[Neuroscientific and psychological explanations for the therapeutic effects of psychedelics].
Psychedelics have a strong therapeutic potential for the treatment of biomedical disorders, but the working mechanisms underlying psychedelics are only poorly understood.
 AIM: To discuss different mechanisms underlying the therapeutic effects of classic psychedelics.
 METHOD: To make a distinction between different levels of explanation: the pharmacological, the neurocognitive and the psychological level.
 RESULTS: At the pharmacological level, classic psychedelics affect via the serotonin-receptor, the production of glutamate and brain-derived neurotrophic factor (bdnf), which stimulate neurogenesis. Psychedelics also have anti-flammatory properties and thereby have a protective effect on the brain. At the neurocognitive level, psychedelics have been associated with a reduced activation of the default mode network, which has been implicated in self-referential processing and rumination. At the same time, the brain's entropy increases, reflected in an increased connectivity between different brain areas. At the psychological level, the therapeutic efficacy of psychedelics has been attributed to the mystical experience, as well as to its awe-inducing potential, the feelings of connectedness and an enhanced awareness of emotions.
 CONCLUSION: Psycholytic and psychedelic therapy act at different levels, but ultimately the combination of different mechanisms will help us to understand how psychedelics - in the right set and setting - can be used successfully in therapeutic practice.


The Nature of Nurture: Using a Virtual-Parent Design to Test Parenting Effects on Children's Educational Attainment in Genotyped Families.
Research on environmental and genetic pathways to complex traits such as educational attainment (EA) is confounded by uncertainty over whether correlations reflect effects of transmitted parental genes, causal family environments, or some, possibly interactive, mixture of both. Thus, an aggregate of thousands of alleles associated with EA (a polygenic risk score; PRS) may tap parental behaviors and home environments promoting EA in the offspring. New methods for unpicking and determining these causal pathways are required. Here, we utilize the fact that parents pass, at random, 50% of their genome to a given offspring to create independent scores for the transmitted alleles (conventional EA PRS) and a parental score based on alleles not transmitted to the offspring (EA VP_PRS). The formal effect of non-transmitted alleles on offspring attainment was tested in 2,333 genotyped twins for whom high-quality measures of EA, assessed at age 17 years, were available, and whose parents were also genotyped. Four key findings were observed. First, the EA PRS and EA VP_PRS were empirically independent, validating the virtual-parent design. Second, in this family-based design, children's own EA PRS significantly predicted their EA (β = 0.15), ruling out stratification confounds as a cause of the association of attainment with the EA PRS. Third, parental EA PRS predicted the SES environment parents provided to offspring (β = 0.20), and parental SES and offspring EA were significantly associated (β = 0.33). This would suggest that the EA PRS is at least as strongly linked to social competence as it is to EA, leading to higher attained SES in parents and, therefore, a higher experienced SES for children. In a full structural equation model taking account of family genetic relatedness across multiple siblings the non-transmitted allele effects were estimated at similar values; but, in this more complex model, confidence intervals included zero. A test using the forthcoming EA3 PRS may clarify this outcome. The virtual-parent method may be applied to clarify causality in other phenotypes where observational evidence suggests parenting may moderate expression of other outcomes, for instance in psychiatry.


Platelet morphology, soluble P selectin and platelet P-selectin in acute ischaemic stroke. The West Birmingham Stroke Project.
The pathophysiology of ischaemic stroke involves the platelet. In this study, we hypothesised that abnormalities in platelet morphology, as well as soluble (sPsel) and total platelet P-selectin (pPsel) levels would be present in patients presenting with an acute ischaemic stroke, and that these changes would improve at > or = 3 months' follow-up. We studied 59 hypertensive patients (34 male; mean age 68 +/- 12 years) who presented with an acute ischaemic stroke (ictus < 24 hours), and compared them with 2 groups: (i) age-, sex- and ethnic- origin matched normotensive healthy controls; and (ii) uncomplicated 'high risk' hypertensive patients as 'risk factor control' subjects. Platelet morphology (volume and mass) was quantified, and sPsel (plasma marker of platelet activation) was measured (ELISA) in citrated plasma. The mass of P-selectin in each platelet (pPsel) was determined by lysing a fixed number of platelets and then determining the levels of P-selectin in the lysate. Results show that patients who presented with a stroke had significantly higher levels of sPsel and pPsel (both p < 0.001), compared to the normal controls and the hypertensive patients. Patients with an acute stroke had lower mean platelet mass (MPM) and mean platelet volume (MPV) as compared to the uncomplicated hypertensive patients, who had significantly higher mean MPM and MPV values, as compared to normal controls. On follow-up, the levels of both sPsel (p = 0.011), pPsel (< 0.001) and MPV (p = 0.03) were significantly lower. Mean MPM levels remained unchanged. We conclude that patients presenting with an acute ischaemic stroke have activated platelets, as evident by the increased levels of soluble and platelet P-selectin. Further study of platelet activation and the role of P-selectin is warranted.


Growth modification of human colon adenocarcinoma cells exposed to a low-frequency electromagnetic field.
The influence of variable low-intensity, low-frequency electromagnetic fields on culture cells is investigated. Human colon adenocarcinoma cells were exposed to a rectangular and variable magnetic field (1 and 25 Hz; 1.5 mT peak). Cultures were exposed to a dose for 15 and 360 minutes, and after 24 hours incubation, cell viability was measured with neutral red stain. The group treated for 15 minutes showed a statistically significant increase in cell growth with 1 Hz (p < 0.002) and 25 Hz (p < 0.003). In contrast, a significant decrease in cell growth was found in those cultures treated with 1 Hz for 360 minutes (p < 0.02). The effects reported could be influenced by the magnetic field frequency and the exposure time.


Timing of the initial muscle biopsy does not affect the measured muscle protein fractional synthesis rate during basal, postabsorptive conditions.
The muscle protein fractional synthesis rate (FSR) is determined by monitoring the incorporation of an amino acid tracer into muscle protein during a constant-rate intravenous tracer infusion. Commonly two sequential muscle biopsies are obtained some time after starting the tracer infusion. However, other protocols, including those with an initial biopsy before starting the tracer infusion to measure the background enrichment and those with only a single biopsy after several hours of tracer infusion have been used. To assess the validity of these approaches, we compared the muscle protein FSR obtained by calculating the difference in [ring-(2)H(5)]phenylalanine and [5,5,5-(2)H(3)]leucine incorporation into muscle protein at approximately 3.5 h after starting the tracer infusion and 1) at 60 min; 2) before starting the tracer infusion (background enrichment); 3) a population average muscle protein background enrichment; and 4) by measuring the tracer incorporation into muscle protein at approximately 3.5 h assuming essentially no background enrichment. Irrespective of the tracer used, the muscle protein FSR calculated from the difference in the muscle protein labeling several hours after starting the tracer infusion and either the labeling at 60 min or the background enrichment were not different (e.g., 0.049 +/- 0.007%/h vs. 0.049 +/- 0.007%/h, respectively, with [(2)H(5)]phenylalanine; P = 0.99). However, omitting the initial biopsy and assuming no background enrichment yielded average FSR values that were approximately 15% (with [(2)H(5)]phenylalanine) to 80% (with [(2)H(3)]leucine) greater (P < or = 0.059); using a population average background enrichment reduced the difference to approximately 3% (P = 0.76) and 22% (P = 0.52) with [(2)H(5)]phenylalanine and [(2)H(3)]leucine, respectively. We conclude that during basal, postabsorptive conditions, valid muscle protein FSR values can be obtained irrespective of the timing of the initial biopsy so long as the protein labeling in two sequential biopsies is measured whereas the single biopsy approach should be avoided.


Experience of wellness recovery action planning in self-help and mutual support groups for people with lived experience of mental health difficulties.
The main aim of this research was to assess the relevance and impact of wellness recovery action planning (WRAP) as a tool for self-management and wellness planning by individuals with mental health problems from pre-existing and newly formed groups, where the possibilities for continued mutual support in the development of WRAPs could be explored. Interviews and focus groups were conducted and pre-post recovery outcome measures completed (Recovery Assessment Scale and Warwick Edinburgh Mental Well Being Scale). 21 WRAP group participants took part in the research. The WRAP approach, used in groups and delivered by trained facilitators who could also share their lived experience, was very relevant and appeared to have a positive impact on many of the participants. The impact on participants varied from learning more about recovery and developing improved self-awareness to integrating a WRAP approach into daily life. The apparent positive impact of WRAP delivered in the context of mutual support groups indicates that it should be given serious consideration as a unique and worthwhile option for improving mental health. WRAP groups could make a significant contribution to the range of self-management options that are available for improving mental health and well-being.


Safety of bariatric surgery in patients with coronary artery disease.
Patients with obesity and established coronary artery disease (CAD) may benefit from surgical weight loss; however, its safety is unknown in this population. To assess the association between CAD and the incidence of 30-day postoperative mortality and major adverse cardiac events (MACEs) in patients undergoing bariatric surgery. Multicenter cohort study. We used the 2017 MBSAQIP database to study patients undergoing bariatric surgery from accredited centers in the United States and Canada between Jan 1, 2017, and Dec 31, 2017. Multivariate logistic regression was used to determine whether established CAD was independently associated with 30-day mortality and MACE, a composite endpoint that included myocardial infarction and/or cardiac arrest. We reviewed data from 167,819 patients from 832 centers. There were 4172 patients with diagnosed CAD, and 163,647 without it. At 30-day follow-up, the endpoints of mortality, cardiac arrest, myocardial infarction, and MACE occurred in 172 (.10%), 82 (.05%), 57 (.03%), and 135 (.08%) patients, respectively. The endpoints occurred more significantly in patients with CAD compared with patients without CAD; 22 (.53%) versus 150 (.09%) for mortality, 13 (.31%) versus 69 (.04%) for cardiac arrest, 17 (.41%) versus 40 (.02%) for myocardial infarction, and 28 (.67%) versus 107 (.07%) for MACE (P < .001 for all comparisons). Postoperative mortality and MACE following bariatric surgery are higher in patients with CAD than those without; however, the absolute incidence is low (<1%). The decision to pursue bariatric surgery and/or preoperative cardiac testing in patients with CAD should include consideration of the overall incidence of adverse cardiac outcomes and the stability of CAD.


[The investigation of differential diagnostic development and incidence of tetrahydrobiopterin deficiency].
To investigate the development of differential diagnosis of tetrahydrobiopterin (BH4) deficiency among patients with hyperphenylalaninemia (HPA) in provinces or cities of China and to investigate the incidence of BH4 deficiency. Of the thirteen hundreds and ninety-two patients with HPA received, the differential diagnosis for BH4 deficiency during 1993 - 2007 were enrolled in this study. Of which, 591 patients came from outpatient and 801 patients' samples from other provinces or cities were sent to author's laboratory to investigate the case number of differential diagnosis for BH4 deficiency in provinces or cities of China according to the data from both outpatient case histories and laboratory as to investigating the development of differential diagnosis in the whole country. To discuss the diagnostic criteria for BH4 deficiency was according to the results of urinary pterin analysis, determination of dihydropteridine reductase (DHPR) activity and the tetrahydrobiopterin loading test as well as to get the incidence of BH4 deficiency and find some provinces or cities with higher incidence of BH4 deficiency in China. (1) The number of HPA patients, who were performed by urinary pterin analysis and the determination of DHPR activity, were remarkably increased in last three years (2005 - 2007). The patient numbers of both urinary pterin analysis and DHPR activity determination were 217 and 198 respectively in 2005. And in 2007 they increased to 511 and 458, which was about 2.3 times than that in 2005. The patients came from 29 provinces or cities in 2007. (2) The urinary biopterin and biopterin percent were key marks for diagnosis of 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency. The less than 5% [(1.41 +/- 1.10)%] biopterin percent and very low biopterin level [(0.14 +/- 0.17) mmol/mol Cr] were found in 96.83% (61/63) patients with PTPS deficiency in this study. The blood phenylalanine level was remarkably decreased to normal range at 2 - 6 hours after BH4 loading test. The very low DHPR activity was a final diagnostic mark for DHPR deficiency. The very low DHPR activities of 0.27 nmol/(min x 5 mm disc) (6.11% - 7.00% of normal controls) were found in two patients with DHPR deficiency in this study. (3) The incidences of PTPS deficiency and DHPR deficiency among 1392 patients with hyperphenylalaninemia were 8.41% (117/1392) and 0.18% (2/1108) respectively. About 67.23% (80/119) patients with BH4 deficiency came from the south of Yangtze liver. The 80% (8/10) provinces or cities with higher incidence of BH4 deficiency are located in eastern and southern China. The incidence of PTPS deficiency among patients with HPA and normal newborns was 10.81% (8/74) and 0.007 per thousand (8/1,121,429) respectively in Shanghai, China according to data from neonatal screening. The awareness of differential diagnosis for BH4 deficiency from clinic pediatricians has been increased in most provinces or cities of China in last three years, but it should be more strengthened.


Algibacter psychrophilus sp. nov., a psychrophilic bacterium isolated from marine sediment.
A Gram-stain-negative, aerobic, yellow-pigmented, flexirubin-negative, rod-shaped, non-motile and psychrophilic bacterial strain, PAMC 27237T, was isolated from marine sediment of the Ross Sea, Antarctica. Strain PAMC 27237T grew at 0-20 °C (optimally at 17 °C), at pH 5.0-9.5 (optimally at pH 7.0) and in the presence of 0-3.5 % (w/v) NaCl (optimally at 1.5-2.5 %). The major fatty acids (≥5 %) were iso-C17 : 0 3-OH, C17 : 0 2-OH, anteiso-C15 : 0, summed feature 3 (C16 : 1ω6c/C16 : 1ω7c), iso-C15 : 0 3-OH, anteiso-C17 : 1ω9c, anteiso-C15 : 1 A, iso-C16 : 0 3-OH and iso-C15 : 1 G. The major polar lipids were phosphatidylethanolamine, two unidentified aminolipids, four unidentified lipids and a glycolipid. The major respiratory quinone was MK-6. Phylogenetic analysis based on the 16S rRNA gene sequence revealed that strain PAMC 27237T belongs to the genus Algibacter, showing high similarities with the type strains of Algibacter agarivorans (97.2 %), Algibacter agarilyticus (97.0 %) and Algibacter mikhailovii (96.4 %). Average nucleotide identity values between strain PAMC 27237T and the type strains of A. agarivorans and A. agarilyticuswere 83.1 and 84.2 %, respectively, and mean genome-to-genome distances were 22.4-24.2 %, indicating that strain PAMC 27237T is clearly distinguished from the most closely related species of the genus Algibacter. The genomic DNA G+C content calculated from genome sequences was 33.5 mol%. Based on the phenotypic, chemotaxonomic and phylogenetic data presented, strain PAMC 27237T is considered to represent a novel species of the genus Algibacter, for which the name Algibacter psychrophilus sp. nov. is proposed. The type strain is PAMC 27237T ( = KCTC 42130T = JCM 30370T).


Chemically induced cyclometalation of 2-(arylazo)phenols. Synthesis, characterization, and redox properties of a family of organoosmium complexes.
Reaction of 2-(arylazo)phenols (H(2)ap-R; R = OCH(3), CH(3), H, Cl, and NO(2)) with [Os(PPh(3))(2)(CO)(2)(HCOO)(2)] affords a family of organometallic complexes of osmium(II) of type [Os(PPh(3))(2)(CO)(ap-R)] where the 2-(arylazo)phenolate ligand is coordinated to the metal center as a tridentate C,N,O-donor. Structure of the [Os(PPh(3))(2)(CO)(ap-H)] complex has been determined by X-ray crystallography. All the [Os(PPh(3))(2)(CO)(ap-R)] complexes are diamagnetic and show characteristic (1)H NMR signals and intense MLCT transitions in the visible region. They also show emission in the visible region at ambient temperature. Cyclic voltammetry on the [Os(PPh(3))(2)(CO)(ap-R)] complexes shows a reversible Os(II)-Os(III) oxidation within 0.39-0.73 V vs SCE, followed by a reversible Os(III)-Os(IV) oxidation within 1.06-1.61 V vs SCE. Coulometric oxidation of the [Os(PPh(3))(2)(CO)(ap-R)] complexes generates the [Os(III)(PPh(3))(2)(CO)(ap-R)](+) complexes, which have been isolated as the hexafluorophosphate salts. The [Os(III)(PPh(3))(2)(CO)(ap-R)]PF(6) complexes are one-electron paramagnetic and show axial ESR spectra. In solution they behave as 1:1 electrolytes and show intense LMCT transitions in the visible region. The [Os(III)(PPh(3))(2)(CO)(ap-R)]PF(6) complexes have been observed to serve as mild one-electron oxidants in a nonaqueous medium.


Non-pathogenic Neisseria species of the oropharynx as a reservoir of antimicrobial resistance: a cross-sectional study.
Commensal Neisseria species of the oropharynx represent a significant reservoir of antimicrobial resistance determinants that can be transferred to Neisseria gonorrhoeae. This aspect is particularly crucial in 'men having sex with men' (MSM), a key population in which pharyngeal co-colonization by N. gonorrhoeae and non-pathogenic Neisseria species is frequent and associated with the emergence of antimicrobial resistance. Here, we explored the antimicrobial susceptibility of a large panel of non-pathogenic Neisseria species isolated from the oropharynx of two populations: a group of MSM attending a 'sexually transmitted infection' clinic in Bologna (Italy) (n=108) and a group of males representing a 'general population' (n=119). We collected 246 strains, mainly belonging to N. subflava (60%) and N. flavescens (28%) species. Their antimicrobial susceptibility was evaluated assessing the minimum inhibitory concentrations (MICs) for azithromycin, ciprofloxacin, cefotaxime, and ceftriaxone using E-test strips. Overall, commensal Neisseria spp. showed high rates of resistance to azithromycin (90%; median MICs: 4.0 mg/L), and ciprofloxacin (58%; median MICs: 0.12 mg/L), whereas resistance to cephalosporins was far less common (<15%). Neisseria strains from MSM were found to have significantly higher MICs for azithromycin (p=0.0001) and ciprofloxacin (p<0.0001) compared to those from the general population. However, there was no significant difference in cephalosporin MICs between the two groups. The surveillance of the antimicrobial resistance of non-pathogenic Neisseria spp. could be instrumental in predicting the risk of the spread of multi-drug resistant gonorrhea. This information could be an early predictor of an excessive use of antimicrobials, paving the way to innovative screening and prevention policies.


Exploring the Effect of Long Naps on Handball Performance and Heart Rate Variability.
This study explored the effect of long naps on handball-related performance and assessed the role of the cardiac autonomic nervous system in this process. Eleven male collegiate handball players performed a repeated sequential trial consisting of a 20-m consecutive turnaround run, 10-m run with a load, and shooting the ball into a target. Participants were allocated randomly and sequentially to have a short (20 minutes) nap, long (60 minutes) nap, or no nap. The Pittsburgh Sleep Quality Index was used to assess regular sleep quality. Subjective sleepiness before and after napping was measured using the Karolinska Sleepiness Scale. Heart rate variability was recorded to assess cardiac autonomic nervous function during napping. The Pittsburgh Sleep Quality Index score was correlated with shot accuracy only after long naps (ρ=0.636, r=0.048). A negative correlation was observed between the root mean square of successive differences and average load run time (ρ=-0.929, p<0.001). Long napping was associated with a significant benefit on performance in athletes with poor sleep quality, implying a role of the autonomic nervous system in this regard. Our findings indicate the effect of sleep quality on the endurance and resistance of handball players.


Changes in Emergency Medical Services Before and During the COVID-19 Pandemic in the United States, January 2018-December 2020.
As a result of the continuing surge of coronavirus disease 2019 (COVID-19), many patients have delayed or missed routine screening and preventive services. Medical conditions, such as coronary heart disease, mental health issues, and substance use disorder, may be identified later, leading to increases in patient morbidity and mortality. National Emergency Medical Services Information System data were used to assess 911 emergency medical services (EMS) activations during 2018-2020. For specific activation types, the percentage of total activations was calculated per week, and Joinpoint analysis was used to identify changes over time. Since March 2020, the number of 911 EMS activations has decreased, while the percentages of on-scene death, cardiac arrest, and opioid use/overdose EMS activations were higher than prepandemic levels. During the early pandemic period, percentages of total EMS activations increased for on-scene death (from 1.3% to 2.4% during weeks 11-15), cardiac arrest (from 1.3% to 2.2% during weeks 11-15), and opioid use/overdose (from 0.6% to 1.1% during weeks 8-18). The percentages then declined but remained above prepandemic levels through calendar week 52. The COVID-19 pandemic has indirect consequences, such as relative increases in EMS activations for cardiac events and opioid use/overdose, possibly linked to disruptions is healthcare access and health-seeking behaviors. Increasing telehealth visits and other opportunities for patient-provider touch points for chronic disease and substance use disorders that emphasize counseling, preventive care, and expanded access to medications can disrupt delayed care-seeking during the pandemic and potentially prevent premature death.


Progression of Carotid Intima-Media Thickness Partly Indicates the Prevention of Hypertension among Older Individuals in the General Population.
Structural atherosclerosis, as evaluated by carotid intima-media thickness (CIMT), is reported to be positively associated with hypertension. However, angiogenesis, which plays an important role in the progression of structural atherosclerosis, prevents hypertension by reducing peripheral vascular resistance. These associations evoke a contradiction: characteristics associated with the progression of structural atherosclerosis, which is related to hypertension, might prevent hypertension. To clarify novel mechanisms underlying the association between structural atherosclerosis and hypertension, multifaceted analyses are necessary. We performed several epidemiological studies based on this concept. This study summarizes those epidemiological studies and adds some discussion. Studies focusing on circulating CD34-positive cells, single-nucleotide polymorphisms (SNPs) of vascular endothelial growth factor (VEGF), SNPs in BRACA1-associated protein (BRAP), platelets, human T-cell leukemia virus type 1 (HTLV-1), and SNPs in aldehyde dehydrogenase 2 (ALDH2) have shown that active endothelial repair, which leads to the progression of structural atherosclerosis, helps prevent hypertension. These associations indicate that the progression of structural atherosclerosis could act as a marker of angiogenesis, which reduces peripheral vascular resistance. In general, a positive association between structural atherosclerosis and hypertension has been reported. However, the progression of structural atherosclerosis could act as a marker of activity that prevents hypertension via reductions in peripheral vascular resistance.


Macroporous Granular Hydrogels Functionalized with Aligned Architecture and Small Extracellular Vesicles Stimulate Osteoporotic Tendon-To-Bone Healing.
Osteoporotic tendon-to-bone healing (TBH) after rotator cuff repair (RCR) is a significant orthopedic challenge. Considering the aligned architecture of the tendon, inflammatory microenvironment at the injury site, and the need for endogenous cell/tissue infiltration, there is an imminent need for an ideal scaffold to promote TBH that has aligned architecture, ability to modulate inflammation, and macroporous structure. Herein, a novel macroporous hydrogel comprising sodium alginate/hyaluronic acid/small extracellular vesicles from adipose-derived stem cells (sEVs) (MHA-sEVs) with aligned architecture and immunomodulatory ability is fabricated. When implanted subcutaneously, MHA-sEVs significantly improve cell infiltration and tissue integration through its macroporous structure. When applied to the osteoporotic RCR model, MHA-sEVs promote TBH by improving tendon repair through macroporous aligned architecture while enhancing bone regeneration by modulating inflammation. Notably, the biomechanical strength of MHA-sEVs is approximately two times higher than the control group, indicating great potential in reducing postoperative retear rates. Further cell-hydrogel interaction studies reveal that the alignment of microfiber gels in MHA-sEVs induces tenogenic differentiation of tendon-derived stem cells, while sEVs improve mitochondrial dysfunction in M1 macrophages (Mφ) and inhibit Mφ polarization toward M1 via nuclear factor-kappaB (NF-κb) signaling pathway. Taken together, MHA-sEVs provide a promising strategy for future clinical application in promoting osteoporotic TBH.


Evaluating the diagnostic accuracy of CT perfusion in patients with cerebral vasospasm after aneurysm rupture: a meta-analysis.
Computed tomography perfusion (CTP) has recently been used to identify regions of potential ischemia due to cerebral vasospasm, and CTP parameters are able to quantitatively evaluate brain parenchymal perfusion. We performed a meta-analysis as an update of a previous paper published in 2010 and aimed at evaluating the diagnostic accuracy of CTP and CTP parameters for vasospasm after aneurysm rupture. Relevant articles published between January 2005 and May 2013 were systematically searched for analysis without language restrictions from the PubMed/MEDLINE, Embase, and Cochrane databases. The data of CTP parameters, including CBV, CBF, MTT and TTP, were extracted for analysis, and the pooled sensitivity, specificity, PLR, NLR, DOR and the sROC curve were determined. Three relevant articles and a total of 98 patients were finally involved in the analysis. The pooled sensitivity, specificity, PLR, NLR, DOR, and AUC of CTP for diagnosing cerebral vasospasm were 94%, 90%, 8.22, 0.06, 141.09, and 0.9802, respectively. Through the evaluation of CTP parameters, MTT had a higher sensitivity (91%) while CBF had a higher specificity (93%). CT perfusion has a great diagnostic value to detect cerebral vasospasm compared with DSA in patients with aneurysmal subarachnoid hemorrhage (aSAH). As CTP parameters, CBF and MTT quantitatively evaluate brain parenchymal perfusion.


Solid-state ice volcanism on the satellites of uranus.
Voyager images of the uranian satellites Ariel and Miranda show flow features with morphologies indicating that ice has been extruded to the satellites' surfaces in the solid state. These images provide the first observational evidence for solid-state ice volcanism in the solar system. Topographic profiles have been measured across a number of flow features on Ariel. With a simple model of extrusion, spreading, and cooling of a viscous flow, the initial viscosity of the flow material is found to have been no more than about 10(16) poise, far lower than expected for H(2)O ice at the ambient surface temperatures in the uranian system. Sharply reduced viscosities may have resulted from incorporation of ices like NH(3) or CH(4) in the uranian satellites.


Androgens Induce Functional CXCR4 through ERG Factor Expression in TMPRSS2-ERG Fusion-Positive Prostate Cancer Cells.
TMPRSS2-ERG fusion transcripts have been shown to be expressed in a majority of prostate cancer (PC) patients because of chromosomal translocations or deletions involving the TMPRSS2 gene promoter and the ERG gene coding sequence. These alterations cause androgen-dependent ERG transcription factor expression in PC patients. We and others have shown that chemokine receptor CXCR4 expression is upregulated in PC tumor cells, and its ligand, CXCL12, is expressed in bone stromal cells. The CXCL12/CXCR4 axis functions in PC progression to enhance invasion and metastasis. To address the regulation of CXCR4 expression, we identified several putative ERG consensus-binding sites in the promoter region of CXCR4. We hypothesized that androgen-dependent regulation of the ERG transcription factor could induce CXCR4 expression in PC cells. Results of the current study show that 1) prostate tumor cells coexpress higher ERG and CXCR4 compared with benign tissue, 2) CXCR4 expression is increased in the TMPRSS2-ERG fusion-positive cell line, 3) ERG transcription factor binds to the CXCR4 gene promoter, 4) synthetic androgen (R1881) upregulates both ERG and CXCR4 in TMPRSS2-ERG fusion-positive VCaP cells, 5) small interfering RNA-mediated down-regulation of ERG resulted in the loss of androgen-dependent regulation of CXCR4 expression in VCaP cells, and 6) R1881-activated TMPRSS2-ERG expression functionally activates CXCR4 in VCaP cells. These findings provide a link between TMPRSS2-ERG translocations and enhanced metastasis of tumor cells through CXCR4 function in PC cells.


Augmenting Basin-Hopping With Techniques From Unsupervised Machine Learning: Applications in Spectroscopy and Ion Mobility.
Evolutionary algorithms such as the basin-hopping (BH) algorithm have proven to be useful for difficult non-linear optimization problems with multiple modalities and variables. Applications of these algorithms range from characterization of molecular states in statistical physics and molecular biology to geometric packing problems. A key feature of BH is the fact that one can generate a coarse-grained mapping of a potential energy surface (PES) in terms of local minima. These results can then be utilized to gain insights into molecular dynamics and thermodynamic properties. Here we describe how one can employ concepts from unsupervised machine learning to augment BH PES searches to more efficiently identify local minima and the transition states connecting them. Specifically, we introduce the concepts of similarity indices, hierarchical clustering, and multidimensional scaling to the BH methodology. These same machine learning techniques can be used as tools for interpreting and rationalizing experimental results from spectroscopic and ion mobility investigations (e.g., spectral assignment, dynamic collision cross sections). We exemplify this in two case studies: (1) assigning the infrared multiple photon dissociation spectrum of the protonated serine dimer and (2) determining the temperature-dependent collision cross-section of protonated alanine tripeptide.


Grooming and control of fleas in cats.
Oral grooming is common in cats, as in rodent and bovid species where grooming has been shown to be effective in removing lice and ticks. In Experiment 1, we examined the effectiveness of oral grooming in removing fleas which are the main ectoparasite of cats. Elizabethan collars (E-collars) which prevented grooming were fitted on nine cats in a flea-infested household and 3 weeks later, flea numbers on these cats were compared with nine control cats in the same household. Flea numbers dropped in the control cats reflecting an apparent drop in adult fleas in the environment, but in the E-collar cats, flea numbers did not drop, and were about twice as numerous as in control cats. The significantly greater number of fleas on the E-collar cats was attributed to their inability to groom off fleas. In Experiment 2, videotaping of nine different cats from the flea-infested household revealed that these cats groomed at about twice the rate of 10 similarly videotaped control cats from a flea-free colony. These results reveal that flea exposure can increase grooming rate in cats and that grooming is effective in removing fleas.


Differences in the effects of phorbol esters and diacylglycerols on protein kinase C.
The binding of protein kinase C (PKC) to membranes and appearance of kinase activity are separable events. Binding is a two-step process consisting of a reversible calcium-dependent interaction followed by an irreversible interaction that can only be dissociated by detergents. The irreversibly bound PKC is constitutively active, and the second step of binding may be a major mechanism of PKC activation [Bazzi & Nelsestuen (1988) Biochemistry 27, 7589]. This study examined the activity of other forms of membrane-bound PKC and compared the effects of phorbol esters and diacylglycerols. Like the membrane-binding event, activation of PKC was a two-stage process. Diacylglycerols (DAG) participated in forming an active PKC which was reversibly bound to the membrane. In this case, both activity and membrane binding were terminated by addition of calcium chelators. DAG functioned poorly in generating the constitutively active, irreversible PKC-membrane complex. These properties differed markedly from phorbol esters which activated PKC in a reversible complex but also promoted constitutive PKC activation by forming the irreversible PKC-membrane complex. The concentration of phorbol esters needed to generate the irreversible PKC-membrane complex was slightly higher than the concentration needed to activate PKC. In addition, high concentrations of phorbol esters (greater than or equal to 50 nM) activated PKC and induced irreversible PKC-membrane binding in the absence of calcium. Despite these striking differences, DAG prevented binding of phorbol esters to high-affinity sites on the PKC-membrane complex.(ABSTRACT TRUNCATED AT 250 WORDS)


Surgery for tympanic membrane retraction pockets.
Tympanic membrane retractions are commonly managed by ENT surgeons. There is currently no consensus as to the indications, timing and options for management of this condition. To study the effectiveness of different surgical options in the management of tympanic membrane retractions. We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2010 Issue 1); PubMed (1950 to 2010); EMBASE (1974 to 2010); CINAHL (1982 to 2010); BIOSIS Previews; ISI Web of Science; CAB Abstracts; LILACS; KoreaMed; IndMed; PakMediNet; China National Knowledge Infrastructure; ISCTRN; UKCRN; ICTRP and Google. The date of the search was 17 March 2010. Randomised controlled trials (RCTs) of the surgical management of tympanic membrane retraction pockets in adults or children. Staging of the retraction using a known system must have been performed. Studies of cholesteatoma or perforations were excluded. Two authors independently collected and analysed data to minimise the effects of selection and reporting bias. Two RCTs were included, involving 71 participants. The first study showed no statistically significant benefit of cartilage graft tympanoplasty over a watch and wait policy for either disease progression or hearing outcome. The second showed no additional benefit from the insertion of ventilation tubes over cartilage tympanoplasty alone with regards to hearing outcome. No evidence currently exists to either support or refute the role of surgery in the management of tympanic membrane retractions. Higher quality studies are much needed to ascertain this.


Urban mental health: challenges and perspectives.
To provide an update on urban mental health and highlight the challenges that require urgent attention. The majority of the world's population live in towns and urbanization is expected to increase in all areas of the world. Challenges to mental health in urban areas include loneliness, violence, high crime rates, homelessness, noise and other pollutants, traffic accidents, drug abuse, and insufficiency of mental health services. Urbanization is a global and growing phenomenon that pose significant challenges to mental health and mental health services. Fast and unstructured urbanization, such as that seen in many developing countries, further exacerbates these challenges. There are promising initiatives emerging including initiatives to end homelessness, to improve access to green areas in urban environments, to provide emergency psychiatric services, and to develop new forms of mental health services adjusted to urban settings. Regrettably there are no universally accepted guidelines that would help governments in structuring health services for people with mental illness in towns and help to prevent mental health problems related to rapid urbanization.


Hyper-eosinophilia in granular acute B-cell lymphoblastic leukemia with myeloid antigen expression.
Acute lymphoblastic leukemia with eosinophilia (ALLEo) is a rare but a distinctive clinical entity. Clinical features of idiopathic hyper-eosinophilic syndrome (HES) can be seen in patients with ALLEo. We report a 10-year-old girl, in whom HES was initially suspected but further investigation confirmed the diagnosis of acute B-cell lymphoblastic leukemia with myeloid antigen expression. Clinical response to chemotherapy was excellent with achievement of complete remission for 4 years. Serum interleukin-3 and -5 were elevated at presentation and normalized with disappearance of eosinophilia after induction therapy, supporting the reactive nature of eosinophilia in ALLEo. Hematologic malignancy should be considered in patients with hyper-eosinophilia, before attributing it to HES.


Hepatic resection for intrahepatic ductal stones.
Intrahepatic stones that have caused irreversible ductal damage may need unusual treatment. When other treatments fail, resection of the affected portion of the liver is usually curative. Clinical features may be misleading: pain and sepsis are common, but jaundice is not. Diagnosis depends on awareness and critical use of special tests; ducts unseen may be culprits. Resection most often is easy, for usually the left hepatic ducts are affected.


The transformation of the cytoplasmic oestradiol-receptor complex into the nuclear complex in a uterine cell-free system.
Experiments performed with a cell-free system in tris-EDTA buffer, pH 7.4, indicate that the high-speed supernatant fraction of the rat uterus contains all the factors necessary to transform the 8S cytoplasmic oestradiol-receptor complex to the nuclear complex. The transformation is temperature-dependent. This nuclear complex was extracted in the form of a 5S particle with 0.4m-KCl from sediments of either uterine or heart nuclei that had been incubated together with the cytoplasmic soluble fraction of the uterus at 2 degrees C for 30min. This complex can also be obtained similarly from the soluble fraction of the uterus, incubated in the absence of nuclei. Previous warming of the soluble fraction to 37 degrees C for 7min was necessary for the successful extraction of the nuclear particle under these conditions of incubation. After an incubation of the transformed complex with the nuclear sediment at 37 degrees C for 7min, the 5S complex was extractable from the uterine nuclear sediment but not from the heart nuclear sediment, which may indicate the tissue specificity of the nuclear acceptor sites for the transformed complex. The extracted uterine nuclear complex sediments in the 5S region, but whether it is the native complex or a subunit or other part of the native complex resulting from the extraction with salt is unknown.


[Patient volume and quality in surgery for abdominal aortic aneurysm].
BACKGROUND Patient volume is assumed to affect quality, whereby complex procedures are best performed by those who perform them frequently. We have conducted a systematic review of the research on the association between patient volume and quality of vascular surgery. In this article we describe the outcomes for abdominal aortic aneurysm surgery.MATERIAL AND METHOD We undertook systematic searches in relevant databases. We searched for systematic reviews, and randomised and observational studies. The search was concluded in December 2015. We have summarised the results descriptively and assessed the overall quality of the evidence.RESULTS Forty-six observational studies fulfilled our inclusion criteria. We found a possible association for both hospital and surgeon volume. Higher patient volume may possibly be associated with lower 30-day mortality and lower hospital mortality for both open and endovascular surgery. Although the association appears to apply to both elective and acute hospitalisations, there is greater uncertainty with regard to the most ill patients. For hospital volume there may also be fewer complications for open and endovascular surgery, as well as for all surgery assessed as a whole. We considered the evidence base to be medium to very low quality.INTERPRETATION We found a possible correlation between patient volume and quality indicators such as mortality and complications. It may be advantageous to allocate planned procedures to institutions and surgeons with high volume, while this is less certain with regard to acute hospitalisations.


Heart Failure With Targeted Cancer Therapies: Mechanisms and Cardioprotection.
Oncology has seen growing use of newly developed targeted therapies. Although this has resulted in dramatic improvements in progression-free and overall survival, challenges in the management of toxicities related to longer-term treatment of these therapies have also become evident. Although a targeted approach often exploits the differences between cancer cells and noncancer cells, overlap in signaling pathways necessary for the maintenance of function and survival in multiple cell types has resulted in systemic toxicities. In particular, cardiovascular toxicities are of important concern. In this review, we highlight several targeted therapies commonly used across a variety of cancer types, including HER2 (human epidermal growth factor receptor 2)+ targeted therapies, tyrosine kinase inhibitors, immune checkpoint inhibitors, proteasome inhibitors, androgen deprivation therapies, and MEK (mitogen-activated protein kinase kinase)/BRAF (v-raf murine sarcoma viral oncogene homolog B) inhibitors. We present the oncological indications, heart failure incidence, hypothesized mechanisms of cardiotoxicity, and potential mechanistic rationale for specific cardioprotective strategies.


Comparative analysis of discoid lateral meniscus size: a distinction between symptomatic and asymptomatic cases.
This study evaluated the differences in meniscal sizes and occupancy between symptomatic and asymptomatic patients diagnosed with discoid lateral meniscus (DLM) using magnetic resonance imaging (MRI) to understand how these variations relate to the presence of symptoms and the patients' age. A retrospective review of 98 patients with DLM was conducted, excluding those with meniscal displacement. Both the width and extrusion of DLM and the percentage of the meniscus to the tibia were measured using mid-coronal and mid-sagittal MRI and compared between symptomatic and asymptomatic DLM groups. The relationships among each parameter, meniscal size, and patient age were evaluated. Symptomatic cases were divided into those with and without horizontal tears on MRI to compare the differences in meniscal morphology. A total of 92 knees from 74 patients were included. Sixty-one knees required surgical intervention for symptomatic DLM, while 31 were asymptomatic and included the contralateral side of symptomatic knees. The symptomatic group exhibited larger morphological variations than the asymptomatic group. Moreover, the sagittal meniscal ratio reduced with age in the asymptomatic group (r = - 0.54, p = 0.002) but remained constant in the symptomatic group. The symptomatic cases with horizontal tears demonstrated larger meniscal dimensions and smaller posterior capsule distances than those without tears. Symptomatic patients with DLM had larger knee morphological changes than asymptomatic ones. Age affected the meniscal occupancy in the sagittal plane only in asymptomatic patients. III.


Preclinical toxicology of zidovudine. An overview.
The toxicologic potential of zidovudine (azidothymidine) has been extensively investigated in several species. In rats and mice, the median lethal dose was greater than 750 mg/kg intravenously and greater than 3,000 mg/kg orally. In subacute intravenous toxicity studies, no significant toxicologic alterations were seen in rats or dogs. In cynomolgus monkeys, which as in humans rapidly and extensively glucuronidate zidovudine, a reversible, dose-related, macrocytic anemia was seen in animals given 35, 100, or 300 mg/kg per day for three or six months. In three-month and six-month oral toxicity studies in rats, treatment-related alterations consisted of a mild increase in glucose level in the blood in female rats in both studies and a reversible, slight-to-mild macrocytic anemia in the six-month study. There was no evidence of teratogenicity in rats or rabbits given the drug during gestation. Results for zidovudine were negative in a bacterial mutagenicity assay, but the drug was weakly mutagenic at concentrations of 1,000 to 5,000 micrograms/ml in mammalian cells. Zidovudine caused chromosomal aberrations in cultured human lymphocytes at concentrations of 3 micrograms/ml and higher and had positive results in a cell transformation assay at concentrations of 0.5 micrograms/ml and higher. No bone marrow chromosomal alterations were noted in a cytogenetics study in rats given zidovudine at several intravenous dose levels up to 300 mg/kg.


Decreased insulin binding and degradation associated with depressed intracellular ATP content.
The effect of metabolic inhibitors, 2,4-dinitrophenol (DNP) and NaF, on insulin binding and degradation has been studied in cultured Buffalo rat liver (BRL) cells. In control studies, 1.8 fmol of 125I-insulin binds to 1.2 x 10(6) cells, possessing approximately 40,000 receptor sites per cell with binding affinity of 5.52 x 10(-8) M. When the cells were preincubated with increasing concentrations of either DNP or NaF, a dose- and time-dependent decrease in both insulin binding and degradation was observed. The total amount of 125I-insulin bound to BRL cells preincubated with metabolic inhibitors was reduced to 1.2 fmol per 1.2 x 10(6) cells. The point of 1/2 B max was achieved in the presence of 50 ng/ml of native insulin, 1.7 times that of the control level. The number of receptor sites was unaffected by either DNP or NaF, but an average affinity profile revealed a decrease in the affinity of the ATP-depleted cells for insulin (KD: 7.31 x 10(-8) M and 7.06 x 10(-8) M in DNP- and NaF-treated cells, respectively). The decrease in insulin binding and degradation following the exposure of the BRL cells to the metabolic inhibitors was associated with a 20% reduction in intracellular ATP and adenylate energy charge. DNP and NaF did not affect the equilibrium constant for the myokinase catalyzed reaction and the intracellular concentration of hypoxanthine was stable, confirming the integrity of the cells during the experiments. It is suggested that ATP levels must remain intact to maintain normal insulin receptor affinity. Furthermore, the rate of insulin degradation by ATP-depleted cells is slower than that of intact cells. It is conceivable that the depression of insulin degradation by partially ATP-depleted cells results from either diminished binding or decreased endocytosis and lysosomal activity, all of which appear to be energy dependent.


A combined theoretical and experimental study of phenol-(acetylene)n (n ≤ 7) clusters.
Structures and vibrational spectra of phenol-(acetylene)n (Ph(Ac)n) clusters are studied by a combination of theoretical calculations and infrared (IR) spectroscopy. The molecular electrostatic potential features are utilized for generating trial geometries of the medium-sized Ph(Ac)n (n = 1, 2, 4, 6, and 7) clusters. These initial geometries are subjected to geometry optimization within the second-order Møller-Plesset (MP2) theory, employing correlation consistent aug-cc-pVDZ (aVDZ) basis set. Minimal nature of the reported structures is confirmed by doing vibrational frequency run at MP2/aVDZ level of theory using full calculations for n = 1 and 2 and employing grafting based molecular tailoring approach for the n = 4, 6, and 7. Several isomers for n ≥ 4 are found to lie in an energy window of 1 kcal mol-1 of each other. Considering the formidability of MP2 level investigation for the large number of isomers for n = 6 and 7, B97-D level theory is used for studying their energetics and IR spectra. It is seen that the number of energetically close isomers increases with increasing n. Moderately size-selected IR spectra of Ph(Ac)n (n = 4 and 7), prepared by a supersonic jet expansion, are measured for the acetylenic C-H and phenolic O-H stretch regions by infrared-ultraviolet (IR-UV) double resonance spectroscopy combined with time-of-flight mass spectrometry. Asymmetric line shape of the C-H stretch band and remarkable line broadening and weakening of the O-H stretch band are noteworthy features of the observed spectra. These findings of the experimental spectra are explained by the theoretical studies. The averaging of the vibrational spectrum of low-lying isomers of the Ph(Ac)n clusters lying in a narrow energy range is found to be responsible for the broadening and weakening of the O-H band.


Nitrogen Fertilization Effects on Biomass Production and Yield Components of Miscanthus ×giganteus.
Grasses such as Miscanthus ×giganteus and Panicum virgatum (switchgrass) can potentially be used to produce bioenergy on a large scale in the Midwestern USA. The biomass productivity of these warm-season perennial grasses, particularly M. × giganteus, can be substantial, even when grown with limited inputs. The literature, however, varies regarding the nitrogen requirements for M. ×giganteus biomass production. In addition, there is a lack of information that identifies the yield-component(s) (including total tiller number, tiller weight, total tiller diameter, total tiller height, phytomer number, reproductive tiller number, vegetative tiller number, reproductive tiller height, vegetative tiller height, reproductive tiller diameter, vegetative tiller diameter, and reproductive tiller phytomer number) that contributes to M. ×giganteus biomass yields. Thus, the objective of this study was to examine the effects of fertilization on biomass yield and individual M. × giganteus plant-yield components. Plots of M. ×giganteus were planted in 2008 in Urbana, IL, USA, and received annual applications of 0, 60, or 120 kg N ha-1. M. ×giganteus productivity increased when nitrogen was applied; between 2011 and 2014, nitrogen applications of 60 or 120 kg N ha-1 produced average annual yields of 22.0 dry Mg ha-1 compared to 11.8 dry Mg ha-1 for unfertilized M. ×giganteus. Both the total number of tillers per m2 and the tiller weight also increased as N-application rates increased. Our results indicate that increased reproductive tiller density and tiller weight with increased N fertilization increased M. ×giganteus biomass yield.


Demonstration of direct effects of growth hormone on neonatal cardiomyocytes.
The cellular and molecular basis of growth hormone (GH) actions on the heart remain poorly defined, and it is unclear whether GH effects on the myocardium are direct or mediated at least in part via insulin-like growth factor (IGF-1). Here, we demonstrate that the cultured neonatal cardiomyocyte is not an appropriate model to study the effects of GH because of artifactual loss of GH receptors (GHRs). To circumvent this problem, rat neonatal cardiomyocytes were infected with a recombinant adenovirus expressing the murine GHR. Functional integrity of GHR was suggested by GH-induced activation of the cognate JAK2/STAT5, MAPK, and Akt intracellular pathways in the cells expressing GHR. Although exposure to GH resulted in a significant increase in the size of the cardiomyocyte and increased expression of c-fos, myosin light chain 2, and skeletal alpha-actin mRNAs, there were no significant changes in IGF-1 or atrial natriuretic factor mRNA levels in response to GH stimulation. In this model, GH increased incorporation of leucine, uptake of palmitic acid, and abundance of fatty acid transport protein mRNA. In contrast, GH decreased uptake of 2-deoxy-d-glucose and levels of Glut1 protein. Thus, in isolated rat neonatal cardiomyocytes expressing GHR, GH induces hypertrophy and causes alterations in cellular metabolic profile in the absence of demonstrable changes in IGF-1 mRNA, suggesting that these effects may be independent of IGF-1.


Treating depression in old age: is it worth the effort?
Physical changes which accompany aging and the presence of concurrent medical problems often complicate the treatment of depression in old age. When physicians treat patients who have a long list of problems and medications they can become overly worried about the potential risks of treatment and deny the patient a chance at recovery. Clinicians should, however, remember that treatment response is generally good for elderly persons who have major depressive episodes while spontaneous remissions are less likely to occur. The risks of treatment can be minimized by careful evaluation of the patient's problems, choosing medications which have a low side effect profile, starting at a low dose and closely monitoring for side effects. The risks of leaving the depression untreated are usually greater than the potential risks of treatment. The consensus among clinicians interested in the care of elderly depressives is that treatment efforts are usually rewarded by improved quality of life and good remission of depressive symptoms. We need, however, to continue to look for rapidly efficacious treatments with fewer side effects.


Magnetic resonance imaging in gastroenterology: time to say good-bye to all that endoscopy?
Magnetic resonance imaging (MRI) has been described as the most important development in medical diagnosis since the discovery of the roentgen ray more than 100 years ago. The effectiveness of MRI has been extended to make it applicable in a wide variety of gastrointestinal disorders. The attention of gastroenterologists is currently focusing on pancreaticobiliary and bowel diseases. Magnetic resonance cholangiopancreatography (MRCP) has become a competitive alternative to diagnostic endoscopic retrograde cholangiopancreatography in a variety of hepatobiliary and pancreatic diseases. Magnetic resonance enteroscopy has the potential to become the preferable method for evaluating the entire small bowel; virtual colonoscopy, on the other hand, is far from the stage at which it could be promoted as a tool for general screening purposes in suspected colonic diseases. Its drawbacks include problems with standardization, implementation of the techniques in generalized settings, and patient acceptance.


Clinical and serological evaluation of a novel CENP-A peptide based ELISA.
Anti-centromere antibodies (ACA) are useful biomarkers in the diagnosis of systemic sclerosis (SSc). ACA are found in 20 to 40% of SSc patients and, albeit with lower prevalence, in patients with other systemic autoimmune rheumatic diseases. Historically, ACA were detected by indirect immunofluorescence (IIF) on HEp-2 cells and confirmed by immunoassays using recombinant CENP-B. The objective of this study was to evaluate a novel CENP-A peptide ELISA. Sera collected from SSc patients (n=334) and various other diseases (n=619) and from healthy controls (n=175) were tested for anti-CENP-A antibodies by the novel CENP-A enzyme linked immunosorbent assay (ELISA). Furthermore, ACA were determined in the disease cohorts by IIF (ImmunoConcepts, Sacramento, CA, USA), CENP-B ELISA (Dr. Fooke), EliA CENP (Phadia, Freiburg, Germany) and line-immunoassay (LIA, Mikrogen, Neuried, Germany). Serological and clinical associations of anti-CENP-A with other autoantibodies were conducted in one participating centre. Inhibition experiments with either the CENP-A peptide or recombinant CENP-B were carried out to analyse the specificity of anti-CENP-A and -B antibodies. The CENP-A ELISA results were in good agreement with other ACA detection methods. According to the kappa method, the qualitative agreements were: 0.73 (vs. IIF), 0.81 (vs. LIA), 0.86 (vs. CENP-B ELISA) and 0.97 (vs. EliA CENP). The quantitative comparison between CENP-A and CENP-B ELISA using 265 samples revealed a correlation value of rho=0.5 (by Spearman equation). The receiver operating characteristic analysis indicated that the discrimination between SSc patients (n=131) and various controls (n=134) was significantly better using the CENP-A as compared to CENP-B ELISA (P<0.0001). Modified Rodnan skin score was significantly lower in the CENP-A negative group compared to the positive patients (P=0.013). Inhibition experiments revealed no significant cross reactivity of anti-CENP-A and anti-CENP-B antibodies. Statistically relevant differences for gender ratio (P=0.0103), specific joint involvement (Jaccoud) (P=0.0006) and anti-phospholipid syndrome (P=0.0157) between ACA positive SLE patients and the entire SLE cohort were observed. Anti-CENP-A antibodies as determined by peptide ELISA represent a sensitive, specific and independent marker for the detection of ACA and are useful biomarkers for the diagnosis of SSc. Our data suggest that anti-CENP-A antibodies are a more specific biomarker for SSc than antibodies to CENP-B. Furthers studies are required to verify these findings.


Mechanic and surface properties of central-venous port catheters after removal: A comparison of polyurethane and silicon rubber materials.
Central venous port devices made of two different polymeric materials, thermoplastic polyurethane (TPU) and silicone rubber (SiR), were compared due their material properties. Both naïve catheters as well as catheters after removal from patients were investigated. In lab experiments the influence of various chemo-therapeutic solutions on material properties was investigated, whereas the samples after removal were compared according to the implanted time in patient. The macroscopic, mechanical performance was assessed with dynamic, specially adapted tests for elasticity. The degradation status of the materials was determined with common tools of polymer characterisation, such as infrared spectroscopy, molecular weight measurements and various methods of thermal analysis. The surface morphology was analysed using scanning electron microscopy. A correlation between material properties and clinical performance was proposed. The surface morphology and chemical composition of the polyurethane catheter materials can potentially result in increased susceptibility of the catheter to bloodstream infections and thrombotic complications. The higher mechanic failure, especially with increasing implantation time of the silicone catheters is related to the lower mechanical performance compared to the polyurethane material as well as loss of barium sulphate filler particles near the surface of the catheter. This results in preformed microscopic notches, which act as predetermined sites of fracture.


[Bilateral juxtapapillary subretinal neovascularization in a case of pseudotumor cerebri].
A 39 year old woman presented a sudden loss of vision in her right eye due to a sero-hemorrhagic retinal detachment associated to bilateral papilledema. A bilateral juxtapapillary subretinal neovascularization was observed on fluorescein angiography. Neurologic examination was normal except for intracranial pressure that was 22 mmHg. Lowering of the intracranial pressure with acetazolamide and prednisone resulted in a rapid improvement of visual acuity, with resorption of the hemorrhages and involution of the subretinal membranes.


The Use of the Addiction Severity Index Psychiatric Composite Scores to Predict Psychiatric Inpatient Admissions.
The high prevalence of co-occurring mental health and substance use disorders indicates a need for integrated behavioral health treatment that addresses both types of disorder simultaneously. One component of this integrated treatment is the use of an assessment process that can concurrently identify the presence of each class of disorder. The Addiction Severity Index (ASI) has been extensively used and researched in the field of substance use disorders for over 30 years. The ASI has seven sections, including a section on substance use disorders and a section on psychiatric symptoms, making it a potential candidate for a co-occurring screen during intake. The following study utilized a receiver operating characteristic curve analysis to determine an optimal cutoff score on the ASI psychiatric composite score to identify which individuals seeking substance use disorder treatment were admitted to the Milwaukee County Behavioral Health Division's psychiatric hospital in the year subsequent to their ASI administration. Of the 19,320 individuals who completed an initial ASI in our system, 343 had an inpatient admission. The receiver operating characteristic curve was statistically significant, with an area under the curve of 0.75. A cutoff of 0.27 had a sensitivity of 0.77 and a specificity of 0.61, such that over 60% (11,963/19,320) of the sample was excluded. These results suggest that the ASI psychiatric composite score may be a useful initial screen to identify those with potential mental health problems/needs in a behavioral health system attempting to integrate addiction and mental health services.


Design and synthesis of benzodiazepine analogs as isoform-selective human lysine deacetylase inhibitors.
A comprehensive investigation was performed to identify new benzodiazepine (BZD) derivatives as potent and selective human lysine deacetylase inhibitors (hKDACis). A total of 108 BZD compounds were designed, synthesized and from that 104 compounds were biologically evaluated against human lysine deacetylases (hKDACs) 1, 3 and 8 (class I) and 6 (class IIb). The most active compounds showed mid-nanomolar potencies against hKDACs 1, 3 and 6 and micromolar activity against hKDAC8, while a promising compound (6q) showed selectivity towards hKDAC3 among the different enzyme isoforms. An hKDAC6 homology model, refined by molecular dynamics simulation was generated, and molecular docking studies performed to rationalize the dominant ligand-residue interactions as well as to define structure-activity-relationships. Experimental results confirmed the usefulness of the benzodiazepine moiety as capping group when pursuing hKDAC isoform-selectivity inhibition, suggesting its continued use when designing new hKDACis.


[Mental and behavior disorders in children placed in long term care institutions in Hunedoara, Cluj and Timis, Romania].
This article originated from a descriptive study done in 1992-1993 in Romania. The study was initiated and coordinated by the French NGO "Médecins du Monde", was directed by three health organizations (the "Observatoire régional de la santé de Languedoc-Roussillon", the "Unité 265 INSERM", the Romanian League for Mental Health) and was granted by the Romanian government and the European Community Commission. There are many publications about children's mental and behavioural disorders. But there are few epidemiological studies concerning the prevalence of these disorders among children suffering from social difficulties. This article explores the prevalence of mental and behavioral disorders among Romanian children institutionalized and examines specifically the prevalence among children in homes for children ("Casa de Copii") to compare it with similar data published in other countries. First, this article explores the prevalence of mental and behavioral disorders among a population of 4.692 children institutionalized in three Romanian districts in 1992. Second, this article examines the prevalence of these disorders among a population of 1.610 children institutionalized in homes for children ("Casa de Copii"), i.e. 1,610 children ages ranging from 4 to 18 years and suffering from social difficulties. Homes for children are out of home care institutions which are specialised neither in physical deficiencies nor in mental disorders. From this population, a randomized sample of 508 children has been screened by physicians and psychologists based on an evaluation protocol. Then each disorder has been coded as a diagnosis, according to the Tenth International Disease Classification (WHO). Fifty-four percent (54%) of the children institutionalized in homes for children in three Romanian districts in 1992 had a main diagnosis of mental or behavioural disorder. Third, this article compares our results to the prevalence found in other studies. Only three studies could be selected for comparison because they were the only ones with the three following criteria: 1) a focus on a population of children or a randomized sample of children ages ranging from 4 to 18 years, 2) a focus on children suffering from social difficulties and living in out of home care, 3) disorders evaluated by health professionals or a validated methodology. Our results lies within the range of prevalence found in the literature (41-70%). A discussion follows regarding methodological matters and critiques that may be launched from such a comparative designs. Finally, the high frequency of institutionalization in Romania in 1992 illustrates how few solutions there were to social difficulties and how exaggerated institutionalization was. This was a very different situation compared to Western Europe and Northern America. This should not hide, however, the actual modifications that took place in Romania. This article concludes with a brief description of the modifications which have been generated by the evaluation protocol used here.


Ascending aortic blood flow dynamics following intense exercise.
The purpose of this study was to compare and contrast aortic blood flow kinetics during recovery from intense aerobic (maximal oxygen uptake test) and anaerobic (Wingate anaerobic power test) exercise. Fifteen healthy male subjects (VO2max = 56.1 +/- 5.8 mk/kg/min) participated in this study. Beat-to-beat peak aortic blood flow velocity (pkV) and acceleration (pkA) measurements were obtained by placing a 3.0 MHz continuous-wave ultrasonic transducer on the suprasternal notch at rest and during recovery (immediately post-exercise, 2.5 min, and 5.0 min) following the two exercise conditions. Peak velocity and acceleration significantly increased (p less than 0.01) from rest to immediately post-exercise and remained elevated throughout the 5-min recovery period. No differences were observed between the aerobic and anaerobic tests. Stroke distance significantly declined (p less than 0.01) immediately following exercise and progressively rose during the 5-min recovery period. The results indicate that: 1) aortic blood flow kinetics remained elevated during short-term recovery, and 2) intense aerobic and anaerobic exercise exhibit similar post-exercise aortic blood flow kinetics.


Attention-deficit/hyperactivity disorder and complementary/alternative medicine.
The use of complementary and alternative medicine (CAM) for treatment of attention-deficit/hyperactivity disorder (ADHD) has increased both by parents and health care providers. Despite scientific evidence supporting the effectiveness of stimulants in the treatment of ADHD, the use of stimulants has received negative publicity and, for many parents, is worrisome. Concerns regarding adverse effects and the prospect of long-term use of pharmacologic treatments make many parents uncomfortable thus they seek "alternative treatments." With the information explosion produced by the Internet, marketing for alternative therapies such as herbal remedies, elimination diets, and food supplements for ADHD has increased. Many people use CAM because they are attracted to the CAM philosophies and health beliefs, dissatisfied with the process or results of conventional treatments, or concerned about adverse effects of stimulants. Although some scientific evidence exists regarding some CAM therapies, for most there are key questions regarding safety and efficacy of these treatments in children. The aim of this article is to provide a general overview and focus on the evidence-based studies of CAM modalities that are commonly used for ADHD.


Performance of isobaric and isotopic labeling in quantitative plant proteomics.
Mass spectrometry has become indispensable for peptide and protein quantification in proteomics studies. When proteomics technologies are applied to understand the biology of plants, two-dimensional gel electrophoresis is still the prevalent method for protein fractionation, identification, and quantitation. In the present work, we have used LC-MS to compare an isotopic (ICPL) and isobaric (iTRAQ) chemical labeling technique to quantify proteins in the endosperm of Ricinus communis seeds at three developmental stages (IV, VI, and X). Endosperm proteins of each stage were trypsin-digested in-solution, and the same amount of peptides was labeled with ICPL and iTRAQ tags in two orders (forward and reverse). Each sample was submitted to nanoLC coupled to an LTQ-Orbitrap high-resolution mass spectrometer. Comparing labeling performance, iTRAQ was able to label 99.8% of all identified unique peptides, while 94.1% were labeled by ICPL. After statistical analysis, it was possible to quantify 309 (ICPL) and 321 (iTRAQ) proteins, from which 95 are specific to ICPL, 107 to iTRAQ, and 214 common to both labeling strategies. We noted that the iTRAQ quantification could be influenced by the tag. Even though the efficiency of the iTRAQ and ICPL in protein quantification depends on several parameters, both labeling methods were able to successfully quantify proteins present in the endosperm of castor bean during seed development and, when combined, increase the number of quantified proteins.


Epithelial-myoepithelial carcinoma of the lung. A case report and review of the literature.
Primary lung tumors mimicking the salivary gland-type neoplasms are extremely rare. These types of tumors originate from submucosal bronchial glands. Epithelial-myoepithelial carcinoma is an uncommon tumor in this group, and only 7 cases have been reported. It is considered to be a low-grade malignant neoplasm. We report a case of epithelial-myoepithelial carcinoma of bronchial gland origin in a 73-year-old man who presented with coughing and dyspnea. The bronchus of the left lower lobe contained a tumor mass that had a polypoid growth pattern. The tumor also extended into the pulmonary parenchyma, forming a well-circumscribed mass with a pushing margin. The tumor consisted of epithelial and myoepithelial cells. The epithelial cells were positive for cytokeratins and epithelial membrane antigen, while the myoepithelial cells were positive for S100 protein and muscle-specific actin. According to these findings, we diagnosed epithelial-myoepithelial carcinoma. After undergoing pneumonectomy, the patient has been disease free for 34 months.


Computer-aided classification of small airways dysfunction using impulse oscillometric features: a children-focused review.
Background and objective Spirometry, which is the most commonly used technique for asthma diagnosis, is often unsuitable for small children as it requires them to follow exact instructions and perform extreme inspiration and expiration maneuvers. In contrast, impulse oscillometry (IOS) is a child-friendly technique that could serve as an alternative pulmonary function test (PFT) for asthma diagnosis and control in children as it offers several advantages over spirometry. However, the complex test results of IOS may be difficult to be understood by practitioners due to its reliance on mechanical and electrical models of the human pulmonary system. Recognizing this reality, computer-aided decision systems could help to improve the utility of IOS. The main objective of this paper is to understand the current computer-aided classification research works on this topic. Methods This paper presents a methodological review of research works related to the computer-aided classification of peripheral airway obstruction using the IOS technique, which is focused on, but not limited to, asthmatic children. Publications that focused on computer-aided classification of asthma, peripheral dysfunction and/or small airway impairment (SAI) based on impulse oscillometric features were selected for this review. Results Out of the 34 articles that were identified using the selected scientific web databases and topic-related parameters, only eight met the eligibility criteria. The most relevant results of the articles reviewed are related to the performance of the different classifiers using static features which are solely based on the first pulmonary function testing measurements (IOS and spirometry). These results included an overall classifiers' accuracy performance ranging from 42.24% to 98.61%. Conclusion There is still a great opportunity to improve the utility of IOS by developing more computer-aided robust classifiers, specifically for the asthmatic children population as the classification studies performed to date (1) are limited in number, (2) include features derived from tests that are not optimally suitable for children, (3) are solely bi-class (mostly asthma and non-asthma) and therefore fail to include different degrees of peripheral obstruction for disease prevention and control and (4) lack of validation in cases that focus on multi-class classification of the different degrees of peripheral airway obstruction.


Characteristics of French users of child pornography: description of a cohort subjected to forensic evaluation.
Child pornography is a form of sexual exploitation of children. The virtual aspect of this offence appears to be encouraged by the internet. It is important to know the profiles of the people downloading these images. The aim of our study was to identify the characteristics of people who are drawn to child pornography. Our study was based on psychiatric assessments carried out at the request of the law courts. The feeling of loneliness and poor social integration are evoked by a lot of users of child pornography. Generally, they have no criminal record.


Work-related musculoskeletal complaints in sonologists.
The prevalence of musculoskeletal complaints of the hand and wrist, and the neck and back, in physicians who operate sonography equipment was evaluated, and associations between these complaints and various work-related and personal variables were studied. A questionnaire survey was distributed among physician sonographers (sonologists) in Italy. The relationship between work habits and musculoskeletal complaints was analyzed by logistic regression models adjusted for gender, age, and duration of work with ultrasound. A total of 2041 physician sonographers completed the questionnaire. It was found that a large proportion of the subjects regularly had work-related complaints, such as neck and back pain (NBP) (18.5%) or hand and wrist cumulative trauma disorder (HWD) (5.3%). Roughly 80% of the sonographers were currently affected, or had been affected in the past, by one or more work-related symptoms. Various work-related factors appeared to be related to musculoskeletal syndromes. The average time spent for each examination was related both to NBP and HWD. Discomfort for transducer design was the best predictor of HWD, whereas a comfortable chair and correct position of the body protected from the onset of NBP. These results support the role of ergonomic factors in the pathogenesis of both NBP and HWD in sonographers.


Eyelash Epilation in the Absence of Trichiasis: Results of a Population-Based Prevalence Survey in the Western Division of Fiji.
The WHO definition of trachomatous trichiasis (TT) is "at least one eyelash touching the globe, or evidence of recent epilation of in-turned eyelashes", reflecting the fact that epilation is used as a self-management tool for TT. In Fiji's Western Division, a high TT prevalence (8.7% in those aged ≥15 years) was reported in a 2012 survey, yet a 2013 survey found no TT and Fijian ophthalmologists rarely see TT cases. Local anecdote suggests that eyelash epilation is a common behaviour, even in the absence of trichiasis. Epilators may have been identified as TT cases in previous surveys. We used a preliminary focus group to design an interview questionnaire, and subsequently conducted a population-based prevalence survey to estimate the prevalence of epilation in the absence of trichiasis, and factors associated with this behaviour, in the Western Division of Fiji. We sampled 695 individuals aged ≥15 years from a total of 457 households in 23 villages. 125 participants (18%) reported epilating their eyelashes at least once within the past year. Photographs were obtained of the eyes of 121/125 (97%) individuals who epilated, and subsequent analysis by an experienced trachoma grader found no cases of trachomatous conjunctival scarring or trichiasis. The age- and sex- adjusted prevalence of epilation in those aged ≥15 years was 8.6% (95% CI 5.7-11.3%). iTaukei ethnicity, female gender, and a higher frequency of drinking kava root were independently associated with epilation. Epilation occurs in this population in the absence of trichiasis, with sufficient frequency to have markedly inflated previous estimates of local TT prevalence. Individuals with epilated eyelashes should be confirmed as having epilated in-turned eyelashes in an eye with scarring of the conjunctiva before being counted as cases of TT.


Hospital infection prevention and control: a model for improving the quality of hospital care in low- and middle-income countries.
Continuous quality improvement (CQI) is a powerful methodology for improving clinical outcomes and patient satisfaction while reducing inefficiency and costs. However, most hospitals in low- and middle-income countries have little experience with CQI methods. Hospital infection prevention is an ideal model for nascent efforts to improve the quality of hospital care because of its proven efficacy in reducing the occurrence of infections that compromise patient outcomes and increase costs. This article describes the design and implementation of a demonstration project to reduce the incidence of surgical-site infections (SSIs) for hospitals with little experience with quality-improvement methods. The project has a high likelihood of producing measurable reductions in SSI rates and hospital costs related to inefficient use of perioperative antimicrobial prophylaxis. Moreover, participating staff will gain experience that can be applied to efforts to improve the quality of other aspects of hospital care.


Intraoral schwannoma--a report of two cases.
Schwannomas, also known as neurilemmomas, are uncommon neoplasms, derived from schwann cells. These neoplasms, although rare, should be considered in the differential diagnosis of slow growing tumour masses of the oral cavity. The growth of these tumours sometimes causes displacement and compression of the nerve of origin, giving rise to clinical signs and symptoms. It can develop at any age and there is no sex predilection. Intraorally, the tongue is the most common site followed by the palate, floor of the mouth, buccal mucosa, lips and jaws. Surgical excision is the treatment of choice for schwannomas, with few reports of recurrence or malignant transformation. In this paper, the authors report two cases of patients with intraoral schwannoma, where the preoperative clinical diagnosis was inconclusive and final diagnosis was established based on radiographic and histopathological examination.


Widespread antimicrobial resistance among bacterial infections in a Rwandan referral hospital.
Resistance among bacterial infections is increasingly well-documented in high-income countries; however, relatively little is known about bacterial antimicrobial resistance in low-income countries, where the burden of infections is high. We prospectively screened all adult inpatients at a referral hospital in Rwanda for suspected infection for seven months. Blood, urine, wound and sputum samples were cultured and tested for antibiotic susceptibility. We examined factors associated with resistance and compared hospital outcomes for participants with and without resistant isolates. We screened 19,178 patient-days, and enrolled 647 unique participants with suspected infection. We obtained 942 culture specimens, of which 357 were culture-positive specimens. Of these positive specimens, 155 (43.4%) were wound, 83 (23.2%) urine, 64 (17.9%) blood, and 55 (15.4%) sputum. Gram-negative bacteria comprised 323 (88.7%) of all isolates. Of 241 Gram-negative isolates tested for ceftriaxone, 183 (75.9%) were resistant. Of 92 Gram-negative isolates tested for the extended spectrum beta-lactamase (ESBL) positive phenotype, 66 (71.7%) were ESBL positive phenotype. Transfer from another facility, recent surgery or antibiotic exposure, and hospital-acquired infection were each associated with resistance. Mortality was 19.6% for all enrolled participants. This is the first published prospective hospital-wide antibiogram of multiple specimen types from East Africa with ESBL testing. Our study suggests that low-resource settings with limited and inconsistent access to the full range of antibiotic classes may bear the highest burden of resistant infections. Hospital-acquired infections and recent antibiotic exposure are associated with a high proportion of resistant infections. Efforts to slow the development of resistance and supply effective antibiotics are urgently needed.


Prognostic and clinicopathological significance of systemic immune-inflammation index in pancreatic cancer: a meta-analysis of 2,365 patients.
The prognostic value of the systemic immune-inflammation index (SII) in patients with pancreatic cancer is conflicting according to previous investigations. Therefore, we performed a meta-analysis to explore the association between SII and pancreatic cancer prognosis. Electronic databases were searched for studies exploring the association of SII with prognostic outcomes in pancreatic cancer. The endpoints were overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS), progression-free survival (PFS), cancer-specific survival (CSS), and clinicopathological parameters. The prognostic value of SII was estimated by hazard ratio (HR) or odds ratio (OR) with a 95% confidence interval (CI). Nine studies containing 11 cohorts with 2,365 subjects in total were included in this meta-analysis. Elevated SII was associated with poor OS (HR=1.50, 95% CI=1.15-1.96, p=0.002), RFS/PFS/DFS (HR=1.52, 95% CI=1.01-2.28, p=0.045), and CSS (HR=2.60, 95% CI=1.65-4.09, p < 0.001) in patients with pancreatic cancer. Additionally, there was no significant association between SII and other parameters in pancreatic cancer such as sex, tumor location, lymph node metastasis, tumor-node-metastasis stage, vascular invasion, and grade. This meta-analysis suggested that elevated SII was a significant prognostic marker for short-term and long-term survival outcomes in patients with pancreatic cancer.


Statin therapy reduces plasma endothelin-1 concentrations: A meta-analysis of 15 randomized controlled trials.
Raised plasma endothelin-1 (ET-1) levels may be a risk factor for vascular dysfunction and cardiovascular (CV) disease. This meta-analysis assessed the effect of statins on circulating ET-1 concentrations. The search included PUBMED, Cochrane Library, Web of Science, Scopus, and EMBASE up to September 30, 2014 to identify randomized controlled trials (RCTs) with ET-1 measurement during statin therapy. Quantitative data synthesis was performed using a random-effects model, with weighed mean difference (WMD) and 95% confidence interval (CI) as summary statistics. Data from 15 RCTs showed that statin therapy significantly reduces plasma ET-1 concentrations (WMD: -0.30 pg/mL, 95%CI: -0.47, -0.13; p < 0.01). This effect was robust in sensitivity analysis, and not largely affected by the duration of statin therapy (<12 weeks - WMD: -0.51 pg/mL, 95%CI: -0.89, -0.14, p < 0.01; >12 week -WMD: -0.19 pg/mL, 95%CI: -0.36, -0.02; p < 0.05) or by dose of statins (<40 mg/day - WMD: -0.27 pg/mL, 95%CI: -0.49, -0.05; p = 0.01; >40 mg/day - WMD: -0.38 pg/mL, 95%CI: -0.68, -0.08; p = 0.01). Lipophilic (atorvastatin, simvastatin, fluvastatin, and cerivastatin - WMD: -0.34 pg/mL, 95%CI: -0.55, -0.13; p < 0.01), but not a hydrophilic statin (pravastatin - WMD: -0.18 pg/mL, 95%CI: -0.44 -0.08; p > 0.05) had a significant effect in promoting ET-1 reduction. Statin therapy significantly reduces circulating ET-1 concentrations, regardless of treatment duration or dose of statins. This effect of statins may be influenced by statin lipophilicity. There is a need to establish whether lowering ET-1 levels has a beneficial effect on CV events.


Molecular Dynamics Simulations Elucidate Conformational Dynamics Responsible for the Cyclization Reaction in TEAS.
The Mg-dependent 5-epi-aristolochene synthase from Nicotiana tabacum (called TEAS) could catalyze the linear farnesyl pyrophosphate (FPP) substrate to form bicyclic hydrocarbon 5-epi-aristolochene. The cyclization reaction mechanism of TEAS was proposed based on static crystal structures and quantum chemistry calculations in a few previous studies, but substrate FPP binding kinetics and protein conformational dynamics responsible for the enzymatic catalysis are still unclear. Herein, by elaborative and extensive molecular dynamics simulations, the loop conformation change and several crucial residues promoting the cyclization reaction in TEAS are elucidated. It is found that the unusual noncatalytic NH2-terminal domain is essential to stabilize Helix-K and the adjoining J-K loop of the catalytic COOH-terminal domain. It is also illuminated that the induce-fit J-K/A-C loop dynamics is triggered by Y527 and the optimum substrate binding mode in a "U-shape" conformation. The U-shaped ligand binding pose is maintained well with the cooperative interaction of the three Mg(2+)-containing coordination shell and conserved residue W273. Furthermore, the conserved Arg residue pair R264/R266 and aromatic residue pair Y527/W273, whose spatial orientations are also crucial to promote the closure of the active site to a hydrophobic pocket, as well as to form π-stacking interactions with the ligand, would facilitate the carbocation migration and electrophilic attack involving the catalytic reaction. Our investigation more convincingly proves the greater roles of the protein local conformational dynamics than do hints from the static crystal structure observations. Thus, these findings can act as a guide to new protein engineering strategies on diversifying the sesquiterpene products for drug discovery.


The building bridges initiative: learning with, from and about to create an interprofessional end-of-life program.
In this paper, the authors outline the rationale, planning, delivery, results, evaluation and knowledge transfer strategies employed in offering an eight-hour education day offered 12 times in 2010, to a total of 200 staff in three Toronto General Hospital (TGH) intensive care units (ICU) at the University Health Network (UHN). The integration of members from the point-of-care staff teams into the planning, development, presentation and attendance was a critical success factor for this initiative. Organizers and participants had the opportunity to build bridges with each other and across teams and programs by engaging in interprofessional learning, sharing narratives and consolidating increasing awareness of resources with facilitation from staff from nursing, medicine, palliative care, bioethics, social work, physiotherapy, respiratory therapy, wellness and spiritual care. The format, which will be outlined with examples and stories of engagement, included an opportunity to explore common elements of ICU work including moral distress, demonstrated wellness and team communication strategies, as well as the introduction of an interprofessional patient/family meeting checklist reviewed and evaluated by participants. An assessment of quality of life in an ICU was explored using a panel, case study and discussion. The results of the evaluation, which included a qualitative reflection on collaborative themes, a program evaluation and an individual learning assessment, will be discussed, as well as sustainability and transferability possibilities specific to interprofessional programming and team development.


Problems and Promises of Health Technologies: The Role of Early Health Economic Modeling.
To assess whether early health economic modeling helps to distinguish those healthcare innovations that are potentially cost-effective from those that are not potentially cost-effective. We will also study what information is retrieved from the health economic models to inform further development, research and implementation decisions. We performed secondary analyses on an existing database of 32 health economic modeling assessments of 30 innovations, performed by our group. First, we explored whether the assessments could distinguish innovations with potential cost-effectiveness from innovations without potential cost-effectiveness. Second, we explored which recommendations were made regarding development, implementation and further research of the innovation. Of the 30 innovations, 1 (3%) was an idea that was not yet being developed and 14 (47%) were under development. Eight (27%) innovations had finished development, and another 7 (23%) innovations were on the market. Although all assessments showed that the innovation had the potential to become cost-effective, due to improved patient outcomes, cost savings or both, differences were found in the magnitude of the potential benefits, and the likelihood of reaching this potential. The assessments informed how the innovation could be further developed or positioned to maximize its cost-effectiveness, and informed further research. The early health economic assessments provided insight in the potential cost-effectiveness of an innovation in its intended context, and the associated uncertainty. None of the assessments resulted in a firm 'no-go' recommendation, but recommendations could be provided on further research and development in order to maximize value for money.


Retrovirus transduction: segregation of the viral transforming function and the herpes simplex virus tk gene in infectious Friend spleen focus-forming virus thymidine kinase vectors.
A series of deletions and insertions utilizing the herpesvirus thymidine kinase gene (tk) were constructed in the murine retrovirus Friend spleen focus-forming virus (SFFV). In all cases, the coding region for the SFFV-specific glycoprotein (gp55), which is implicated in erythroleukemic transformation, was left intact. These SFFV-TK and SFFV deletion vectors were analyzed for expression of tk and gp55 after DNA-mediated gene transfer. In addition, virus rescued by cotransfection of these vectors with Moloney murine leukemia virus was analyzed for infectious TK-transducing virus, gp55 expression, and erythroleukemia-inducing ability. The experiments demonstrated that deletions or insertions within the intron for the gp55 env gene can interfere with expression of gp55 after both DNA-mediated gene transfer and virus infection. In contrast, the gene transfer efficiency of the tk gene was unaffected in the SFFV-TK vectors, and high-titer infectious TK virus could be recovered. Revertant viruses capable of inducing erythroleukemia and expressing gp55 were generated after cotransfection of the SFFV-TK vectors with murine leukemia virus. The revertant viruses lost both tk sequences and the ability to transduce TK- fibroblasts to a TK+ phenotype. These experiments demonstrate that segregation of the TK and erythroleukemia functions can occur in retrovirus vectors which initially carry both markers.


An Accurate Quantum Monte Carlo Calculation of the Barrier Height for the Reaction H + H2 rarr H2 + H.
An improved quantum Monte Carlo method has been used to calculate the classical barrier height for the hydrogen exchange reaction H + H(2) --> H(2) + H with accuracies greater than previously attained. The method is exact in that, except for the easily estimated Monte Carlo statistical or sampling error, it requires no mathematical approximations or physical approximations beyond those of the Schrödinger equation. The minimum in the barrier, occurring for the collinear nuclear configuration with the protons separated by 1.757 bohrs, was found to be 9.61 +/- 0.01 kilocalories per mole above H + H(2).


Methaemoglobinaemia after cardiac catheterisation: a rare cause of cyanosis.
Two young women had unexpected cyanosis a few hours after cardiac catheterisation for electrophysiological investigation. The first patient had atrioventricular septal defect, had undergone repeated surgical interventions, and was referred because of atrial flutter. The second patient had ablation of an accessory pathway in Wolff-Parkinson-White syndrome. Local anaesthesia was performed with 40 ml prilocaine 2%. Cyanosis with oxygen saturation of 85% developed in both patients a few hours after the electrophysiological investigation. The patients were transferred to the intensive care unit and for the first patient a considerable diagnostic effort was made to rule out morphological complication. Finally methaemoglobinaemia of 16.7% and 33.4%, respectively, was found. Cyanosis resolved within 24 hours and did not reappear. Underlying glucose-6-phosphate dehydrogenase deficiency and erythrocyte-methaemoglobin reductase deficiency were ruled out. Physicians should be aware of this rare side effect of local anaesthetics in patients with unexpected cyanosis.


Precise Enzymatic Cleavage Sites for Improved Bioactivity of siRNA Lipo-Polyplexes.
Sequence-defined cationic lipo-oligomers are potent siRNA carriers, forming stable lipo-polyplexes based on both electrostatic and hydrophobic interactions and, after endocytosis and endosomal protonation, facilitating the delivery of siRNA into the cytosol. After completion of the nucleic acid delivery process, carriers should be readily biodegradable to ensure minimum accumulation of amphiphilic molecules that are harmful to lysosomes and other intracellular organelles. Endolysosomal enzymes may degrade a surplus of carrier molecules left over in lysosomes and thereby facilitate the generation and rapid excretion of cleavage products. By solid-phase supported synthesis, a library of sequence-defined lipo-oligomers was generated containing artificial and natural amino acids comprising precise enzymatic cleavage sites. Incorporating either short cleavable l-arginine sequences (RR), noncleavable d-arginine linkers (rr), or varieties of both tailored the degradability of lipo-oligomers, as demonstrated upon incubation with the endolysosomal protease cathepsin B. Cleavage products were identified by MALDI-TOF mass spectrometry. The effect of improved intracellular degradation on cell tolerability was studied by transfecting Huh7-eGFPLuc and DU145-eGFPLuc cells. Positioning of enzymatic cleavage sites between a lipophilic diacyl domain and an ionizable oligocationic siRNA binding unit enabled efficient enzymatic degradation of the carrier and reduced the lytic potential under lysosomal conditions. Highly degradable carriers containing at least one l-arginine dipeptide linker significantly improved the viability of transfected cells without hampering gene silencing activity. Therefore, the precise integration of enzymatic cleavage sites in lipo-oligomers is a promising strategy toward biocompatible nucleic acid carriers.


Review: Increasing Awareness and Education on Health Disparities for Health Care Providers.
The focus of this review is to highlight health care disparities and trends in several common diseases in selected populations while offering evidence-based approaches to mitigating health care disparities. Health care disparities cross many barriers and affect multiple populations and diseases. Ethnic minorities, the elderly, and those of lower socioeconomic status (SES) are more at-risk than others. However, many low SES Whites and higher SES racial minorities have poorer health than their racial or SES peers. Also, recent immigrant groups and Hispanics, in particular, maintain high health ratings. The so-called Hispanic Paradox provides an example of how culture and social background can be used to improve health outcomes. These groups have unique determinants of disparity that are based on a wide range of cultural and societal factors. Providing improved access to care and reducing the social determinants of disparity is crucial to improving public health. At the same time, for providers, increasing an understanding of the social determinants promotes better models of individualized care to encourage more equitable care. These approaches include increasing provider education on disparities encountered by different populations, practicing active listening skills, and utilizing a patient's cultural background to promote healthy behaviors.