Interpolated retrieval effects on list isolation: Individual differences in working memory capacity.
We examined the effects of interpolated retrieval from long-term memory (LTM) and short-term memory (STM) on list isolation in dual-list free recall and whether individual differences in working memory capacity (WMC) moderated those effects. Ninety-seven subjects completed study-test trials that included two study lists separated by either an exemplar generation task (LTM retrieval) or a two-back task (STM retrieval). Subjects then completed an externalized free recall task that allowed for the examination of response accessibility and monitoring. Individual differences in WMC were assessed using three complex span tasks: operation span, reading span, and rotation span. Correct recall and intratrial intrusion summary scores showed no effect of interpolated retrieval on either response accessibility or monitoring. However, serial-position curves for correct recall of List 1 showed larger primacy in the two-back than in the exemplar generation task for high-WMC subjects. We interpreted these results from a context change perspective, as showing that interpolated LTM retrieval accelerated context change for subjects who processed the context more effectively. We consider the implications of these findings for models of memory.


Efficacy of supplementary vitamins C and E on anxiety, depression and stress in type 2 diabetic patients: a randomized, single-blind, placebo-controlled trial.
Diabetes mellitus as one of the most prevalent endocrine disease is associated with high oxidative stress. Anxiety, stress and depression are common neuropsychiatric features in diabetic patients. Hyperglycemia leads to increased oxidative stress which in turn diminishes antioxidant defense system. On the other hand oxidative stress is the leading cause of depression and anxiety disorders. Thus, it seems that diabetes could accelerate the trend of psychiatric diseases. In this randomized single-blind study, evaluation of the effects of two antioxidants (vitamin C and vitamin E) was done on Stress, depression and anxiety levels in 45 diabetic patients for six weeks. The patients were randomly divided in three groups of vitamin E (400 IU day(-1)), vitamin C (1000 mg day(-1)) and placebo. DASS-21 (Depression Anxiety Stress Scales 21-item) questionnaire items were read to each patient and completed by the main investigator of this study before and after six weeks of supplementation. The scores of depression, anxiety and stress were evaluated separately based on the DASS questionnaire. The results showed a significant decrease in anxiety level (p = 0.005) in vitamin C group compared to other groups but there were no significant differences between groups in terms of changes in stress and depression scores. In conclusion, this study suggests that short-term supplementation of vitamin C is safe and beneficial for reducing anxiety levels in diabetic patients through alleviating oxidative damage.


Intrauterine Contraception Among Women Living With Human Immunodeficiency Virus: A Randomized Controlled Trial.
To compare discontinuation rates of the levonorgestrel and copper intrauterine devices (IUDs) among women with human immunodeficiency virus. A double-masked randomized trial was conducted at Mulago Hospital, Uganda. Women received either a copper or levonorgestrel IUD. The primary outcome was discontinuation of intrauterine contraception within 1 year of placement. The secondary outcomes were incidence of side effects and severe adverse events. To discern a difference of 10% from a copper IUD discontinuation rate of 18%, power of 80%, and 95% confidence interval (CI), a sample size of 351 per arm was estimated. Analysis of the primary outcome was by intension-to-treat principle. From September 2013 to December 2014, 979 were screened and 703 randomized as follows: 349 to the copper group and 354 to the levonorgestrel group. In total, 8.6% (29/338) women in the copper group compared with 8.1% (27/334) in the levonorgestrel group discontinued intrauterine conception within 1 year of placement (incidence rate ratio 1.1 [95% CI 0.64-1.96]). Overall, the incidence of heavy bleeding was higher in the copper group (37% [125/338]) than in the levonorgestrel group (19.5% [65/334]). However, the incidence of amenorrhea, which occurred in 3.3% (11/338) of women, was lower in the copper group than the 19.8% (66/334) of women who reported amenorrhea in the levonorgestrel group. There was no difference in discontinuation rates between the copper and levonorgestrel devices. Women in the levonorgestrel group had reduced incidence of heavy bleeding and a higher incidence of amenorrhea compared with those in the copper group. Pan African Clinical Trial Registry, www.pactr.org, PACTR 201308000561212. I.


Antigens expressed by myelinating glia cells induce peripheral cross-tolerance of endogenous CD8+ T cells.
Auto-reactivity of T cells is largely prevented by central and peripheral tolerance. Nevertheless, immunization with certain self-antigens emulsified in CFA induces autoimmunity in rodents, suggesting that tolerance to some self-antigens is not robust. To investigate the fate of nervous system-specific CD8(+) T cells, which only recently came up as being important contributors for MS pathogenesis, we developed a mouse model that allows inducible expression of lymphocytic choriomeningitis virus-derived CD8(+) T-cell epitopes specifically in oligodendrocytes and Schwann cells, the myelinating glia of the nervous system. These transgenic CD8(+) T-cell epitopes induced robust tolerance of endogenous auto-reactive T cells, which proved thymus-independent and was mediated by cross-presenting bone-marrow-derived cells. Immunohistological staining of secondary lymphoid organs demonstrated the presence of glia-derived antigens in DC, suggesting that peripheral tolerance of CD8(+) T cells results from uptake and presentation by steady state DC.


Distributed temperature-change sensor based on Rayleigh backscattering in an optical fiber.
A frequency-modulated continuous-wave technique is used to detect the presence of frequency shifts in the Rayleigh-backscattered light in a single-mode optical fiber as a result of a changing temperature. The system is able to detect a rate of temperature change of 0.014 K/s, when a 20-cm length of fiber is heated. The system is also able to demonstrate a spatial resolution of better than 15 cm.


The genetic ancestry of American Creole cattle inferred from uniparental and autosomal genetic markers.
Cattle imported from the Iberian Peninsula spread throughout America in the early years of discovery and colonization to originate Creole breeds, which adapted to a wide diversity of environments and later received influences from other origins, including zebu cattle in more recent years. We analyzed uniparental genetic markers and autosomal microsatellites in DNA samples from 114 cattle breeds distributed worldwide, including 40 Creole breeds representing the whole American continent, and samples from the Iberian Peninsula, British islands, Continental Europe, Africa and American zebu. We show that Creole breeds differ considerably from each other, and most have their own identity or group with others from neighboring regions. Results with mtDNA indicate that T1c-lineages are rare in Iberia but common in Africa and are well represented in Creoles from Brazil and Colombia, lending support to a direct African influence on Creoles. This is reinforced by the sharing of a unique Y-haplotype between cattle from Mozambique and Creoles from Argentina. Autosomal microsatellites indicate that Creoles occupy an intermediate position between African and European breeds, and some Creoles show a clear Iberian signature. Our results confirm the mixed ancestry of American Creole cattle and the role that African cattle have played in their development.


A Network of Topographic Maps in Human Association Cortex Hierarchically Transforms Visual Timing-Selective Responses.
Accurately timing sub-second sensory events is crucial when perceiving our dynamic world. This ability allows complex human behaviors that require timing-dependent multisensory integration and action planning. Such behaviors include perception and performance of speech, music, driving, and many sports. How are responses to sensory event timing processed for multisensory integration and action planning? We measured responses to viewing systematically changing visual event timing using ultra-high-field fMRI. We analyzed these responses with neural population response models selective for event duration and frequency, following behavioral, computational, and macaque action planning results and comparisons to alternative models. We found systematic local changes in timing preferences (recently described in supplementary motor area) in an extensive network of topographic timing maps, mirroring sensory cortices and other quantity processing networks. These timing maps were partially left lateralized and widely spread, from occipital visual areas through parietal multisensory areas to frontal action planning areas. Responses to event duration and frequency were closely linked. As in sensory cortical maps, response precision varied systematically with timing preferences, and timing selectivity systematically varied between maps. Progressing from posterior to anterior maps, responses to multiple events were increasingly integrated, response selectivity narrowed, and responses focused increasingly on the middle of the presented timing range. These timing maps largely overlap with numerosity and visual field map networks. In both visual timing map and visual field map networks, selective responses and topographic map organization may facilitate hierarchical transformations by allowing neural populations to interact over minimal distances.


Advances in liquid metals for biomedical applications.
To date, liquid metals have been widely applied in many fields such as electronics, mechanical engineering and energy. In the last decade, with a better understanding of the physicochemical properties such as low viscosity, good fluidity, high thermal/electrical conductivity and good biocompatibility, gallium and gallium-based low-melting-point (near or below physiological temperature) alloys have attracted considerable attention in bio-related applications. This tutorial review introduces the common performances of liquid metals, highlights their featured properties, as well as summarizes various state-of-the-art bio-applications involving carriers for drug delivery, molecular imaging, cancer therapy and biomedical devices. Challenges for the clinical translation of liquid metals are also discussed.


Taming the adolescent mind: preliminary report of a mindfulness-based psychological intervention for adolescents with clinical heterogeneous mental health diagnoses.
Mindfulness-based interventions such as Mindfulness-based Stress Reduction (MBSR) and Mindfulness Cognitive Behavior Therapy (MCBT) have been used to treat adults with psychiatric disorders. This article describes initial modification and development of a mindfulness-based intervention group program for adolescents with psychiatric disorders. It was hypothesized that the intervention would improve mindfulness, mental health outcomes and decrease psychological distress and symptoms. Adolescents from a mental health clinic attended a 5-week group pilot mindfulness-based intervention. Adolescents and parents completed questionnaires at pre- and post-intervention and at 3-month follow-up. Baseline measures indicated moderate to severe range of mental health symptoms. After the intervention, adolescents reported significant decreases in psychological distress and increases in mindfulness and self-esteem. Qualitative data revealed the intervention to be engaging and beneficial. Parents also reported significant overall improvements of adolescents' functioning. These promising preliminary results suggest that the intervention was feasible, acceptable and offered positive impact on mental health problems, and the intervention warrants further research in a randomized controlled study.


Diagnosing Carpal Tunnel Syndrome: Diagnostic Test Accuracy of Scales, Questionnaires, and Hand Symptom Diagrams-A Systematic Review.
To summarize and evaluate research on the accuracy of clinical diagnostic scales, questionnaires, and hand symptom diagrams/maps used for diagnosis of carpal tunnel syndrome (CTS). Systematic review of diagnostic test accuracy. A comprehensive literature search of the MEDLINE, CINAHL, and Embase databases was conducted on January 20, 2020. Studies that assessed at least 1 diagnostic accuracy property of the scales, questionnaires, and hand symptom diagrams used for the diagnosis of CTS. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines were followed. Risk of bias and applicability concerns were assessed using the revised Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Diagnostic accuracy properties were summarized. Out of 4052 citations after removing duplicates, 21 articles met the inclusion criteria. Twelve articles reported on the diagnostic accuracy of scales and questionnaires, including the Bland questionnaire, Kamath and Stothard questionnaire, 6-item carpal tunnel syndrome symptoms scale (CTS-6), Boston Carpal Tunnel Questionnaire, Wainner clinical prediction rule, and Lo clinical prediction rule. Positive likelihood ratios ranged from 0.94 for the Boston Carpal Tunnel Questionnaire to 10.5 for the CTS-6, and negative likelihood ratios ranged from 1.04 to 0.05 for the same diagnostic tools, respectively. Nine studies reported the diagnostic accuracy of the Katz and Stirrat hand symptom diagram. Positive and negative likelihood ratios ranged from 1.42 to 8 and from 0.78 to 0.05, respectively. Only 4 studies had high methodologic quality. Limited evidence supports high accuracy of the CTS-6, Kamath and Stothard questionnaire, and Katz and Stirrat hand symptom diagram. Other scales have lesser and more conflicting evidence. Further high-quality studies are necessary to examine the diagnostic accuracy of these tests to assist ruling in or ruling out CTS. J Orthop Sports Phys Ther 2020;50(11):622-631. Epub 16 Sep 2020. doi:10.2519/jospt.2020.9599.


Thromboembolic and bleeding risk of periprocedural bridging anticoagulation: A systematic review and meta-analysis.
The risk and benefit of periprocedural heparin bridging is not completely clarified. We aimed to assess the safety and efficacy of bridging anticoagulation prior to invasive procedures or surgery. Heparin bridging was associated with lower risks of thromboembolism and bleeding compared to non-bridging. PubMed, Ovid and Elsevier, and Cochrane Library (2000-2016) were searched for English-language studies. Studies comparing interrupted anticoagulation with or without bridging and continuous oral anticoagulation in patients at moderate-to-high thromboembolic risk before invasive procedures were included. Primary outcomes were thromboembolic events and bleeding events. Mantel-Haenszel method and random-effects models were used to analyze the pooled risk ratio (RR) and 95% confidence interval (CI) for thromboembolic and bleeding risks. Eighteen studies (six randomized controlled trials and 12 cohort studies) were included (N = 23 364). There was no difference in thromboembolic risk between bridged and non-bridged patients (RR: 1.26, 95% CI: 0.61-2.58; RCTs: RR: 0.71, 95% CI: 0.23-2.24; cohorts: RR: 1.45, 95% CI: 0.63-3.37). However, bridging anticoagulation was associated with higher risk of overall bleeding (RR: 2.83, 95% CI: 2.00-4.01; RCTs: RR: 2.24, 95% CI: 0.99-5.09; cohorts: RR: 3.09, 95% CI: 2.07-4.62) and major bleeding (RR: 3.00, 95% CI: 1.78-5.06; RCTs: RR: 2.48, 95% CI: 1.29-4.76; cohorts: RR: 3.22, 95% CI: 1.65-6.32). Bridging anticoagulation was associated with increased bleeding risk compared to non-bridging. Thromboembolism risk was similar between two strategies. Our results do not support routine use of bridging during anticoagulation interruption.


Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults.
To investigate the ability of cerebrospinal fluid (CSF) and plasma measures to discriminate early-stage Alzheimer disease (AD) (defined by clinical criteria and presence/absence of brain amyloid) from nondemented aging and to assess whether these biomarkers can predict future dementia in cognitively normal individuals. Evaluation of CSF beta-amyloid(40) (Abeta(40)), Abeta(42), tau, phosphorylated tau(181), and plasma Abeta(40) and Abeta(42) and longitudinal clinical follow-up (from 1 to 8 years). Longitudinal studies of healthy aging and dementia through an AD research center. Community-dwelling volunteers (n = 139) aged 60 to 91 years and clinically judged as cognitively normal (Clinical Dementia Rating [CDR], 0) or having very mild (CDR, 0.5) or mild (CDR, 1) AD dementia. Individuals with very mild or mild AD have reduced mean levels of CSF Abeta(42) and increased levels of CSF tau and phosphorylated tau(181). Cerebrospinal fluid Abeta(42) level completely corresponds with the presence or absence of brain amyloid (imaged with Pittsburgh Compound B) in demented and nondemented individuals. The CSF tau/Abeta(42) ratio (adjusted hazard ratio, 5.21; 95% confidence interval, 1.58-17.22) and phosphorylated tau(181)/Abeta(42) ratio (adjusted hazard ratio, 4.39; 95% confidence interval, 1.62-11.86) predict conversion from a CDR of 0 to a CDR greater than 0. The very mildest symptomatic stage of AD exhibits the same CSF biomarker phenotype as more advanced AD. In addition, levels of CSF Abeta(42), when combined with amyloid imaging, augment clinical methods for identifying in individuals with brain amyloid deposits whether dementia is present or not. Importantly, CSF tau/Abeta(42) ratios show strong promise as antecedent (preclinical) biomarkers that predict future dementia in cognitively normal older adults.


An attempt to correlate cattle breed origins and diseases associated with or transmitted by the tick Amblyomma variegatum in the French West Indies.
By using biological data and historical research, we have tried to explain the difference between resistance and susceptibility to the diseases transmitted (cowdriosis) or associated (dermatophilosis) with the tick Amblyomma variegatum, in two cattle breeds of the French West Indies: the Creole crossbred cattle of Guadeloupe and the Brahman zebu cattle of Martinique. Have been studied the polymorphisms of 5 independent genetic systems (erythrocytic haemoglobin, serum albumin and transferrin, the class I region of the BoLA complex and the gamma S crystallin gene) in different breeds comprising Bos taurus cattle of Europe and Africa, Bos indicus of West and East Africa, as well as the Brahman of Martinique and the Creole crossbred of Guadeloupe. By comparing the different allele frequencies of these 5 non related polymorphic loci and by using the two different mathematical matrices of NEI and of CAVALLI-SFORZA, have been established the genetic distances between these breeds. It appears clearly that the Creole cattle of Guadeloupe are in an intermediate position between the Bos taurus N'Dama breed of West Africa and two Bos indicus zebu breeds, namely the West African Sudan zebu and the Brahman. Thanks to studies of different archieves in the Caribbean and in Europe, historical evidence have been accumulated on the geographical origins and on the chronology of the establishment of Creole and Brahman cattle in the French West Indies. The high resistance of the Creole cattle of Guadeloupe to diseases associated with or transmitted by the "Senegalese" tick Amblyomma variegatum seems to be due to the inheritance of a pool of genes from West African cattle and more particularly from the N'Dama breed.(ABSTRACT TRUNCATED AT 250 WORDS)


The ethics of the missing straw.
This case report details the emergency department course of a 34 year-old female who presented with abdominal pain and vaginal bleeding after reportedly falling one week earlier. She was subsequently found to have a drinking straw within her uterus next to an eight week-old live intrauterine pregnancy on ultrasound. This case report and discussion reviews the literature on retained foreign bodies in pregnancy while addressing the added complications of an evasive patient and a difficult consultant with significant intra-specialty disagreement.


Predicting malaria vector distribution under climate change scenarios in China: Challenges for malaria elimination.
Projecting the distribution of malaria vectors under climate change is essential for planning integrated vector control activities for sustaining elimination and preventing reintroduction of malaria. In China, however, little knowledge exists on the possible effects of climate change on malaria vectors. Here we assess the potential impact of climate change on four dominant malaria vectors (An. dirus, An. minimus, An. lesteri and An. sinensis) using species distribution models for two future decades: the 2030 s and the 2050 s. Simulation-based estimates suggest that the environmentally suitable area (ESA) for An. dirus and An. minimus would increase by an average of 49% and 16%, respectively, under all three scenarios for the 2030 s, but decrease by 11% and 16%, respectively in the 2050 s. By contrast, an increase of 36% and 11%, respectively, in ESA of An. lesteri and An. sinensis, was estimated under medium stabilizing (RCP4.5) and very heavy (RCP8.5) emission scenarios. in the 2050 s. In total, we predict a substantial net increase in the population exposed to the four dominant malaria vectors in the decades of the 2030 s and 2050 s, considering land use changes and urbanization simultaneously. Strategies to achieve and sustain malaria elimination in China will need to account for these potential changes in vector distributions and receptivity.


[ANESTHETIC DRUGS IN CHILDREN AND PREGNANT WOMEN - IMPLICATIONS OF THE RECENT FDA WARNING].
Recent animal studies demonstrated neuronal apoptosis following early life exposure to most anesthetic drugs. Further research into this question demonstrated neonatal neuronal damage in multiple species (including primates) and evidence that this damage has cognitive and social sequela. These results raised the suspicion that general anesthesia in neonates, infants and pregnant women may injure the developing brain. Follow-up human studies were inconclusive. Retrospective studies suffer from tremendous selection bias due to the surgical effect and the baseline condition that required the surgical intervention. A number of large retrospective studies yield contradicting results, leaving the issue unsettled. Results of new, high quality prospective studies suggest that a short, single exposure does not lead to any measurable damage, but we are still awaiting final long term results. Despite the inconclusive evidence, the American Food and Drug Administration (FDA) published a warning mandating drug manufacturers to disclose the risk with the package insert, and clinicians to discuss the possible risks with the parents or the pregnant woman before the planned procedure. The European Society of Anesthesiologists, as well as the Israeli Society of Anesthesiologists, did not adopt this FDA policy. Despite the possible uncertain risk, it was decided that the evidence is inconclusive in regards to clinical human scenarios. It was agreed that such warnings would lead to delaying necessary procedures based on unfounded information. It was therefore decided to avoid changing the informed consent form and consent process until further information is available.


The cancer glycocalyx mechanically primes integrin-mediated growth and survival.
Malignancy is associated with altered expression of glycans and glycoproteins that contribute to the cellular glycocalyx. We constructed a glycoprotein expression signature, which revealed that metastatic tumours upregulate expression of bulky glycoproteins. A computational model predicted that these glycoproteins would influence transmembrane receptor spatial organization and function. We tested this prediction by investigating whether bulky glycoproteins in the glycocalyx promote a tumour phenotype in human cells by increasing integrin adhesion and signalling. Our data revealed that a bulky glycocalyx facilitates integrin clustering by funnelling active integrins into adhesions and altering integrin state by applying tension to matrix-bound integrins, independent of actomyosin contractility. Expression of large tumour-associated glycoproteins in non-transformed mammary cells promoted focal adhesion assembly and facilitated integrin-dependent growth factor signalling to support cell growth and survival. Clinical studies revealed that large glycoproteins are abundantly expressed on circulating tumour cells from patients with advanced disease. Thus, a bulky glycocalyx is a feature of tumour cells that could foster metastasis by mechanically enhancing cell-surface receptor function.


The role of the B cells in the adoptive transfer of collagen-induced arthritis from DBA/1 (H-2q) to SCID (H-2d) mice.
Collagen-induced arthritis (CIA) can be transferred from DBA/1 to SCID mice when native type II collagen (CII) is administered together with spleen cells, arthritis appearing some 14 days after cell transfer. In the present study, we demonstrate that both donor T- and B-lymphocyte populations play a role in this model, and that arthritis arises in SCID recipients of either murine or bovine native CII. Furthermore, the requirement for administration of soluble native CII can be replaced by subarthritogenic doses of serum from Wistar rats with CIA. In this case a fully developed arthritis appears as early as 2 days after cell transfer. However, protein G-purified IgG from CIA rat serum together with splenocytes from arthritic DBA/1 mice does not transfer arthritis. A key role of B cells in this model appears to be the production of a humoral arthritogenic factor since arthritis can be successfully transferred to SCID mice by CIA rat serum administered together with a B cell-depleted splenocyte population consisting of T cells and donor-histocompatible antigen-presenting cells. By contrast, transfer of disease cannot be achieved by co-administration of CIA rat serum and purified donor T cells, indicating that the presence of donor antigen-presenting cells is a requirement for adoptive transfer of arthritis. We propose that joint damage initiated by arthritogenic product(s) of the B cell lineage releases soluble antigens that are presented to T cells which perpetuate the disease. The finding that arthritis can be generated in SCID recipients of CIA rat serum together with splenocytes from non-arthritic DBA/1 mice immunized with denatured CII supports the hypothesis that T cells with specificity for denatured joint components perpetuate disease initiated by humoral factors.


Structure of supported bilayers composed of lipopolysaccharides and bacterial phospholipids: raft formation and implications for bacterial resistance.
Lipopolysaccharide (LPS), the major lipid on the surface of Gram-negative bacteria, plays a key role in bacterial resistance to hydrophobic antibiotics and antimicrobial peptides. Using atomic force microscopy (AFM) we characterized supported bilayers composed of LPSs from two bacterial chemotypes with different sensitivities to such antibiotics and peptides. Rd LPS, from more sensitive "deep rough" mutants, contains only an inner saccharide core, whereas Ra LPS, from "rough" mutants, contains a longer polysaccharide region. A vesicle fusion technique was used to deposit LPS onto either freshly cleaved mica or polyethylenimine-coated mica substrates. The thickness of the supported bilayers measured with contact-mode AFM was 7 nm for Rd LPS and 9 nm for Ra LPS, consistent with previous x-ray diffraction measurements. In water the Ra LPS bilayer surface was more disordered than Rd LPS bilayers, likely due to the greater volume occupied by the longer Ra LPS polysaccharide region. Since deep rough mutants contain bacterial phospholipid (BPL) as well as LPS on their surfaces, we also investigated the organization of Rd LPS/BPL bilayers. Differential scanning calorimetry and x-ray diffraction indicated that incorporation of BPL reduced the phase transition temperature, enthalpy, and average bilayer thickness of Rd LPS. For Rd LPS/BPL mixtures, AFM showed irregularly shaped regions thinner than Rd LPS bilayers by 2 nm (the difference in thickness between Rd LPS and BPL bilayers), whose area increased with increasing BPL concentration. We argue that the increased permeability of deep rough mutants is due to structural modifications caused by BPL to the LPS membrane, in LPS hydrocarbon chain packing and in the formation of BPL-enriched microdomains.


Cell cycle and aging, morphogenesis, and response to stimuli genes are individualized biomarkers of glioblastoma progression and survival.
Glioblastoma is a complex multifactorial disorder that has swift and devastating consequences. Few genes have been consistently identified as prognostic biomarkers of glioblastoma survival. The goal of this study was to identify general and clinical-dependent biomarker genes and biological processes of three complementary events: lifetime, overall and progression-free glioblastoma survival. A novel analytical strategy was developed to identify general associations between the biomarkers and glioblastoma, and associations that depend on cohort groups, such as race, gender, and therapy. Gene network inference, cross-validation and functional analyses further supported the identified biomarkers. A total of 61, 47 and 60 gene expression profiles were significantly associated with lifetime, overall, and progression-free survival, respectively. The vast majority of these genes have been previously reported to be associated with glioblastoma (35, 24, and 35 genes, respectively) or with other cancers (10, 19, and 15 genes, respectively) and the rest (16, 4, and 10 genes, respectively) are novel associations. Pik3r1, E2f3, Akr1c3, Csf1, Jag2, Plcg1, Rpl37a, Sod2, Topors, Hras, Mdm2, Camk2g, Fstl1, Il13ra1, Mtap and Tp53 were associated with multiple survival events.Most genes (from 90 to 96%) were associated with survival in a general or cohort-independent manner and thus the same trend is observed across all clinical levels studied. The most extreme associations between profiles and survival were observed for Syne1, Pdcd4, Ighg1, Tgfa, Pla2g7, and Paics. Several genes were found to have a cohort-dependent association with survival and these associations are the basis for individualized prognostic and gene-based therapies. C2, Egfr, Prkcb, Igf2bp3, and Gdf10 had gender-dependent associations; Sox10, Rps20, Rab31, and Vav3 had race-dependent associations; Chi3l1, Prkcb, Polr2d, and Apool had therapy-dependent associations. Biological processes associated glioblastoma survival included morphogenesis, cell cycle, aging, response to stimuli, and programmed cell death. Known biomarkers of glioblastoma survival were confirmed, and new general and clinical-dependent gene profiles were uncovered. The comparison of biomarkers across glioblastoma phases and functional analyses offered insights into the role of genes. These findings support the development of more accurate and personalized prognostic tools and gene-based therapies that improve the survival and quality of life of individuals afflicted by glioblastoma multiforme.


Targeted therapy resistance mediated by dynamic regulation of extrachromosomal mutant EGFR DNA.
Intratumoral heterogeneity contributes to cancer drug resistance, but the underlying mechanisms are not understood. Single-cell analyses of patient-derived models and clinical samples from glioblastoma patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) demonstrate that tumor cells reversibly up-regulate or suppress mutant EGFR expression, conferring distinct cellular phenotypes to reach an optimal equilibrium for growth. Resistance to EGFR TKIs is shown to occur by elimination of mutant EGFR from extrachromosomal DNA. After drug withdrawal, reemergence of clonal EGFR mutations on extrachromosomal DNA follows. These results indicate a highly specific, dynamic, and adaptive route by which cancers can evade therapies that target oncogenes maintained on extrachromosomal DNA.


Cytosine methylation effects on the repair of O6-methylguanines within CG dinucleotides.
O(6)-alkyldeoxyguanine adducts induced by tobacco-specific nitrosamines are repaired by O(6)-alkylguanine DNA alkyltransferase (AGT), which transfers the O(6)-alkyl group from the damaged base to a cysteine residue within the protein. In the present study, a mass spectrometry-based approach was used to analyze the effects of cytosine methylation on the kinetics of AGT repair of O(6)-methyldeoxyguanosine (O(6)-Me-dG) adducts placed within frequently mutated 5'-CG-3' dinucleotides of the p53 tumor suppressor gene. O(6)-Me-dG-containing DNA duplexes were incubated with human recombinant AGT protein, followed by rapid quenching, acid hydrolysis, and isotope dilution high pressure liquid chromatography-electrospray ionization tandem mass spectrometry analysis of unrepaired O(6)-methylguanine. Second-order rate constants were calculated in the absence or presence of the C-5 methyl group at neighboring cytosine residues. We found that the kinetics of AGT-mediated repair of O(6)-Me-dG were affected by neighboring 5-methylcytosine ((Me)C) in a sequence-dependent manner. AGT repair of O(6)-Me-dG adducts placed within 5'-CG-3' dinucleotides of p53 codons 245 and 248 was hindered when (Me)C was present in both DNA strands. In contrast, cytosine methylation within p53 codon 158 slightly increased the rate of O(6)-Me-dG repair by AGT. The effects of (Me)C located immediately 5' and in the base paired position to O(6)-Me-dG were not additive as revealed by experiments with hypomethylated sequences. Furthermore, differences in dealkylation rates did not correlate with AGT protein affinity for cytosine-methylated and unmethylated DNA duplexes or with the rates of AGT-mediated nucleotide flipping, suggesting that (Me)C influences other kinetic steps involved in repair, e.g. the rate of alkyl transfer from DNA to AGT.


Evidence for two distinct thalamocortical circuits in retrosplenial cortex.
Retrosplenial cortex (RSC) lies at the interface between sensory and cognitive networks in the brain and mediates between these, although it is not yet known how. It has two distinct subregions, granular (gRSC) and dysgranular (dRSC). The present study investigated how these subregions differ with respect to their electrophysiology and thalamic connectivity, as a step towards understanding their functions. The gRSC is more closely connected to the hippocampal formation, in which theta-band local field potential oscillations are prominent. We, therefore, compared theta-rhythmic single-unit activity between the two RSC subregions and found, mostly in gRSC, a subpopulation of non-directional cells with spiking activity strongly entrained by theta oscillations, suggesting a stronger coupling of gRSC to the hippocampal system. We then used retrograde tracers to test for differential inputs to RSC from the anteroventral thalamus (AV). We found that gRSC and dRSC differ in their afferents from two AV subfields: dorsomedial (AVDM) and ventrolateral (AVVL). Specifically: (1) as a whole AV projects more strongly to gRSC; (2) AVVL targets both gRSC and dRSC, while AVDM provides a selective projection to gRSC, (3) the gRSC projection is layer-specific: AVDM targets specifically gRSC superficial layers. These same AV projections are topographically organized with ventral AV neurons innervating rostral RSC and dorsal AV neurons innervating caudal RSC. These combined results suggest the existence of two distinct but interacting RSC subcircuits: one connecting AVDM to gRSC that may comprise part of the cognitive hippocampal system, and the other connecting AVVL to both RSC regions that may link hippocampal and perceptual regions. We suggest that these subcircuits are distinct to allow for differential weighting during integration of converging sensory and cognitive computations: an integration that may take place in thalamus, RSC, or both.


Growth hormone stimulates transcription of the fibroblast growth factor 21 gene in the liver through the signal transducer and activator of transcription 5.
Fibroblast growth factor 21 (FGF21) is a recently discovered metabolic regulator. Interestingly, FGF21 is also known to inhibit Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5) signaling from the GH receptor in the liver, where FGF21 mRNA is predominantly expressed. In this study, we tested the hypothesis that FGF21 gene expression in the liver is controlled by GH through STAT5. We found that GH injection to cattle increased FGF21 mRNA expression in the liver. Mapped by a 5'-rapid amplification of cDNA ends assay, transcription of the FGF21 gene in the bovine liver was mainly initiated from a nucleotide 24 bp downstream of a TATA box. The bovine FGF21 promoter contains three putative STAT5-binding sites. EMSA confirmed the ability of them to bind to liver STAT5 protein from GH-injected cattle. Chromatin immunoprecipitation assays demonstrated that GH administration increased the binding of STAT5 to the FGF21 promoter in the liver. Cotransfection analyses showed that GH induced reporter gene expression from the FGF21 promoter in a STAT5-dependent manner. GH also stimulated FGF21 mRNA expression in cultured mouse hepatocytes. These data together indicate that GH directly stimulates FGF21 gene transcription in the liver, at least in part, through STAT5. This finding, together with the fact that FGF21 inhibits GH-induced JAK2-STAT5 signaling in the liver, suggests a novel negative feedback loop that prevents excessive JAK2-STAT5 signaling from the GH receptor in the liver.


Design of efficient all-optical code-division multiplexing systems supporting multiple-bit-rate and equal-bit-rate transmissions.
We present the design of efficient all-optical code-division multiplexing (AOCDM) systems that can transmit multiple-bit-rate (MBR) data signals over a common optical fiber. This is achieved when the proposed strict optical orthogonal code (OOC) of autocorrelation and cross-correlation constraints of 1 are used but without performance degradation compared with the use of conventional OOC. We describe the design of various strict OOC's by employing the useful concept of slot distances, and methods of code construction are also presented. Moreover, we give the principle of MBR data transmissions in an AOCDM system. It is shown that AOCDM systems using the proposed OOC can effectively transmit multiuser MBR and equal-bit-rate (EBR) data with no increase of system complexity. In principle, optimal strict OOC's need the same or a slightly larger system bandwidth compared with optimal conventional OOC's for EBR operation, whereas the former can require a smaller system bandwidth and have a better system performance than the latter for MBR transmissions. A new, to our knowledge, family of strict OOC's is also introduced, whose code words can have nonconstant weights to support multiuser communications with different transmission quality. Furthermore, we design low-cost AOCDM transmitters that are based on an efficient gain-switching scheme that does not require an electro-optic intensity modulator to on-off modulate an optical clock pulse stream at each transmitter. The basic operation principle is also experimentally demonstrated.


Coronary microvascular dysfunction in women with nonobstructive ischemic heart disease as assessed by positron emission tomography.
Traditional approaches for risk assessment of ischemic heart disease (IHD) are based on the physiological consequences of an epicardial coronary stenosis. Of note, normal coronary arteries or nonobstructive coronary artery disease (CAD) is a common finding in women with signs and symptoms of ischemia. Therefore, assessment of risk based on a coronary stenosis approach may fail in women. Positron emission tomography (PET) quantifies absolute myocardial blood flow (MBF) which may help to elucidate other mechanisms involved such as endothelial dysfunction and alterations in the smooth muscle cell relaxation responsible for IHD in women. The objective of the present review is to describe the current state of the art of PET imaging in assessing IHD in women with nonobstructive CAD.


Achieving 1% NMR polarization in water in less than 1min using SABRE.
The development of biocompatible hyperpolarized media is a crucial step towards application of hyperpolarization in vivo. This article describes the achievement of 1% hyperpolarization of 3-amino-1,2,4-triazine protons in water using the parahydrogen induced polarization technique based on signal amplification by reversible exchange (SABRE). Polarization was achieved in less than 1 min.


Validation of a blood protein signature for non-small cell lung cancer.
CT screening for lung cancer is effective in reducing mortality, but there are areas of concern, including a positive predictive value of 4% and development of interval cancers. A blood test that could manage these limitations would be useful, but development of such tests has been impaired by variations in blood collection that may lead to poor reproducibility across populations. Blood-based proteomic profiles were generated with SOMAscan technology, which measured 1033 proteins. First, preanalytic variability was evaluated with Sample Mapping Vectors (SMV), which are panels of proteins that detect confounders in protein levels related to sample collection. A subset of well collected serum samples not influenced by preanalytic variability was selected for discovery of lung cancer biomarkers. The impact of sample collection variation on these candidate markers was tested in the subset of samples with higher SMV scores so that the most robust markers could be used to create disease classifiers. The discovery sample set (n = 363) was from a multi-center study of 94 non-small cell lung cancer (NSCLC) cases and 269 long-term smokers and benign pulmonary nodule controls. The analysis resulted in a 7-marker panel with an AUC of 0.85 for all cases (68% adenocarcinoma, 32% squamous) and an AUC of 0.93 for squamous cell carcinoma in particular. This panel was validated by making blinded predictions in two independent cohorts (n = 138 in the first validation and n = 135 in the second). The model was recalibrated for a panel format prior to unblinding the second cohort. The AUCs overall were 0.81 and 0.77, and for squamous cell tumors alone were 0.89 and 0.87. The estimated negative predictive value for a 15% disease prevalence was 93% overall and 99% for squamous lung tumors. The proteins in the classifier function in destruction of the extracellular matrix, metabolic homeostasis and inflammation. Selecting biomarkers resistant to sample processing variation led to robust lung cancer biomarkers that performed consistently in independent validations. They form a sensitive signature for detection of lung cancer, especially squamous cell histology. This non-invasive test could be used to improve the positive predictive value of CT screening, with the potential to avoid invasive evaluation of nonmalignant pulmonary nodules.


Identification of oral bacteria associated with crevicular epithelial cells from chronic periodontitis lesions.
Bacterial invasion of host epithelial cells plays an important role in the pathogenesis of periodontal diseases; however, the interactions between subgingival species and the gingival crevice cells are not fully understood. This study determined the prevalence of a group of oral bacterial species on or in epithelial cells derived from periodontal pockets and the gingival crevice of subjects with periodontitis. Samples of epithelial cells were obtained from 120 sites with periodontal pockets > or =4 mm and 92 periodontally healthy sites from 49 patients (mean age 46.3+/-1.4 years; 43% males) with chronic periodontitis. Bacteria in or on epithelial cells were separated from unattached bacteria by Percoll density-gradient centrifugation. The presence and levels of 33 oral species were determined in epithelial cell samples by whole genomic DNA probes and the checkerboard method. The most frequently detected species were Porphyromonas gingivalis (42%), Treponema denticola (38%), Prevotella intermedia (37%), Streptococcus intermedius (36%), Campylobacter rectus (35%), Streptococcus sanguinis (35%) and Streptococcus oralis (34%). Species of Actinomyces were found in low prevalence and levels. The data indicated that there were more micro-organisms on or in epithelial cells obtained from periodontal pockets than from healthy sulci; however, no significant differences regarding the percentage and level of any specific species were found between these sites. Veillonella parvula, S. oralis, Streptococcus gordonii and Streptococcus mitis tended to be more prevalent in sites without disease. These findings demonstrated that a wide range of oral species may be detected on or in crevicular epithelial cells from sites with periodontitis and from periodontally healthy sulci.


Medical and Dental Visits of Chronic Kidney Disease-Diagnosed Participants Analyzed From the Specific Health Checkups Results in Japan: TAMA MED Project-CKD.
Since 2012, Tama City has promoted the early detection of chronic kidney disease (CKD), through an initiative that measures serum creatinine as part of the specific health checkups. We examined preventive measures against CKD deterioration based on the outcomes of this initiative. The complications, medication status, body mass index, smoking status and other determining factors were surveyed among CKD-diagnosed participants over 3 years between 2013 and 2015. Moreover, factors aggravating CKD were investigated via a survey of medical and dental visits based on health insurance claim data over the same period. There was an increased rate of comorbid hypertension with each increase in the CKD stage. Comorbidity rates of diabetes mellitus, dyslipidemia, obesity, and smoking increased until CKD stage G4, and then decreased from stage G5. A substantial number of participants with CKD stage G3b and above were not medicated despite comorbidities like hypertension, diabetes mellitus and dyslipidemia. While the rate of regular visits at medical institutions was seen to increase significantly in accordance with the worsening degree of CKD, there were also individuals who, despite having severe CKD, did not visit medical institutions specializing in internal medicine. The rate of dental visits decreased as the CKD stage increased, and further decreased as the diabetic control status worsened. CKD patients should become aware of the importance of the dental visit because only a limited number of patients with advanced CKD received dental care.


Compact and multiplexible hydrogen gas sensor assisted by self-referencing technique.
We have experimentally implemented a multiplexible but compact fiber sensor system suitable for multipoint sensing of hydrogen gas leakage. By making dual cavities along an optical fiber and coating a palladium film only at the end of the fiber tip, the measurement errors induced by the optical source power fluctuation and the mechanical perturbation in the lead fiber could be compensated. By adjusting the length of the dual-cavity, the capability of multiplexing several hydrogen sensors could be achieved. The experiment results showed that the response speed of the sensor was increasing with temperature, but at a low temperature the response amplitude became large.


Developments and recent advancements in the field of endogenous amino acid selective bond forming reactions for bioconjugation.
Bioconjugation methodologies have proven to play a central enabling role in the recent development of biotherapeutics and chemical biology approaches. Recent endeavours in these fields shed light on unprecedented chemical challenges to attain bioselectivity, biocompatibility, and biostability required by modern applications. In this review the current developments in various techniques of selective bond forming reactions of proteins and peptides were highlighted. The utility of each endogenous amino acid-selective conjugation methodology in the fields of biology and protein science has been surveyed with emphasis on the most relevant among reported transformations; selectivity and practical use have been discussed.


A novel instrumented ring for the measurement of grip force adjustments during precision grip tasks.
A wide range of scientific and clinical research studies use the measurement of grip force to quantify hand function and activities during daily living. Many applications of instrumented objects can be found in the biomechanical and neurophysiological literature. However, these were found not to be suitable for the measurement of grip force and force modulations during precision grip independently from the hand orientation. The low-cost precision grip force transducer described here is capable of recording magnitude, direction and modulation of the force exerted on a closed ring. The design is based on a standard proving ring, onto which a second set of strain gauges is applied. The outputs of both Wheatstone bridges yield a unique signature for every position under a two-point load. The tested aluminium ring had an outer diameter of 83 mm, a wall thickness of 3 mm and a height of 12 mm. With eight single bending strain gauges used, the maximum load was 100 N. During a grip task, tremor components from d.c. to 45 Hz could be detected. The newly developed ring might therefore find a use in many biomechanical and neurophysiological studies as a tool for measuring grip force and its fine modulations.


A meta-analysis of 1,119 manipulative experiments on terrestrial carbon-cycling responses to global change.
Direct quantification of terrestrial biosphere responses to global change is crucial for projections of future climate change in Earth system models. Here, we synthesized ecosystem carbon-cycling data from 1,119 experiments performed over the past four decades concerning changes in temperature, precipitation, CO2 and nitrogen across major terrestrial vegetation types of the world. Most experiments manipulated single rather than multiple global change drivers in temperate ecosystems of the USA, Europe and China. The magnitudes of warming and elevated CO2 treatments were consistent with the ranges of future projections, whereas those of precipitation changes and nitrogen inputs often exceeded the projected ranges. Increases in global change drivers consistently accelerated, but decreased precipitation slowed down carbon-cycle processes. Nonlinear (including synergistic and antagonistic) effects among global change drivers were rare. Belowground carbon allocation responded negatively to increased precipitation and nitrogen addition and positively to decreased precipitation and elevated CO2. The sensitivities of carbon variables to multiple global change drivers depended on the background climate and ecosystem condition, suggesting that Earth system models should be evaluated using site-specific conditions for best uses of this large dataset. Together, this synthesis underscores an urgent need to explore the interactions among multiple global change drivers in underrepresented regions such as semi-arid ecosystems, forests in the tropics and subtropics, and Arctic tundra when forecasting future terrestrial carbon-climate feedback.


Analysis of the contributions of magnetic susceptibility to effective refractive indices of photonic crystals at long-wavelength limits.
Since the magnetic susceptibility of materials is significant for low-wavelength regions, we investigated magnetic effects on refractive indices for long-wavelength electromagnetic waves propagating in photonic crystals (PCs). The PCs consisted of triangularly arrayed long rods, and were made of either dielectric or magnetic material, with air as the interstitial medium. According to calculated photonic band structures, the magnetism of rods plays a role in TM modes. Instead of using complicated calculating processes for band structures to find long-wavelength refractive indices, an analytic method was developed to estimate the effective refractive indices of long-wavelength TM modes. The refractive indices obtained through the band structures and the analytic method were consistent with each other. This demonstrates the validity of the analytic method, which we used to further clarify the physical mechanism involving the effects of rod magnetism on the refractive indices of long-wavelength TM modes propagating along magnetic PCs.


Cardiovascular side effects of cancer therapies: a position statement from the Heart Failure Association of the European Society of Cardiology.
The reductions in mortality and morbidity being achieved among cancer patients with current therapies represent a major achievement. However, given their mechanisms of action, many anti-cancer agents may have significant potential for cardiovascular side effects, including the induction of heart failure. The magnitude of this problem remains unclear and is not readily apparent from current clinical trials of emerging targeted agents, which generally under-represent older patients and those with significant co-morbidities. The risk of adverse events may also increase when novel agents, which frequently modulate survival pathways, are used in combination with each other or with other conventional cytotoxic chemotherapeutics. The extent to which survival and growth pathways in the tumour cell (which we seek to inhibit) coincide with those in cardiovascular cells (which we seek to preserve) is an open question but one that will become ever more important with the development of new cancer therapies that target intracellular signalling pathways. It remains unclear whether potential cardiovascular problems can be predicted from analyses of such basic signalling mechanisms and what pre-clinical evaluation should be undertaken. The screening of patients, optimization of therapeutic schemes, monitoring of cardiovascular function during treatment, and the management of cardiovascular side effects are likely to become increasingly important in cancer patients. This paper summarizes the deliberations of a cross-disciplinary workshop organized by the Heart Failure Association of the European Society of Cardiology (held in Brussels in May 2009), which brought together clinicians working in cardiology and oncology and those involved in basic, translational, and pharmaceutical science.


Metal binding by bacteria from uranium mining waste piles and its technological applications.
Uranium mining waste piles, heavily polluted with radionuclides and other toxic metals, are a reservoir for bacteria that have evolved special strategies to survive in these extreme environments. Understanding the mechanisms of bacterial adaptation may enable the development of novel bioremediation strategies and other technological applications. Cell isolates of Bacillus sphaericus JG-A12 from a uranium mining waste pile in Germany are able to accumulate high amounts of toxic metals such as U, Cu, Pb, Al, and Cd as well as precious metals. Some of these metals, i.e. U, Cu, Pd(II), Pt(II) and Au(III), are also bound by the highly orderd paracrystalline proteinaceous surface layer (S-layer) that envelopes the cells of this strain. These special capabilities of the cells and the S-layer proteins of B. sphaericus JG-A12 are highly interesting for the clean-up of uranium contaminated waste waters, for the recovery of precious metals from electronic wastes, and for the production of metal nanoclusters. The fabricated nanoparticles are promising for the development of novel catalysts. This work reviews the molecular biology of the S-layer of the strain JG-A12 and the S-layer dependent interactions of the bacterial cells with metals. It presents future perspectives for their application in bioremediation and nanotechnology.


Meta-analysis of emotion recognition deficits in major depressive disorder.
Many studies have explored associations between depression and facial emotion recognition (ER). However, these studies have used various paradigms and multiple stimulus sets, rendering comparisons difficult. Few studies have attempted to determine the magnitude of any effect and whether studies are properly powered to detect it. We conducted a meta-analysis to synthesize the findings across studies on ER in depressed individuals compared to controls. Studies of ER that included depressed and control samples and published before June 2013 were identified in PubMed and Web of Science. Studies using schematic faces, neuroimaging studies and drug treatment studies were excluded. Meta-analysis of k = 22 independent samples indicated impaired recognition of emotion [k = 22, g = -0.16, 95% confidence interval (CI) -0.25 to -0.07, p < 0.001]. Critically, this was observed for anger, disgust, fear, happiness and surprise (k's = 7-22, g's = -0.42 to -0.17, p's < 0.08), but not sadness (k = 21, g = -0.09, 95% CI -0.23 to +0.06, p = 0.23). Study-level characteristics did not appear to be associated with the observed effect. Power analysis indicated that a sample of approximately 615 cases and 615 controls would be required to detect this association with 80% power at an alpha level of 0.05. These findings suggest that the ER impairment reported in the depression literature exists across all basic emotions except sadness. The effect size, however, is small, and previous studies have been underpowered.


Implantation of biomaterial as an efficient method to harvest mesenchymal stem cells.
Autologous mesenchymal stem cell (MSC) transplants have been used successfully to treat a number of diseases, and patients undergoing cell transplantation must have stem cells collected before transplantation. In this study, we developed a new method to harvest MSCs. Biomaterials were implanted into the spatium intermuscular of mice hind limbs, and a large number of migrating cells (MCs) were isolated from the transplanted biomaterials. The adherent cells in MCs showed the characteristics of MSCs. Further comparative study demonstrated that the characteristics of MC-MSCs were similar to that of bone marrow (BM)-MSCs, including morphology, phenotype, proliferation potential, multilineage differentiation capacity and hematopoiesis-supportive function. The colony-forming unit-fibroblast frequency of the MCs was equivalent to approximately 20-fold of that of the BM. In addition, a BM transplantation experiment demonstrated that MC-MSCs were derived from the peripheral blood. In conclusion, we successfully establish an efficient method to harvest MSCs, and together with the distinct advantages of this method, such as accessibility and possibility for autologous cell therapy, we conclude that our efficient method may be a promising alternative for clinical application.


Evaluation of the stability of creatine in solution prepared from effervescent creatine formulations.
The objectives of this study were to determine the cause of the crystallization in a large volume creatine supplement solution made from effervescent powders containing di-creatine citrate, and to characterize these crystals using thermal analyses and x-ray diffractometry. Creatine effervescent powders were dissolved in deionized water (pH 6.2) and stored both at room temperature (RT) (25 degrees C) and refrigerated condition (4 degrees C) over a period of 45 days. Creatine concentration was determined using high-performance liquid chromatography (HPLC). Intrinsic dissolution and saturated solubility of creatine, creatine monohydrate, and di-creatine citrate in water were determined and compared. Crystal growth was detected only in the refrigerated samples on the seventh day of storage. Differential Scanning Calorimetry (DSC) and x-ray diffraction (XRD) studies revealed that the crystals formed were of creatine monohydrate. Ninety percent creatine degradation was observed within 45 days for RT samples. However, at refrigerated condition this degradation was 80% within the same time period. The pH of the RT samples also increased from 3.6 to 4.5 during storage. No such increase was observed in the case of refrigerated samples. The intrinsic dissolution rate constants of the compounds decreased in the following order: di-creatine citrate > creatine > creatine monohydrate. In conclusion, di-creatine citrate used in effervescent formulation dissociates to creatine in aqueous solution and eventually crystallizes out as creatine monohydrate. Significant decrease in solubility and effect of pH contribute to this crystallization process.


Examination of nasopharyngeal and tracheal somatosensory evoked potential recordings in dogs.
To investigate the value of nasopharyngeal and tracheal recordings of somatosensory evoked potentials (SSEP) in anesthetized dogs. 10 healthy mixed-breed dogs (5 males and 5 females). Square-ware electrical stimuli (50 microseconds duration, 4Hz) were delivered through bipolar surface electrodes to the median nerve of the right forelimb with 7 to 12 mA constant current. The SSEP were recorded with soft electrodes placed on the epipharynx and dorsal wall of the trachea, respectively. Traditional scalp and neck recordings of SSEP were also performed, using SC-inserted needle electrodes. The potentials recorded dorsally and ventrally from the neuraxis were compared to assess the application of these signals for intraoperative neurophysiologic monitoring. Electrical stimulation of the median nerve resulted in multiphasic potentials recorded from all 4 recording sites. Latency and phase shifts were observed between the far-field potentials placed ventrally and dorsally from the neuraxis. Potentials recorded with nasopharyngeal and tracheal electrodes are regarded suitable for intraoperative neurophysiologic monitoring in anesthized dogs.


The impact of liver reductions in pediatric liver transplantation.
Reduced-size liver transplantation (RSLT) in children was introduced to alleviate a shortage of small-organ donors. The impact of RSLT on the waiting time for an organ and on morbidity and mortality was investigated. Between March 25, 1988, and August 11, 1990, 61 hepatic transplantations were performed in 55 children at the Pacific Transplant Institute in San Francisco, Calif. Full-size liver transplantation was performed in 41 cases and RSLT in 20 cases. The overall 30-month actuarial patient and graft survival rates were 89% and 73%, respectively. A comparison between full-size liver transplantation and RSLT showed no difference in patient and graft survival, reoperations, infections, or rejection. Benefits of RSLT were an increase in the donor pool size, a decrease in waiting time for a suitable donor, and a decrease in the rate of arterial thrombosis. The main morbidity of RSLT was an increase in perioperative blood requirement. We conclude that RSLT offers small children with end-stage liver disease a chance for long-term survival.


Real-time t(11;14) and t(14;18) PCR assays provide sensitive and quantitative assessments of minimal residual disease (MRD).
Non-Hodgkin's lymphoma (NHL) arises as a clonal transformation of normal B and T cell differentiation and is often characterized by a higher incidence of specific chromosomal translocations. We have developed real-time TaqMan PCR assays directed toward two of these tumor-associated DNA markers, the t(14;18)(q32;q21.3) at the major breakpoint region of the bcl-2 gene and the t(11;14)(q13;q32) at the bcl-1 major translocation cluster. During analysis of serial dilutions of t(14;18)-positive DNA, the t(14;18) real-time PCR was at least as sensitive as nested PCR and demonstrated enhanced quantitative potential. Moreover, in a blinded comparison of the t(14;18) real-time PCR and a clinically validated nested PCR protocol using 134 cell line and patient DNA samples, the real-time PCR detected the translocation in 30.0% more cases than nested PCR. Both the t(14;18) and t(11;14) real-time PCR assays were used to quantitate minimal residual disease (MRD) in an NHL clinical trial assessing the safety and efficacy of a tumor-purging protocol in autologous stem cell transplantation. The assays were also used to evaluate disease depletion in an ex vivo tumor spiking model in which normal peripheral blood was spiked with tumor cell lines and processed according to the clinical purging method. PCR data from both the clinical trial and the ex vivo model demonstrated a 4 to 6 log reduction in tumor cells during CD34+ and CD34+ Thy-1+ enrichment. Because the t(14;18) and t(11;14) real-time PCR assays are very sensitive, quantitative, rapid, and require no post-PCR manipulation, they may serve as practical alternatives to nested PCR.


Coupling to Surface Waves with Prisms via Attenuated Total Reflection.
A summary of the prism technique for optical coupling to nonradiative surface waves, particularly surface plasmons, is given. Equations for dispersion relations, lifetimes, and leakages are presented in approximate form for small absorption, and in some cases, the exact equations are given. The details of design, fabrication, and use of a parallelopiped prism are discussed for commercial spectrometers. The information presented here should suffice for study of surface plasmons, surface phonons, etc., from the visible to the far infrared wavelengths.


The probability of epidemic fade-out is non-monotonic in transmission rate for the Markovian SIR model with demography.
Epidemic fade-out refers to infection elimination in the trough between the first and second waves of an outbreak. The number of infectious individuals drops to a relatively low level between these waves of infection, and if elimination does not occur at this stage, then the disease is likely to become endemic. For this reason, it appears to be an ideal target for control efforts. Despite this obvious public health importance, the probability of epidemic fade-out is not well understood. Here we present new algorithms for approximating the probability of epidemic fade-out for the Markovian SIR model with demography. These algorithms are more accurate than previously published formulae, and one of them scales well to large population sizes. This method allows us to investigate the probability of epidemic fade-out as a function of the effective transmission rate, recovery rate, population turnover rate, and population size. We identify an interesting feature: the probability of epidemic fade-out is very often greatest when the basic reproduction number, R0, is approximately 2 (restricting consideration to cases where a major outbreak is possible, i.e., R0>1). The public health implication is that there may be instances where a non-lethal infection should be allowed to spread, or antiviral usage should be moderated, to maximise the chance of the infection being eliminated before it becomes endemic.


The relationship between socioeconomic position and depression among a US nationally representative sample of African Americans.
Findings from previous studies have not revealed significant, inverse relationships between socioeconomic position (SEP) and depression among African Americans. This study examined the relationship between multiple indicators of SEP and Major Depressive Episode (MDE) among African Americans. Data were drawn from the National Survey of American Life main interview and re-interview. MDE, at both 12 month and lifetime intervals, was assessed using the World Mental Health version of the Composite International Diagnostic Interview. Logistic regression models were adjusted for demographics. For 12-month MDE, household income and unemployment predicted greater odds of MDE among African American men, while there was an inverse relationship between education and 12-month MDE. Only unemployment was significantly associated with lifetime MDE among African American men. For African American women, a significant inverse relationship between household income and 12-month MDE was observed. Findings garnered from this study indicate that it is important to consider multiple measures of SEP in the prediction of depression among African Americans, and that the pattern of association between SEP and depression varies according to sex. Considering the paucity of studies that have explored the relationship between SEP and depression, additional research is needed to more firmly establish the relationship between SEP and depression. It is also important to consider stressors that may affect the relationship between SEP and depression among African Americans.


Misperfusion of the liver during hepatic artery infusion chemotherapy: value of preoperative angiography and postoperative pump scintigraphy.
One purpose of this study was to determine if patients who have anatomic variations in their hepatic arteries are at increased risk for complications associated with the use of intrahepatic arterial infusion pumps. We also tried to determine the value of perfusion studies obtained with 99mTc-microspheres or 99mTc-macroaggregated albumin in detecting postoperative hepatic or visceral misperfusion and in predicting complications in patients with anatomic variants despite pre- or intraoperative attempts to correct the arterial abnormality. We prospectively compared findings on scintigrams obtained after delivering the radionuclide through intrahepatic arterial infusion pumps with anatomic variations in hepatic arteries seen on celiac and superior mesenteric hepatic arteriograms obtained before placement of the pump in 49 consecutive patients with colon carcinoma metastatic to the liver. Despite pre- or intraoperative attempts to correct arterial abnormalities to ensure optimal perfusion of the liver in 24 patients with hepatic arterial anomalies seen on preoperative arteriograms, only two patients had normal findings on postoperative perfusion studies performed with 99mTc-microspheres and/or 99mTc-macroaggregated albumin. Abnormalities included perfusion of extrahepatic organs, including the spleen in 12 patients, stomach in seven, bowel in four, and pancreas in three. Eight patients had no perfusion of the left lobe of the liver, and three had no perfusion of the right lobe. Two patients had minimal or no perfusion of both lobes. In 23 of 25 patients with no demonstrable variations in vascular anatomy on preoperative celiac and superior mesenteric arteriograms, findings on hepatic pump scintigrams were normal. Of the 24 patients with abnormal scintigraphic findings, 20 had subsequent clinical complications. However, only two of the 25 patients with normal scintigraphic findings had clinical complications. Our results indicate that patients with anatomic variations in the hepatic arterial system are at high risk for misperfusion during chemotherapy despite pre- or intraoperative efforts to alter the perfusion for chemotherapeutic agents delivered by intrahepatic arterial infusion pumps. Misperfusion can be detected by using pump scintigraphy, and therefore patients should be closely monitored with 99mTc-macroaggregated albumin perfusion studies to ensure successful delivery of the chemotherapeutic agents and to avoid serious clinical complications caused by inadvertent perfusion of other organs.


Oesophageal motor response to reflux is not impaired in reflux oesophagitis.
Whether the oesophageal motor response to reflux, as recorded over 24 hours, is impaired in patients with reflux oesophagitis was investigated. Twenty three patients with oesophagitis (Savary-Miller grades I-IV) and 23 control subjects matched for age and sex underwent 24 hour ambulatory pH and pressure monitoring. All contractions occurring in the 2 minute period after the onset of each reflux episode were analysed automatically using dedicated computer algorithms. A total of 2085 reflux episodes occurred--1513 in patients and 572 in controls. Oesophageal acid exposure was greater (p < 0.01) in patients than in controls (mean (SEM) % time pH < 4 13.3 (1.7) and 5.3 (0.9)%, respectively). The mean duration of the supine reflux episodes was longer (p < 0.01) in patients (11.2 (2.8) minutes) than in controls (5.1 (1.8) minutes). In the upright period, no significant differences in the motor response to reflux were found. In the supine period, the patients showed a higher number of reflux induced contractions (4.40 (0.61) v 1.62 (0.31), p < 0.01), a higher contraction amplitude (4.55 (0.42) v 2.99 (0.71) kPa, p < 0.02) and longer contractions (1.86 (0.19) v 1.32 (0.29) seconds, p < 0.05). The percentages of peristaltic and simultaneous contractions that occurred in response to supine reflux did not differ between the two groups. In patients with reflux oesophagitis the motor response of the oesophagus to reflux is not impaired. During the supine period the response is even stronger than in healthy controls.


Elucidation of the metal-binding properties of the Klenow fragment of Escherichia coli polymerase I and bacteriophage T4 DNA polymerase by lanthanide(III) luminescence spectroscopy.
The exonuclease active site of the Klenow fragment (KF) of Escherichia coli DNA polymerase I has a double binding site for the two essential divalent metal ions in the presence of the nucleotide monophosphate dTMP. The luminescence spectroscopy observed upon binding of Eu3+ to the exonuclease active site of T4 DNA polymerase was interpreted relative to the binding of Eu3+ or Tb3+ observed with KF. Both wild-type enzymes tightly bind a single Ln3+ ion but in two isomeric forms. The single mutants of KF (D424A) and T4 (D219A) also bind a single Eu3+ ion tightly, but the alignment of the coordinating ligands is altered. The KF double mutant (D355A, E357A) exhibits a markedly altered and weakened binding site (Kd = 20-26 microM). Eu3+ serves as a competitive inhibitor of Mg2+-induced polymerase and exonuclease activity, validating its use as a probe for these active sites. Ln3+ luminescence spectroscopy is established as a sensitive way to determine the consequences of exonuclease binding-site mutations and to examine binding site similarities and differences among DNA polymerases from different sources. The binding sites of KF and T4 DNA polymerase are shown to be quite similar.


The pitfalls of overreaching in health reform.
Although fundamental reform of U.S. health care is clearly necessary, the obstacles remain daunting. These include the sheer size of the health sector, the multiplicity of powerful groups with conflicting interests, and the factionalized U.S. political system. Because the nation can ill afford to come away empty-handed from another reform effort, it is vital that the new administration focus on achievable steps that will support and encourage a process of reform. Doing so would lay the groundwork for a series of changes that may take a generation, instead of risking everything on the highly unlikely passage of one "big bill."


The metabolic core and catalytic switches are fundamental elements in the self-regulation of the systemic metabolic structure of cells.
Experimental observations and numerical studies with dissipative metabolic networks have shown that cellular enzymatic activity self-organizes spontaneously leading to the emergence of a metabolic core formed by a set of enzymatic reactions which are always active under all environmental conditions, while the rest of catalytic processes are only intermittently active. The reactions of the metabolic core are essential for biomass formation and to assure optimal metabolic performance. The on-off catalytic reactions and the metabolic core are essential elements of a Systemic Metabolic Structure which seems to be a key feature common to all cellular organisms. In order to investigate the functional importance of the metabolic core we have studied different catalytic patterns of a dissipative metabolic network under different external conditions. The emerging biochemical data have been analysed using information-based dynamic tools, such as Pearson's correlation and Transfer Entropy (which measures effective functionality). Our results show that a functional structure of effective connectivity emerges which is dynamical and characterized by significant variations of bio-molecular information flows. We have quantified essential aspects of the metabolic core functionality. The always active enzymatic reactions form a hub--with a high degree of effective connectivity--exhibiting a wide range of functional information values being able to act either as a source or as a sink of bio-molecular causal interactions. Likewise, we have found that the metabolic core is an essential part of an emergent functional structure characterized by catalytic modules and metabolic switches which allow critical transitions in enzymatic activity. Both, the metabolic core and the catalytic switches in which also intermittently-active enzymes are involved seem to be fundamental elements in the self-regulation of the Systemic Metabolic Structure.


Management of liver cirrhosis in patients with hepatocellular carcinoma.
Management of hepatocellular carcinoma (HCC) is challenging compared to other common malignancies because of the nature of the associated background of chronic liver dysfunction. Most of the patients with HCC have underlying cirrhosis. While progression of the tumor is a major contributor to mortality, cirrhosis and its complications often accounts for a significant portion of the morbidity and mortality seen in this group of patients. Severity of underlying liver disease and degree of decompensation predicts prognosis and dictates the tumor treatment options and responses. A multidisciplinary approach is considered the standard of care and paramount to optimal patient outcomes. This review provides information on the general management of cirrhosis, cirrhosis-related complications and commonly associated symptoms, mainly focusing when available on high-level evidence and guidelines.


Optimal Medical Management Reduces Risk of Disease Progression and Ischemic Events in Asymptomatic Carotid Stenosis Patients: A Long-Term Follow-Up Study.
To assess the effect of optimal medical management including atherosclerotic risk factor control on ischemic stroke (IS), transient ischemic attack (TIA), carotid revascularization (CRV), and progression of severity of carotid stenosis (PSCS) in patients with asymptomatic carotid artery stenosis (ACAS). We conducted a retrospective analysis of patients with ACAS (who had at least 3 serial carotid duplex ultrasounds) for incidence of IS, TIA, and PSCS. Eight hundred sixty-four patients with a mean follow-up duration of 79 ± 36 months were included. IS/TIA and CRV occurred in 12.2% of the patients and PCSS was observed in 21.5% vessels. On univariate analysis it was found that low-density lipoprotein (LDL) levels >100 mg/dL, no statin or low-potency statins, average systolic blood pressure (SBP) ≥140 mm Hg and/or diastolic blood pressure (DBP) ≥90 mm Hg and history of smoking were predictors of the combined endpoint of IS/TIA/CRV and PSCS. On multivariate analysis, it was found that LDL >100 mg/dL, no statin or low-potency statin, SBP ≥140 mm Hg and/or DBP ≥90 mm Hg, and Hx of smoking were independent predictors of PSCS. Similarly no statin or low-potency statin, SBP ≥140 mm Hg and/or DBP ≥90 mm Hg, Hx of atrial fibrillation/flutter, Hx of chronic kidney disease, and PSCS were independent predictors of IS/TIA. No statin or low-potency statin, SBP ≥140 mm Hg and/or DBP ≥90 mm Hg, diabetes mellitus, baseline carotid artery stenosis ≥70%, and PSCS were found to be independent predictors of combined endpoint IS/TIA and CRV. Intensive medical therapy in the patients with ACAS results in lower incidence of IS/TIA, CRV, and PSCS with a significant incremental beneficial effect.


Effects of Novel Laser Dental Implant Microtopography on Human Osteoblast Proliferation and Bone Deposition.
The aim of this study was to compare how two innovative laser titanium surfaces and sandblasted and acid-etched surfaces influence human osteoblast behavior during osteogenesis and the initial phases of bone deposition. Human osteoblasts from human adipose stem cells were sorted by flow cytometric analysis and induced to differentiate. After 40 days, the osteogenic differentiation was detected by alizarin red staining, and the alkaline phosphatase (ALP) was evaluated with western blot (WB) and real-time reverse transcriptase-polymerase chain reaction (RT-PcR) analysis. After confluence, human osteoblasts were cultured onto two different innovative laser-obtained titanium surfaces (L1 and L2) and compared with one sandblasted and acid-etched (SBAE) surface as the control. At different times, human osteoblast behavior was evaluated with cell proliferation viability assay (MTT), scanning electron microscopy (SEM), energy-dispersive x-rays (EDAX), osteogenic markers with RT-PcR, and WB analysis of matrix extracellular phosphoglycoprotein (MEPE), ALP, and osteocalcin (OCN). After cell sorting, the human osteoblasts from human adipose stem cells showed increasing values of ALP mRNA and protein expression. The osteogenic differentiation was confirmed by quantitative alizarin red staining assay. Profilometric and SEM analysis showed relevant differences between SBAE, L1, and L2 specimens. After 20 days of culture onto titanium samples, SEM evaluation showed a small number of human osteoblasts and isolated sites of bone matrix deposition in SBAE specimens. At the same time, on L1 surfaces, only an osteoblast mono-layer with initial bone deposition was found, while on L2 specimens, there was a thick network with flattened large stellate cells, many cellular interconnections with strong titanium adhesion, and a large complex mineralized structure of crystal bone. After 20 days, for all titanium samples, human osteoblasts culturing EDAX analysis showed the absence of impurities and a higher bone matrix deposition in L2 specimens compared with L1 and SBAE samples. The innovative microtopography and nanotopography laser-induced surface showed high biocompatibility with primary human osteoblast cultures and the absence of impurities. The innovative laser texture was capable of influencing the osteogenic process, confirming the critical role of titanium surface characteristics in the cell adhesion and bone deposition during the early phases of osseointegration. The association of human adipose stem cells and titanium surfaces laser-induced with an innovative procedure could generate promising improvements and developments in orthopedics, maxillofacial, and dental implant surgery.


Probiotics prevent IgE-associated allergy until age 5 years in cesarean-delivered children but not in the total cohort.
Less microbial exposure in early childhood is associated with more allergic disease later. Allergic children have a different fecal microflora, with less lactobacilli and bifidobacteria. Beneficial effects regarding the development of allergy have been suggested to come through probiotic supplementation. We sought to study the effect of probiotic and prebiotic supplementation in preventing allergies. In a double-blinded, placebo-controlled study we randomized 1223 mothers with infants at high risk for allergy to receive a probiotic mixture (2 lactobacilli, bifidobacteria, and propionibacteria) or placebo during the last month of pregnancy and their infants to receive it from birth until age 6 months. Infants also received a prebiotic galacto-oligosaccharide or placebo. At 5 years, we evaluated the cumulative incidence of allergic diseases (eczema, food allergy, allergic rhinitis, and asthma) and IgE sensitization. Of the 1018 intent-to-treat infants, 891 (88%) attended the 5-year visit. Frequencies of allergic and IgE-associated allergic disease and sensitization in the probiotic and placebo groups were similar: 52.6% versus 54.9% and 29.5% versus 26.6%, respectively, and 41.3% in both. No significant difference appeared in frequencies of eczema (39.3% vs 43.3%), atopic eczema (24.0% vs 25.1%), allergic rhinitis (20.7% vs 19.1%), or asthma (13.0% vs 14.1%) between groups. However, less IgE-associated allergic disease occurred in cesarean-delivered children receiving probiotics (24.3% vs 40.5%; odds ratio, 0.47; 95% CI, 0.23% to 0.96%; P = .035). No allergy-preventive effect that extended to age 5 years was achieved with perinatal supplementation of probiotic bacteria to high-risk mothers and children. It conferred protection only to cesarean-delivered children.


Interference of backscatter from two droplets in a focused continuous-wave CO2 Doppler lidar beam.
With a focused continuous-wave CO(2) Doppler lidar at 9.1-microm wavelength, the superposition of backscatter from two appromately 14.12-microm-diameter silicone oil droplets in the lidar beam produced interference that resulted in a single backscatter pulse from the two droplets with a distinct periodic structure. This interference is caused by the phase difference in backscatter from the two droplets while they are traversing the lidar beam at different speeds, and thus the droplet separation is not constant. The complete cycle of interference, with periodicity 2pi, gives excellent agreement between measurements and lidar theory.


WebStruct and VisualStruct: Web interfaces and visualization for Structure software implemented in a cluster environment.
Structure, is a widely used software tool to investigate population genetic structure with multi-locus genotyping data. The software uses an iterative algorithm to group individuals into "K" clusters, representing possibly K genetically distinct subpopulations. The serial implementation of this programme is processor-intensive even with small datasets. We describe an implementation of the program within a parallel framework. Speedup was achieved by running different replicates and values of K on each node of the cluster. A web-based user-oriented GUI has been implemented in PHP, through which the user can specify input parameters for the programme. The number of processors to be used can be specified in the background command. A web-based visualization tool "Visualstruct", written in PHP (HTML and Java script embedded), allows for the graphical display of population clusters output from Structure, where each individual may be visualized as a line segment with K colors defining its possible genomic composition with respect to the K genetic sub-populations. The advantage over available programs is in the increased number of individuals that can be visualized. The analyses of real datasets indicate a speedup of up to four, when comparing the speed of execution on clusters of eight processors with the speed of execution on one desktop. The software package is freely available to interested users upon request.


Does double electron capture lead to the formation of biradicals? An ECD-SORI-CID study on lacticin 481.
We studied lacticin 481, a small lantibiotic with three lanthionine bridges, by electron capture dissociation (ECD) in a Fourier transform ion cyclotron resonance (FTICR) mass spectrometer. Following electron capture, very little fragmentation was observed, but species formed by nondissociative single and multiple electron capture were abundant. Ions formed by double electron capture were subjected to sustained off resonance irradiation collision induced dissociation (SORI-CID) to determine whether stable biradicals were formed. In the SORI-CID spectra of the ions formed by double electron capture, some, but minor, H* radical loss was observed, which was not observed at all for regularly protonated ions. A small part of the ions formed by double electron capture are thus long-lived biradicals. Apart from the observed H* loss, the SORI-CID spectra of ions that captured two electrons was similar to that of regularly protonated ions and quite different from the SORI-CID spectra of radical ions formed by single electron capture. This implies that recombination of the two radical sites is the dominant process in biradical lacticin 481 ions, at least on the time scale of our SORI-CID experiments.


Antibacterial effect of the adhering human Lactobacillus acidophilus strain LB.
The spent culture supernatant of the human Lactobacillus acidophilus strain LB produces an antibacterial activity against a wide range of gram-negative and gram-positive pathogens. It decreased the in vitro viability of Staphylococcus aureus, Listeria monocytogenes, Salmonella typhimurium, Shigella flexneri, Escherichia coli, Klebsiella pneumoniae, Bacillus cereus, Pseudomonas aeruginosa, and Enterobacter spp. In contrast, it did not inhibit lactobacilli and bifidobacteria. The activity was heat stable and relatively sensitive to enzymatic treatments and developed under acidic conditions. The antimicrobial activity was independent of lactic acid production. Activity against S. typhimurium SL1344 infecting human cultured intestinal Caco-2 cells was observed as it was in the conventional C3H/He/oujco mouse model with S. typhimurium C5 infection and oral treatment with the LB spent culture supernatant.


Credentialing preclinical pediatric xenograft models using gene expression and tissue microarray analysis.
Human tumor xenografts have been used extensively for rapid screening of the efficacy of anticancer drugs for the past 35 years. The selection of appropriate xenograft models for drug testing has been largely empirical and has not incorporated a similarity to the tumor type of origin at the molecular level. This study is the first comprehensive analysis of the transcriptome of a large set of pediatric xenografts, which are currently used for preclinical drug testing. Suitable models representing the tumor type of origin were identified. It was found that the characteristic expression patterns of the primary tumors were maintained in the corresponding xenografts for the majority of samples. Because a prerequisite for developing rationally designed drugs is that the target is expressed at the protein level, we developed tissue arrays from these xenografts and corroborated that high mRNA levels yielded high protein levels for two tested genes. The web database and availability of tissue arrays will allow for the rapid confirmation of the expression of potential targets at both the mRNA and the protein level for molecularly targeted agents. The database will facilitate the identification of tumor markers predictive of response to tested agents as well as the discovery of new molecular targets.


Producer-level benefits of sustainability certification.
Initiatives certifying that producers of goods and services adhere to defined environmental and social-welfare production standards are increasingly popular. According to proponents, these initiatives create financial incentives for producers to improve their environmental, social, and economic performance. We reviewed the evidence on whether these initiatives have such benefits. We identified peer-reviewed, ex post, producer-level studies in economic sectors in which certification is particularly prevalent (bananas, coffee, fish products, forest products, and tourism operations), classified these studies on the basis of whether their design and methods likely generated credible results, summarized findings from the studies with credible results, and considered how these findings might guide future research. We found 46 relevant studies, most of which focused on coffee and forest products and examined fair-trade and Forest Stewardship Council certification. The methods used in 11 studies likely generated credible results. Of these 11 studies, nine examined the economic effects and two the environmental effects of certification. The results of four of the 11 studies, all of which examined economic effects, showed that certification has producer-level benefits. Hence, the evidence to support the hypothesis that certification benefits the environment or producers is limited. More evidence could be generated by incorporating rigorous, independent evaluation into the design and implementation of projects promoting certification.


Women and health coverage: the affordability gap.
Although men and women have some similar challenges with regard to health insurance, women face unique barriers to becoming insured. More significantly, women have greater difficulty affording health care services even once they are insured. On average, women have lower incomes than men and therefore have greater difficulty paying premiums. Women also are less likely than men to have coverage through their own employer and more likely to obtain coverage through their spouses; are more likely than men to have higher out-of-pocket health care expenses; and use more healthcare services than men and consequently are in greater need of comprehensive coverage. Proposals for improving health policy need to address these disparities.


Time-resolved optical backscattering model in highly scattering media.
A time-resolved backscattering model, which combines a single large-angle scattering with multiple small-angle scatterings, is used to produce a scattered-light profile about a medium. Inhomogeneity of the medium is included in the model. Some multidimensional integrals can be evaluated analytically.


Targeted disruption of Shp2 in chondrocytes leads to metachondromatosis with multiple cartilaginous protrusions.
Metachondromatosis is a benign bone disease predominantly observed in the hands and feet of children or young adults demonstrating two different manifestations: a cartilage-capped bony outgrowth on the surface of the bone called exostosis and ectopic cartilaginous nodules inside the bone called enchondroma. Recently, it has been reported that loss-of-function mutations of the SHP2 gene, which encodes the SHP2 protein tyrosine phosphatase, are associated with metachondromatosis. The purpose of this study was to investigate the role of SHP2 in postnatal cartilage development, which is largely unknown. We disrupted Shp2 during the postnatal stage of mouse development in a chondrocyte-specific manner using a tamoxifen-inducible system. We found tumor-like nodules on the hands and feet within a month after the initial induction. The SHP2-deficient mice demonstrated an exostosis-like and enchondroma-like phenotype in multiple bones of the hands, feet, and ribs as assessed by X-ray and micro-computed tomography (CT). Histological assessment revealed the disorganization of the growth plate cartilage, a cartilaginous protrusion from the epiphyseal bone, and ectopic cartilage nodules within the bones, which is consistent with the pathological features of metachondromatosis in humans (ie, both exostosis and enchondroma). At molecular levels, we observed an abundant expression of Indian hedgehog protein (IHH) and fibroblast growth factor 2 (FGF2) and impaired expression of mitogen-activated protein kinases (MAPK) in the affected cartilage nodules in the SHP2-deficient mice. In summary, we have generated a mouse model of metachondromatosis that includes manifestations of exostosis and enchondroma. This study provides a novel model for the investigation of the pathophysiology of the disease and advances the understanding of metachondromatosis. This model will be useful to identify molecular mechanisms for the disease cause and progression as well as to develop new therapeutic strategies in the future.


Effect of pH, salt and chemical rinses on bacterial attachment to extracellular matrix proteins.
Microbial contamination of carcass surfaces occurs during slaughter and post-slaughter processing steps, therefore interventions are needed to enhance meat safety and quality. Although many studies have been done at the macro-level, little is known about specific processes that influence bacterial attachment to carcass surfaces, particularly the role of extracellular matrix (ECM) proteins. In the present study, the effect of pH and salt (NaCl, KCl and CaCl2) on attachment of Escherichia coli and Salmonella isolates to dominant ECM proteins: collagen I, fibronectin, collagen IV and laminin were assessed. Also, the effects of three chemical rinses commonly used in abattoirs (2% acetic acid, 2% lactic acid and 10% trisodium phosphate (TSP)) were tested. Within a pH range of 5-9, there was no significant effect on attachment to ECM proteins, whereas the effect of salt type and concentration varied depending on combination of strain and ECM protein. A concentration-dependant effect was observed with NaCl and KCl (0.1-0.85%) on attachment of E. coli M23Sr, but only to collagen I. One-tenth percent CaCl2 produced the highest level of attachment to ECM proteins for E. coli M23Sr and EC614. In contrast, higher concentrations of CaCl2 increased attachment of E. coli EC473 to collagen IV. Rinses containing TSP produced >95% reduction in attachment to all ECM proteins. These observations will assist in the design of targeted interventions to prevent or disrupt contamination of meat surfaces, thus improving meat safety and quality.