Renal responses of the cardiac-denervated nonhuman primate to blood volume expansion.
Experiments were performed to determine whether total, specific cardiac denervation affects the renal responses of the nonhuman primate to acute intravascular volume expansion. Adult male Macaca fascicularis monkeys underwent chronic intrapericardial cardiac denervation or sham surgery. After a 14- to 30-day recovery period, each animal was anesthetized with sodium pentobarbital and estimated blood volume was volume-expanded 20% with 6% dextran in isotonic saline. Control renal excretory function did not differ between the two groups, and both groups had similar increases in urine flow, sodium and potassium excretion, osmolar clearance, free water clearance, and renal plasma flow after volume expansion. The times to peak diuresis and natriuresis also were similar in both groups. These results demonstrate that the cardiac-denervated monkey shows unattenuated renal excretory responses to volume expansion. This could indicate that either cardiac receptors do not play a major role in eliciting these responses in the primate or that eliminating a role of cardiac afferents is compensated for by redundant afferents from arterial baroreceptors.


Macrophage-elicited loss of estrogen receptor-α in breast cancer cells via involvement of MAPK and c-Jun at the ESR1 genomic locus.
Estrogen receptor-α (ERα, ESR1) is a pivotal transcriptional regulator of breast cancer physiology and is targeted by endocrine therapies. Loss of ERα activity or expression is an indication of endocrine resistance and is associated with increased risk of tumor recurrence and worse prognosis. In this study, we sought to investigate whether elements of the tumor microenvironment, namely macrophages, would impact on ERα and we found that macrophage-derived factors caused loss of ERα expression in breast cancer cells. Conditioned media from macrophages caused activation of several intracellular pathways in breast cancer cells of which c-Src, protein kinase c and mitogen-activated protein kinase (MAPK) were essential for loss of ERα expression. Moreover, a prolonged hyperactivation of MAPK was observed. The activation of this kinase cascade resulted in recruitment of extracellular signal regulated kinase 2 (ERK2) directly to chromatin at the ESR1 gene locus in a process that was dependent upon activation and recruitment of the c-Jun transcription factor. Thus, we identify a novel mechanism for loss of ERα expression in breast cancer cells via macrophage activation of kinase cascades in the cancer cells causing transcriptional repression of the ESR1 gene by a direct chromatin action of a c-Jun/ERK2 complex. The findings in this study support an alternative mechanism, not intrinsic to the tumor cell but derived from the cross-talk with the tumor microenvironment, that could lead to endocrine resistance and might be targeted therapeutically to prevent loss of ERα expression in breast tumors.


A late-onset congenital myasthenic syndrome due to a heterozygous DOK7 mutation.
Congenital myasthenic syndromes are disorders of the neuromuscular junction resulting from genetic defects in its components. Clinical presentations are diverse and virtually always of early onset. We report a 67-year-old female patient first presenting with episodes of sudden respiratory failure. A diagnosis of seronegative myasthenia gravis was put forward based on the presence of a limb-girdle pattern of muscle weakness with pathological decremental responses on Repetitive Nerve Stimulation. Lack of response to steroids, intravenous human immunoglobulin and acetylcholinesterase inhibitors lead us to test for classical congenital myasthenic syndrome genes. A c.1378dup heterozygotic mutation in DOK7 was found, classically (albeit not exclusively) described as pathogenic only when inherited in a homozygotic fashion. Patients with such a single, heterozygous mutation have been previously described, but these have been left unexplained. Thus, under certain still poorly understood circumstances, a heterozygotic state may allow for disease manifestation. These patients may benefit from tailored therapies akin to those normally reserved to homozygotic/compound heterozygotic patients. Awareness for and recognition of such conditions are expected to allow for better provided care and improved quality of life.


Identification of an N2 line protein of striated muscle.
Three unusually large myofibrillar proteins (Mr, > 500,000) are present in major amounts in the striated muscle of various species. the molecular properties and localization of two of these proteins (Mr, approximately 1 X 10(6)), named "titin," have been reported recently [Wang, K., McClure, J. & Tu, A.(1979) Proc. Natl. Acad. Sci. USA 76, 3698-3702]. We have now purified the third protein (Mr, approximately 5-6 X 10(5)), designated "band 3," from rabbit psoas myofibrils. Band 3 is distinct chemically and immunochemically from titin and myosin heavy chain. Immunofluorescent localization studies of band 3 in glycerinated rabbit psoas myofibrils indicated a biphasic distribution. In sarcomeres 1.8-3.7 micrometer long, band 3 is localized predominately on the N2 line in the phase-contrast lucent region of the I band. Quantitative analysis of light micrographs confirmed the unique behavior of N2 lines described in early electron microscopic studies. As the sarcomeres lengthen, the N2 line moves away from both the Z line and the M line, maintaining the same proportional distance. In very short sarcomeres (1.5-1.8 micrometer), band 3 is found mainly in the A band, suggesting that either the N2 line moves into the A band or that band 3 has dissociated from the N2 line which remains near the Z line. We conclude that band 3 is an N2 line component of rabbit skeletal myofibrils.


Performing a Definitive Fusion in Juvenile CP Patients is a Good Surgical Option.
In juveniles with progressive curves, there is debate regarding the use of growth friendly implants versus definitive fusion. This study presents outcomes of juvenile cerebral palsy (CP) scoliosis patients who underwent definitive fusion before age 11. A review of a prospective, multicenter registry identified patients 10 years and younger who had a definitive posterior fusion for their CP scoliosis. Preoperative and postoperative demographic and radiographic changes were evaluated with descriptive statistics. Repeated measures analysis of variance were utilized to compare outcome scores. Fourteen children with a mean age of 9.7 years (8.3 to 10.8 y) and a minimum of 2 years follow-up (range 2 to 3 y) were identified. The mean preoperative curve magnitude and pelvic obliquity was 84±25 degrees (range 63 to 144 degrees) and 25±14 degrees, respectively. All patients were skeletally immature with open triradiate cartilage. Three patients had unit rods with wires while the rest incorporated pedicle screws. Immediately postoperation, the average major curve was 25±17 degrees (P≤0.001, 71% correction rate). At most recent follow-up, the average major curve increased to 30±18 degrees (P≤0.001) for a 65% correction rate. Pelvic obliquity improved to 4±4 degrees (84% correction, P≤0.001) immediately postoperation and to 6±5 degrees (P=0.002) at latest follow-up for a 76% correction rate. None of the patients required revision surgery for progression. From pre to most recent follow-up, the CPchild Health outcome scores improved from 47 to 58 (P=0.019). One patient had a deep infection, and 1 patient had a broken rod that did not require any further treatment. Progressive scoliosis in juvenile CP patients requires the surgeon to balance the need for further growth with the risks of progression or repeated surgical procedures. Our study demonstrates that definitive fusion once the curves approach 90 degrees results in significant radiographic and quality of life improvements, but further follow-up is needed to determine whether those results remain after skeletal maturity. Level IV-therapeutic.


Neuronal repellent Slit2 inhibits dendritic cell migration and the development of immune responses.
One of the essential functions of dendritic cells is to take up Ags in peripheral tissues and migrate into secondary lymphoid organs to present Ags to lymphocytes for the induction of immune responses. Although many studies have demonstrated that the migration of dendritic cells is closely associated with the development of immune responses, little is known about factors that inhibit dendritic cell migration and control the extent of immune responses to Ag stimulation. We show that Slit2, a neuronal repellent factor, is up-regulated in the skin by allergen sensitization and down-regulates the migration of Langerhans cells. The effect is mediated by direct interaction of Slit2 with cells that express a Slit-specific receptor, Robo1. Slit2-mediated inhibition of Langerhans cell migration results in suppression of contact hypersensitivity responses. These findings provide insights into a novel mechanism by which Slit2 functions as an anti-inflammatory factor for the initiation of immune responses.


The bodily experience of cerebral palsy: a journey to self-awareness.
The aim of the study was to describe the lived bodily experience of cerebral palsy (CP). This was a descriptive phenomenological inquiry. Ten participants were interviewed about their bodily experiences of living with CP. Interviews were semi-structured around pain and fatigue. Inductive thematic analysis was used to identify themes. The bodily experience of CP centered on issues of fatigue and pain as a feeling of muscle soreness. An overwhelming amount of the discussion on fatigue emphasized the fatigue that occurs with walking and prolonged activity. Self-awareness of the individuals' own bodies and adapting activity to continue to participate in various aspects of their lives emerged as the most important theme. Some participants used strategies to manage their pain or fatigue; other participants were not yet fully aware of how to recognize signs of fatigue and/or how to adapt their activities. Self-awareness appears to be an important process to be fostered by service providers and parents. Specifically, encouraging youth with CP to be aware of their own bodies and the effects (positive and negative) of activity on pain and fatigue should be incorporated into transition programs as the individual becomes responsible for his or her own health care needs. Implications for Rehabilitation Fatigue is a major concern for some youth and young adults with cerebral palsy. Adolescents and young adults with cerebral palsy use a variety of techniques (including adapting or restricting activity and building in rest breaks) to manage fatigue. The process of self-awareness should be fostered by health care professionals leading up to and during transition from pediatric to adult care. Clinical conversations should explore the role of exercise, adaptive equipment, rest and other strategies for dealing with fatigue with a focus on understanding each client's needs individually.


Lafora-body disease with optic atrophy, macular degeneration and cardiac failure.
A 17-year-old boy was admitted to hospital in acute cardiac failure and psychosis. The clinical course, EEG records and tissue diagnosis, including biopsies of brain, skin, skeletal muscle, peripheral nerve and liver were compatible with Lafora-body disease (LBD). Unusual features were those of optic atrophy and macular degeneration, signs generally regarded as negative criteria for the diagnosis of this disease. We also present the findings on endomyocardial biopsy which was performed because cardiac failure as an early symptom of LBD has not been previously described. The patient died in status epilepticus a few months after discharge from hospital.


Integrated Genomic and Proteomic Analyses of High-level Chloramphenicol Resistance in Campylobacter jejuni.
Campylobacter jejuni is a major zoonotic pathogen, and its resistance to antibiotics is of great concern for public health. However, few studies have investigated the global changes of the entire organism with respect to antibiotic resistance. Here, we provide mechanistic insights into high-level resistance to chloramphenicol in C. jejuni, using integrated genomic and proteomic analyses. We identified 27 single nucleotide polymorphisms (SNPs) as well as an efflux pump cmeB mutation that conferred modest resistance. We determined two radical S-adenosylmethionine (SAM) enzymes, one each from an SNP gene and a differentially expressed protein. Validation of major metabolic pathways demonstrated alterations in oxidative phosphorylation and ABC transporters, suggesting energy accumulation and increase in methionine import. Collectively, our data revealed a novel rRNA methylation mechanism by a radical SAM superfamily enzyme, indicating that two resistance mechanisms existed in Campylobacter. This work provided a systems biology perspective on understanding the antibiotic resistance mechanisms in bacteria.


The Assessment of Clinical Outcomes and Prognostic Factors in Glioblastoma Patients.
To assess the outcomes of glioblastoma patients treated in our clinic over the last 10 years using a multimodality approach and cutting-edge techniques. In our study, we included 169 glioblastoma patients who were admitted to our clinic between 2009 and 2019 and received concurrent radiotherapy (RT) + temozolomide (TMZ) after surgery. Patients were collected retrospectively and analyzed using appropriate statistical methods. The average follow-up period was 19 months. The average overall survival (OS) was 20.5 months. PFS and PPS were found to be 10.8 and 8.9 months, respectively. In the multivariate analysis for prognostic factors on OS, the Karnofsky Performance Score (KPS), the extent of resection (EOR), and the use of adjuvant TMZ were significant. PFS was significantly predicted by KPS, EOR, adjuvant TMZ, and planning target volume (PTV). Acute severe lymphopenia (ASL) following RT reduced the OS and PFS. There was no statistical difference in OS, PFS, recurrence patterns, or ASL incidence between the RTOG and EORTC regimens and RT techniques (IMRT vs. 3D-CRT). The association between dose-volume parameters (V3, V5, V10, V15, and V20 and V25, V30, V40, and V60 Gy) and post-treatment ASL frequency was studied. For each parameter, threshold levels were discovered. Furthermore, patients with recurrent glioblastoma who received salvage therapies had better outcomes. A multidisciplinary, and intensive treatment approach using modern techniques improved the OS of glioblastoma patients. Furthermore, in glioblastoma patients, larger RT fields were not associated with better outcomes. As a result, lymphocytesparing RT may be more beneficial in increasing patients' compliance to adjuvant TMZ, which is an important prognostic factor of OS.


Dissecting the first and the second meiotic divisions using a marker-less drug-hypersensitive fission yeast.
Faithful chromosome segregation during meiosis is indispensable to prevent birth defects and infertility. Canonical genetic manipulations have not been very useful for studying meiosis II, since mutations of genes involved in cell cycle regulation or chromosome segregation may affect meiosis I, making interpretations of any defects observed in meiosis II complicated. Here we present a powerful strategy to dissect meiosis I and meiosis II, using chemical inhibitors in genetically tractable model organism fission yeast (Schizosaccharomyces pombe). As various chemical probes are not active in fission yeast, mainly due to an effective multidrug resistance (MDR) response, we have recently developed a drug-hypersensitive MDR-sup strain by suppression of the key genes responsible for MDR response. We further developed the MDR-supML (marker-less) strain by deleting 7 MDR genes without commonly used antibiotic markers. The new strain makes fluorescent tagging and gene deletion much simpler, which enables effective protein visualization in varied genetic backgrounds. Using the MDR-supML strain with chemical inhibitors and live cell fluorescence microscopy, we established cell cycle arrest at meiosis I and meiosis II and examined Aurora-dependent spindle assembly checkpoint (SAC) regulation during meiosis. We found that Aurora B/Ark1 kinase activity is required for recruitment of Bub1, an essential SAC kinase, to unattached kinetochore in prometaphase I and prometaphase II as in mitosis. Thus, Aurora's role in SAC activation is likely conserved in mitosis, meiosis I, and meiosis II. Together, our MDR-supML strain will be useful to dissect complex molecular mechanisms in mitosis and 2 successive meiotic divisions.


Amygdala and nucleus accumbens in responses to receipt and omission of gains in adults and adolescents.
Adolescents' propensity for risk-taking and reward-seeking behaviors suggests a heightened sensitivity for reward, reflected by greater feedback-related activity changes in reward circuitry (e.g., nucleus accumbens), and/or a lower sensitivity to potential harm reflected by weaker feedback-related activity changes in avoidance circuitry (e.g., amygdala) relative to adults. Responses of nucleus accumbens and amygdala to valenced outcomes (reward receipt and reward omission) were assayed using an event-related functional magnetic resonance imaging procedure paired with a monetary reward task in 14 adults and 16 adolescents. Bilateral amygdala and nucleus accumbens showed significantly greater activation when winning than when failing to win in both groups. Group comparisons revealed stronger activation of left nucleus accumbens by adolescents, and of left amygdala by adults. When examining responses to reward receipts and to reward omissions separately, the most robust group difference was within the amygdala during reward omission. The reduction of the fMRI BOLD signal in the amygdala in response to reward omission was larger for adults than for adolescents. Correlations showed a close link between negative emotion and amygdala decreased BOLD signal in adults, and between positive emotion and nucleus accumbens activation in adolescents. Overall, these findings support the notion that the signal differences between positive and negative outcomes involve the nucleus accumbens more in adolescents than in adults, and the amygdala more in adults than in adolescents. These developmental differences, if replicated, may have important implications for the development of early-onset disorders of emotion and motivation.


FGF23 expression is stimulated in transgenic α-Klotho longevity mouse model.
Observations in transgenic α-Klotho (Kl) mice (KlTg) defined the antiaging role of soluble Klotho (sKL130). A genetic translocation that elevates sKL levels in humans is paradoxically associated with increased circulating fibroblast growth factor 23 (FGF23) levels and the potential of both membrane KL (mKL135) and sKL130 to act as coreceptors for FGF23 activation of fibroblast growth factor receptors (FGFRs). Neither FGF23 expression nor the contributions of FGF23, mKL135, and sKL130 codependent and independent functions have been investigated in KlTg mice. In the current study, we examined the effects of Kl overexpression on FGF23 levels and functions in KlTg mice. We found that mKL135 but not sKL130 stimulated FGF23 expression in osteoblasts, leading to elevated Fgf23 bone expression and circulating levels in KlTg mice. Elevated FGF23 suppressed 1,25(OH)2D and parathyroid hormone levels but did not cause hypophosphatemic rickets in KlTg mice. KlTg mice developed low aldosterone-associated hypertension but not left ventricular hypertrophy. Mechanistically, we found that mKL135 and sKL130 are essential cofactors for FGF23-mediated ERK activation but that they inhibited FGF23 stimulation of PLC-γ and PI3K/AKT signaling. Thus, increased longevity in KlTg mice occurs in the presence of excess FGF23 that interacts with mKL and sKL to bias FGFR pathways.


Risk of acute myeloid leukaemia and multiple myeloma in workers exposed to benzene.
To determine the risk of developing acute myeloid leukaemia (AML) and multiple myeloma in a cohort of workers exposed to benzene. The results were used to show the importance of taking specificity of disease into consideration in causation analysis. Data were derived from a cohort of workers employed at two Goodyear plants in Ohio in the manufacture of Pliofilm. Based on data in the Pliofilm study, several papers that examined the relation between exposure to benzene and leukaemia (all cell types combined) have been published. In the current analyses based on updated data in the study, standardised mortality ratios (SMRs) and 95% confidence intervals (95% CIs) were calculated for AML and multiple myeloma by cumulative exposure to benzene. The results based on AML were compared with those for leukaemia (all cell types combined) published previously. An exposure response relation was shown between cumulative exposure to benzene and AML. No increased risk of AML was detected for cumulative exposure to benzene below 200 ppm-years (SMR 0.91). Above 200 ppm-years, risk of AML rose drastically; reaching a significant SMR of 98.37 for > 400 ppm-years. For multiple myeloma, no relation with exposure to benzene was detected. Analysis specific to AML shows the importance of taking specificity of disease into consideration in causation analysis. This investigation shows that previous analyses based on all leukaemia cell types combined have incorrectly set the estimated threshold too low, and have underestimated risk above the threshold. Current regulatory policies that rely on previous analyses based on all leukaemia cell types combined should be re-examined.


Activation of the multiple drug resistance gene MDR1 in fluconazole-resistant, clinical Candida albicans strains is caused by mutations in a trans-regulatory factor.
Resistance of Candida albicans against the widely used antifungal agent fluconazole is often due to active drug efflux from the cells. In many fluconazole-resistant C. albicans isolates the reduced intracellular drug accumulation correlates with constitutive strong expression of the MDR1 gene, encoding a membrane transport protein of the major facilitator superfamily that is not detectably expressed in vitro in fluconazole-susceptible isolates. To elucidate the molecular changes responsible for MDR1 activation, two pairs of matched fluconazole-susceptible and resistant isolates in which drug resistance coincided with stable MDR1 activation were analyzed. Sequence analysis of the MDR1 regulatory region did not reveal any promoter mutations in the resistant isolates that might account for the altered expression of the gene. To test for a possible involvement of trans-regulatory factors, a GFP reporter gene was placed under the control of the MDR1 promoter from the fluconazole-susceptible C. albicans strain CAI4, which does not express the MDR1 gene in vitro. This MDR1P-GFP fusion was integrated into the genome of the clinical C. albicans isolates with the help of the dominant selection marker MPA(R) developed for the transformation of C. albicans wild-type strains. Integration was targeted to an ectopic locus such that no recombination between the heterologous and resident MDR1 promoters occurred. The transformants of the two resistant isolates exhibited a fluorescent phenotype, whereas transformants of the corresponding susceptible isolates did not express the GFP gene. These results demonstrate that the MDR1 promoter was activated by a trans-regulatory factor that was mutated in fluconazole-resistant isolates, resulting in deregulated, constitutive MDR1 expression.


Role of the β3-adrenergic receptor subtype in catecholamine-induced myocardial remodeling.
β3-Adrenoceptors (AR) stimulate cardiac Na+/K+ pump in healthy hearts. β3-ARs are upregulated by persistent sympathetic hyperactivity; however, their effect on Na+/K+ ATPase activity and ventricular function in this condition is still unknown. Here, we investigate preventive effects of additional β3-AR activation (BRL) on Na+/K+ ATPase activity and in vivo hemodynamics in a model of noradrenaline-induced hypertrophy. Rats received NA or NA plus simultaneously administered BRL in vivo infusion for 14 days; their cardiac function was investigated by left ventricular pressure-volume analysis. Moreover, fibrosis and apoptosis were also assessed histologically. NA induced an hypertrophic pattern, as detected by morphological, histological, and biochemical markers. Additional BRL exposure reversed the hypertrophic pattern and restored Na+/K+ ATPase activity. NA treatment increased systolic function and depressed diastolic function (slowed relaxation). Additional BRL treatment reversed most NA-induced hemodynamic changes. NA decreased Na+/K+ pump α2 subunit expression selectively, a change also reversed by additional BRL treatment. Increasing β3-AR stimulation may prevent the consequences of chronic NA exposure on Na+/K+ pump and in vivo hemodynamics. β3-AR agonism may thus represent a new therapeutic strategy for pharmacological modulation of hypertrophy under conditions of chronically enhanced sympathetic activity.


Import of fructose bisphosphate aldolase into the glycosomes of Trypanosoma brucei.
The glycolytic enzymes of Trypanosomatids are compartmentalized within peroxisome-like microbodies called glycosomes. Fructose bisphosphate aldolase is synthesized on free polysomes and imported into glycosomes within 5 min. Peptide mapping reveals no primary structural differences between the in vivo-synthesized protein and that made in vitro from a synthetic template. However, native aldolase from glycosomes is partially protease resistant, whereas the in vitro translation product is not. Pulse-chase results indicate that aldolase in bloodstream trypanosomes has a much longer half-life than in the procyclic tsetse fly form.


Study of parameters to ensure quality control in histopathology reporting: a meta-analysis at a tertiary care center.
When surgical pathology reports are dispatched to patients and clinicians, sometimes they are discovered to have errors, and it is a common practice for the pathologists to issue amended reports. Measuring the rate at which surgical pathology reports are amended can be used as a tool for assuring quality control in histopathology. The aim of this study was determine the parameters that can be used as an assessment tool to minimize errors in histopathology. This study was carried out at a major histopathology center. The duration of this study was from January 2001 through January 2011(ten years). Following parameters were looked for: Interpretational errors, permanent and frozen section correlation, intradepartmental consultation and cases sent for second opinion, cases brought in tissue committee meetings, audits, and cases discussed in hospital meetings. A total of 28,1931 surgical pathology cases were signed out during the ten-year period. On these, addendums were issued on 5730 cases (2.0%). Additional report issued on 3521 (1.3%). Addendum/corrected report issued for 2209 cases, which was 0.7%, representing the true interpretational error. And out of this number, a second opinion was taken for 5980 cases, and 78 were sent abroad for second opinion. Review by a second pathologist is a strong tool to minimize errors in surgical pathology reporting. This may be done prior to or after the report is dispatched and the case is discussed in the hospital for treatment purposes. This analysis concludes that true interpretational error occurred only in 0.7% of cases, which is an attribute to the strong peer review in the department.


Active and passive fatigue in simulated driving: discriminating styles of workload regulation and their safety impacts.
Despite the known dangers of driver fatigue, it is a difficult construct to study empirically. Different forms of task-induced fatigue may differ in their effects on driver performance and safety. Desmond and Hancock (2001) defined active and passive fatigue states that reflect different styles of workload regulation. In 2 driving simulator studies we investigated the multidimensional subjective states and safety outcomes associated with active and passive fatigue. Wind gusts were used to induce active fatigue, and full vehicle automation to induce passive fatigue. Drive duration was independently manipulated to track the development of fatigue states over time. Participants were undergraduate students. Study 1 (N = 108) focused on subjective response and associated cognitive stress processes, while Study 2 (N = 168) tested fatigue effects on vehicle control and alertness. In both studies the 2 fatigue manipulations produced different patterns of subjective response reflecting different styles of workload regulation, appraisal, and coping. Active fatigue was associated with distress, overload, and heightened coping efforts, whereas passive fatigue corresponded to large-magnitude declines in task engagement, cognitive underload, and reduced challenge appraisal. Study 2 showed that only passive fatigue reduced alertness, operationalized as speed of braking and steering responses to an emergency event. Passive fatigue also increased crash probability, but did not affect a measure of vehicle control. Findings support theories that see fatigue as an outcome of strategies for managing workload. The distinction between active and passive fatigue is important for assessment of fatigue and for evaluating automated driving systems which may induce dangerous levels of passive fatigue.


Common cues in vascular and axon guidance.
Blood vessels and nerves are structured in architecturally similar organ systems and show functional relationships. Indeed, vascular and neuronal cells are guided in their journey throughout the body by the same attractive and repulsive factors that respectively activate and inhibit the function of integrin-adhesive receptors.


Motor coordination, activity, and fitness at 6 years of age relative to activity and fitness at 10 years of age.
Health benefits of physical activity (PA) and physical fitness (PF) are reasonably well established, but tracking studies of PA and PF in childhood have not ordinarily considered the role of motor coordination. To compare the growth status, gross motor coordination (GMC), PA, and PF characteristics of children at 6 years of age relative to aerobic fitness (fit, unfit) and PA (active, sedentary) at 10 years. 285 primary school children (142 girls, 143 boys) resident on the 4 main Azorean islands, Portugal, were measured annually (in the fall) from 6 to 10 years. ANOVA and t tests were computed with SPSS 17. Children with either high aerobic fitness or with high level of PA at 10 years of age tended to have a more favorable profile at 6 years compared with those with low fitness or low activity, respectively. Children who were both fit and active at 10 years of age had a more favorable activity and fitness profile and had better GMC at 6 years compared with children who were unfit and sedentary. Results highlight the need to consider not only PA, but also PF and GMC in health promotion through the primary school years.


Molecular analysis of a Saccharomyces cerevisiae mutant with improved ability to utilize xylose shows enhanced expression of proteins involved in transport, initial xylose metabolism, and the pentose phosphate pathway.
Differences between the recombinant xylose-utilizing Saccharomyces cerevisiae strain TMB 3399 and the mutant strain TMB 3400, derived from TMB 3399 and displaying improved ability to utilize xylose, were investigated by using genome-wide expression analysis, physiological characterization, and biochemical assays. Samples for analysis were withdrawn from chemostat cultures. The characteristics of S. cerevisiae TMB 3399 and TMB 3400 grown on glucose and on a mixture of glucose and xylose, as well as of S. cerevisiae TMB 3400 grown on only xylose, were investigated. The strains were cultivated under chemostat conditions at a dilution rate of 0.1 h(-1), with feeds consisting of a defined mineral medium supplemented with 10 g of glucose liter(-1), 10 g of glucose plus 10 g of xylose liter(-1) or, for S. cerevisiae TMB 3400, 20 g of xylose liter(-1). S. cerevisiae TMB 3400 consumed 31% more xylose of a feed containing both glucose and xylose than S. cerevisiae TMB 3399. The biomass yields for S. cerevisiae TMB 3400 were 0.46 g of biomass g of consumed carbohydrate(-1) on glucose and 0.43 g of biomass g of consumed carbohydrate(-1) on xylose. A K(s) value of 33 mM for xylose was obtained for S. cerevisiae TMB 3400. In general, the percentage error was <20% between duplicate microarray experiments originating from independent fermentation experiments. Microarray analysis showed higher expression in S. cerevisiae TMB 3400 than in S. cerevisiae TMB 3399 for (i) HXT5, encoding a hexose transporter; (ii) XKS1, encoding xylulokinase, an enzyme involved in one of the initial steps of xylose utilization; and (iii) SOL3, GND1, TAL1, and TKL1, encoding enzymes in the pentose phosphate pathway. In addition, the transcriptional regulators encoded by YCR020C, YBR083W, and YPR199C were expressed differently in the two strains. Xylose utilization was, however, not affected in strains in which YCR020C was overexpressed or deleted. The higher expression of XKS1 in S. cerevisiae TMB 3400 than in TMB 3399 correlated with higher specific xylulokinase activity in the cell extracts. The specific activity of xylose reductase and xylitol dehydrogenase was also higher for S. cerevisiae TMB 3400 than for TMB 3399, both on glucose and on the mixture of glucose and xylose.


Changes in intracellular pH associated with glutamate excitotoxicity.
Excitotoxic neuronal injury is known to be associated with increases in cytosolic calcium ion concentrations. However, it is not known if perturbations in other intracellular ions are also associated with glutamate (GLU)-induced neuronal death. Accordingly, intracellular hydrogen ion concentrations were measured in cultured hippocampal neurons with the fluorescent dye BCECF during and after toxic exposures. Five minute GLU applications produced an initial cytosolic acidification. During the hour after GLU removal, intracellular pH (pHi) recovered steadily, resulting in a rebound cytosolic alkalinization. Lowering extracellular calcium depressed the initial GLU-induced acidification, suggesting that the rapid acidification may result partly as a consequence of calcium entry. An acidification-induced rebound alkalinization appeared to be activated by GLU exposure. Inhibitors of intracellular pH regulation, harmaline, 4,4'-disothiocyanatostilbene-2,2'-disulfonic acid (DIDS), and replacement of external Na+ with N-methyl-glucamine+ (NMG+), retarded the rate of recovery from GLU-induced acidification. The rapid acidification and rebound alkalinization could be mimicked by challenging neurons with elevated external K+ or replacement of external Na+ with NMG+. Two or more hours following toxic GLU exposure, hydrogen ion concentration did not stabilize at initial levels but progressively increased. High K+ or Na+ removal did not produce this long-term acidification and were not toxic. The cumulative increase in intracellular hydrogen ion may reflect the declining health of injured neurons and could contribute directly to neuronal death. Therefore, cytosolic acidification may act synergistically with increases in calcium concentration in mediating excitotoxicity.


Effects of low-level laser therapy and eccentric exercises in the treatment of recreational athletes with chronic achilles tendinopathy.
Eccentric exercises (EEs) are recommended for the treatment of Achilles tendinopathy, but the clinical effect from EE has a slow onset. The addition of low-level laser therapy (LLLT) to EE may cause more rapid clinical improvement. Randomized controlled trial; Level of evidence, 1. A total of 52 recreational athletes with chronic Achilles tendinopathy symptoms were randomized to groups receiving either EE + LLLT or EE + placebo LLLT over 8 weeks in a blinded manner. Low-level laser therapy (lambda = 820 nm) was administered in 12 sessions by irradiating 6 points along the Achilles tendon with a power density of 60 mW/cm(2) and a total dose of 5.4 J per session. The results of the intention-to-treat analysis for the primary outcome, pain intensity during physical activity on the 100-mm visual analog scale, were significantly lower in the LLLT group than in the placebo LLLT group, with 53.6 mm versus 71.5 mm (P = .0003) at 4 weeks, 37.3 mm versus 62.8 mm (P = .0002) at 8 weeks, and 33.0 mm versus 53.0 mm (P = .007) at 12 weeks after randomization. Secondary outcomes of morning stiffness, active dorsiflexion, palpation tenderness, and crepitation showed the same pattern in favor of the LLLT group. Low-level laser therapy, with the parameters used in this study, accelerates clinical recovery from chronic Achilles tendinopathy when added to an EE regimen. For the LLLT group, the results at 4 weeks were similar to the placebo LLLT group results after 12 weeks.


Engineering entangled photon pairs with metal-organic frameworks.
The discovery and design of new materials with competitive optical frequency conversion efficiencies can accelerate the development of scalable photonic quantum technologies. Metal-organic framework (MOF) crystals without inversion symmetry have shown potential for these applications, given their nonlinear optical properties and the combinatorial number of possibilities for MOF self-assembly. In order to accelerate the discovery of MOF materials for quantum optical technologies, scalable computational assessment tools are needed. We develop a multi-scale methodology to study the wavefunction of entangled photon pairs generated by selected non-centrosymmetric MOF crystals via spontaneous parametric down-conversion (SPDC). Starting from an optimized crystal structure, we predict the shape of the G (2) intensity correlation function for coincidence detection of the entangled pairs, produced under conditions of collinear type-I phase matching. The effective nonlinearities and photon pair correlation times obtained are comparable to those available with inorganic crystal standards. Our work thus provides fundamental insights into the structure-property relationships for entangled photon generation with metal-organic frameworks, paving the way for the automated discovery of molecular materials for optical quantum technology.


Coding Human Factors Observations in Surgery.
The reliability of the Human Factors Analysis and Classification System (HFACS) for classifying retrospective observational human factors data in the cardiovascular operating room is examined. Three trained analysts independently used HFACS to categorize observational human factors data collected at a teaching and nonteaching hospital system. Results revealed that the framework was substantially reliable overall (Study I: k = 0.635; Study II: k = 0.642). Reliability increased when only preconditions for unsafe acts were investigated (Study I: k =0.660; Study II: k = 0.726). Preconditions for unsafe acts were the most commonly identified issues, with HFACS categories being similarly populated across both hospitals. HFACS is a reliable tool for systematically categorizing observational data of human factors issues in the operating room. Findings have implications for the development of a HFACS tool for proactively collecting observational human factors data, eliminating the necessity for classification post hoc.


Y chromosome haplogroups and prostate cancer in populations of European and Ashkenazi Jewish ancestry.
Genetic variation on the Y chromosome has not been convincingly implicated in prostate cancer risk. To comprehensively analyze the role of inherited Y chromosome variation in prostate cancer risk in individuals of European ancestry, we genotyped 34 binary Y chromosome markers in 3,995 prostate cancer cases and 3,815 control subjects drawn from four studies. In this set, we identified nominally significant association between a rare haplogroup, E1b1b1c, and prostate cancer in stage I (P = 0.012, OR = 0.51; 95% confidence interval 0.30-0.87). Population substructure of E1b1b1c carriers suggested Ashkenazi Jewish ancestry, prompting a replication phase in individuals of both European and Ashkenazi Jewish ancestry. The association was not significant for prostate cancer overall in studies of either Ashkenazi Jewish (1,686 cases and 1,597 control subjects) or European (686 cases and 734 control subjects) ancestry (P(meta) = 0.078), but a meta-analysis of stage I and II studies revealed a nominally significant association with prostate cancer risk (P(meta) = 0.010, OR = 0.77; 95% confidence interval 0.62-0.94). Comparing haplogroup frequencies between studies, we noted strong similarities between those conducted in the US and France, in which the majority of men carried R1 haplogroups, resembling Northwestern European populations. On the other hand, Finns had a remarkably different haplogroup distribution with a preponderance of N1c and I1 haplogroups. In summary, our results suggest that inherited Y chromosome variation plays a limited role in prostate cancer etiology in European populations but warrant follow-up in additional large and well characterized studies of multiple ethnic backgrounds.


Bovine viral diarrhea virus in free-ranging wild ruminants in Switzerland: low prevalence of infection despite regular interactions with domestic livestock.
In the frame of an eradication program for bovine viral diarrhea (BVD) in Swiss livestock, the question was raised whether free-ranging wildlife could threaten the success of this sanitary measure. Therefore, we conducted serological and virological investigations on BVD virus (BVDV) infections in the four indigenous wild ruminant species (roe deer, red deer, Alpine chamois and Alpine ibex) from 2009 to 2011, and gathered information on interactions between wild and domestic ruminants in an alpine environment by questionnaire survey. Thirty-two sera out of 1'877 (1.7%, 95% confidence interval [CI] 1.2-2.4) were seropositive for BVDV, and a BVDV1 sub genotype h virus was found in a seropositive chamois (0.05%, 95% CI 0.001-0.3). The seropositive animals originated from sub-alpine or alpine regions and significantly more seropositive red deer, chamois and ibex than roe deer were found. There were no statistically significant differences between sampling units, age classes, genders, and sampling years. The obtained prevalences were significantly lower than those documented in livestock, and most positive wild ruminants were found in proximity of domestic outbreaks. Additionally, BVDV seroprevalence in ibex was significantly lower than previously reported from Switzerland. The survey on interspecific interactions revealed that interactions expected to allow BVDV transmission, from physical contacts to non-simultaneous use of the same areas, regularly occur on pastures among all investigated ruminant species. Interactions involving cervids were more often observed with cattle than with small ruminants, chamois were observed with all three domestic species, and ibex interacted mostly with small ruminants. Interactions related to the use of anthropogenic food sources were frequently observed, especially between red deer and cattle in wintertime. To our knowledge, this is the first report of BVDV RNA isolated from an Alpine chamois. Nevertheless, our results suggest that BVDV infections are only sporadic in Swiss wild ruminants, despite regular occurrence of interactions with potentially infected livestock. Overall, serological, virological and ethological data indicate that wildlife is currently an incidental spill-over host and not a reservoir for BVDV in Switzerland.


Stroke. Revolution in therapy.
Stroke remains the third leading cause of death in this country, although recent advances in both clinical and basic science research have revolutionized the concept of stroke. Studies of primary and secondary stroke prevention have now documented the means to prevent thousands of cases of stroke each year. Three distinct strategies are evolving for intervention in the acute stroke process. Evidence is clear that ischemia leads to a toxic accumulation of intracellular calcium, in part mediated by excitatory neurotransmitters such as glutamate. Glutamate antagonists have shown clear benefit in experimental stroke models, and early clinical trials are underway. Acute revascularization to restore perfusion is also feasible and may minimize the extent of infarction. Studies of fibrinolytic agents are promising, with randomized clinical studies being done. While reperfusion is desired, it may be associated with additional neuronal injury. The development of anaerobic metabolism followed by reperfusion and aerobic conditions favors oxidation and free-radical formation. This mechanism of injury can be decreased by agents known to scavenge free radicals, and clinical trials are also testing this. This revolution in the understanding of ischemia, as well as the outpouring of new pharmacologic agents, is making stroke a true neurologic emergency requiring immediate intervention.


PPAR delta: a dagger in the heart of the metabolic syndrome.
Obesity is a growing threat to global health by virtue of its association with insulin resistance, glucose intolerance, hypertension, and dyslipidemia, collectively known as the metabolic syndrome or syndrome X. The nuclear receptors PPARalpha and PPARgamma are therapeutic targets for hypertriglyceridemia and insulin resistance, respectively, and drugs that modulate these receptors are currently in clinical use. More recent work on the less-described PPAR isotype PPARdelta has uncovered a dual benefit for both hypertriglyceridemia and insulin resistance, highlighting the broad potential of PPARdelta in the treatment of metabolic disease. PPARdelta enhances fatty acid catabolism and energy uncoupling in adipose tissue and muscle, and it suppresses macrophage-derived inflammation. Its combined activities in these and other tissues make it a multifaceted therapeutic target for the metabolic syndrome with the potential to control weight gain, enhance physical endurance, improve insulin sensitivity, and ameliorate atherosclerosis.


Disposition of valpromide, valproic acid, and valnoctamide in the brain, liver, plasma, and urine of rats.
Valpromide (VPD) and valnoctamide (VCD) are amide derivatives of valproic acid (VPA), one of the major antiepileptic drugs (AEDs). In rodent models, both VPD and VCD are more potent as anticonvulsants than VPA. However, in humans, VPD served as a prodrug to VPA, whereas VCD acts as a drug on its own, which is not biotransformed to its corresponding acid--valnoctic acid (VCA). The present study investigates the pharmacokinetics (PKs of VPD and VCD in rats by monitoring the levels of these two amide isomers in the brain, liver, plasma, and urine of rats. The disposition of VPD and VCD was analyzed in a comparative manner with that of VPA. The following PK parameters were obtained for VPD and VCD, respectively: clearance, 6.1 and 3 ml/min/kg; volume of distribution (Vss), 0.63 and 0.58 liter/kg; half-life (t1/2), 42 and 94 min; and mean residence time (MRT), 102 and 196 min. The clearance of VCD in rats was half of that of VPD, and their Vss was similar. Therefore, VCD, t1/2, and MRT were twice as long as those of VPD.PK analysis of VPD and VCD liver and brain levels gave similar major PK parameters to those obtained from the plasma data. VPD underwent hepatic biotransformation to VPA, which persisted in the liver and brain for a longer period than VPD. The fraction metabolized of VPD to VPA was 42%. The brain was not found to be a metabolic site of the VPD-VPA biotransformation. Unlike VPD, VCD did not undergo amid-acid biotransformation to its corresponding acid, but was eliminated by biotransformation to unidentified metabolites. In contrast to VPD and VCD that distributed about evenly between the plasma, liver, and brain, VPA showed different disposition patterns in the plasma, liver, and brain. VCD and VPD distribute better into the brain than VPA, a fact that may contribute to their better anticonvulsant activity.


Coupling between catalytic loop motions and enzyme global dynamics.
Catalytic loop motions facilitate substrate recognition and binding in many enzymes. While these motions appear to be highly flexible, their functional significance suggests that structure-encoded preferences may play a role in selecting particular mechanisms of motions. We performed an extensive study on a set of enzymes to assess whether the collective/global dynamics, as predicted by elastic network models (ENMs), facilitates or even defines the local motions undergone by functional loops. Our dataset includes a total of 117 crystal structures for ten enzymes of different sizes and oligomerization states. Each enzyme contains a specific functional/catalytic loop (10-21 residues long) that closes over the active site during catalysis. Principal component analysis (PCA) of the available crystal structures (including apo and ligand-bound forms) for each enzyme revealed the dominant conformational changes taking place in these loops upon substrate binding. These experimentally observed loop reconfigurations are shown to be predominantly driven by energetically favored modes of motion intrinsically accessible to the enzyme in the absence of its substrate. The analysis suggests that robust global modes cooperatively defined by the overall enzyme architecture also entail local components that assist in suitable opening/closure of the catalytic loop over the active site.


Estimating the number of whales entering trade using DNA profiling and capture-recapture analysis of market products.
Surveys of commercial markets combined with molecular taxonomy (i.e. molecular monitoring) provide a means to detect products from illegal, unregulated and/or unreported (IUU) exploitation, including the sale of fisheries bycatch and wild meat (bushmeat). Capture-recapture analyses of market products using DNA profiling have the potential to estimate the total number of individuals entering the market. However, these analyses are not directly analogous to those of living individuals because a 'market individual' does not die suddenly but, instead, remains available for a time in decreasing quantities, rather like the exponential decay of a radioactive isotope. Here we use mitochondrial DNA (mtDNA) sequences and microsatellite genotypes to individually identify products from North Pacific minke whales (Balaenoptera acutorostrata ssp.) purchased in 12 surveys of markets in the Republic of (South) Korea from 1999 to 2003. By applying a novel capture-recapture model with a decay rate parameter to the 205 unique DNA profiles found among 289 products, we estimated that the total number of whales entering trade across the five-year survey period was 827 (SE, 164; CV, 0.20) and that the average 'half-life' of products from an individual whale on the market was 1.82 months (SE, 0.24; CV, 0.13). Our estimate of whales in trade (reflecting the true numbers killed) was significantly greater than the officially reported bycatch of 458 whales for this period. This unregulated exploitation has serious implications for the survival of this genetically distinct coastal population. Although our capture-recapture model was developed for specific application to the Korean whale-meat markets, the exponential decay function could be modified to improve the estimates of trade in other wildmeat or fisheries markets or abundance of living populations by noninvasive genotyping.


Bradykinin antagonism and prostaglandins in blood pressure regulation.
These experiments were designed to analyze the interaction of a bradykinin antagonist with prostaglandins in blood pressure regulation of normotensive rats. Male Wistar rats, divided into three groups, received a 5-minute intra-arterial infusion of the bradykinin antagonist [( DArgo-Hyp3-Thi5,8-DPhe7]BK-TFA) at 250 micrograms/min. Groups were either intact rats (group I, n = 5), pretreated with indomethacin (group II, n = 10), or pretreated with both indomethacin and prazosin (group III, n = 8). The bradykinin antagonist infusion, which was shown to inhibit exogenous bradykinin by greater than 76% in intact animals, did not alter mean arterial pressure in group I rats despite a twofold increase in norepinephrine and a threefold increase in epinephrine. Group II rats presented a progressive increase in mean arterial pressure during the bradykinin antagonist infusion (14 +/- 3 mm Hg), with no statistically significant change in plasma catecholamines. Group III, with lower baseline mean arterial pressure due to alpha 1-adrenergic blockade, had an increase in mean arterial pressure comparable with group II during bradykinin antagonist infusion (22 +/- 5 mm Hg), confirming that this response was not sympathetically mediated. We conclude that in normotensive rats bradykinin plays a role in blood pressure regulation that is closely linked to that of prostaglandins and that points to a balance between these systems.


Probing electronic coherences by combined two- and one-photon excitation in atomic vapors.
Wave mixing in a three-level quantum system induced by two-photon resonant pump and one-photon resonant coupling at lower transition has been studied theoretically and experimentally. Resonantly enhanced difference-frequency generation efficiency was observed clearly dependent on the time delay and its sign between the femtosecond pump and probe. The role of the atomic coherences on the amplification without inversion during different sequences of interaction in a closed three-level system has been also stressed. These findings were confirmed experimentally in atomic potassium, where strong parametric amplification, induced by the pump delayed with respect to the probe, has been observed for the first time.


A systematic computational study of the structure crossover and coordination number distribution of metallic nanoparticles.
In this study, we identified stable configurations for three nanoparticle structure motifs (icosahedral, decahedral and cuboctahedral) of eight transition metals (Cu, Ag, Au, Pd, Ni, Rh, Ir, and Pt) ranging in size from 140 to 3000 atoms. We made simple yet precise analytical approximations of the energy of the stable configurations as a function of nanoparticle size and calculated the structure crossover sizes from these approximations. We then analyzed the surface structure of the nanoparticles in terms of the distribution of the coordination numbers and active sites. We found that low-coordinated atoms are most preferable for cuboctahedral forms and for lighter metals - Cu, Ni and Rh. Compared to other considered metals, gold nanoparticles exhibited unique features as follows: the least amount of low-coordinated atoms, the largest fraction of (111) faces on its surface and a concave reconstruction of five-fold vertices.


Kaposi's sarcoma-associated herpesvirus-encoded protein kinase and its interaction with K-bZIP.
The oncogenic herpesvirus, Kaposi's sarcoma-associated herpesvirus, also identified as human herpesvirus 8, contains genes producing proteins that control transcription and influence cell signaling. Open reading frame 36 (ORF36) of this virus encodes a serine/threonine protein kinase, which is designated the viral protein kinase (vPK). Our recent efforts to elucidate the role of vPK in the viral life cycle have focused on identifying viral protein substrates and determining the effects of vPK-mediated phosphorylation on specific steps in viral replication. The vPK gene was transcribed into 4.2-kb and 3.6-kb mRNAs during the early and late phases of viral reactivation. vPK is colocalized with viral DNA replication/transcription compartments as marked by a polymerase processivity factor, and K-bZIP, a protein known to bind the viral DNA replication origin (Ori-Lyt) and to regulate viral transcription. The vPK physically associated with and strongly phosphorylated K-bZIP at threonine 111, a site also recognized by the cyclin-dependent kinase Cdk2. Both K-bZIP and vPK were corecruited to viral promoters targeted by K-bZIP as well as to the Ori-Lyt region. Phosphorylation of K-bZIP by vPK had a negative impact on K-bZIP transcription repression activity. The extent of posttranslational modification of K-bZIP by sumoylation, a process that influences its repression function, was decreased by vPK phosphorylation at threonine 111. Our data thus identify a new role of vPK as a modulator of viral transcription.


[Clinical forms and prognosis of hepatitis C].
Hepatitis C virus infects around 600,000 French people, mainly after parenteral exposure (in association with transfusion before 1990 and with intravenous drug use). Spontaneous resolution at the acute stage of the infection occurs in around 30% of cases while chronic infection is observed in around 70% of cases and its main risk is evolution to cirrhosis. Three predictive factors of cirrhosis have been identified: the duration of infection (greater than 20 years), the age at contamination (greater than 40 years) and a chronic alcohol consumption (> 80 g/day). Immunosuppressive situations (drug-related immune suppression for the prevention of graft rejection in allograft recipients or human immune deficiency virus-coinfection) as well as hepatitis B virus coinfection enhance the risk of cirrhosis and reduce the time of occurrence of cirrhosis. These predictors have to be considered in the information to the patients and in therapeutic decisions. They explain that any hepatitis C virus-infected patient has to undergo a liver biopsy to evaluate the necro-inflammatory activity and the fibrosis of the liver disease to delineate the place of a follow-up with a control of aggravation factors (alcohol discontinuation) and of an antiviral therapy.


Coherent reflectance in a system of random Mie scatterers and its relation to the effective-medium approach.
We consider the coherent reflection and transmission of electromagnetic waves from a slab of a dilute system of randomly located, polarizable, spherical particles. We focus our attention on the case where the size of the spheres is comparable to the wavelength of the incident radiation. First, using wave-scattering and Mie theories, we derive expressions for the coherent fields that are transmitted and reflected by a very thin slab. Then we find the effective-current distribution that would act as a source of these fields. We conclude that if the effective currents were induced in an effective medium, this medium must possess, besides an effective electric permittivity, also an effective magnetic permeability. We find that both of these optical coefficients become functions of the angle of incidence and the polarization of the incident wave. Then we calculate the reflection coefficient of a half-space by considering a semi-infinite pile of thin slabs and compare the result with Fresnel relations. Numerical results are presented for the optical coefficients as well as for the half-space reflectance as a function of several parameters. The reflectance is compared with that obtained without considering the magnetic response. Finally, we discuss the relevance and the physics behind our results and indicate as well the measurements that could be performed to obtain an experimental verification of our theory.


Interaction-induced transition in the quantum chaotic dynamics of a disordered metal.
We demonstrate that a weakly disordered metal with short-range interactions exhibits a transition in the quantum chaotic dynamics when changing the temperature or the interaction strength. For weak interactions, the system displays exponential growth of the out-of-time-ordered correlator (OTOC) of the current operator. The Lyapunov exponent of this growth is temperature-independent in the limit of vanishing interaction. With increasing the temperature or the interaction strength, the system undergoes a transition to a non-chaotic behaviour, for which the exponential growth of the OTOC is absent. We conjecture that the transition manifests itself in the quasiparticle energy-level statistics and also discuss ways of its explicit observation in cold-atom setups.


Seasonality and increasing frequency of Greenland glacial earthquakes.
Some glaciers and ice streams periodically lurch forward with sufficient force to generate emissions of elastic waves that are recorded on seismometers worldwide. Such glacial earthquakes on Greenland show a strong seasonality as well as a doubling of their rate of occurrence over the past 5 years. These temporal patterns suggest a link to the hydrological cycle and are indicative of a dynamic glacial response to changing climate conditions.


Uterine involution and endometrial function in postpartum pony mares.
To determine endometrial regeneration in postpartum mares by analysis of histologic features, apoptosis and cell proliferation markers, lectin binding, cytokines, and progesterone and estrogen receptors in endometrial biopsy specimens. 9 postpartum mares. Mares were examined on postpartum days 1, 9, and 16, and uterine biopsy specimens were obtained for histologic examination. Lectin binding was analyzed histochemically, and expressions of Ki-67 antigen (proliferation marker), lysozyme, and caspase 3 (apoptosis marker) were studied immunohistochemically. Gene expressions for cytokines (interleukin-1beta, -6 and -8 and tumor necrosis factor-alpha), cyclooxygenase 2, prostaglandin-E-synthase, and estrogen and progesterone receptors were determined by use of quantitative real-time PCR assay. On day 1, neutrophils predominated but by day 9 had largely been replaced by lymphocytes and macrophages. High numbers of cells with staining for caspase 3 were found on day 1, but numbers decreased by day 9. In contrast, the number of cells with staining for Kiel 67 antigen increased between days 1 and 9. Lectin binding to the endometrium changed over time. Relative mRNA expressions for cytokines and prostaglandin-E-synthase did not differ among days. Expressions of progesterone and estrogen receptors were minimal on day 1 and increased by day 9. Early postpartum endometrial cells underwent apoptosis, but during the second week, postpartum proliferation of cells predominated. Lectin binding reflected changes in endometrial glycocalyx patterns. Increased expression of estrogen receptors allowed the endometrium to respond to estrogen during foal heat, and in subsequent diestrus, the endometrium was able to respond to progesterone.


Atomistic spin dynamics and surface magnons.
Atomistic spin dynamics simulations have evolved to become a powerful and versatile tool for simulating dynamic properties of magnetic materials. It has a wide range of applications, for instance switching of magnetic states in bulk and nano-magnets, dynamics of topological magnets, such as skyrmions and vortices and domain wall motion. In this review, after a brief summary of the existing investigation tools for the study of magnons, we focus on calculations of spin-wave excitations in low-dimensional magnets and the effect of relativistic and temperature effects in such structures. In general, we find a good agreement between our results and the experimental values. For material specific studies, the atomistic spin dynamics is combined with electronic structure calculations within the density functional theory from which the required parameters are calculated, such as magnetic exchange interactions, magnetocrystalline anisotropy, and Dzyaloshinskii-Moriya vectors.


Therapeutic Advances in the Treatment of Holmes Tremor: Systematic Review.
We aimed to formulate a practical clinical treatment algorithm for Holmes tremor (HT) by reviewing currently published clinical data. We performed a systematic review of articles discussing the management of HT published between January 1990 and December 2018. We examined data from 89 patients published across 58 studies detailing the effects of pharmacological or surgical interventions on HT severity. Clinical outcomes were measured by a continuous 1-10 ranked scale. The majority of studies addressing treatment response were case series or case reports. No randomized control studies were identified. Our review included 24 studies focusing on pharmacologic treatments of 25 HT patients and 34 studies focusing on the effect of deep brain stimulation (DBS) in 64 patients. In the medical intervention group, the most commonly used drugs were levetiracetam, trihexyphenidyl, and levodopa. In the surgically treated group, the thalamic ventralis intermedius nucleus (VIM) and globus pallidus internus (GPi) were the most common brain targets for neuromodulation. The two targets accounted for 57.8% and 32.8% of total cases, respectively. Overall, compared to the medically treated group, DBS provided greater tremor suppression (p = 0.025) and was more effective for the management of postural tremor in HT. Moreover, GPi DBS displayed greater benefit in the resting tremor component (p = 0.042) and overall tremor reduction (p = 0.022). There is a highly variable response to different medical treatments in HT without randomized clinical trials available to dictate treatment decisions. A variety of medical and surgical treatment options can be considered for the management of HT. Collaborative research between different institutions and researchers are warranted and needed to improve our understanding of the pathophysiology and management of this condition. In this review, we propose a practical treatment algorithm for HT based on currently available evidence.


The rat as an experimental animal.
The development and characterization of many inbred, congenic, and recombinant strains of rats in recent years has led to the detailed genetic description of this species, especially in regard to its major histocompatibility complex. This information has contributed substantially to the study of comparative genetics and has greatly enhanced the utility of the rat in a variety of areas of biomedical research. This article focuses on the use of the rat in immunogenetics, transplantation, cancer-risk assessment, cardiovascular diseases, and behavior.


Feasibility of real time next generation sequencing of cancer genes linked to drug response: results from a clinical trial.
The successes of targeted drugs with companion predictive biomarkers and the technological advances in gene sequencing have generated enthusiasm for evaluating personalized cancer medicine strategies using genomic profiling. We assessed the feasibility of incorporating real-time analysis of somatic mutations within exons of 19 genes into patient management. Blood, tumor biopsy and archived tumor samples were collected from 50 patients recruited from four cancer centers. Samples were analyzed using three technologies: targeted exon sequencing using Pacific Biosciences PacBio RS, multiplex somatic mutation genotyping using Sequenom MassARRAY and Sanger sequencing. An expert panel reviewed results prior to reporting to clinicians. A clinical laboratory verified actionable mutations. Fifty patients were recruited. Nineteen actionable mutations were identified in 16 (32%) patients. Across technologies, results were in agreement in 100% of biopsy specimens and 95% of archival specimens. Profiling results from paired archival/biopsy specimens were concordant in 30/34 (88%) patients. We demonstrated that the use of next generation sequencing for real-time genomic profiling in advanced cancer patients is feasible. Additionally, actionable mutations identified in this study were relatively stable between archival and biopsy samples, implying that cancer mutations that are good predictors of drug response may remain constant across clinical stages.


[Intracranial Hemorrhage and Pneumocephalus after Spinal Cord Tumor Resection: A Case Report].
A 75-year-old woman was scheduled for spinal cord tumor resection. General anesthesia was induced and maintained using propofol, remifentanil and fentanyl. Aside from fluctuations in intraoperative blood pres- sure, the surgery was uneventful, but emergence from anesthesia was delayed and the patient showed partial paralysis. Emergent brain CT revealed multiple intracranial hemorrhages and pneumocephalus. Since a large amount of fluid was observed from the drainage tube at the surgical site, loss of cerebrospinal fluid and subsequent low intracranial pressure were considered to be the cause of the hemorrhage and pneumocepha- lus. Intracranial hemorrhage and pneumocephalus are rare complications after spinal surgery, but they can lead to serious neurological dysfunction. Dural tear and/or excessive drainage are considered to be the causes of these complications, and careful observation of the property, amount and rate of drainage is there- fore warranted.


Prolonged impairment of coronary vasodilation after reversible ischemia. Evidence for microvascular "stunning".
Reperfusion after brief, reversible myocardial ischemia is associated with prolonged depression of contractile function (myocardial "stunning"); however, the effect on coronary vascular function has not been defined. Thus, open-chest dogs (n = 14) underwent a 15-minute left anterior descending coronary artery (LAD) occlusion followed by reflow. Four hours after reperfusion, regional myocardial blood flow (microspheres) was significantly (p less than 0.01) lower and coronary vascular resistance significantly (p less than 0.01) higher in the postischemic as compared with the nonischemic endocardium. Furthermore, during maximal vasodilation elicited by intravenous adenosine (n = 6), myocardial blood flow was lower (p less than 0.05) and coronary vascular resistance higher (p less than 0.05) in the postischemic as compared with the nonischemic myocardium, both in the endocardial and in the epicardial layers. Similarly, during maximal dilation elicited by intravenous papaverine (n = 8), myocardial blood flow was lower (p less than 0.05) and vascular resistance higher (p less than 0.05) in the postischemic as compared with the nonischemic endocardium; a directionally similar trend was observed in the epicardium. Four hours after reperfusion, all indexes of reactive hyperemia after a 40-second coronary occlusion were significantly lower in the LAD than in the control circumflex coronary artery (n = 8). There was no appreciable correlation between systolic wall thickening in the stunned myocardium and 1) the resting myocardial perfusion, 2) the hyperemia attained during adenosine or papaverine, and 3) the hyperemic response to a 40-second coronary occlusion. In control dogs that did not undergo a 15-minute LAD occlusion (n = 15), there were no differences in myocardial blood flow or vascular resistance between the LAD-dependent and the circumflex-dependent bed, either before or during adenosine (n = 7) or papaverine (n = 8). Furthermore, reactive hyperemia after a 40-second occlusion did not differ between the LAD and the circumflex artery (n = 8). In conclusion, a brief (15 minute), reversible ischemic insult causes a prolonged increase in resting vascular resistance and a prolonged impairment in vasodilator responsiveness, both of which persist for at least 4 hours. The severity of these vascular derangements is not related to the severity of contractile depression, suggesting that they may represent a relatively independent phenomenon. It is proposed that, in addition to myocardial "stunning," reversible ischemia also causes a microvascular "stunning."


Vulnerability of Dopaminergic Amacrine Cells to Chronic Ischemia in a Mouse Model of Oxygen-Induced Retinopathy.
Retinal dopamine deficiency is a potential cause of myopia and visual deficits in retinopathy of prematurity (ROP). We investigated the cellular mechanisms responsible for lowered levels of retinal dopamine in an oxygen-induced retinopathy (OIR) mouse model of ROP. Retinopathy was induced by exposing mice to 75% oxygen from postnatal day 7 (P7) to P12. Oxygen-induced retinopathy and age-matched control mice were euthanized at P12, P17, P25, or P42 to P50. Immunohistochemistry, electrophysiology, and biochemical approaches were used to determine the effect of OIR on the structure and function of dopaminergic amacrine cells (DACs). The total number of DACs was unchanged in OIR retinas at P12 despite significant capillary dropout in the central retina. However, a significant loss of DACs was observed in P17 OIR retinas (in which neovascularization was maximal), with the cell loss being more profound in the central (avascular) than in the peripheral (neovascular) regions. Cell loss was persistent in both regions at P25, at which time retinal neovascularization had regressed. At P42, the percentage of DACs lost (54%) was comparable to the percent decrease in total dopamine content (53%). Additionally, it was found that DACs recorded in OIR retinas at P42 to P50 had a complete dendritic field and exhibited relatively normal spontaneous and light-induced electrical activity. The results suggest that remaining DACs are structurally and functionally intact and that loss of DACs is primarily responsible for the decreased levels of retinal dopamine observed after OIR.


Lithium controls central nervous system autoimmunity through modulation of IFN-γ signaling.
Inhibitors of glycogen synthase kinase 3 (GSK3) are being explored as therapy for chronic inflammatory diseases. We previously demonstrated that the GSK inhibitor lithium is beneficial in experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis. In this study we report that lithium suppresses EAE induced by encephalitogenic interferon-γ (IFN-γ)-producing T helper (Th1) cells but not by interleukin (IL)-17-producing T helper (Th17) cells. The therapeutic activity of lithium required functional IFN-γ-signaling, but not the receptor for type I IFN (IFNAR). Inhibitor/s of GSK3 attenuated IFN-γ dependent activation of the transcription factor STAT1 in naïve T cells as well as in encephalitogenic T cells and Th1 cells. The inhibition of STAT1 activation was associated with reduced IFN-γ production and decreased expansion of encephalitogenic Th1 cells. Furthermore, lithium treatment induced Il27 expression within the spinal cords of mice with EAE. In contrast, such treatment of Ifngr(-/-) mice did not induce Il27 and was associated with lack of therapeutic response. Our study reveals a novel mechanism for the efficacy of GSK3 targeting in EAE, through the IFN-γ-STAT1 axis that is independent IFNAR-STAT1 axis. Overall our findings set the framework for the use of GSK3 inhibitors as therapeutic agents in autoimmune neuroinflammation.


Reelin transiently promotes N-cadherin-dependent neuronal adhesion during mouse cortical development.
Reelin is an essential glycoprotein for the establishment of the highly organized six-layered structure of neurons of the mammalian neocortex. Although the role of Reelin in the control of neuronal migration has been extensively studied at the molecular level, the mechanisms underlying Reelin-dependent neuronal layer organization are not yet fully understood. In this study, we directly showed that Reelin promotes adhesion among dissociated neocortical neurons in culture. The Reelin-mediated neuronal aggregation occurs in an N-cadherin-dependent manner, both in vivo and in vitro. Unexpectedly, however, in a rotation culture of dissociated neocortical cells that gradually reaggregated over time, we found that it was the neural progenitor cells [radial glial cells (RGCs)], rather than the neurons, that tended to form clusters in the presence of Reelin. Mathematical modeling suggested that this clustering of RGCs could be recapitulated if the Reelin-dependent promotion of neuronal adhesion were to occur only transiently. Thus, we directly measured the adhesive force between neurons and N-cadherin by atomic force microscopy, and found that Reelin indeed enhanced the adhesiveness of neurons to N-cadherin; this enhanced adhesiveness began to be observed at 30 min after Reelin stimulation, but declined by 3 h. These results suggest that Reelin transiently (and not persistently) promotes N-cadherin-mediated neuronal aggregation. When N-cadherin and stabilized β-catenin were overexpressed in the migrating neurons, the transfected neurons were abnormally distributed in the superficial region of the neocortex, suggesting that appropriate regulation of N-cadherin-mediated adhesion is important for correct positioning of the neurons during neocortical development.


Saethre-Chotzen mutations cause TWIST protein degradation or impaired nuclear location.
H-TWIST belongs to the family of basic helix-loop-helix (bHLH) transcription factors known to exert their activity through dimer formation. We have demonstrated recently that mutations in H-TWIST account for Saethre-Chotzen syndrome (SCS), an autosomal dominant craniosynostosis syndrome characterized by premature fusion of coronal sutures and limb abnormalities of variable severity. Although insertions, deletions, nonsense and missense mutations have been identified, no genotype-phenotype correlation could be found, suggesting that the gene alterations lead to a loss of protein function irrespective of the mutation. To assess this hypothesis, we studied stability, dimerization capacities and subcellular distribution of three types of TWIST mutant. Here, we show that: (i) nonsense mutations resulted in truncated protein instability; (ii) missense mutations involving the helical domains led to a complete loss of H-TWIST heterodimerization with the E12 bHLH protein in the two-hybrid system and dramatically altered the ability of the TWIST protein to localize in the nucleus of COS-transfected cells; and (iii) in-frame insertion or missense mutations within the loop significantly altered dimer formation but not the nuclear location of the protein. We conclude that at least two distinct mechanisms account for loss of TWIST protein function in SCS patients, namely protein degradation and subcellular mislocalization.


Ligand binding to Fc gamma R induces c-myc-dependent apoptosis in IL-2-stimulated NK cells.
The role of signals transduced via Fc gamma RIIIA in the modulation of the proliferative potential of NK cells has been investigated. Fc gamma R stimulation does not induce NK cell proliferation, and inhibits that induced by IL-2, but not by IL-12, as measured by [3H]TdR incorporation, without affecting entrance or progression through cell cycle. The inhibitory effect depends, at least in part, on induced apoptosis of the cells, detected by both light and electron microscopy examination. Fc gamma R stimulation induces apoptosis only in NK cells that have been previously activated by IL-2: this occurs within 3 h from receptor stimulation and is independent from de novo receptor-induced RNA or protein synthesis, but requires receptor-induced activation of protein tyrosine kinases and extracellular Ca2+ influx. IL-2 induces accumulation of c-myc mRNA in NK cells, and treatment of the cells with c-myc antisense oligodeoxyribonucleotides during the IL-2 stimulation phase inhibits the susceptibility to Fc gamma RIIIA-induced cell death, indicating that the induction of sustained levels of this proto-oncogene is necessary for the phenomenon. Thus, a two-step model is suggested for the Fc gamma R-induced apoptosis in IL-2 activated NK cells: the first step involves induced expression of c-myc, and possibly other permissive factors, upon IL-2 prestimulation; the second depends directly on the stimulation of the receptor, independently of additional gene induction. The evidence presented here suggests a mechanism of control of NK cell expansion at the latest stages of Ab-dependent immune responses.


Reducing distress and improving social functioning in daily life in people with auditory verbal hallucinations: study protocol for the 'Temstem' randomised controlled trial.
Auditory verbal hallucinations (AVH) are prevalent experiences that can induce distress and impede social functioning. While most voice hearers benefit from antipsychotic medication or cognitive-behavioural therapy, additional effective interventions are needed to reduce the burden of experiencing AVH. 'Temstem' is an easily accessible and useable smartphone application that was developed by designers in close cooperation with voice hearers and experts. By using language games, Temstem aims to reduce distress and improve social functioning. This is a single-blind multicentre randomised controlled trial with two arms: 'Temstem+AVH monitoring' versus 'AVH monitoring' (total n=100). Participants are adult patients who suffer daily from AVH and will be recruited in outpatient units. Primary assessment in daily life is made by the Experience Sampling Method (ESM) and daily monitoring with the PsyMate app. During an ESM period of 6 days, participants assess their mental state (including AVH and context) several times a day by filling in short questionnaires. There are three 6-day ESM periods: at baseline (week 0-1), post-treatment (weeks 5-6) and follow-up (weeks 9-10). In addition, during the entire 10-week study period, all participants monitor their AVH two times a day with a short assessment via the PsyMate app. Participants in the Temstem+AVH monitoring condition are provided with the Temstem app from week 1 to 6. Other assessments made at baseline, post-treatment and follow-up are based on questionnaires and a clinical interview. The results from this study will provide an evaluation of the effectiveness of Temstem, a non-invasive and easily accessible app for voice hearers, and insight into the determinants of optimal use. Results will be disseminated unreservedly, irrespective of the magnitude or direction of the effects. This study protocol was approved by the Medical Ethics Committee of the VU University Medical Centre (METC number: 2015.435/NL53684.029.15). ISRCTN75717636; Pre-results.


Transfection of embryonal carcinoma cells at high efficiency using liposome-mediated transfection.
Embryonal carcinoma (EC) cells are recognized as an excellent model system for studying the early stages of mammalian development. Many studies performed with EC cells involve transient transfection with promoter/reporter gene constructs and/or mammalian expression vectors. One of the limitations of working with EC cells is their inability to be transfected at high efficiency. In most cases, EC cells are transfected using the calcium phosphate method. The objective of this study was to identify protocols and culture conditions that significantly increase the transfection efficiency of EC cells. F9 EC cells were used for this purpose, because they are the EC cell line studied most commonly. We show that the transfection efficiency of F9 EC cells using the calcium phosphate method is less than 5%; whereas, their transfection efficiency can be improved approximately 15-fold using optimized culture conditions and liposome-based transfection reagents. Specifically, we demonstrate that more than 50% of F9 EC cells can be transfected using LipofectAMINE 2000. In addition to higher levels of transfection, there is much less plate-to-plate variation with liposome-based reagents as compared to transfection with calcium phosphate. Interestingly, transfection efficiency using these reagents was found to be inversely related to cell density. This contrasts sharply with the recommendation that transfection with LipofectAMINE 2000 or LipofectAMINE in conjunction with the PLUS reagent be performed at high cell densities. Given the improvements in transfection efficiency reported here, it will now be possible to perform studies with F9 EC cells that require transfection at significantly higher levels than that achieved using the calcium phosphate method. Overall, the highest transfection efficiencies were consistently obtained using LipofectAMINE 2000.


Association of Emergency-Only vs Standard Hemodialysis With Mortality and Health Care Use Among Undocumented Immigrants With End-stage Renal Disease.
Undocumented immigrants with end-stage renal disease have variable access to hemodialysis in the United States despite evidence-based standards for frequency of dialysis care. To determine whether mortality and health care use differs among undocumented immigrants who receive emergency-only hemodialysis vs standard hemodialysis (3 times weekly at a health care center). A retrospective cohort study was conducted of undocumented immigrants with incident end-stage renal disease who initiated emergency-only hemodialysis (Denver Health, Denver, Colorado, and Harris Health, Houston, Texas) or standard (Zuckerberg San Francisco General Hospital, San Francisco, California) hemodialysis between January 1, 2007, and July 15, 2014. Access to emergency-only hemodialysis vs standard hemodialysis. The primary outcome was mortality. Secondary outcomes were health care use (acute care days and ambulatory care visits) and rates of bacteremia. Outcomes were adjusted for propensity to undergo emergency hemodialysis vs standard hemodialysis. A total of 211 undocumented patients (86 women and 125 men; mean [SD] age, 46.5 [14.6] years; 42 from the standard hemodialysis group and 169 from the emergency-only hemodialysis group) initiated hemodialysis during the study period. Patients receiving standard hemodialysis were more likely to initiate hemodialysis with an arteriovenous fistula or graft and had higher albumin and hemoglobin levels than patients receiving emergency-only hemodialysis. Adjusting for propensity score, the mean 3-year relative hazard of mortality among patients who received emergency-only hemodialysis was nearly 5-fold (hazard ratio, 4.96; 95% CI, 0.93-26.45; P = .06) greater compared with patients who received standard hemodialysis. Mean 5-year relative hazard of mortality for patients who received emergency-only hemodialysis was more than 14-fold (hazard ratio, 14.13; 95% CI, 1.24-161.00; P = .03) higher than for those who received standard hemodialysis after adjustment for propensity score. The number of acute care days for patients who received emergency-only hemodialysis was 9.81 times (95% CI, 6.27-15.35; P < .001) the expected number of days for patients who had standard hemodialysis after adjustment for propensity score. Ambulatory care visits for patients who received emergency-only hemodialysis were 0.31 (95% CI, 0.21-0.46; P < .001) times less than the expected number of days for patients who received standard hemodialysis. Undocumented immigrants with end-stage renal disease treated with emergency-only hemodialysis have higher mortality and spend more days in the hospital than those receiving standard hemodialysis. States and cities should consider offering standard hemodialysis to undocumented immigrants.


Benefits of walking and solo experiences in UK wild places.
This paper examines human-nature interaction and how therapeutic this relationship is by investigating the efficacy of structured outdoor experience. Two walking and solo experience (WSEs) explored university students' (aged 20-43 years) perceptions of walking through and being with nature. The first was a 5-day journey (n = 4; 3 females and 1 male) and the second (n = 5; 3 females and 2 males) took place over two weekends, with a 2-week interval in-between. Pre- and post-experience interviews, journal writing, group discussions and a 9-month follow-up interviews were used to collect data and thematic analysis [Braun and Clarke (Using thematic analysis in psychology. Qual Res Psychol 2006;3:77-101.)] was applied. Both WSEs were considered together during analysis, as well as comparisons made between the two, in order to evaluate implications for practice. Benefits of the WSE that contributed to a general sense of well-being were: (i) gaining a sense of freedom and escape; (ii) gaining a sense of awareness and sensitivity to one's environment and its influence (iii) gaining confidence in being able to cope and take action; (iv) gaining a sense of perspective on and appreciation for life. Furthermore, the meaning participants formed in relation to their environment before, during and after the WSE, and the activity within that environment, played a role in their sense of well-being and in their motivations to re-access nature in other places. Findings suggest that WSEs are a cost effective way to give rise to beneficial and durable experiences, but a more holistic approach to policy is needed.


Effectiveness of glucagon in relieving esophageal foreign body impaction: a multicenter study.
Glucagon is thought to decrease lower esophageal sphincter tone and is used as an alternative to invasive endoscopy for esophageal foreign body impaction (EFBI). The purpose of this study was to evaluate efficacy and safety of glucagon and identify characteristics associated with success. A multicenter, retrospective study of patients receiving glucagon for EFBI at 2 academic emergency departments was conducted between 2006 and 2010. A control group of patients that did not receive glucagon was evaluated. Data collection included demographics, type of foreign body, glucagon dose, resolution of impaction, incidence of vomiting, additional medication, and endoscopy required. Descriptive and univariate analysis was performed as appropriate. A total of 133 doses of glucagon were administered in 127 patients. Glucagon-related resolution of EFBI occurred in 18 patients (14.2%) and vomiting in 16 patients (12.6%). No statistical differences between successful and unsuccessful groups were seen with the exception of concomitant medication administration (benzodiazepine or nitroglycerin) being associated with less glucagon success, 33.3% vs 59.6%, respectively (P = .04). Eighty-four percent of patients in the unsuccessful group underwent endoscopy. Comparing those that received glucagon (n = 127) and the control group (n = 29), there was no significant difference in resolution of EFBI, 14.2% vs 10.3%, respectively (P = .586). Glucagon-related resolution occurred in 14.2% of patients and was not significantly different compared with those that did not receive glucagon (10.3%). Concomitant medication administration was associated with lower success. Overall, glucagon had a low success rate, was related to adverse effects, and does not offer advantages for treatment.


Seroprevalence of Toxoplasma gondii infection in arthritis patients in eastern China.
There is accumulating evidence for an increased susceptibility to infection in patients with arthritis. We sought to understand the epidemiology of Toxoplasma gondii infection in arthritis patients in eastern China, given the paucity of data on the magnitude of T. gondii infection in these patients. Seroprevalence of T. gondii infection was assessed by enzyme-linked immunosorbent assay using a crude antigen of the parasite in 820 arthritic patients, and an equal number of healthy controls, from Qingdao and Weihai cities, eastern China. Sociodemographic, clinical and lifestyle information on the study participants were also obtained. The prevalence of anti-T. gondii IgG was significantly higher in arthritic patients (18.8%) compared with 12% in healthy controls (P < 0.001). Twelve patients with arthritis had anti-T. gondii IgM antibodies - comparable with 10 control patients (1.5% vs 1.2%). Demographic factors did not significantly influence these seroprevalence frequencies. The highest T. gondii infection seropositivity rate was detected in patients with rheumatoid arthritis (24.8%), followed by reactive arthritis (23.8%), osteoarthritis (19%), infectious arthritis (18.4%) and gouty arthritis (14.8%). Seroprevalence rates of rheumatoid arthritis and reactive arthritis were significantly higher when compared with controls (P < 0.001 and P = 0.002, respectively). A significant association was detected between T. gondii infection and cats being present in the home in arthritic patients (odds ratio [OR], 1.68; 95% confidence interval [CI]: 1.24 - 2.28; P = 0.001). These findings are consistent with and extend previous results, providing further evidence to support a link between contact with cats and an increased risk of T. gondii infection. Our study is also the first to confirm an association between T. gondii infection and arthritis patients in China. Implications for better prevention and control of T. gondii infection in arthritis patients are discussed. This is an epidemiological survey, therefore trial registration was not required.


Targeting Tat-TAR RNA Interaction for HIV-1 Inhibition.
The HIV-1 Tat protein interacts with TAR RNA and recruits CDK9/cyclin T1 and other host factors to induce HIV-1 transcription. Thus, Tat-TAR RNA interaction, which is unique for HIV-1, represents an attractive target for anti-HIV-1 therapeutics. To target Tat-TAR RNA interaction, we used a crystal structure of acetylpromazine bound to the bulge of TAR RNA, to dock compounds from the Enamine database containing over two million individual compounds. The docking procedure identified 173 compounds that were further analyzed for the inhibition of HIV-1 infection. The top ten inhibitory compounds with IC50 ≤ 6 µM were selected and the three least toxic compounds, T6780107 (IC50 = 2.97 μM), T0516-4834 (IC50 = 0.2 μM) and T5628834 (IC50 = 3.46 μM), were further tested for HIV-1 transcription inhibition. Only the T0516-4834 compound showed selective inhibition of Tat-induced HIV-1 transcription, whereas the T6780107 compound inhibited equally basal and Tat-induced transcription and the T5628834 compound only inhibited basal HIV-1 transcription. The compounds were tested for the inhibition of translation and showed minimal (<25%) effect. The T0516-4834 compound also showed the strongest inhibition of HIV-1 RNA expression and p24 production in CEM T cells and peripheral blood mononuclear cells infected with HIV-1 IIIB. Of the three compounds, only the T0516-4834 compound significantly disrupted Tat-TAR RNA interaction. Additionally, of the three tested compounds, T5628834 and, to a lesser extent, T0516-4834 disrupted Tat-CDK9/cyclin T1 interaction. None of the three compounds showed significant inhibition of the cellular CDK9 and cyclin T1 levels. In silico modelling showed that the T0516-4834 compound interacted with TAR RNA by binding to the bulge formed by U23, U25, C39, G26,C39 and U40 residues. Taken together, our study identified a novel benzoxazole compound that disrupted Tat-TAR RNA interaction and inhibited Tat-induced transcription and HIV-1 infection, suggesting that this compound might serve as a new lead for anti-HIV-1 therapeutics.


One size may not fit all: anti-aging therapies and sarcopenia.
Sarcopenia refers to age-related loss of muscle mass and function. Several age-related changes occur in skeletal muscle including a decrease in myofiber size and number and a diminished ability of satellite cells to activate and proliferate upon injury leading to impaired muscle remodeling. Although the molecular mechanisms underlying sarcopenia are unknown, it is tempting to hypothesize that interplay between biological and environmental factors cooperate in a positive feedback cycle contributing to the progression of sarcopenia. Indeed many essential biological mechanisms such as apoptosis and autophagy and critical signaling pathways involved in skeletal muscle homeostasis are altered during aging and have been linked to loss of muscle mass. Moreover, the environmental effects of the sedentary lifestyle of older people further promote and contribute the loss of muscle mass. There are currently no widely accepted therapeutic strategies to halt or reverse the progression of sarcopenia. Caloric restriction has been shown to be beneficial as a sarcopenia and aging antagonist. Such results have made the search for caloric restriction mimetics (CRM) a priority. However given the mechanisms of action, some of the currently investigated CRMs may not combat sarcopenia. Thus, sarcopenia may represent a unique phenotypic feature of aging that requires specific and individually tailored therapeutic strategies.


The public health impact of Alzheimer's disease, 2000-2050: potential implication of treatment advances.
Recent developments in basic research suggest that therapeutic breakthroughs may occur in Alzheimer's disease treatment over the coming decades. To model the potential magnitude and nature of the effect of these advances, historical data from congestive heart failure and Parkinson's disease were used. Projections indicate that therapies which delay disease onset will markedly reduce overall disease prevalence, whereas therapies to treat existing disease will alter the proportion of cases that are mild as opposed to moderate/severe. The public health impact of such changes would likely involve both the amount and type of health services needed. Particularly likely to arise are new forms of outpatient services, such as disease-specific clinics and centers. None of our models predicts less than a threefold rise in the total number of persons with Alzheimer's disease between 2000 and 2050. Therefore, Alzheimer's care is likely to remain a major public health problem during the coming decades.


Assessment of the interphotoreceptor matrix proteoglycan-1 (IMPG1) gene localised to 6q13-q15 in autosomal dominant Stargardt-like disease (ADSTGD), progressive bifocal chorioretinal atrophy (PBCRA), and North Carolina macular dystrophy (MCDR1).
We have recently characterised the genomic organisation of a novel interphotoreceptor matrix proteoglycan, IMPG1, and have mapped the gene locus to chromosome 6q13-q15 by fluorescence in situ hybridisation. As the interphotoreceptor matrix (IPM) is thought to play a critical role in retinal adhesion and the maintenance of photoreceptor cells, it is conceivable that a defect in one of the IPM components may cause degenerative lesions in retinal structures and thus may be associated with human retinopathies. By genetic linkage analysis, several retinal dystrophies including one form of autosomal dominant Stargardt-like macular dystrophy (STGD3), progressive bifocal chorioretinal atrophy (PBCRA), and North Carolina macular dystrophy (MCDR1) have previously been localised to a region on proximal 6q that overlaps the IMPG1 locus. We have therefore assessed the entire coding region of IMPG1 by exon amplification and subsequent single stranded conformational analysis in patients from 6q linked multigeneration families diagnosed with PBCRA and MCDR1, as well as a single patient from an autosomal dominant STGD pedigree unlinked to either of the two known STGD2 and STGD3 loci on chromosomes 13q and 6q, respectively. No disease associated mutations were identified. In addition, using an intragenic polymorphism, IMPG1 was excluded by genetic recombination from both the PBCRA and the MCDR1 loci. However, as the autosomal dominant Stargardt-like macular dystrophies are genetically heterogeneous, other forms of this disorder, in particular STGD3 previously linked to 6q, may be caused by mutations in IMPG1.