under-five and neonatal mortality by 29.3 and 45.2 %. This projected neonatal mortality reduction achieved by eliminating coverage disparities is almost comparable to that already achieved by Peru over the past decade. Although Peru has made great strides in improving child survival, further improvement in child health, especially in newborn health can be achieved if there is universal and equitable coverage of proven, quality health facility-based interventions. The magnitude of reduction in mortality will be similar to what has been achieved in the past decade. Strengthening health system to identify, understand, and direct resources to the poor and rural areas will ensure that Peru achieve the Sustainable Development Goals by 2030.


Selective down-regulation of KV2.1 function contributes to enhanced arterial tone during diabetes.
Enhanced arterial tone is a leading cause of vascular complications during diabetes. Voltage-gated K(+) (KV) channels are key regulators of vascular smooth muscle cells (VSMCs) contractility and arterial tone. Whether impaired KV channel function contributes to enhance arterial tone during diabetes is unclear. Here, we demonstrate a reduction in KV-mediated currents (IKv) in VSMCs from a high fat diet (HFD) mouse model of type 2 diabetes. In particular, IKv sensitive to stromatoxin (ScTx), a potent KV2 blocker, were selectively reduced in diabetic VSMCs. This was associated with decreased KV2-mediated regulation of arterial tone and suppression of the KV2.1 subunit mRNA and protein in VSMCs/arteries isolated from HFD mice. We identified protein kinase A anchoring protein 150 (AKAP150), via targeting of the phosphatase calcineurin (CaN), and the transcription factor nuclear factor of activated T-cells c3 (NFATc3) as required determinants of KV2.1 suppression during diabetes. Interestingly, substantial reduction in transcript levels for KV2.1 preceded down-regulation of large conductance Ca(2+)-activated K(+) (BKCa) channel β1 subunits, which are ultimately suppressed in chronic hyperglycemia to a similar extent. Together, our study supports the concept that transcriptional suppression of KV2.1 by activation of the AKAP150-CaN/NFATc3 signaling axis contributes to enhanced arterial tone during diabetes.


A novel phosphatidylinositol(3,4,5)P3 pathway in fission yeast.
The mammalian tumor suppressor, phosphatase and tensin homologue deleted on chromosome 10 (PTEN), inhibits cell growth and survival by dephosphorylating phosphatidylinositol-(3,4,5)-trisphosphate (PI[3,4,5]P3). We have found a homologue of PTEN in the fission yeast, Schizosaccharomyces pombe (ptn1). This was an unexpected finding because yeast (S. pombe and Saccharomyces cerevisiae) lack the class I phosphoinositide 3-kinases that generate PI(3,4,5)P3 in higher eukaryotes. Indeed, PI(3,4,5)P3 has not been detected in yeast. Surprisingly, upon deletion of ptn1 in S. pombe, PI(3,4,5)P3 became detectable at levels comparable to those in mammalian cells, indicating that a pathway exists for synthesis of this lipid and that the S. pombe ptn1, like mammalian PTEN, suppresses PI(3,4,5)P3 levels. By examining various mutants, we show that synthesis of PI(3,4,5)P3 in S. pombe requires the class III phosphoinositide 3-kinase, vps34p, and the phosphatidylinositol-4-phosphate 5-kinase, its3p, but does not require the phosphatidylinositol-3-phosphate 5-kinase, fab1p. These studies suggest that a pathway for PI(3,4,5)P3 synthesis downstream of a class III phosphoinositide 3-kinase evolved before the appearance of class I phosphoinositide 3-kinases.


Neural correlates of unstructured motor behaviors.
We studied the relationship between uninstructed, unstructured movements and neural activity in three epilepsy patients with intracranial electroencephalographic (iEEG) recordings. We used a custom system to continuously record high definition video precisely time-aligned to clinical iEEG data. From these video recordings, movement periods were annotated via semi-automatic tracking based on dense optical flow. We found that neural signal features (8-32 Hz and 76-100 Hz power) previously identified from task-based experiments are also modulated before and during a variety of movement behaviors. These movement behaviors are coarsely labeled by time period and movement side (e.g. 'Idle' and 'Move', 'Right' and 'Left'); movements within a label can include a wide variety of uninstructed behaviors. A rigorous nested cross-validation framework was used to classify both movement onset and lateralization with statistical significance for all subjects. We demonstrate an evaluation framework to study neural activity related to natural movements not evoked by a task, annotated over hours of video. This work further establishes the feasibility to study neural correlates of unstructured behavior through continuous recording in the epilepsy monitoring unit. The insights gained from such studies may advance our understanding of how the brain naturally controls movement, which may inform the development of more robust and generalizable brain-computer interfaces.


The Dimensionality of Spanish in Young Spanish-English Dual-Language Learners.
This study examined the latent dimensionality of Spanish in young Spanish-English dual-language learners (DLLs). Two hundred eighty-six children participated. In their prekindergarten year, children completed norm-referenced and experimental language measures in Spanish requiring different levels of cognitive processing in both receptive and expressive language modalities. The best-fitting model suggested a bifactor solution with a single general language factor L plus two additional factors word knowledge and integrative language knowledge. The general trait L reflects the proportion of common item variance for all of the items, and the group traits of word knowledge and integrative language knowledge explain additional domain-specific variance for those item subsets. Results suggest that the Spanish language in preschool-age Spanish-English DLLs is not separable into content, form, and use, nor is it separable by higher- and lower-level language domains or processing demands. Instead it appears that a general language factor underlies oral language in Spanish in DLL preschoolers and that other factors account for additional variance over and above L. Findings are discussed in relation to a companion study of monolingual English-speaking prekindergarteners.


UV-induced modification of stress distribution in optical fibers and its contribution to Bragg grating birefringence.
This paper discusses the importance of stress-induced contributions to the photo-induced birefringence observed in fiber Bragg gratings. Optical tomography measurements are performed in exposed and unexposed fibers to extract the stress profiles induced by UV-writing of fiber Bragg gratings for various exposure levels. A photoelastic analysis and a high-order isoparametric finite elements method are then used to calculate the birefringence caused by stress profile modifications. The results are compared to the birefringence directly measured by spectral analysis of a chirped fiber grating with multiple phase-shifts. We can therefore estimate the fraction of the photo-induced birefringence due to stress-induced anisotropy following UV exposure.


Intrawound Vancomycin Decreases the Risk of Surgical Site Infection After Posterior Spine Surgery: A Multicenter Analysis.
Secondary analysis of data from a prospective multicenter observational study. The aim of this study was to evaluate the occurrence of surgical site infection (SSI) in patients with and without intrawound vancomycin application controlling for confounding factors associated with higher SSI after elective spine surgery. SSI is a morbid and expensive complication associated with spine surgery. The application of intrawound vancomycin is rapidly emerging as a solution to reduce SSI following spine surgery. The impact of intrawound vancomycin has not been systematically studied in a well-designed multicenter study. Patients undergoing elective spine surgery over a period of 4 years at seven spine surgery centers across the United States were included in the study. Patients were dichotomized on the basis of whether intrawound vancomycin was applied. Outcomes were occurrence of SSI within postoperative 30 days and SSI that required return to the operating room (OR). Multivariable random-effect log-binomial regression analyses were conducted to determine the relative risk of having an SSI and an SSI with return to OR. .: A total of 2056 patients were included in the analysis. Intrawound vancomycin was utilized in 47% (n = 966) of patients. The prevalence of SSI was higher in patients with no vancomycin use (5.1%) than those with use of intrawound vancomycin (2.2%). The risk of SSI was higher in patients in whom intrawound vancomycin was not used (relative risk (RR) -2.5, P < 0.001), increased number of levels exposed (RR -1.1, P = 0.01), and those admitted postoperatively to intensive care unit (ICU) (RR -2.1, P = 0.005). Patients in whom intrawound vancomycin was not used (RR -5.9, P < 0.001), increased number of levels were exposed (RR-1.1, P = 0.001), and postoperative ICU admission (RR -3.3, P < 0.001) were significant risk factors for SSI requiring a return to the OR. The intrawound application of vancomycin after posterior approach spine surgery was associated with a reduced risk of SSI and return to OR associated with SSI. 2.


Peeling-angle dependence of the stick-slip instability during adhesive tape peeling.
The influence of peeling angle on the dynamics observed during the stick-slip peeling of an adhesive tape has been investigated. This study relies on a new experimental setup for peeling at a constant driving velocity while keeping constant the peeling angle and peeled tape length. The thresholds of the instability are shown to be associated with a subcritical bifurcation and bistability of the system. The velocity onset of the instability is moreover revealed to strongly depend on the peeling angle. This could be the consequence of peeling angle dependance of either the fracture energy of the adhesive-substrate joint or the effective stiffness at play between the peeling front and the point at which the peeling is enforced. The shape of the peeling front velocity fluctuations is finally shown to progressively change from typical stick-slip relaxation oscillations to nearly sinusoidal oscillations as the peeling angle is increased. We suggest that this transition might be controlled by inertial effects possibly associated with the propagation of the peeling force fluctuations through elongation waves in the peeled tape.


Immunohistochemical assessment of cyclic guanosine monophosphate (cGMP) and soluble guanylate cyclase (sGC) within the rostral ventrolateral medulla.
Functional evidence suggests that nitric oxide (NO) signalling in the rostral ventrolateral medulla (RVLM) is cGMP-dependent and that this pathway is impaired in hypertension. We examined cGMP expression as a marker of active NO signalling in the C1 region of the RVLM, comparing adult (>18 weeks) Wistar-Kyoto (WKY, n = 4) and spontaneously hypertensive rats (SHR, n = 4). Double label immunohistochemistry for cGMP-immunoreactivity (IR) and C1 neurons [as identified by phenylethanolamine N-methyltransferase (PNMT-IR) or tyrosine hydroxylase TH-IR)], or neuronal NO synthase (nNOS) neurones, failed to reveal cGMP-IR neurons in the RVLM of either strain, despite consistent detection of cGMP-IR in the nucleus ambiguus (NA). This was unchanged in the presence of isobutylmethylxanthine (IBMX; 0.5 mM, WKY, n = 4, SHR n = 2) and in young animals (WKY, 10-weeks, n = 3). Incubation of RVLM-slices (WKY, 10-weeks, n = 9) in DETA-NO (100 mum; 10 min) or NMDA (10 muM; 2 min) did not uncover cGMP-IR. In all studies, cGMP was prominent within the vasculature. Soluble guanylate cyclase (sGC)-IR was found throughout neurones of the RVLM, but did not co-localise with PNMT, TH or nNOS-IR neurons (WKY, 10-weeks, n = 6). Results indicate that within the RVLM, cGMP is not detectable using immunohistochemistry in the basal state and cannot be elicited by phosphodiesterase inhibition, NMDA receptor stimulation or NO donor application.


Effects of circuit resistance training intensity on the plasma ghrelin to obestatin ratios in healthy young women.
Ghrelin and obestatin are orexigenic and anorexigenic peptides, respectively. It appears that an accurate balance between theses peptides is important for regulating energy homeostasis and body weight. The aim of this study was to identify the possible mechanisms by which circuit resistance training influences energy homeostasis and weight control. Twenty-seven female students with the mean age of 22 ± 1.54 years and mean body mass index (BMI) of 20.76 ± 1.86 kg/m(2) were selected and randomly divided into experimental and control groups. Subjects performed circuit resistance training with 40% and 80% of 1 repetition maximum (1RM) for 4 weeks. Total plasma ghrelin, obestatin, and glucose levels and the ghrelin to obestatin ratio were measured for all subjects before and after training. One-way ANOVA tests showed that, the plasma ghrelin to obestatin ratio increased significantly in the 80% 1RM group (P < 0.05). Furthermore, a significant reduction of the plasma obestatin level was found in this group (P < 0.05). It appears that an energy deficit caused by circuit resistance training in 80% of the 1RM group resulted in the ghrelin precursor being increasingly used for ghrelin production. Thus, obestatin secretion decreased and the ghrelin to obestatin ratio increased in order to stimulate food intake and lost energy resource consumption to eventually restore the energy balance in the body.


The gut microbiota promotes hepatic fatty acid desaturation and elongation in mice.
Interactions between the gut microbial ecosystem and host lipid homeostasis are highly relevant to host physiology and metabolic diseases. We present a comprehensive multi-omics view of the effect of intestinal microbial colonization on hepatic lipid metabolism, integrating transcriptomic, proteomic, phosphoproteomic, and lipidomic analyses of liver and plasma samples from germfree and specific pathogen-free mice. Microbes induce monounsaturated fatty acid generation by stearoyl-CoA desaturase 1 and polyunsaturated fatty acid elongation by fatty acid elongase 5, leading to significant alterations in glycerophospholipid acyl-chain profiles. A composite classification score calculated from the observed alterations in fatty acid profiles in germfree mice clearly differentiates antibiotic-treated mice from untreated controls with high sensitivity. Mechanistic investigations reveal that acetate originating from gut microbial degradation of dietary fiber serves as precursor for hepatic synthesis of C16 and C18 fatty acids and their related glycerophospholipid species that are also released into the circulation.


Dietary supplementation with tributyrin alleviates intestinal injury in piglets challenged with intrarectal administration of acetic acid.
Tributyrin (TBU) is a good dietary source of butyrate and has beneficial effects on the maintenance of normal intestinal morphology. The present study tested the hypothesis that dietary TBU supplementation could alleviate intestinal injury in the acetic acid (ACA)-induced porcine model of colitis. A total of eighteen piglets (25 d old) were randomly allocated to one of three treatment groups (control, ACA and TBU). The control and ACA groups were fed a basal diet and the TBU group was fed the basal diet supplemented with 0·1 % TBU. On day 15 of the trial, under anaesthesia, a soft catheter was inserted into the rectum of piglets (20-25 cm from the anus), followed by administration of either saline (control group) or ACA (10 ml of 10 % ACA solution for ACA and TBU groups). On day 22 of the trial, after venous blood samples were collected, piglets were killed to obtain mid-ileum and mid-colon mucosae. Compared with the control group, the ACA group exhibited an increase (P< 0·05) in lymphocyte counts, creatinine, PGE2, and malondialdehyde concentrations and diamine oxidase and inducible NO synthase activities in the plasma and lymphocyte density in the colon and a decrease in insulin concentrations and glutathione peroxidase activity, ileal villus height:crypt depth ratios and goblet cell numbers in the colon. These adverse effects of ACA were attenuated by TBU supplementation. Moreover, TBU prevented the ACA-induced increase in caspase-3 levels while enhancing claudin-1 protein and epidermal growth factor receptor (EGFR) mRNA expression in the colonic mucosa. Collectively, these results indicate that dietary supplementation with 0·1 % TBU alleviates ACA-induced intestinal injury possibly by inhibiting apoptosis, promoting tight-junction formation and activating EGFR signalling.


The Cognitive Role of the Globus Pallidus interna; Insights from Disease States.
The motor symptoms of both Parkinson's disease and focal dystonia arise from dysfunction of the basal ganglia, and are improved by pallidotomy or deep brain stimulation of the Globus Pallidus interna (GPi). However, Parkinson's disease is associated with a greater degree of basal ganglia-dependent learning impairment than dystonia. We attempt to understand this observation in terms of a comparison of the electrophysiology of the output of the basal ganglia between the two conditions. We use the natural experiment offered by Deep Brain Stimulation to compare GPi local field potential responses in subjects with Parkinson's disease compared to subjects with dystonia performing a forced-choice decision-making task with sensory feedback. In dystonic subjects, we found that auditory feedback was associated with the presence of high gamma oscillations nestled on a negative deflection, morphologically similar to sharp wave ripple complexes described in human rhinal cortex. These were not present in Parkinson's disease subjects. The temporal properties of the high gamma burst were modified by incorrect trial performance compared to correct trial performance. Both groups exhibited a robust low frequency response to 'incorrect' trial performance in dominant GPi but not non-dominant GPi at theta frequency. Our results suggest that cellular processes associated with striatum-dependent memory function may be selectively impaired in Parkinson's disease even if dopaminergic drugs are administered, but that error detection mechanisms are preserved.


Renal handling of X-ray contrast media imaging and exploration with electron beam CT.
Physiologic changes in renal hemodynamics and function reflect its role as a regulatory organ in maintaining homeostasis, whereas other alterations may mirror development of renal injury and often precede overt signs of morphologic changes. Furthermore, intrarenal alterations may be discreet and manifest only in the renal cortical, medullary, or papillary zones. The high spatial and temporal resolution of electron-beam computed tomography enables external detection and quantification of cortical, medullary, and papillary tissue density changes following an intravenous bolus injection of X-ray contrast media. These changes reflect flow of contrast media in these renal zones through the successive renal vascular, glomerular, and tubular compartments that can be individually plotted as time-density curves (TDC). Mathematical modeling then allows calculation of unique parameters of renal function from these TDC. This ability to quantify renal regional attributes may not only shed light on the physiologic mechanisms that the kidney controls, but also assist in detecting subtle impairment in its function.


Attenuation of oxidative stress, inflammation, and endothelial dysfunction in hypercholesterolemic rabbits by allicin.
Allicin, the active substance of garlic, exerts a broad spectrum of pharmacological activities and is considered to have potential therapeutic applications. The present study was designed to investigate the possible beneficial effects of allicin against oxidative stress, inflammation, and endothelial dysfunction in hypercholesterolemic rabbits. Male New Zealand white rabbits were used in this study. Rabbits randomly received 1 of the following treatments: normal chow diet for 4 weeks, 1% high cholesterol diet (HCD), HCD plus allicin (10 mg/kg/day), or HCD plus atorvastatin (10 mg/kg/day). Blood samples were collected at the end of experimental diets for measurement of serum total cholesterol (TC), triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), C-reactive protein (CRP), malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase (SOD). In addition, the aorta was removed for measurement of vascular reactivity, histopathological changes, intima/media (I/M) ratio, and immunohistochemical staining of both tumor necrosis-alpha (TNF-α) and nuclear factor (NF)-κB. HCD induced significant increases in serum TC, TGs, low-density lipoprotein cholesterol (LDL-C), CRP, and MDA. Moreover, HCD caused significant decrease in serum GSH and SOD. In addition, aortic relaxation response to acetylcholine (ACh) was impaired. Immunohistochemical staining of aortic specimens from HCD-fed rabbits revealed high expression levels of both TNF-α and the oxidant-induced transcription factor, NF-κB. Allicin supplementation significantly decreased serum MDA and CRP, increased serum HDL-C, GSH, and SOD levels while nonsignificantly affecting HCD-induced elevations in serum TC and LDL-C. Additionally, allicin significantly protected against HCD-induced attenuation of rabbit aortic endothelium-dependent relaxation to ACh and elevation in I/M ratio. This effect was confirmed by histopathological examination of the aorta. Moreover, allicin has substantially beneficial effects on aortic expression of TNF-α and NF-κB compared with HCD-fed rabbits. In conclusion, these findings demonstrate that allicin may be useful in reducing oxidative stress, inflammation, vascular dysfunction, and the aortic pathology in hypercholesterolemic rabbits.


The 10th anniversary of the Junior Members and Affiliates of the European Academy of Allergy and Clinical Immunology.
This year is the 10th anniversary of the European Academy of Allergy and Clinical Immunology (EAACI) Junior Members and Affiliates (JMAs). The aim of this review is to highlight the work and activities of EAACI JMAs. To this end, we have summarized all the initiatives taken by JMAs during the last 10 yr. EAACI JMAs are currently a group of over 2380 clinicians and scientists under the age of 35 yr, who support the continuous education of the Academy's younger members. For the past decade, JMAs enjoy a steadily increasing number of benefits such as free online access to the Academy's journals, the possibility to apply for Fellowships and the Mentorship Program, travel grants to attend scientific meetings, and many more. In addition, JMAs have been involved in task forces, cooperation schemes with other scientific bodies, organization of JMA focused sessions during EAACI meetings, and participation in the activities of EAACI communication platforms. EAACI JMA activities represent an ideal example of recruiting, training, and educating young scientists in order for them to thrive as future experts in their field. This model may serve as a prototype for other scientific communities, several of which have already adapted similar policies.


Neurosurgery Education and Development program to treat hydrocephalus and to develop neurosurgery in Africa using mobile neuroendoscopic training.
OBJECT A shortage of neurosurgeons and a lack of knowledge of neuroendoscopic management of hydrocephalus limits modern care in sub-Saharan Africa. Hence, a mobile teaching project for endoscopic third ventriculostomy (ETV) procedures and a subsequent program to develop neurosurgery as a permanent specialty in Kenya and Zanzibar were created and sponsored by the Neurosurgery Education and Development (NED) Foundation and the Foundation for International Education in Neurological Surgery. The objective of this work was to evaluate the results of surgical training and medical care in both projects from 2006 to 2013. METHODS Two portable neuroendoscopy systems were purchased and a total of 38 ETV workshops were organized in 21 hospitals in 7 different countries. Additionally, 49 medical expeditions were dispatched to the Coast General Hospital in Mombasa, Kenya, and to the Mnazi Moja Hospital in Zanzibar. RESULTS From the first project, a total of 376 infants with hydrocephalus received surgery. Six-month follow-up was achieved in 22%. In those who received follow-up, ETV efficacy was 51%. The best success rates were achieved with patients 1 year of age or older with aqueductal stenosis (73%). The main causes of hydrocephalus were infection (56%) and spina bifida (23%). The mobile education program interacted with 72 local surgeons and 122 nurses who were trained in ETV procedures. The second project involved 49 volunteer neurosurgeons who performed a total of 360 nonhydrocephalus neurosurgical operations since 2009. Furthermore, an agreement with the local government was signed to create the Mnazi Mmoja NED Institute in Zanzibar. CONCLUSIONS Mobile endoscopic treatment of hydrocephalus in East Africa results in reasonable success rates and has also led to major developments in medicine, particularly in the development of neurosurgery specialty care sites.


CXCR2 expression in tumor cells is a poor prognostic factor and promotes invasion and metastasis in lung adenocarcinoma.
CXCR2 in non-small cell lung cancer (NSCLC) has been studied mainly in stromal cells and is known to increase tumor inflammation and angiogenesis. Here, we examined the prognostic importance of CXCR2 in NSCLC and the role of CXCR2 and its ligands in lung cancer cells. The effect of CXCR2 expression on tumor cells was studied using stable knockdown clones derived from a murine KRAS/p53-mutant lung adenocarcinoma cell line with high metastatic potential and an orthotopic syngeneic mouse model and in vitro using a CXCR2 small-molecule antagonist (SB225002). CXCR2 protein expression was analyzed in tumor cells from 262 NSCLC. Gene expression profiles for CXCR2 and its ligands (CXCR2 axis) were analyzed in 52 human NSCLC cell lines and 442 human lung adenocarcinomas. Methylation of CXCR2 axis promoters was determined in 70 human NSCLC cell lines. Invasion and metastasis were decreased in CXCR2 knockdown clones in vitro and in vivo. SB225002 decreased invasion in vitro. In lung adenocarcinomas, CXCR2 expression in tumor cells was associated with smoking and poor prognosis. CXCR2 axis gene expression profiles in human NSCLC cell lines and lung adenocarcinomas defined a cluster driven by CXCL5 and associated with smoking, poor prognosis, and RAS pathway activation. Expression of CXCL5 was regulated by promoter methylation. The CXCR2 axis may be an important target in smoking-related lung adenocarcinoma.


Retinoids as important regulators of terminal differentiation: examining keratin expression in individual epidermal cells at various stages of keratinization.
When human epidermal cells were seeded on floating rafts of collagen and fibroblasts, they stratified at the air-liquid interface. The suprabasal cells synthesized the large type II (K1) and type I (K10/K11) keratins characteristic of terminal differentiation in skin. At earlier times in culture, expression of the large type II keratins appeared to precede the expression of their type I partners. At later times, all suprabasal cells expressed both types, suggesting that the accumulation of a critical level of K1 keratin may be a necessary stimulus for K10 and K11 expression. Expression of the terminal differentiation-specific keratins was completely suppressed by adding retinoic acid to the culture medium, or by submerging the cultures in normal medium. In submerged cultures, removal of vitamin A by delipidization of the serum restored the keratinization process. In contrast, calcium and transforming growth factor-beta did not influence the expression of the large keratins in keratinocytes grown in the presence of retinoids, even though they are known to induce certain morphological features of terminal differentiation. Retinoic acid in the raft medium not only suppressed the expression of the large keratins, but, in addition, induced the synthesis of two new keratins not normally expressed in epidermis in vivo. Immunofluorescence localized one of these keratins, K19, to a few isolated cells of the stratifying culture. In contrast, the other keratin, K13, appeared uniformly in a few outer layers of the culture. Interestingly, K13 expression correlated well with the gradient of retinoid-mediated disruptions of intercellular interactions in the culture. These data suggest that K13 induction may in some way relate to the reduction in either the number or the strength of desmosomal contacts between suprabasal cells of stratified squamous epithelial tissues.