Interventions and practice models for improving health and psychosocial outcomes of children and young people in out-of-home care: protocol for a systematic review.
Children and young people placed in out-of-home care (OoHC) are often affected by a history of trauma and adverse childhood experiences. Trauma in early childhood can impact on children's health and psychosocial development, whereas early interventions can improve children's development and placement stability. Although several interventions and practice models have been developed to improve health and psychosocial outcomes for children and young people in OoHC, there remains a lack of rigorous research examining the impact of these interventions in OoHC settings, as there are no systematic reviews examining the impact these interventions and practice models have on the children and young people they serve. We aim to conduct a comprehensive systematic review to examine the effectiveness of interventions and practice models for improving health and psychosocial outcomes in children and young people living in OoHC and to identify relevant knowledge gaps. Major electronic databases including Medline, Medline in-process and other non-indexed citations, Embase, Cumulative Index to Nursing and Allied Health Literature, PsycInfo, Sociological Abstracts and all Evidence-Based Medicine Reviews incorporating: Cochrane Database of Systematic Reviews, American College of PhysiciansJournal Club, Database of Abstracts of Reviews of Effects,Cochrane Central Register of Controlled Trials, CochraneMethodology Register, Health Technology Assessment and National Health Service Economic Evaluation Database, will be systematically searched for any studies published between 2008 and 2018 of interventions and practice models developed to improve health and psychosocial outcomes for children and young people in OoHC. Two independent reviewers will assess titles and abstracts for eligibility according to prespecified selection criteria and will perform data extraction and quality appraisal. Meta-analyses and/or metaregression will be conducted where appropriate. This study will not collect primary data and formal ethical approval is therefore not required. Findings from this systematic review will be disseminated in a peer-reviewed publication and conference presentations. CRD42019115082.


Do left atrial strain and strain rate reflect intrinsic atrial function, or are they determined by left ventricular function?
Left atrial (LA) strain (S) and strain rate (SR) are reported as measures of intrinsic function. Since the LA and left ventricle (LV) are connected through the mitral annulus, we investigated: (1) if deformation indices in the LA are mostly predicted by deformation of the LV; (2) if timings of S and SR events are similar in both the LA and LV; and (3) if alteration of S and SR in patients with primarily LV dysfunction would be similar in the LA and LV. We retrospectively assessed 50 asymptomatic women (Group 1) and 20 patients with recent (< 96 h) acute pulmonary oedema (10 women) (Group 2). Using speckle tracking, the amplitude and timings of S and SR were averaged from three apical views, for one cardiac cycle, starting from the P-wave. In Group 1, all deformation indices were higher in the LA compared with the LV (p < 0.001 for all). In Group 2, S and SR during LA contraction were higher in the LA vs. LV (p < 0.05 for both), but all other deformation indices were not different in the LA vs. LV. All timings of S and SR occurred simultaneously in LA and LV in both groups, except S during LA contraction in Group 1, which occurred slightly earlier in LA than in LV. By multiple regression analysis, the most important predictors of LA deformation indices were the corresponding LV deformation indices, especially in patients with LV dysfunction (Group 1: r = 0.35-0.52; Group 2: r = 0.76-0.85; p < 0.05 by Fisher r-to-z transform). LA deformation strongly reflects LV deformation both in asymptomatic subjects and in patients with LV dysfunction. With the possible exception of LA contraction in asymptomatic individuals, discriminating intrinsic LA function from LV influence is difficult using deformation analysis.


Cerebrovascular events in inflammatory bowel disease patients treated with anti-tumour necrosis factor alpha agents.
Cerebrovascular accidents [CVA] have rarely been reported in inflammatory bowel disease [IBD] patients treated with anti-tumour necrosis alpha [anti-TNF alpha] agents. Our aim here was to describe the clinical course of CVA in these patients. This was a European Crohn's and Colitis Organisation [ECCO] retrospective observational study, performed as part of the CONFER [COllaborative Network For Exceptionally Rare case reports] project. A call to all ECCO members was made to report on IBD patients afflicted with CVA during treatment with anti-TNF alpha agents. Clinical data were recorded in a standardised case report form and analysed for event association with anti-TNF alpha treatment. A total of 19 patients were identified from 16 centres: 14 had Crohn's disease, four ulcerative colitis and one IBD colitis unclassified [median age at diagnosis: 38.0 years, range: 18.6-62.5]. Patients received anti-TNF alpha for a median duration of 11.8 months [range: 0-62] at CVA onset; seven had previously been treated with at least one other anti-TNF alpha agent. Complete neurological recovery was observed in 16 patients. Anti-TNF alpha was discontinued in 16/19 patients. However, recurrent CVA or neurological deterioration was not observed in any of the 11 patients who received anti-TNF alpha after CVA [eight resumed after temporary cessation, three continued without interruption] for a median follow-up of 39.8 months [range: 5.6-98.2]. These preliminary findings do not unequivocally indicate a causal role of anti-TNF alpha in CVA complicating IBD. Resuming or continuing anti-TNF alpha in IBD patients with CVA may be feasible and safe in selected cases, but careful weighing of IBD activity versus neurological status is prudent.


Acidosis alters fluorescein permeability. Differential tracer penetration through pigment epithelium.
The permeability of the blood-retinal barrier to infusion of fluorescent tracers was examined in tissue sections of frozen eyes from conscious rats that had breathed either air (control) or 25% carbon dioxide in air for one hour. For all animals the blood-retinal barrier remained impermeable to either carboxyfluorescein or Evans blue, indicating a functionally intact tight junctional barrier during hypercapnia. However, in hypercapnic animals, fluorescein penetrated into the neural retina, mainly via the pigment epithelium. Fluorescein also passed through the pigment epithelium in rats with metabolic acidosis induced by intravenous infusion of ammonium chloride, which lowered arterial blood pH without raising the Paco2 or BP. The results indicate an increased permeability of fluorescein through the cell membranes of the pigment epithelium during respiratory and metabolic acidosis. The effect on fluorescein may be due to a pH-dependent increase in the plasma concentration of the associated, more lipid-soluble form of this weak acid.


Advanced Nursing Education: Critical Factors That Influence Diploma and Associate Degree Nurses to Advance.
The purpose of this study was to gain an understanding of the social processes associated with the decision of diploma and associate degree nurses to advance academically. Advanced nursing education needs to be pursued along the continuum of the nursing career path. This education process is indispensable to the role of nurses as educator, manager, nurse leader, and researcher who will effect policy changes, assume leadership roles as revolutionary thinkers, and implement paradigmatic shifts. Data were collected from two groups of participants using face-to-face, semistructured interviews. Group 1 consisted of diploma and associate degree nurses; Group 2 consisted of baccalaureate, masters, and doctoral degree nurses who have progressed academically. Emerging from the thick, rich data were core categories of rewarding, motivating, and supporting as critical factors that influence professional advancement. This qualitative study elucidated that professional advancement was the social process that grounds. The emergent theory was the theory of professional advancement.


Coexistence of GABA and glutamate in mossy fiber terminals of the primate hippocampus: an ultrastructural study.
One of the links in the trisynaptic circuit of the hippocampus is the synapse between the mossy fibre terminals of dentate granule cells and CA3 pyramidal cells of Ammon's horn. This synapse has been physiologically characterized as excitatory, and there is pharmacological and immunohistochemical evidence that mossy fibre terminals utilize glutamate as a neurotransmitter. This study demonstrates the presence of GABA-immunoreactivity in mossy fibre axons and terminals of the monkey at the electron microscopic level. We combined Golgi impregnation to identify CA3 pyramidal neurones, with postembedding immunocytochemistry to characterize the inputs to the identified cells. GABA immunoreactivity was present in mossy fibre terminals that made synaptic contact with complex embedded spines of identified Golgi-impregnated CA3 pyramidal neurones. GABA immunoreactivity could be demonstrated in serial sections of the same mossy fibre terminals by using 3 different antisera raised against GABA. In serial sections, the mossy fibre terminals were shown to be immunoreactive for both glutamate and GABA. In contrast, glutamate immunoreactivity but not GABA immunoreactivity was found in other terminals that did not have the morphological characteristics of mossy fibre terminals. GABA immunoreactivity in mossy fibre terminals was also demonstrated in a human surgical specimen of hippocampus. The coexistence of an "excitatory" amino acid and of an "inhibitory" amino acid in the same "excitatory" nerve terminal raises the possibility of corelease of the two transmitters, suggesting that the control of hippocampal neural activity is more complex than hitherto suspected.


Human apolipoproteins AI, AII, CII and CIII. cDNA sequences and mRNA abundance.
The structure and function of the genes encoding the polypeptide components of plasma lipoproteins are of interest because of the central role they play in the regulation of lipid metabolism. We have now completed our previous studies on the human apoAI gene and furthermore isolated and sequenced cDNA clones for apoAII , CII and CIII. The nucleotide sequences show the signal peptides of apoAII , CII and CIII to be 18, 22 and 20 amino acids in length, respectively, and in addition that prepro apoAII bears a classical propeptide structure of 5 amino acids. The amino acid homology detected between apoCII and pro- apoAI is discussed, as is the gene arrangement of the 5' non-coding region of apoAI mRNA. The relative liver mRNA levels of the 4 apolipoproteins analysed in this study have been estimated and compared with their corresponding plasma products. The data reported here provide an essential basis for further studies of structural and functional alleles of apo AI, AII, CII and CIII genes.


Neurocognitive risk phenotyping to predict mood symptoms in adolescence.
Predicting mood disorders in adolescence is a challenge that motivates research to identify neurocognitive predictors of symptom expression and clinical profiles. This study used machine learning to test whether neurocognitive variables predicted future manic or anhedonic symptoms in two adolescent samples risk-enriched for lifetime mood disorders (Sample 1, n = 73, ages = 13-25, M [SD] = 19.22 [2.49] years, 68% lifetime mood disorder) or familial mood disorders (Sample 2, n = 154, ages = 13-21, M [SD] = 16.46 [1.95] years, 62% first-degree family history of mood disorder). Participants completed cognitive testing and functional magnetic resonance imaging at baseline, for behavioral and neural measures of reward processing and executive functioning. Next, participants completed a daily diary procedure for 8-16 weeks. Penalized mixed-effects models identified neurocognitive predictors of future mood symptoms and stress-reactive changes in mood symptoms. Results included the following. In both samples, adolescents showing ventral corticostriatal reward hyposensitivity and lower reward performance reported more severe stress-reactive anhedonia. Poorer executive functioning behavior was associated with heightened anhedonia overall in Sample 1, but lower stress-reactive anhedonia in both samples. In Sample 1, adolescents showing ventral corticostriatal reward hypersensitivity and poorer executive functioning reported more severe stress-reactive manic symptoms. Clustering analyses identified, and replicated, five neurocognitive subgroups. Adolescents characterized by neural or behavioral reward hyposensitivities together with average-to-poor executive functioning reported unipolar symptom profiles. Adolescents showing neural reward hypersensitivity together with poor behavioral executive functioning reported a bipolar symptom profile (Sample 1 only). Together, neurocognitive phenotypes may hold value for predicting symptom expression and profiles of mood pathology. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Phosphorylation of the yeast heat shock transcription factor is implicated in gene-specific activation dependent on the architecture of the heat shock element.
Heat shock transcription factor (HSF) binds to the heat shock element (HSE) and regulates transcription, where the divergence of HSE architecture provides gene- and stress-specific responses. The phosphorylation state of HSF, regulated by stress, is involved in the activation and inactivation of the transcription activation function. A domain designated as CTM (C-terminal modulator) of the Saccharomyces cerevisiae HSF is required for the activation of genes containing atypical HSE but not typical HSE. Here, we demonstrate that CTM function is conserved among yeast HSFs and is necessary not only for HSE-specific activation but also for the hyperphosphorylation of HSF upon heat shock. Moreover, both transcription and phosphorylation defects due to CTM mutations were restored concomitantly by a set of intragenic suppressor mutations. Therefore, the hyperphosphorylation of HSF is correlated with the activation of genes with atypical HSE but is not involved in that of genes with typical HSE. The function of CTM was circumvented in an HSF derivative lacking CE2, a yeast-specific repression domain. Taken together, we suggest that CTM alleviates repression by CE2, which allows HSF to be heat-inducibly phosphorylated and presume that phosphorylation is a prerequisite for the activator function of HSF when it binds to an atypical HSE.


Behavioral evidence for cholecystokinin modulation of dopamine in the mesolimbic pathway.
Cholecystokinin octapeptide sulfate (CCK) injected bilaterally into the nucleus accumbens significantly potentiated dopamine-induced hyperlocomotion and apomorphine-induced stereotypy. CCK had no effect alone on locomotion or stereotypy, suggesting that this peptide acts as a neuromodulator. CCK did not potentiate dopamine or apomorphine when injected into the caudate nucleus, where CCK and DA are located in separate neurons, indicating that CCK potentiation of dopamine is specific for the mesolimbic pathway, where CCK and dopamine co-exist in the same neuron. Unsulfated CCK had no effect alone or in conjunction with dopamine or apomorphine, suggesting that the facilitory effect of CCK on dopamine-mediated behaviors is specific for the sulfated form of CCK.


Predicting success: stakeholder readiness for home telecare diabetic support.
Readiness to adopt a new technology is one factor that contributes to the success of a telehealth programme. Since one goal of telehealth is to improve care, it is appropriate to determine its success through a quality-of-care framework that addresses structure, process and outcome. A qualitative case study of home care in the Calgary Health Region in Alberta set out to understand how clients, nurses, physicians and managers perceived their readiness to use video-visits for home care. Focus groups, home visits, and telephone and face-to-face interviews were used to collect data. Readiness to adopt home telecare was compared between groups, as well as with behaviour predicted in the literature. Differences in perceptions were identified among the four participant groups. Clients and managers identified a higher degree of readiness-clients because of the potential to support independence in their homes and managers because of the potential efficiencies in the system.


Nanoscale Infrared Spectroscopy and Chemometrics Enable Detection of Intracellular Protein Distribution.
Determination of the intracellular location of proteins is one of the fundamental tasks of microbiology. Conventionally, label-based microscopy and super-resolution techniques are employed. In this work, we demonstrate a new technique that can determine intracellular protein distribution at nanometer spatial resolution. This method combines nanoscale spatial resolution chemical imaging using the photothermal-induced resonance (PTIR) technique with multivariate modeling to reveal the intracellular distribution of cell components. Here, we demonstrate its viability by imaging the distribution of major cellulases and xylanases in Trichoderma reesei using the colocation of a fluorescent label (enhanced yellow fluorescence protein, EYFP) with the target enzymes to calibrate the chemometric model. The obtained partial least squares model successfully shows the distribution of these proteins inside the cell and opens the door for further studies on protein secretion mechanisms using PTIR.


Bacterial macroscopic rope-like fibers with cytopathic and adhesive properties.
We present a body of ultrastructural, biochemical, and genetic evidence that demonstrates the oligomerization of virulence-associated autotransporter proteins EspC or EspP produced by deadly human pathogens enterohemorrhagic and enteropathogenic Escherichia coli into novel macroscopic rope-like structures (>1 cm long). The rope-like structures showed high aggregation and insolubility, stability to anionic detergents and high temperature, and binding to Congo Red and thioflavin T dyes. These are properties also exhibited by human amyloidogenic proteins. These macroscopic ropes were not observed in cultures of nonpathogenic Escherichia coli or isogenic espP or espC deletion mutants of enterohemorrhagic or enteropathogenic Escherichia coli but were produced by an Escherichia coli K-12 strain carrying a plasmid expressing espP. Purified recombinant EspP monomers were able to self-assemble into macroscopic ropes upon incubation, suggesting that no other protein was required for assembly. The ropes bound to and showed cytopathic effects on cultured epithelial cells, served as a substratum for bacterial adherence and biofilm formation, and protected bacteria from antimicrobial compounds. We hypothesize that these ropes play a biologically significant role in the survival and pathogenic scheme of these organisms.


[Cytotoxic activity and activation ability of Syrian hamster NK cells isolated in the Percoll density gradient].
Natural killer cells possessing cytotoxic activity (CTA) and the ability to be activated by an interferon inductor and Newcastle disease virus, were isolated from blood, spleen and bone marrow of Syrian hamsters in the discontinuous Percoll density gradient. According to morphological criteria these cells were identified as large granular lymphocytes (LGL). The largest amount of LGL was isolated in the fraction containing 52-55% Percoll. CTA of cells from this fraction was the highest as compared to nonfractionated control or cells from other Percoll fractions. Effective (3-fold) activation of bone marrow cells isolated in the fraction of 49% Percoll with initially low CTA suggests that this Percoll fraction contains noncytotoxic precursors of NK cells.


A Perfused In Vitro Human iPSC-Derived Blood-Brain Barrier Faithfully Mimics Transferrin Receptor-Mediated Transcytosis of Therapeutic Antibodies.
Delivering biologics to elicit a therapeutic response in the central nervous system (CNS) remains challenging due to the presence of the blood-brain barrier (BBB). Receptor-mediated transcytosis is a strategy to improve brain exposure after systemic drug administration. The availability of a clinically relevant in vitro BBB model is crucial to investigate transcytosis pathways and to predict the penetration of biologics into the CNS. We created a perfused human in vitro BBB model made of induced pluripotent stem cells (iPSC)-derived brain microvascular endothelial cells (BMEC) for studying transferrin receptor-mediated transcytosis. iPSC-derived BMEC were seeded in the top channel of a three-lane microfluidic device (OrganoPlate®). After 2 days in culture, the established cell model exhibited relevant BBB features, including physiological transendothelial electrical resistance in a transwell setting (1500 Ω*cm2), reduced apparent permeability (Papp) to the fluorescence tracer Lucifer yellow (20-fold less than cell-free chips), expression of key BBB markers such as tight junctions proteins, transporters, receptors and functional P-gp efflux pump. Moreover, the model exhibited functional transferrin receptor-mediated uptake and transcytosis. To assess selective transferrin receptor-mediated transcytosis, a mixture of anti-human transferrin receptor (MEM-189) and control (sheep IgG anti-bovine serum albumin) antibodies was perfused in the top channel for 2 h. The Papp of MEM-189 was 11-fold higher than that of the control antibody, demonstrating facilitated receptor-mediated transcytosis. Compared to published work reporting a 2-fold ratio, this result is remarkable and establishes the suitability of our model for exploring receptor-mediated transcytosis and screening of antibodies for putative brain shuttle application. A perfused in vitro human model made of iPSC-derived BMEC with the chief characteristics (barrier tightness, functionality) of the human BBB can be applied to study transferrin receptor (TfR)-mediated transcytosis of therapeutic antibodies. This may bring critical advances in drug shuttle technology. Graphical abstract generated with biorender.com.


Perinatal changes of transport systems for amino acids in slices of mouse brain.
Perinatal changes in the uptake of amino acids were measured in slices of fetal (15- and 19-day) and newborn (4-, 24-, and 48-hr-old) mouse brain. Uptake increased with age; smaller changes occurred with basic and neutral amino acid transport systems, and the largest changes occurred in fetal brain with amino acids of putative neurotransmitter function (taurine, glycine, GABA, and the acidic amino acids). The pattern of increase in uptake was similar at high and at low external amino acid concentrations. Developmental changes in tissue content of Na(+), K(+), or ATP were small during this period, and so are unlikely to be responsible for the observed changes in uptake. It appears that by the 15th day of fetal life, the transport systems for essential amino acids are fairly well developed in the brain, and the transport systems for neurotransmitter amino acids are not so well developed, but undergo a rapid increase in the 15-19-day period. From birth to adulthood, the concentrative capacity of slices of mouse brain for nonessential (putative neurotransmitter) amino acids is much greater than for essential amino acids.


Small gene family encoding an eggshell (chorion) protein of the human parasite Schistosoma mansoni.
We have isolated six independent genomic clones encoding schistosome chorion or eggshell proteins from a Schistosoma mansoni genomic library. A linkage may of five of the clones spanning 35 kilobase pair (kbp) of the S. mansoni genome was constructed. The region contained two eggshell protein genes closely linked, separated by 7.5 kbp of intergenic DNA. The two genes of the cluster were arranged in the same orientation, that is, they were transcribed from the same strand. The sixth clone probably represents a third copy of the eggshell gene that is not contained within the 35-kbp region. The 5' end of the mRNA transcribed from these genes was defined by primer extension directly off the RNA. The ATCAT cap site sequence was homologous to a silkmoth chorion PuTCATT cap site sequence, where Pu indicates any purine. DNA sequence analysis showed that there were no introns in these genes. The DNA sequences of the three genes were very homologous to each other and to a cDNA clone, pSMf61-46, differing only in three or four nucleotides. A multiple TATA box was located at positions -23 to -31, and a CAAAT sequence was located at -52 upstream of the eggshell transcription unit. Comparison of sequences in regions further upstream with silkmoth and Drosophila sequences revealed several very short elements that were shared. One such element, TCACGT, recently shown to be an essential cis-regulatory element for silkmoth chorion gene promoter function, was found at a similar position in all three organisms.


Type 2 diabetes mellitus increases the severity of non-fatal injuries, but not the risk of fatal injuries, among driver victims of motor vehicle crashes in Taiwan.
Limited information is available on whether diabetes increases the severity of injuries from motor vehicle crashes (MVCs). This study aimed to investigate the association of type 2 diabetes with injury severity among driver victims of MVCs. This cohort study involved 75,737 adult driver victims with type 2 diabetes from Taiwan's Police-Reported Traffic Accident Registry in 2015-2017, along with 150,911 sex-, age-, and calendar year-matched controls. The severity level of non- fatal injuries was derived from the International Classification of Diseases Programs for Injury Categorization based on the diagnostic codes of National Health Insurance claims within 3 days after an MVC. Information on fatal injuries within 3 days after an MVC was obtained from the Taiwan Death Registry. Logistic regression models were used to estimate the odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) of injury severity in association with type 2 diabetes. After adjusting for potential confounders, driver victims with type 2 diabetes experienced significantly higher risks of mild and severe non-fatal injuries than their counterparts without diabetes, with covariate-adjusted ORs of 1.08 (95% CI, 1.05 to 1.11) and 1.28 (95% CI, 1.20 to 1.37), respectively. By contrast, the adjusted OR for fatal injuries was not significantly elevated, at 1.02 (95% CI, 0.89 to 1.18). Similar results were found when car and scooter driver victims were analyzed separately. Type 2 diabetes was found to moderately increase the severity of non-fatal injuries from MVCs among car and scooter driver victims.


EEG microstates during different phases of Transcendental Meditation practice.
Two phases of Transcendental Meditation (TM)-transcending and undirected mentation-were compared to each other and to task-free resting using multichannel EEG recorded from 20 TM practitioners. An EEG microstate analysis identified four classes of microstates which were labeled A, B, C and D, based on their similarity to previously published classes. For each class of microstates, mean duration, coverage and occurrence were computed. Resting and transcending differed from undirected mentation with decreased prominence of Class A and increased prominence of Class D microstates. In addition, transcending showed decreased prominence of Class C microstates compared to undirected mentation. Based on previous findings on the functional significance of the microstate classes, the results indicate an increased reference to reality and decreased visualization during resting and transcending compared to undirected mentation. Also, our results indicate decreased saliency of internally generated mentations during transcending compared to undirected mentation reflecting a more detached and less evaluative processing. It is proposed that the continuous cycling through these two phases of meditation during a TM session might facilitate and train the flexible modulation of the parameters of these microstates of these particular classes which are known to be altered in psychiatric disorders. This might promote beneficial stabilizing effects for the practitioner of TM.


AGO-bound mature miRNAs are oligouridylated by TUTs and subsequently degraded by DIS3L2.
MicroRNAs (miRNAs) associated with Argonaute proteins (AGOs) regulate gene expression in mammals. miRNA 3' ends are subject to frequent sequence modifications, which have been proposed to affect miRNA stability. However, the underlying mechanism is not well understood. Here, by genetic and biochemical studies as well as deep sequencing analyses, we find that AGO mutations disrupting miRNA 3' binding are sufficient to trigger extensive miRNA 3' modifications in HEK293T cells and in cancer patients. Comparing these modifications in TUT4, TUT7 and DIS3L2 knockout cells, we find that TUT7 is more robust than TUT4 in oligouridylating mature miRNAs, which in turn leads to their degradation by the DIS3L2 exonuclease. Our findings indicate a decay machinery removing AGO-associated miRNAs with an exposed 3' end. A set of endogenous miRNAs including miR-7, miR-222 and miR-769 are targeted by this machinery presumably due to target-directed miRNA degradation.


Personalized cancer therapy for gastrointestinal stromal tumor: synergizing tumor genotyping with imatinib plasma levels.
Imatinib has exceptional activity in controlling gastrointestinal stromal tumor (GIST) due to inhibition of the constitutively active conformation of KIT and platelet-derived growth factor-alpha (PDGFRA), which is commonly seen in this tumor. This review explores the current available data on the correlation between imatinib plasma levels, response to treatment, and the mutational status of KIT and PDGFRA. A recent retrospective analysis demonstrated a relationship between imatinib plasma levels and progression-free survival in patients with advanced GIST. Plasma imatinib levels were notably unrelated to the daily administered dose of imatinib in this small series. Prior phase III trials have demonstrated that dose escalation of imatinib may lead to increased disease control in a subset of patients with advanced GIST who progress on standard dose imatinib. Moreover, patients with GIST carrying an exon 9 mutation may benefit from higher doses of imatinib. Current available data suggest a possible correlation between imatinib plasma level and progression-free survival in patients with advanced GIST. A prospective trial is underway to evaluate whether modification of imatinib dose to achieve a target imatinib plasma level will impact patient outcome when compared with standard imatinib dosing (www.clinicaltrials.gov, NCT01031628).


Genetic effects and modifiers of radiotherapy and chemotherapy on survival in pancreatic cancer.
Germ-line genetic variation may affect clinical outcomes of cancer patients. We applied a candidate-gene approach to evaluate the effect of putative markers on survival of patients with pancreatic cancer. We also examined gene-radiotherapy and gene-chemotherapy interactions, aiming to explain interindividual differences in treatment outcomes. In total, 211 patients with pancreatic cancer were recruited in a population-based study. Sixty-four candidate genes associated with cancer survival or treatment response were selected from existing publications. Genotype information was obtained from a previous genome-wide association study data set. The main effects of genetic variation and gene-specific treatment interactions on overall survival were examined by proportional hazards regression models. Fourteen genes showed evidence of association with pancreatic cancer survival. Among these, rs1760217, located at the DPYD gene; rs17091162 at SERPINA3; and rs2231164 at ABCG2 had the lowest P of 10(-4.60), 0.0013, and 0.0023, respectively. We also observed that 2 genes, RRM1 and IQGAP2, had significant interactions with radiotherapy in association with survival, and 2 others, TYMS and MET, showed evidence of interaction with 5-fluorouracil and erlotinib, respectively. Our study suggested significant associations between germ-line genetic polymorphisms and overall survival in pancreatic cancer, as well as survival interactions between various genes and radiotherapy and chemotherapy.


Chronic hypersensitivity pneumonitis: CT features comparison with pathologic evidence of fibrosis and survival.
To retrospectively compare in patients with chronic hypersensitivity pneumonitis (HP) the computed tomographic (CT) imaging features suggestive of fibrosis with pathologic evidence of fibrosis at surgical lung biopsy and to compare a usual interstitial pneumonia (UIP) pattern at CT with survival. Institutional review board approval and informed consent were obtained for this study, which was HIPAA compliant. Twenty-six patients (15 women, 11 men; age range, 37-76 years) with chronic HP had their surgical lung biopsy results reviewed by two pathologists for the presence of fibrosis. Two radiologists systematically reviewed the CT scans. The two radiologists were blinded to all clinical information, including pathologic diagnosis, patient information, and outcomes. The combination of a subpleural reticular pattern and lower zone predominance was considered a UIP pattern. CT findings were compared with the histopathologic presence of fibrosis, physiologic parameters, symptoms, and survival. The chi(2) or Fisher exact test (each two-tailed) was used to compare nominal and ordinal variables. A t test (with unequal variances) was used to compare continuous variables. The log-rank procedure was used to compare Kaplan-Meier survival curves. Fifteen patients had fibrotic HP at biopsy, and 11 had nonfibrotic HP. Patients with fibrotic HP had more extensive reticular pattern and were more likely to have traction bronchiectasis, honeycombing, and a UIP pattern than those with nonfibrotic HP (P = .015, P = .007, P = .007, respectively). Although the presence of histologic fibrosis was associated with decreased survival (P = .003), the CT features were not associated with decreased survival. CT findings of extensive reticular pattern, traction bronchiectasis, and honeycombing are closely related to the presence of histologic fibrosis in chronic HP.


Interventions for cutaneous Bowen's disease.
Bowen's disease is the clinical term for in situ squamous cell carcinoma of the skin. Cutaneous lesions present as largely asymptomatic, well-defined, scaly erythematous patches on sun-exposed skin. In general, people with Bowen's disease have an excellent prognosis because the disease is typically slow-growing and responds favourably to treatment. Lesions are persistent and can be progressive, with a small potential (estimated to be 3%) to develop into invasive squamous cell carcinoma. The relative effectiveness of the available treatments is not known for Bowen's disease, and this review attempts to address which is the most effective intervention, with the least side-effects, for cutaneous Bowen's disease. To assess the effects of therapeutic interventions for cutaneous Bowen's disease. We searched the following databases up to September 2012: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2012, Issue 9), MEDLINE (from 1946), EMBASE (from 1974), PsycINFO (from 1806), and LILACS (from 1982). We also searched online trials registers. We checked the bibliographies of included and excluded studies and reviews, for further references to relevant randomised controlled trials (RCTs). We included all randomised controlled trials assessing interventions used in Bowen's disease, preferably histologically proven. Two authors independently carried out study selection and assessment of methodological quality. The primary outcome measures were complete clearance of lesions after the first treatment cycle and recurrence rate at 12 months. Our secondary outcomes included the number of lesions that cleared after each treatment cycle, the number of treatment cycles needed to achieve clearance, the recurrence rates at > 12 months, cosmetic outcome, quality of life assessment, and adverse outcomes as reported by both participant and clinician.We included 9 studies, with a total of 363 participants. One study demonstrated statistically significantly greater clearance of lesions of Bowen's disease with MAL-PDT (methyl aminolevulinate with photodynamic therapy) when compared with placebo-PDT (RR (risk ratio) 1.68, 95% CI (confidence interval) 1.12 to 2.52; n = 148) or cryotherapy (RR 1.17, 95% CI 1.01 to 1.37; n = 215), but there was no significant difference when MAL-PDT was compared to 5-FU (5-fluorouracil). One study demonstrated statistically significantly greater clearance of lesions with ALA-PDT (5-aminolevulinic acid with photodynamic therapy) versus 5-FU (RR 1.83, 95% CI 1.10 to 3.06; n = 66), but no statistically significant difference in recurrence rates at 12 months (RR 0.33, 95% CI 0.07 to 1.53).Cryotherapy showed no statistically significant difference in clearance rates (RR 0.99, 95% CI 0.78 to 1.26) or recurrences at 1 year (RR 1.48, 95% CI 0.53 to 4.17) when compared to 5-FU in 1 study of 127 participants.One study compared imiquimod to placebo and demonstrated statistically significantly greater clearance rates in the imiquimod group (9/15 lesions) compared to placebo (0/16) (Fisher's Exact P value < 0.001). The imiquimod group did not report any recurrences at 12 months, but at 18 months, 2/16 participants in the placebo group had developed early invasive squamous cell carcinoma. Overall, there has been very little good-quality research on treatments for Bowen's disease. There is limited evidence from single studies to suggest MAL-PDT is an effective treatment. Although cosmetic outcomes appear favourable with PDT, five-year follow-up data are needed. Significantly more lesions cleared with MAL-PDT compared to cryotherapy. No significant difference in clearance was seen when MAL-PDT was compared with 5-FU, but one study found a significant difference in clearance in favour of ALA-PDT when compared to 5-FU. There was no significant difference in clearance when cryotherapy was compared to 5-FU.The lack of quality data for surgery and topical cream therapies has limited the scope of this review to one largely about PDT studies. The age group, number, and size of lesions and site(s) affected may all influence therapeutic choice; however, there was not enough evidence available to provide guidance on this. More studies are required in the immunosuppressed populations as different therapeutic options may be preferable. Specific recommendations cannot be made from the data in this review, so we cannot give firm conclusions about the comparative effectiveness of treatments.


Structural and bioactive characteristics of a dextran produced by Lactobacillus kunkeei AK1.
In this study, structural and techno-functional characteristics of an exopolysaccharide (EPS) produced by Lactobacillus kunkeei AK1 were determined. High-performance liquid chromatography (HPLC) analysis demonstrated that EPS AK1 was composed of only glucose units. 1H and 13C Nuclear magnetic resonance (NMR) analysis revealed that EPS AK1 was a dextran type EPS containing 4.78% (1 → 4)-linked α-d-glucose branches. The molecular weight of EPS AK1 was determined to be 45 kDa by Gel Permeation Chromatography (GPC) analysis. A high level of thermal stability up to 280 °C was determined for dextran AK1 detected by Differential scanning calorimetry (DSC) and Thermogravimetric analysis (TGA). Dextran AK1 appeared as regular spheres with compact morphology and as irregular particles in the solution with no clear cross-linking between the chains of the polysaccharide observed by Scanning electron microscopy (SEM) and Atomic force microscopy (AFM) analysis, respectively. X-ray diffraction analysis (XRD) analysis demonstrated that dextran AK1 had a crystalline structure. A relatively strong antioxidant activity was observed for dextran AK1 determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging and cupric reducing antioxidant capacity (CUPRAC) tests. Finally, only a digestion ratio of 3.1% was observed for dextran AK1 following the in vitro simulated gastric digestion test.


Research Self-Efficacy and Research-Related Behavior Among Nurses in Qatar: A Cross-Sectional Study.
Research self-efficacy helps predict the individual interest and confidence in conducting research. The study was conducted to identify the research self-efficacy among nurses working in a group of tertiary hospitals and their research-related behavior. The study design was descriptive cross-sectional and conducted among nurses at Hamad Medical Corporation, Qatar Convenient sampling was done and 500 is the sample size. Data were collected through an online survey during 2 months in 2019 by using a validated "Nursing Research Self-Efficacy Scale" questionnaire. The scale includes 38 items under five domains, and the response was collected on a Likert scale from 1 to 5. The authors of the scale suggested excellent reliability score for the subscales, ranging from .94 to .97 and the existence of subscales was supported by exploratory and confirmatory factor analysis. A completed survey was collected from 780 nurses. The mean self-efficacy score was 2.92 ± 0.97. The mean score for the subscale of obtaining science-based knowledge resources was the highest (3.24 ± 1.03) and the lowest for critically read and evaluate qualitative research literature (2.63 ± 1.12). Nurses with higher educational qualifications and those who enrolled in any educational program further to their nursing education have statistically significantly high research self-efficacy. The overall research self-efficacy of working nurses is moderate. However, nurses' confidence in the ability to perform critiquing research and understand the concept and methodology in research is minimal. Introduction of nurse-tailored research training, which covers fundamental aspects of research to an advanced level, will help make them more confident in research.


[Determination of ten pesticides of pyrazoles and pyrroles in tea by accelerated solvent extraction coupled with gas chromatography-tandem mass spectrometry].
An effective method was developed and applied to determine the residues of ten pesticides of pyrazoles and pyrroles in tea by accelerated solvent extraction coupled with gas chromatography-tandem mass spectrometry (ASE-GC-MS/MS). The samples were extracted with ethyl acetate-hexane (1:1, v/v) for 5 min at 1.03 x 10(7) Pa and 100 degree C for one cycle. Then, they were purified by Envi-Carb/PSA column, and eluted by ethyl acetate-hexane (1:1, v/v). The analytes were determined by GC-MS/MS and quantified by external standard method. The limits of quantification were 0.003 mg/kg for fenpyroximate, 0.001 mg/kg for fipronil-sulfide, 0.002 mg/kg for fipronil, 0.005 mg/kg for fipronil-sulfone, 0.002 mg/kg for chlorfenapyr, 0.006 mg/kg for flusilazole, 0.001 mg/kg for difenzoquat, 0.001 mg/kg for pyraflufen-ethyl, 0.000 3 mg/kg for tebufenpyrad and 0.005 mg/kg for tolfenpyrad. The results show that the proposed method is sensitive and accurate for the determination of the ten pesticide residues.


An expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis.
The adaptive immune response in rheumatoid arthritis (RA) is influenced by an interaction between host genetics and environment, particularly the host microbiome. Association of the gut microbiota with various diseases has been reported, though the specific components of the microbiota that affect the host response leading to disease remain unknown. However, there is limited information on the role of gut microbiota in RA. In this study we aimed to define a microbial and metabolite profile that could predict disease status. In addition, we aimed to generate a humanized model of arthritis to confirm the RA-associated microbe. To identify an RA biomarker profile, the 16S ribosomal DNA of fecal samples from RA patients, first-degree relatives (to rule out environment/background as confounding factors), and random healthy non-RA controls were sequenced. Analysis of metabolites and their association with specific taxa was performed to investigate a potential mechanistic link. The role of an RA-associated microbe was confirmed using a human epithelial cell line and a humanized mouse model of arthritis. Patients with RA exhibited decreased gut microbial diversity compared with controls, which correlated with disease duration and autoantibody levels. A taxon-level analysis suggested an expansion of rare taxa, Actinobacteria, with a decrease in abundant taxa in patients with RA compared with controls. Prediction models based on the random forests algorithm suggested that three genera, Collinsella, Eggerthella, and Faecalibacterium, segregated with RA. The abundance of Collinsella correlated strongly with high levels of alpha-aminoadipic acid and asparagine as well as production of the proinflammatory cytokine IL-17A. A role for Collinsella in altering gut permeability and disease severity was confirmed in experimental arthritis. These observations suggest dysbiosis in RA patients resulting from the abundance of certain rare bacterial lineages. A correlation between the intestinal microbiota and metabolic signatures could determine a predictive profile for disease causation and progression.


Gambling participation and policies in Malaysia.
Regulatory policies for responsible gambling practices in Asia are constantly evolving as the gambling industry and technological landscape change over time. Malaysia makes an interesting case study for a commentary on gambling participation and policies, as this country has a unique dual justice system with religious and ethnic diversity that may impact on the way in which gambling activities are regulated. This regulatory ecosystem has important consequences on behaviour change, treatment approaches and recovery processes involved in gambling disorder. This commentary will discuss evidence for Malaysian gambling antecedents, public policy and socioeconomic impacts of gambling, possible costs and benefits of gambling legalization, and issues pertinent to regulating gambling activities in Malaysia.


Isoxazole ionotropic glutamate neurotransmitters.
Analogs of the excitatory neurotransmitter glutamate are potential medicinal agents for a wide variety of neurological disorders. The isoxazole glutamate derivatives represent an important class of compounds because of their receptor specificity and binding affinity. Since the discovery of (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl) propionic acid (AMPA) in 1980, numerous analogs built around the isoxazole scaffold have shown remarkable selectivity for specific ionotropic glutamate receptors, but strong side effects in human clinical trials have shown the need for improvement. Trends revealed by structure activity relationship and crystallographic studies indicate the role of stereochemistry may be important in uncovering the prerequisite selectivity, which would give rise to effective therapeutics for neurological dysfunction of the glutamate receptor.


Endogenous galanin protects mouse hippocampal neurons against amyloid toxicity in vitro via activation of galanin receptor-2.
Expression of the neuropeptide galanin is known to be upregulated in the brain of patients with Alzheimer's disease (AD). We and others have shown that galanin plays a neuroprotective role in a number of excitotoxic injury paradigms, mediated by activation of the second galanin receptor subtype (GAL2). In the present study, we investigated whether galanin/GAL2 plays a similar protective role against amyloid-β(Aβ) toxicity. Here we report that galanin or the GAL2/3-specific peptide agonist Gal2-11, both equally protect primary dispersed mouse wildtype (WT) neonatal hippocampal neurons from 250 nM Aβ1-42 toxicity in a dose dependent manner. The amount of Aβ1-42 induced cell death was significantly greater in mice with loss-of-function mutations in galanin (Gal-KO) or GAL2 (GAL2-MUT) compared to strain-matched WT controls. Conversely, cell death was significantly reduced in galanin over-expressing (Gal-OE) transgenic mice compared to strain-matched WT controls. Exogenous galanin or Gal2-11 rescued the deficits in the Gal-KO but not the GAL2-MUT cultures, confirming that the protective effects of endogenous or exogenous galanin are mediated by activation of GAL2. Despite the high levels of endogenous galanin in the Gal-OE cultures, the addition of exogenous 100 nM or 50 nM galanin or 100 nM Gal2-11 further significantly reduced cell death, implying that GAL2-mediated neuroprotection is not at maximum in the Gal-OE mice. These data further support the hypothesis that galanin over-expression in AD is a neuroprotective response and imply that the development of a drug-like GAL2 agonist might reduce the progression of symptoms in patients with AD.


Nucleic Acid Delivery with α-Tocopherol-Polyethyleneimine-Polyethylene Glycol Nanocarrier System.
Nucleic acid-based therapies are a promising therapeutic tool. The major obstacle in their clinical translation is their efficient delivery to the desired tissue. We developed a novel nanosized delivery system composed of conjugates of α-tocopherol, polyethyleneimine, and polyethylene glycol (TPP) to deliver nucleic acids. We synthesized a panel of TPP molecules using different molecular weights of PEG and PEI and analyzed with various analytical approaches. The optimized version of TPP (TPP111 - the 1:1:1 molecular ratio) was self-assembled in water to produce nanostructures and then evaluated in diversified in vitro and in vivo studies. Through a panel of synthesized molecules, TPP111 conjugate components self-assembled in water, forming globular shaped nanostructures of ~90 nm, with high nucleic acid entrapment efficiency. The polymer had low cytotoxicity in vitro and protected nucleic acids from nucleases. Using a luciferase-expressing plasmid, TPP111-plasmid nano-complexes were rapidly up-taken by cancer cells in vitro and induced strong transfection, comparable to PEI. Colocalization of the nano-complexes and endosomes/lysosomes suggested an endosome-mediated uptake. Using a subcutaneous tumor model, intravenously injected nano-complexes preferentially accumulated to the tumor area over 24 h. These results indicate that we successfully synthesized the TPP111 nanocarrier system, which can deliver nucleic acids in vitro and in vivo and merits further evaluation.


Return to play following muscle injuries in professional footballers.
This prospective cohort study described return-to-play (RTP) data for different types of muscle injuries in male elite-level football players in Europe. Eighty-nine European professional teams were followed between 2001 and 2013. Team medical staff recorded individual player exposure and time-loss injuries. A total of 17,371 injuries occurred, including 5603 (32%) muscle injuries. From 2007, we received results from 386 magnetic resonance imaging (MRI) examinations, and radiological grading was performed. A negative MRI was associated with shorter recovery time (6 ± 7 days). Lay-off days were correlated with MRI grading of thigh muscle injuries (P < 0.001). Among hamstring injuries, 83% occurred to the biceps femoris, 12% affected the semimembranosus and 5% the semitendinosus. Recurrence rate was higher among biceps femoris injuries (18%) compared with semitendinosus and semimembranosus injuries (2% together). Groin muscle injuries caused shorter median absence (9 days) than hamstring (13 days; P < 0.001), quadriceps (12 days; P < 0.001) and calf muscle (13 days; P < 0.001) injuries. Overall, we found that MRI was valuable for prognosticating RTP, with radiological grading associated with lay-off times after injury. Re-injuries were common in biceps femoris injuries but rare in semitendinosus and semimembranosus injuries.


Neurosteroid modulation of glutamate release in hippocampal neurons: lack of an effect of a chronic prenatal ethanol exposure paradigm.
Pregnenolone sulfate (PREGS) is a promnesic neurosteroid that is abundantly expressed in the hippocampus of rodents. Studies have shown that the modulation of postsynaptic ligand-gated ion channels by this neurosteroid is impaired in preparations from the brains of fetal ethanol-exposed animals. In this study, we examined whether the presynaptic actions of PREGS also are affected by exposure to ethanol in utero. Rat dams were exposed to one of the following diets during pregnancy: (1) 5% ethanol liquid diet, (2) 0% ethanol liquid diet with pair-feeding, and (3) ad libitum controls. We then studied the presynaptic actions of PREGS on (1) alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor-mediated miniature excitatory postsynaptic currents (mEPSCs) recorded from cultured hippocampal neurons in the whole-cell patch-clamp configuration and (2) paired-pulse facilitation of NMDA receptor-dependent excitatory postsynaptic potentials that were intracellularly recorded from CA1 pyramidal neurons in hippocampal slices from adult rats. Chronic prenatal ethanol exposure affected neither basal mEPSC frequency nor its potentiation by PREGS. Basal paired-pulse facilitation (i.e., in the absence of PREGS) was unaffected by fetal ethanol exposure. Chronic prenatal ethanol exposure did not affect the PREGS-induced potentiation of paired-pulse facilitation. Chronic prenatal ethanol exposure does not affect the basal probability of glutamate release in immature or mature hippocampal neurons. Moreover, the presynaptic actions of the neurosteroid PREGS also are unaffected by this exposure. Given that modulation of glutamate release could have a role in the mechanism of the promnesic actions of this neurosteroid, future studies are warranted to determine whether PREGS can ameliorate learning and memory deficits in fetal ethanol-exposed animals.


Tetanus immunization in pregnant women. Serum levels of antitetanus antibodies at time of delivery.
The objective of this study was to determine the tetanus immunity status of pregnant women at the time of delivery according to tetanus toxoid (TT) vaccination coverage during their most pregnancy. The serum anti-tetanus antibody levels of 493 mothers who had live births at a hospital in Ankara were determined by enzyme-linked immunosorbent assay (ELISA). Protected women were defined as those with serum antibody levels > or = 0.6 IU/ml. Overall, 69.0% of mothers had protective tetanus antibody titers at the time of delivery. The rates of protection for mothers who had received no vaccination, one TT dose, or two TT doses during pregnancy were 46.4, 93.5, and 95.6%, respectively. Vaccinating every pregnant woman with at least one dose of TT would be an affordable and effective way to protect against neonatal tetanus, and would be a step toward eliminating the deaths that continue to occur due to this preventable disease in Turkey.


Chicken cognin interactome and the memory of filial imprinting.
Visual imprinting is a learning process whereby young animals come to prefer a visual stimulus after exposure to it (training). The intermediate medial mesopallium in the domestic chick forebrain is critical for visual imprinting and contributes to molecular regulation of memory formation. Criteria used to infer that a change following training is learning-related have been formulated and published. Cognin (protein disulphide isomerase) is one of several identified plasma membrane and mitochondrial proteins that are upregulated in a learning-related way 24 hours after training. Since virtually nothing is known about the cognin interactome, we have used immunoaffinity chromatography and mass spectrometry to identify proteins that interact with cognin in the cytoplasmic and plasma membrane-mitochondrial fractions. As the learning-related upregulation of cognin has been shown to occur in the plasma membrane-mitochondrial fraction and not in the cytoplasmic fraction, we studied the effect of training on three cognin-interacting partners in the plasma membrane-mitochondrial fraction: the b5 subunit of mitochondrial ATP synthase and the alpha-2 and alpha-3 subunits of sodium-potassium ATPase. Learning-related upregulation was found in the left intermediate medial mesopallium 24 hours after training for the b5 subunit of mitochondrial ATP synthase and the alpha-2 subunit of sodium-potassium ATPase. The hemispheric asymmetry revealed here is consistent with the predominance of many other learning-related effects in the left intermediate medial mesopallium. The alpha-2 subunit of sodium-potassium ATPase is mainly expressed in astrocytes, supporting a role for these glial cells in memory.


Simultaneous production of industrially important alkaline xylanase-pectinase enzymes by a bacterium at low cost under solid-state fermentation conditions.
Simultaneous production of alkaline xylanase and all seven types of pectinases by a bacterial isolate, under solid-state fermentation was checked in this study. Under optimized conditions, high concurrent production of xylanase (22,800 ± 578 IU/g substrate) and pectinase (4,832 ± 189 IU/g substrate) was achieved. The different types of pectinases produced were exo-polymethylgalacturonase (782 IU/g), endo-polymethylgalacturonase (6.42 U/g), exo-polygalacturonase (2,250 IU/g), endo-polygalacturonase (11.57 U/g), polymethylgalacturonate lyase (53.99 IU/g), polygalacturonate lyase (59.78 IU/g), and pectin esterase (5.78 IU/g). Wheat bran resulted in the highest titer of both enzymes. The maximum xylanase-pectinase yield was detected after 7 days of incubation with 2 mM MgSO4 and 1.5 g/L K2 HPO4 at wheat bran to moisture ratio 1:1.5 (w/v), media to flask volume ratio 1:25, pH 7.0, temperature 37 °C, and inoculum size 15%. Xylanase was most stable at pH 8.0, retained more than 75% activity up to 24 H, whereas pectinase was most stable at pH 9.0, having full activity even after 24 H. At 45 °C, the xylanase showed 82% residual activity after 6 H of incubation. The pectinase was 97% and 61% stable up to 3 H at 50 and 55 °C, respectively. This is the first report showing the production of xylanase-pectinases by bacterium along with high titer of seven types of pectinases, suitable for industries.


The effect of etomoxir on 24-h substrate oxidation and satiety in humans.
The carnitine O-palmitoyltransferase I (EC 22.214.171.124) inhibitor etomoxir inhibits fatty acid oxidation, and hepatic fatty acid oxidation has been suggested to be a metabolic satiety signal in subjects who consume high-fat diets. We investigated substrate oxidation and satiety after repeated administrations of etomoxir or placebo in subjects who consumed a high-fat diet. In a randomized crossover design consisting of three 5-d treatments, we fed 10 healthy men [mean +/- SE age: 25.6 +/- 1.7 y; mean +/- SE body mass index (in kg/m(2)): 21.8 +/- 0.3] a high-fat diet twice and a low-fat diet once. The subjects consumed each diet at home for 3 consecutive days, after which they spent 36 h in energy balance in a respiration chamber. During the chamber stays with the high-fat treatments, etomoxir or placebo was administered in 5 doses (600 mg etomoxir in total). Blood samples were obtained on the mornings of days 4 and 5 of each treatment, and appetite profiles were assessed. Mean (+/-SE) 24-h respiratory quotients were significantly (P < 0.05) higher with repeated administrations of etomoxir (0.833 +/- 0.004) than with repeated administrations of placebo (0.814 +/- 0.006), and mean (+/-SE) 24-h whole-body fat oxidation tended to be less (13.7%, P = 0.06) with administration of etomoxir (136.0 +/- 5.2 g/d) than with administration of placebo (157.5 +/- 5.6 g/d). With the etomoxir treatment, fat balance was positive (P < 0.0001) and carbohydrate balance was negative (P < 0.001), whereas with the placebo treatment, neither of the balances was significantly different from zero. Hunger and satiety ratings were not affected under these conditions. Etomoxir decreased whole-body fat oxidation, as indicated by the respiratory quotients in the healthy subjects. With the current protocol, however, hunger and satiety ratings were not affected.


Disability in chronic migraine patients with medication overuse: treatment effects at 1-year follow-up.
To determine (1) the clinical course of a sample of chronic migraine patients with drug overuse 6 and 12 months following in-patient treatment and (2) whether functional impairment, assessed by the Migraine Disability Assessment (MIDAS) questionnaire, improved upon treatment. Patients with chronic migraine and medication overuse are particularly difficult to treat (prophylactic medications that otherwise are effective become ineffective; discontinuation of the offending medication can lead to withdrawal headache; physical and emotional dependence can be present, as well as increased psychological involvement; initial treatment gains can be difficult to maintain). Of the 106 patients meeting criteria for chronic migraine with medication overuse, 84 went on to complete a structured in-patient treatment, consisting of medication withdrawal and then prophylactic treatment. As a group, the patients were improved at both 6- and 12-month follow-up, with respect to two headache parameters (frequency and medication use) and three measures of functional impact extracted from the MIDAS questionnaire (Total Score, Headache Frequency, and Headache Intensity). Chronic migraine accompanied with medication overuse led to the considerable disability prior to treatment. However, notable improvement occurred coincident with the treatment. This suggests that successful treatment has more wide-ranging positive benefits beyond mere symptom reduction. To our knowledge, this is the first investigation where the MIDAS questionnaire has been used prospectively as an outcome measure in patients with chronic migraine and medication overuse to assess disability subsequent to a semi-standardized treatment program.


Why go the extra mile? A longitudinal study on sojourn goals and their impact on sojourners' adaptation.
Although international student mobility has become a ubiquitous phenomenon in many parts of the world, the goals that student sojourners pursue when moving abroad have received little systematic attention in psychological research. Likewise, their effects on psychological outcomes such as sojourners' psychological and sociocultural adaptation abroad have not yet been examined. Hence, the purpose of the present research was twofold: First, we established the parsimonious Sojourn Goals Scale and confirmed its psychometric quality and construct validity. Second, we used a longitudinal sample of student sojourners to investigate the role of sojourn goals for sojourners' sociocultural (i.e., sojourners' social relationships) and psychological (i.e., sojourn satisfaction) adaptation abroad at 3 months into the sojourn. Regression analyses revealed substantial effects of sojourn goals on measures of sociocultural adaptation. Response surface analyses served to examine the interplay of sojourn goals and respective sojourn experiences on sojourn satisfaction. We discuss implications for both psychological and applied research and identify future research needs.


EBF recommendation on practical management of critical reagents for antidrug antibody ligand-binding assays.
Immunogenicity assays are required to measure antidrug antibodies that are generated against biotherapeutic modalities. As for any ligand-binding assays, critical reagents (CR) play a crucial role in immunogenicity assays, as the robustness and reliability of an assay are defined by the quality and long-term availability of these reagents. The current regulatory guidelines do not provide clear directions on how to implement and verify lot-to-lot changes of CR during an assay life cycle, or the acceptance criteria that should be used when implementing new lots of CR. These aspects were extensively discussed within the European Bioanalysis Forum community. In this paper, CR for immunogenicity assays are identified and the minimum requirements for introducing new lots of CR in immunogenicity assays are described.


Toward an account of clinical anxiety predicated on basic, neurally mapped mechanisms of Pavlovian fear-learning: the case for conditioned overgeneralization.
The past two decades have brought dramatic progress in the neuroscience of anxiety due, in no small part, to animal findings specifying the neurobiology of Pavlovian fear-conditioning. Fortuitously, this neurally mapped process of fear learning is widely expressed in humans, and has been centrally implicated in the etiology of clinical anxiety. Fear-conditioning experiments in anxiety patients thus represent a unique opportunity to bring recent advances in animal neuroscience to bear on working, brain-based models of clinical anxiety. The current presentation details the neural basis and clinical relevance of fear conditioning, and highlights generalization of conditioned fear to stimuli resembling the conditioned danger cue as one of the more robust conditioning markers of clinical anxiety. Studies testing such generalization across a variety of anxiety disorders (panic, generalized anxiety disorder, and social anxiety disorder) with systematic methods developed in animals will next be presented. Finally, neural accounts of overgeneralization deriving from animal and human data will be described with emphasis given to implications for the neurobiology and treatment of clinical anxiety.


Preliminary Results From a Randomized Controlled Study for an App-Based Cognitive Behavioral Therapy Program for Depression and Anxiety in Cancer Patients.
Cancer patients experience various psychological and social difficulties, the most common being depression and anxiety. The purpose of this study was to develop and evaluate the effectiveness of an app-based cognitive behavioral therapy program for depression and anxiety in cancer patients. For this purpose, 63 participants who met the inclusion criteria were randomly assigned to either a mobile-application-based cognitive behavioral therapy program (HARUToday), a simple information-provision mobile-application-based program (HARUCard), or a waitlist control group. Self-report questionnaires including the Beck Depression Inventory, State-Trait Anxiety Inventory, Health-Related Quality of Life Scale, Dysfunctional Attitude Scale, and two computer tasks including the dot-probe task and the Implicit Association Test, were administered before and after 66 days of intervention. The results showed that the Beck Depression Inventory and State-Trait Anxiety Inventory scores of the cognitive behavioral therapy program (HARUToday) group decreased significantly after the intervention compared to the attention control (HARUCard) and waitlist control groups. However, there were no significant changes in scores of the Health-Related Quality of Life Scale and Dysfunctional Attitude Scale, and the two computer tasks. Such results suggest that a mobile-application-based cognitive behavioral therapy program may be an effective intervention for alleviating depression and anxiety, but not the general quality of life of cancer patients. Taking into consideration that psychosocial problems may not the topmost priority for cancer patients who are facing a chronic and possibly mortal disease, a mobile-application cognitive behavioral therapy program may be a possible solution for the alleviation of depression and anxiety in cancer patients who have many restraints in terms of time and space.


Exercise and glycemic control in diabetes: benefits, challenges, and adjustments to pharmacotherapy.
Exercise, along with dietary intervention, represents first-line therapy for diabetes mellitus. Aerobic exercise is recommended for its beneficial effects on glucose control as well as its abilities to retard the progression of other comorbidities common in patients with diabetes, such as cardiovascular disease. The capability of aerobic exercise to improve glycemic control in diabetes is well documented, although adherence to exercise regimens is problematic. More recently, the glucose-lowering effects of resistance training have also been documented; this form of exercise has additional benefits, such as the capability to counteract sarcopenia, which is common in older people with type 2 diabetes. Exercise in people with diabetes, however, also can present significant challenges to glycemic control. Excessive glucose lowering can occur under certain conditions, enhancing the threat of hypoglycemia; in other situations, hyperglycemia can be accentuated. An understanding of the interactions between specific antidiabetic medications and various forms and intensities of exercise is essential to optimizing glycemic control while minimizing the potential for acute derangements in plasma glucose levels. Exogenous forms of insulin and agents that stimulate insulin secretion in a glucose-independent manner (such as sulfonylureas and glinides) increase the propensity for hypoglycemia during low- to moderate-intensity aerobic exercise. In contrast, exercise protocols characterized by high intensity are more likely to result in episodes of hyperglycemia. Strategies to minimize inappropriate swings in glycemic control are reviewed.


A lateral minimal-incision technique in total hip replacement: a prospective, randomizes, controlled trial.
Minimally invasive surgery has become a trend over the last few years in all aspects of orthopaedic surgery, including total hip arthroplasty. So-called mini-incision techniques involve limiting the length of the skin incision to 10 cm with use of either an anterior, lateral or posterior approach. Between March 2004 and December 2005 one hundred consecutive unilateral total hip replacements were performed by the same senior surgeon in our institute. All patients were randomly assigned to study group (group A) or control group (group B). In group A (50 patients) the skin incision was 8 cm; in group B (50 patients) the skin incision was standard (about 12-14 cm). Patient demographic data, including sex, age, height, weight, BMI, diagnosis and preoperative Harris hip score were recorded. Other criteria evaluated included the perioperative and postoperative complications, the surgical time, the blood loss, the length of the incision, the acetabular and stem positions, the length of hospital stay, Harris Hip Score (HHS) and the WOMAC osteoarthritis index at six months. No significant differences were found between the groups with respect to the average surgical time, the acetabular and stem position, the length of hospital stay and the Harris Hip Score (HHS) and the WOMAC osteoarthritis index at six months. A significant lower blood loss was found in the mini-incision group. A higher percentage of peri-operative complications was recorded in Group A (two stupor of sciatic nerve and one fracture of the greater trochanter). On the basis of our experience we could speculate that minimally invasive surgery should be directed to the new surgical approach with muscle sparing, instead of a shorter skin incision using standard approaches.


Frizzled-8 receptor is activated by the Wnt-2 ligand in non-small cell lung cancer.
Wnt-2 plays an oncogenic role in cancer, but which Frizzled receptor(s) mediates the Wnt-2 signaling pathway in lung cancer remains unclear. We sought to (1) identify and evaluate the activation of Wnt-2 signaling through Frizzled-8 in non-small cell lung cancer, and (2) test whether a novel expression construct dominant negative Wnt-2 (dnhWnt-2) reduces tumor growth in a colony formation assay and in a xenograft mouse model. Semi-quantitative RT-PCR was used to identify the expression of Wnt-2 and Frizzled-8 in 50 lung cancer tissues from patients. The TCF reporter assay (TOP/FOP) was used to detect the activation of the Wnt canonical pathway in vitro. A novel dnhWnt-2 construct was designed and used to inhibit activation of Wnt-2 signaling through Frizzled-8 in 293T, 293, A549 and A427 cells and in a xenograft mouse model. Statistical comparisons were made using Student's t-test. Among the 50 lung cancer samples, we identified a 91% correlation between the transcriptional increase of Wnt-2 and Frizzled-8 (p<0.05). The Wnt canonical pathway was activated when both Wnt-2 and Frizzled-8 were co-expressed in 293T, 293, A549 and A427 cells. The dnhWnt-2 construct we used inhibited the activation of Wnt-2 signaling in 293T, 293, A549 and A427 cells, and reduced the colony formation of NSCLC cells when β-catenin was present (p<0.05). Inhibition of Wnt-2 activation by the dnhWnt-2 construct further reduced the size and mass of tumors in the xenograft mouse model (p<0.05). The inhibition also decreased the expression of target genes of Wnt signaling in these tumors. We demonstrated an activation of Wnt-2 signaling via the Frizzled-8 receptor in NSCLC cells. A novel dnhWnt-2 construct significantly inhibits Wnt-2 signaling, reduces colony formation of NSCLC cells in vitro and tumor growth in a xenograft mouse model. The dnhWnt-2 construct may provide a new therapeutic avenue for targeting the Wnt pathway in lung cancer.


Symposium review: Host-rumen microbe interactions may be leveraged to improve the productivity of dairy cows.
The rumen is a large bioreactor that enables dairy cattle to derive nutrition from otherwise indigestible plant polymers and compounds. Despite the direct contribution of the rumen's microbial community toward the nutrition of the dairy cow, only a general knowledge has been gained of the metabolic processes within the rumen, and less still is known about most of the individual microbial species that colonize the organ. What has been discovered is that the rumen contains a diverse community of microbial species from all of the major domains of life, and that the contents of the rumen can vary greatly among individual animals. Preliminary evidence also indicates that rumen microbial profiles are heritable and sustainable within an individual, and that rumen microbial community structure can revert to its original profile within a short period following substantial perturbation. Much progress has been made in recent years to identify the diversity of microbial species in the rumen; however, the most popular methods used to identify microbial species often lack the predictive power necessary to associate particular microbial profiles with rumen metabolic activity. This represents the most significant barrier to the design of models that can estimate the direct effects of rumen microbial content on downstream dairy production traits. If such challenges can be overcome, it is possible that rumen microbial content could be assessed as a new phenotypic trait in cattle. In the future, we may estimate dairy production using a "genotype × environment × microbial" interaction model that accurately combines all factors affecting milk production.


Efficient and error-free fluorescent gene tagging in human organoids without double-strand DNA cleavage.
CRISPR-associated nucleases are powerful tools for precise genome editing of model systems, including human organoids. Current methods describing fluorescent gene tagging in organoids rely on the generation of DNA double-strand breaks (DSBs) to stimulate homology-directed repair (HDR) or non-homologous end joining (NHEJ)-mediated integration of the desired knock-in. A major downside associated with DSB-mediated genome editing is the required clonal selection and expansion of candidate organoids to verify the genomic integrity of the targeted locus and to confirm the absence of off-target indels. By contrast, concurrent nicking of the genomic locus and targeting vector, known as in-trans paired nicking (ITPN), stimulates efficient HDR-mediated genome editing to generate large knock-ins without introducing DSBs. Here, we show that ITPN allows for fast, highly efficient, and indel-free fluorescent gene tagging in human normal and cancer organoids. Highlighting the ease and efficiency of ITPN, we generate triple fluorescent knock-in organoids where 3 genomic loci were simultaneously modified in a single round of targeting. In addition, we generated model systems with allele-specific readouts by differentially modifying maternal and paternal alleles in one step. ITPN using our palette of targeting vectors, publicly available from Addgene, is ideally suited for generating error-free heterozygous knock-ins in human organoids.


The brain stem response SN10, its frequency selectivity, and its value in classifying neural hearing lesions.
The component P6 of the brain stem is only to be related to the hearing ability in the high tone range of greater than or equal to 2 kHZ, but it can be traced up to the hearing threshold. The cortex response N90, on the other hand, is frequency-specific, but it can hardly be recorded up to the subjective hearing threshold. The slow brain stem response SN10 (Davis and Hirsh 1979), unaffected by medicamented sleep, shall give information about hearing ability in the low and medium frequency range and may thus be an ideal complement to the fast response P6. In a number of normal hearing people and patients with sensorial hearing impairment of different frequency characteristics the brain stem responses P6 and SN10 were simultaneously recorded. As stimuli we used tone pips of a rise and fall time independent of frequency of about 2 ms and with a plateau of 2 ms as well. The mean threshold of the SN10 response is about 10 dB above the subjective hearing threshold. The constancy of the latencies corresponds to that of P6. The frequency selectivity of this relatively slow brain stem response is proved by comparing the P6 and SN10 responses with the course of the subjective hearing threshold. The topodiagnostic significance of the wave SN10 in connection with the brain stem response P6 and the cortical response N90 is shown in a case of neural hearing impairment.


The core molecule from type H proteoglycan. Release of mannose-containing oligosaccharides by digestion with N-oligosaccharide glycopeptidase.
Chick-embryo cartilage contains a unique set of proteoglycans. Type H proteoglycan (PG-H) is the most abundant, constituting over 90% of the total cartilage hexuronate. We previously showed that treatment of PG-H with chondroitinase ACII and keratanase yields a protein-enriched core molecule [PG(-CS,KS)] with enzymically modified linkage oligosaccharides of the chondroitin sulphate and keratan sulphate chains. We report here that further treatment of PG(-CS,KS) with pepsin and N-oligosaccharide glycopeptidase (almond glycopeptidase) released four distinct types of mannose-containing oligosaccharide. Two of them were shown to be: (Formula: see text). Of the mannose-containing glycopeptides formed by pepsin digestion, about 40% (as mannose) were resistant to N-oligosaccharide glycopeptidase. Since the resistant fraction was enriched in keratan sulphate remnants, it is suggest that the mannose-containing oligosaccharides in this fraction represent those located in a keratan sulphate-enriched region of PG-H.


Technical protocol for the use of esophageal manometry in the diagnosis of sleep-related breathing disorders.
A time-tested protocol for intrathoracic pressure monitoring during sleep is described. This method of esophageal manometry uses a fluid-filled catheter to measure variations in transmitted intrathoracic pressure with respiration. Esophageal manometry is an invaluable tool for the sleep specialist in the diagnosis of sleep-related breathing disorders, especially for detecting cases of upper airway resistance syndrome and for distinguishing subtle central apneas from obstructive events. The methods for scoring esophageal pressure, the indications and contraindications for esophageal manometry, the use of esophageal manometry as the 'gold standard' for the measurement of respiratory effort, and directions for future research are also discussed.


The relationship between outpatient drug costs and disease progression in the human immunodeficiency virus-infected population. The Military Medical Consortium for Applied Retroviral Research.
As the focus of the management of human immunodeficiency virus (HIV) infection turns from the treatment of AIDS to the entire continuum of the disease, projection of long-term healthcare costs becomes increasingly important. Rather than a fulminant disease treated primarily inside the hospital, HIV infection will become a chronic condition requiring years of outpatient monitoring and pharmacologic intervention with attending increases in pharmacy costs. The objective of this study was to characterize outpatient drug costs by Walter Reed (WR) disease stage in order to estimate the association of disease progression and outpatient prescription drug costs. We hypothesized that there was an association between HIV disease progression, measured by the WR Staging Classification System, and outpatient prescription drug costs. Outpatient drug costs were summarized for 190 HIV-positive patients during a three-month period who presented at Walter Reed Army Medical Center for staging and follow-up. The overall median cost per day per patient for all stages was $3.21 (range $0.01-53.45) with wide variation between patients. Daily costs for patients in WR stage V were the greatest (median $9.26). There was a significant association between WR stage of disease and outpatient drug costs (Spearman rho = 0.51, t = 6.9, df = 188, p less than 0.001). The association was not completely linear because costs in WR stage VI were less than WR stages IV or V. Annual extrapolated outpatient drug costs for these 190 patients would be nearly $0.5 million.


Utilization of bioelectrical impedance to predict carcass composition of Holstein steers at 3, 6, 9, and 12 months of age.
The objective of this experiment was to study the usefulness of bioelectrical impedance analysis (BIA) in determining soft tissue composition (STC) and carcass fat-free mass (CFFM) of Holstein steers at different ages. Growth data and prediction of STC and CFFM were determined for four groups of Holstein steers: 12 of 3 mo, 12 of 6 mo, 15 of 9 mo, and 16 of 12 mo of age. Average weight for animals at 3, 6, 9, and 12 mo were 96.6, 204.7, 354.1, and 465.9 kg, respectively. Average fat content of carcass soft tissue at 3, 6, 9, and 12 mo were 2.6, 9.8, 18.2, and 24.6%, respectively. Average protein content of the carcass soft tissue was 20.7% at 3 mo, 20% at 6 mo, 18.30% at 9 mo, and 16.9% at 12 mo of age. Feed and water were withheld for 20 h before the BIA was applied. Steers were sedated and forced to recumbency in a lateral position on their right sides over a nonconductive surface. Two electrodes were placed on each limb of the right side (metatarsal and metacarpal regions on back and front foot, respectively). Resistance (Rs) and reactance (Xc) were obtained by attaching four terminals to the electrodes. Impedance and other predictors such as Vol1 (L/Rs), Vol2 (L2/(RS2+Xc2).5, Vol3 (geometrical animal volume), L (2 x height + body length), and L2 were calculated from Rs and Xc, and body measurements and were used to generate prediction equations for CFFM and carcass soft tissue composition. Carcass fat-free mass was predicted accurately for all age groups and the pooled data (r2 = .99 at 3 mo, .99 at 6 mo, .97 at 9 mo, .77 at 12 mo, and .98 for the pooled data). Correlation coefficients between impedance readings and CFFM and carcass composition were calculated. Carcass CFFM and kilograms of H2O for the pooled data (across age groups) were both correlated highly to Vol1 (.97), Vol2 (.95), L (.97), and L2 (.97).


How to stop or change a motor response: Laplacian and independent component analysis approach.
Response inhibition is an essential control function necessary to adapt one's behavior. This key cognitive capacity is assumed to be dependent on the prefrontal cortex and basal ganglia. It is unresolved whether varying inhibitory demands engage different control mechanisms or whether a single motor inhibitory mechanism is involved in any situation. We addressed this question by comparing electrophysiological activity in conditions that require stopping a response to conditions that require switching to an alternate response. Analyses of electrophysiological data obtained from stop-signal tasks are complicated by overlapping stimulus-related activity that is distributed over frontal and parietal cortical recording sites. Here, we applied Laplacian transformation and independent component analysis (ICA) to overcome these difficulties. Participants were faster in switching compared to stopping a response, but we did not observe differences in neural activity between these conditions. Both stop- and change-trials Laplacian transformed ERPs revealed a comparable bilateral parieto-occipital negativity around 180 ms and a frontocentral negativity around 220 ms. ICA results suggested an inhibition-related frontocentral component which was characterized by a negativity around 200 ms with a likely source in anterior cingulate cortex. The data provide support for the importance of posterior mediofrontal areas in inhibitory response control and are consistent with a common neural pathway underlying stopping and changing of a motor response. The methodological approach proved useful to distinguish frontal and parietal sources despite similar timing and the ICA approach allowed assessment of single-trial data with respect to behavioral data.


Is coronary artery disease a multifactorial inherited disorder with a sex-influenced trait?
The genetic linkage of coronary artery disease is well-established. However, the transmission of this disease is not clearly defined. Although the Mendelian autosomal dominant pattern has been seen in familial hypercholesterolemia and mutant MEF2A induced familiar myocardial infarction, and a multifactorial genetic model has been proposed for non-familial CAD, the gender difference in this disease is not well explained. We hypothesized that CAD is a multifactorial inherited disorder with a sex-influenced trait, which shows an autosomal dominant pattern in men and autosomal recessive transmission in women. This hypothesis is supported by the facts including an age-dependent higher prevalence in men, the autosomal locations of CAD associated genes, the gender difference seen even in familiar CAD, and the potential gene-gene interactions between CAD associated genes on autosomal chromosomes and those found on the X chromosome. Further investigation of genetic components will provide not only the critical information about the etiology of CAD, but also help to clarify the confusion in the use of exogenous female hormones in the prevention and/or the treatment of the disease.


Do evidence-based treatments provide incremental benefits to patients with congestive heart failure already receiving angiotensin-converting enzyme inhibitors? A secondary analysis of one-year outcomes from the Assessment of Treatment with Lisinopril and Survival (ATLAS) study.
In patients with congestive heart failure (CHF), use of submaximal doses of angiotensin-converting enzyme (ACE) inhibitors (ie, low-dose ACE inhibitors) represents usual care in routine clinical practice, whereas high-dose ACE inhibitors, beta-blockers, and digoxin have each been shown to improve outcomes. We examined whether treatment with high dose-ACE inhibitors, beta-blockers, and digoxin would each provide incremental benefits over that achieved with usual care and whether concurrent use of high-dose ACE inhibitors, beta-blockers, and digoxin would provide maximal benefits. We conducted a secondary analysis of a randomized, controlled, active-comparator trial. Specifically, we studied 1-year outcomes data from the Assessment of Treatment with Lisinopril and Survival trial (ATLAS), which assessed high-dose ACE inhibitors (mean dosage, 33.2 mg daily lisinopril) versus low-dose ACE inhibitors (mean dosage, 4.5 mg daily lisinopril) in patients of any age with advanced CHF in 287 centers in 19 countries in the 1990s. In our analysis, patients were classified by their use of low-dose or high-dose ACE inhibitors, beta-blockers, and/or digoxin at the time of randomization. The primary outcome of interest was the ATLAS composite end point of all-cause mortality or hospitalization for any reason at 1 year. Multiple logistic regression analyses were used to adjust for baseline differences in patient characteristics. The 3164 patients in the ATLAS study had a mean (SD) age of 64 (10) years; 2516 patients (80%) were men and 648 (20%) were women; mean (SD) left-ventricular ejection fraction was 23% (6%); and 2671 patients (84%) had New York Heart Association class III or IV symptoms. At 1 year, the mortality rate was 13% (408 patients); 43% (1369 patients) had > or =1 hospitalization; and the composite end point of mortality or hospitalization was 47% (1489 patients). Most patients (2873; 91%) remained on their initial treatment regimen. Compared with low-dose ACE inhibitors (n = 471), the composite end point decreased incrementally with the use of high-dose ACE inhibitors (n = 475) (adjusted odds ratio [aOR], 0.93; P = NS), high-dose ACE inhibitors plus beta-blockers (n = 72) (aOR, 0.89; P = NS), and high-dose ACE inhibitors plus beta-blockers plus digoxin (n = 77) (aOR, 0.47; P = 0.006). In absolute proportions, patients receiving high-dose ACE inhibitors plus beta-blockers plus digoxin for 1 year had 12% fewer deaths and hospitalizations than patients receiving low-dose ACE inhibitors alone. Compared with usual care for patients with CHF, in this analysis, an evidence-based strategy that incorporated high-dose ACE inhibitors plus beta-blockers plus digoxin was associated with incrementally greater reductions in morbidity and mortality. These findings support treatment guidelines that recommend the concurrent use of all available proven efficacious treatment in patients with advanced CHF.


Fe3O4@SiO2@KIT-6 as an Efficient and Reusable Catalyst for the Synthesis of Novel Derivatives of 3,3'-((Aryl-1-phenyl-1H-pyrazol-4- yl)methylene)bis (1H-indole).
Korea advanced institute of science and technology cubic ordered mesoporous silica (KIT-6 mesoporous) silica coated magnetite nanoparticles, is an effective, ecobenign and recyclable catalyst for the electrophilic substitution reactions of indoles with various synthetized aldehydes to afford the corresponding novel diindolylmethanes in high yields and short reaction times. The catalyst can be recovered and reused without loss of activity. The work-up of the reaction consists of a simple separation, followed by concentration of the crude product and purification. The present methodology offers several advantages such as aqueous media, excellent yields, simple procedure, mild conditions and reduced environmental consequences. All of synthesized compounds are new and were characterized by IR, NMR and elemental analyses. A mixture of synthetized pyrazolecarbaldehydes [24] (2.0mmol), indole (4.0mmol) and Fe3O4@SiO2@KIT-6 (0.04mmol) and H2O (10mL) were stirred at room temperature for the required reaction time according to Table 2. After completion of the reaction, the product was solved in CHCl3 (3×10 mL) and insoluble catalyst was removed by filtration in the presence of an efficient magnetic bar. The organic phase including the product and CHCl3 was evaporated under vacuum. The resulting crude material was purified by recrystallization from EtOH to afford pure products. As part of our on interest for the development of efficient and environmentally friendly procedures for the synthesis of heterocyclic and pharmaceutical compounds, an efficient, facile and aqueous media was introduced for the synthesis of novel derivatives of diindolylmethanes containing pyrazole moiety. A variety of synthetized aldehyde compounds reacted smoothly with indoles to produce diindolylmethanes under these reaction conditions. The electron deficiency and the nature of the substituents on the aromatic ring show some effects on this conversion. All the reactions were run with catalytic amounts of catalysts. The best results gained with 0.04mmol of Fe3O4@SiO2@KIT-6 as a strong Lewis acid at room temperature in aqueous media. In conclusion, we have investigated the synthesized KIT-6 mesoporous silica coated magnetite nanoparticles (MMNPs) as a mild and efficient catalyst for the synthesis of novel diindolylmethanes coupled with pyrazole moiety in aqua media. The simplicity, easy workup together with the use of inexpensive, environmentally friendly and reusable catalyst, is the notable features of this catalytic procedure. To the best of our knowledge, this is the first report for the synthesis of a new library of diindolylmethane compound bearing pyrazole moiety that enhance the biological and pharmacological activity.


Measurement of blood flow in the rotator cuff using laser Doppler flowmetry.
The aim of this study was to define the microcirculation of the normal rotator cuff during arthroscopic surgery and investigate whether it is altered in diseased cuff tissue. Blood flow was measured intra-operatively by laser Doppler flowmetry. We investigated six different zones of each rotator cuff during the arthroscopic examination of 56 consecutive patients undergoing investigation for impingement, cuff tears or instability; there were 336 measurements overall. The mean laser Doppler flowmetry flux was significantly higher at the edges of the tear in torn cuffs (43.1, 95% confidence interval (CI) 37.8 to 48.4) compared with normal cuffs (32.8, 95% CI 27.4 to 38.1; p = 0.0089). It was significantly lower across all anatomical locations in cuffs with impingement (25.4, 95% CI 22.4 to 28.5) compared with normal cuffs (p = 0.0196), and significantly lower in cuffs with impingement compared with torn cuffs (p < 0.0001). Laser Doppler flowmetry analysis of the rotator cuff blood supply indicated a significant difference between the vascularity of the normal and the pathological rotator cuff. We were unable to demonstrate a functional hypoperfusion area or so-called 'critical zone' in the normal cuff. The measured flux decreases with advancing impingement, but there is a substantial increase at the edges of rotator cuff tears. This might reflect an attempt at repair.


Recording and Reading Alchemy and Art-Technology in Medieval and Premodern German Recipe Collections.
In the Middle Ages and the premodern period knowledge of alchemical practices and materials was transmitted via collections of recipes often grouped concomitantly with art-technological instructions. In both alchemy and chemical technology particular importance is placed on artisanal and craft practices. Both are concerned with the description of colours. Both require procedures involving precise and specifically defined actions, prescriptions and ingredients. Assuming that alchemical and artistic texts have the same textual format, this raises the question: were they produced, diffused and read by the same people? This paper investigates the authorship and the context of production behind a sample of German alchemical manuscripts dating from the fourteenth to the sixteenth century. It scrutinizes their process of production, compilation and dissemination. This paper also sheds light on the various types of marginalia, and correlates them with their diverse functions. It thus delivers significant information about the readers and users of these manuscripts.


The importance of blood pressure variability in hypertension.
Use of ambulatory blood pressure monitoring (ABPM) techniques has revealed that blood pressure is characterized by a considerable degree of variability over a 24 h period as a result, not only of the well-known fluctuations that occur between wakefulness and sleep, but also of the minute-to-minute changes induced by a variety of behavioural conditions. The degree of these variations is also influenced by neural mechanisms responsible for cardiovascular regulation, such as the arterial baroreflex. Blood pressure variability increases with age and blood pressure values, and its magnitude has been shown to correlate independently with the target-organ damage of hypertension. This has stimulated both the development of antihypertensive drugs able to reduce blood pressure homogeneously over 24 h, and recent proposals to develop more accurate indices, such as the smoothness index, to quantify the distribution of the antihypertensive effect over the entire day and night. Despite the important information that ABPM can provide concerning daily-life blood pressure variations and their modification by treatment, international guidelines suggest that it should not yet be used routinely in daily practice, but rather reserved for selected patients.


Validity and reliability of the Japanese version of the selected anger expression scale and age, sex, occupation and regional differences in anger expression among Japanese.
To examine the reliability and construct validity of the Japanese version of the Anger Expression Scale among four Japanese communities, and to examine distributions of anger expression scores according to sex, age, occupation, and community, we performed a cross-sectional study among 1,802 men and 3,229 women aged 20-70 in four geographic populations in 1995-97. We handed a self-administered questionnaire, which was selected from the Spielberger Anger Expression Scale, to the participants in the risk factor surveys and measured anger-in and anger-out as the anger expression scale. These scales had high internal consistency (Cronbach's alpha coefficient was 0.97-0.98 for anger-out and 0.77-0.86 for anger-in) and were of almost the same structure as the original. The Pearson correlation coefficients for the anger expression scale examined in 1995 and 1996 were 0.69 for anger-out and 0.57 for anger-in (both p < 0.001). The mean scores of both anger-out and anger-in were inversely associated with age. The mean anger-out score was higher for men than for women (p < 0.001), whereas the mean anger-in score did not vary significantly between the sexes. Furthermore, the mean scores of anger-out and anger-in varied among populations and occupational groups. The present study suggests that the Japanese version of the selected Anger Expression Scale is an acceptable scale for evaluating anger expression among Japanese.