Missed myocardial infarctions in ED patients prospectively categorized as low risk by established risk scores.
Few studies have prospectively compared multiple cardiac risk prediction scores. We compared the rate of missed acute myocardial infarction (AMI) in chest pain patients prospectively categorized as low risk by unstructured clinical impression, and by HEART, TIMI, GRACE, and EDACS scores, in combination with two negative contemporary cardiac troponins (cTn) available in the U.S. We enrolled 434 patients with chest pain presenting to one of seven emergency departments (ED). Risk scores were prospectively calculated and included the first two cTn. Low risk was defined for each score as HEART≤3, TIMI≤0, GRACE≤50, and EDACS≤15. AMI incidence was calculated for low risk patients and compared across scores using Χ2 tests and C statistics. The patients' median age was 57, 58% were male, 60% white, and 80 (18%) had AMI. The missed AMI rate in low risk patients for each of the scores when combined with 2 cTn were HEART 3.6%, TIMI 0%, GRACE 6.3%, EDACS 0.9%, and unstructured clinical impression 0%. The C-statistic was greatest for the EDACS score, 0.94 (95% CI, 0.92-0.97). Using their recommended cutpoints and non high sensitivity cTn, TIMI and unstructured clinical impression were the only scores with no missed cases of AMI. Using lower cutpoints (GRACE≤48, TIMI=0, EDACS≤11, HEART≤2) missed no case of AMI, but classified less patients as low-risk.


Ectodermal dysplasia with hypodontia in a set of Nigerian twins--a case report.
A set of Nigerian male twins with features of ectodermal dysplasia born to apparently normal parents are presented. The main findings in both children were hypodontia, abnormally shaped teeth and hypotrichosis. The general treatment modalities of the condition, especially in a tropical environment, are discussed.


Synthesis of polyoxometalate clusters using carbohydrates as reducing agents leads to isomer-selection.
By using sugars as the reducing agents, we demonstrate that it is possible to control the self-assembly of polyoxomolybdates through selective preparation of a single heteropolyanion isomer. d-(-)-Fructose has been proved to be an effective reducing sugar compared to the chemically similar carbohydrate d-(+)-glucose. The gentle reduction results in favourable formation of the Wells-Dawson type gamma isomer in 6-fold reduced form at room temperature.


Effects of exercise in normoxia and acute hypoxia on respiratory muscle metabolites.
We determined changes in rat plantaris, diaphragm, and intercostal muscle metabolites following exercise of various intensities and durations, in normoxia and hypoxia (FIO2 = 0.12). Marked alveolar hyperventilation occurred during all exercise conditions, suggesting that respiratory muscle motor activity was high. [ATP] was maintained at rest levels in all muscles during all normoxic and hypoxic exercise bouts, but at the expense of creatine phosphate (CP) in plantaris muscle and diaphragm muscle following brief exercise at maximum O2 uptake (VO2max) in normoxia. In normoxic exercise plantaris [glycogen] fell as exercise exceeded 60% VO2max, and was reduced to less than 50% control during exhaustive endurance exercise (68% VO2max for 54 min and 84% for 38 min). Respiratory muscle [glycogen] was unchanged at VO2max as well as during either type of endurance exercise. Glucose 6-phosphate (G6P) rose consistently during heavy exercise in diaphragm but not in plantaris. With all types of exercise greater than 84% VO2max, lactate concentration ([LA]) in all three muscles rose to the same extent as arterial [LA], except at VO2max, where respiratory muscle [LA] rose to less than half that in arterial blood or plantaris. Exhaustive exercise in hypoxia caused marked hyperventilation and reduced arterial O2 content; glycogen fell in plantaris (20% of control) and in diaphragm (58%) and intercostals (44%). We conclude that respiratory muscle glycogen stores are spared during exhaustive exercise in the face of substantial glycogen utilization in plantaris, even under conditions of extreme hyperventilation and reduced O2 transport. This sparing effect is due primarily to G6P inhibition of glycogen phosphorylase in diaphragm muscle. The presence of elevated [LA] in the absence of glycogen utilization suggests that increased lactate uptake, rather than lactate production, occurred in the respiratory muscles during exhaustive exercise.


The relationship between suicidal behavior and perceived stress: The role of cognitive emotional regulation and problematic alcohol use in Spanish adolescents.
Suicidal behavior has become an important public health problem, correlating with stress and emotional deficits in recent research. This study examined the relationship between perceived stress and suicidal behavior risk, testing the mediating roles of cognitive emotion regulation and impulsivity, and the moderating role of problematic alcohol use in stress-suicidal behavior association in a sample of 121 Spanish adolescents surveyed online. Results showed positive and significant associations between perceived stress and suicidal behavior risk, as well a mediation role of adaptive cognitive emotion regulation strategies and a moderation role of problematic alcohol use between perceived stress and suicidal behavior risk, supporting stress as an influential factor in suicidal behavior. Our findings emphasize adaptive emotional regulation strategies in stressful situations, as well as the importance of promoting responsible alcohol consumption to decrease suicide risk in adolescents. Additionally, they contribute to effective educational suicide prevention programs for young people.


Characterization of active oxygen-producing proteins in response to hypo-osmolarity in tobacco and Arabidopsis cell suspensions: identification of a cell wall peroxidase.
The oxidative response induced by hypo-osmolarity is characterized in tobacco and Arabidopsis cells in order to identify the corresponding active oxygen-producing proteins. The pharmacological profiles of the oxidative responses were clearly different in the two plant materials, leading to the identification of distinct active oxygen producers in tobacco and Arabidopsis cells. In tobacco cells, a 100 kDa protein, localized in the plasma membrane, was demonstrated to produce active oxygen in the presence of NADPH. This production can be activated by fatty acids and is strongly depressed by diphenylene iodonium, as measured by an in vivo response. In Arabidopsis, 30 kDa and 34 kDa proteins localized in the cell wall were shown to be able to produce active oxygen in the presence of cofactors and the production is prevented by peroxidase inhibitors, as is the in vivo response. The two purified proteins were identified by mass spectrometry and both correspond to the peroxidase gene At5g64120.


Working memory supports listening in noise for persons with hearing impairment.
Previous studies have demonstrated a relation between cognitive capacity, in particular working memory, and the ability to understand speech in noise with different types of hearing aid signal processing. The present study investigates the relation between working memory capacity and the speech recognition performance of persons with hearing impairment under both aided and unaided conditions, following a period of familiarization to both fast- and slow-acting compression settings in the participants' own hearing aids. Speech recognition was tested in modulated and steady state noise with fast and slow compression release settings (for aided conditions) with each of two materials. Working memory capacity was also measured. Thirty experienced hearing aid users with a mean age of 70 yr (SD = 7.8) and pure-tone average hearing threshold across the frequencies 0.25, 0.5, 1, 2, 3, 4, and 6 kHz (PTA7) and for both ears of 45.8 dB HL (SD = 6.6. 9 wk experience with each of fast-acting and slow-acting compression. Speech recognition data were analyzed using repeated measures analysis of variance with the within-subjects factors of material (high constraint, low constraint), noise type (steady state, modulated), and compression (fast, slow), and the between-subjects factor working memory capacity (high, low). With high constraint material, there were three-way interactions including noise type and working memory as well as compression, in aided conditions, and performance level, in unaided conditions, but no effects of either working memory or compression with low constraint material. Investigation of simple main effects showed a significant effect of working memory during speech recognition under conditions of both "high degradation" (modulated noise, fast-acting compression, low signal-to-noise ratio [SNR]) and "low degradation" (steady state noise, slow-acting compression, high SNR). The finding of superior performance of persons with high working memory capacity in modulated noise with fast-acting compression agrees with findings of previous studies including a familiarization period of at least 9 wk, in contrast to studies with familiarization of 4 wk or less that have shown that persons with lower cognitive capacity may benefit from slow-acting compression. Working memory is a crucial factor in speech understanding in noise for persons with hearing impairment, irrespective of whether hearing is aided or unaided. Working memory supports speech understanding in noise under conditions of both "high degradation" and "low degradation." A subcomponent view of working memory may contribute to our understanding of these phenomena. The effect of cognition on speech understanding in modulated noise with fast-acting compression may only pertain after a period of 4-9 wk of familiarization and that prior to such a period, persons with lower cognitive capacity may benefit more from slow-acting compression.


[3rd Hungarian Breast Cancer Consensus Conference - Surgery Guidelines].
Therapy for breast cancer today is characterised by ever more precise diagnostic methods and ever more effective oncological treatments, a trend which will certainly continue in the future. Breast preservation and the application of oncoplastic principles are increasingly popular. A sentinel lymph node biopsy in the surgical treatment of the axilla is primary, with the indication for axillary block dissection (ABD) narrowing and radiation therapy becoming an alternative to ABD in certain cases. This publication summarises our recommendations on the surgical treatment of breast cancer based on the content of the 2nd Breast Cancer Consensus Conference and considering the latest international studies and professional recommendations.


A fast universal immobilization of immunoglobulin G at 4 °C for the development of array-based immunoassays.
To maintain the antibody activity and enhance performance of array-based immunoassays, protein G was used to allow a shorter duration of immunoglobulin G immobilization at 4 °C, with the antibody placed in the appropriate orientation. The multiplexed detection of six pain-related message molecules (PRMMs) was used as examples for the development of array-based immunoassays: substance P, calcitonin gene-related peptide, nerve growth factor, brain-derived neurotrophic factor, tumor necrosis factor-α, and β-endorphin. Protein G- and non-protein G-coated slides were tested. Compared to non-protein G immunoassays, protein G shortened the antibody immobilization time at 4 °C from overnight to 2 hours. Only protein G-facilitated immunoassays succeeded in simultaneously detecting all six PRMMs with high specificity. Dose-response curves showed that the limits of detection of the protein G-multiplexed immunoassays for the PRMMs was approximately 164, 167, 120, 60, 80, and 92 pg/ml, respectively. Thus, protein G effectively shortens the duration of antibody immobilization at 4 °C, allowing the use of sensitive array-based immunoassays for the simultaneous detection of PRMMs.


Coordinated effects of microRNA-494 induce G₂/M arrest in human cholangiocarcinoma.
MicroRNA (miRs) have emerged as salient regulators in cancer homeostasis and, recently, as putative therapeutics. Cholangiocarcinomas (CCA) are aggressive cancers with survival usually measured in months. mRNA arrays followed by pathway analysis revealed that miR-494 is a major modulator of the cell cycle progression from gap 2 (G₂) to mitosis (M). We performed fluorescence activated cell sorting (FACS) as well as differential interference contrast (DIC) microscopy, and confirmed that miR-494 induces a significant arrest in G₂/M in CCA cells. Furthermore, we verified that miR-494 modulates the protein level of six genes involved in the G₂/M transition: Polo-like Kinase 1 (PLK1), pituitary tumor-transforming gene 1 (PTTG1), Cyclin B1 (CCNB1), cell-division cycle 2 (CDC2), cell-division cycle 20 (CDC20) and topoisomerase II α (TOP2A). Next, we identified direct binding of miR-494 to the open reading frame (ORF) and downregulation of PTTG1 and TOP2A. In summary, our findings suggest that miR-494 has a global regulatory role in cell cycle progression, exerted by concerted effects on multiple proteins involved in gap 1 (G₁) to synthesis (S), as described previously, as well as G₂ to M progression. Therefore, it appears that the simultaneous effects of a single miR species on multiple targets along the same canonical pathway is advantageous for the usage of miRs as therapeutics. In addition, our data suggest that miRs act within a narrow range. miR expression above the upper threshold does not appear to induce further effects, which is reassuring in terms of off-target effects of miR surrounding noncancerous tissue.


Expression and modulation of p42/p44 MAPKs and cell cycle regulatory proteins in rat pancreas regeneration.
Pancreatic growth occurs after CCK, CCK-induced pancreatitis, and pancreatectomy; the mechanisms involved remain unknown. This study evaluates mitogen-activated protein kinase (MAPK) activation and expression of cell cycle regulatory proteins after pancreatectomy to understand the cellular and molecular mechanisms involved in pancreas regeneration. Rats were killed 1-12 days after pancreatectomy, and p42/p44 MAPK activation, expression of the cyclins D and E, cyclin-dependent kinase (Cdk)-2 activity, retinoblastoma protein (pRb) hyperphosphorylation, and expression of the cyclin kinase inhibitors p15, p21, and p27 were examined. Pancreatic remnants exhibited sustained p42/p44 MAPK activation within 8 h. Cyclins D1 and E showed maximal expression after 2 and 6 days, coinciding with maximal hyperphosphorylation of pRb and Cdk2 activity. The expression of p15 vanished after 12 h, p27 disappeared gradually, and p21 increased early. The p27 complexed with Cdk2 dissociated after 2 days, whereas p21 associated in a reverse fashion. In conclusion, sustained activation of p42/p44 MAPKs and Cdk2 along with overexpression of cyclins D1 and E and reduction of p15 and p27 cyclin inhibitors occurred early after pancreatectomy and are active factors involved in signaling that leads to pancreas regeneration.


Concomitant malignancies in the neck: follicular dendritic cell sarcoma; a rare tumour presenting as a right-sided neck nodal mass and papillary carcinoma thyroid.
Follicular dendritic cell sarcoma is a rare low-grade sarcoma of mesenchymal origin. It involves the lymph nodes more commonly and rarely extranodal sites. The most common lymph node is cervical and usually presents as a painless asymptomatic mass. More often, it is a misdiagnosis, and there is a delay in treatment. It is rarely associated with Castleman disease, myasthenia gravis. Diagnosis of this condition is by histopathology and immunochemistry. Surgery is the primary modality of treatment, and adjuvant therapy has been tried with no definite trials due to the rarity of the disease. Here, we report a case of concomitant follicular dendritic sarcoma of the right cervical lymph node and papillary carcinoma of the thyroid managed in our institute. There was a line of investigations approaching towards a diagnosis, and she underwent total thyroidectomy and right modified radical neck dissection.


Effects of different levels of controlled hypotension on regional cerebral oxygen saturation and postoperative cognitive function in patients undergoing total knee arthroplasty.
Controlled hypotension technique was usually used to reduce intraoperative bleeding, and it could improve visualization of the surgical field during total knee arthroplasty (TKA). However, inappropriate controlled hypotension, through reducing cerebral blood flow or cerebral perfusion pressure, may cause postoperative cognitive dysfunction (POCD), so it is important to identify the appropriate level of controlled hypotension. Objective: To investigate the effects of different levels of controlled hypotension on regional cerebral oxygen saturation and postoperative cognitive function in patients undergoing TKA. Patients meeting inclusion criteria were enrolled through preoperative visits and basic information was obtained. The patients were randomly divided into three groups: Group A, MAP was maintained at 90-100% of the baseline; Group B, MAP was maintained at 80-90% of the baseline; Group C, MAP was maintained at 70-80% of the baseline. The MAP, HR, and rSO2 were observed and recorded during the operation. The C-reactive protein (CRP), hemoglobin (Hb) and MMSE score at 1, 3, and 7 days after operation were recorded. SPSS25.0 was used for data analysis. When the MAP had a decrease among the three groups, rSO2 did not decrease significantly, and none of the patients experienced POCD which was measured by MMSE. And there was no correlation between the decline in rSO2 and that in MAP. No POCD was experienced in the three groups, and we recommend that the controlled hypotensive target indicated by MAP was maintained at 70-80% of the baseline which not only decreases intraoperative bleeding and improve the quality of the surgical field, but also is still within safe levels.


Intracranial hemorrhage in patients with atrial fibrillation receiving anticoagulation therapy.
We investigated the frequency and characteristics of intracranial hemorrhage (ICH), the factors associated with the risk of ICH, and outcomes post-ICH overall and by randomized treatment. We identified patients with ICH from the overall trial population enrolled in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial who received ≥1 dose of the study drug (n = 18 140). ICH was adjudicated by a central committee. Cox regression models were used to identify factors associated with ICH. ICH occurred in 174 patients; most ICH events were spontaneous (71.7%) versus traumatic (28.3%). Apixaban resulted in significantly less ICH (0.33% per year), regardless of type and location, than warfarin (0.80% per year). Independent factors associated with increased risk of ICH were enrollment in Asia or Latin America, older age, prior stroke/transient ischemic attack, and aspirin use at baseline. Among warfarin-treated patients, the median (25th, 75th percentiles) time from most recent international normalized ratio (INR) to ICH was 13 days (6, 21 days). Median INR prior to ICH was 2.6 (2.1, 3.0); 78.5% of patients had a pre-ICH INR <3.0. After ICH, the modified Rankin scale score at discharge was ≥4 in 55.7% of patients, and the overall mortality rate at 30 days was 43.3% with no difference between apixaban- and warfarin-treated patients. ICH occurred at a rate of 0.80% per year with warfarin regardless of INR control and at a rate of 0.33% per year with apixaban and was associated with high short-term morbidity and mortality. This highlights the clinical relevance of reducing ICH by using apixaban rather than warfarin and avoiding concomitant aspirin, especially in patients of older age. This trial was registered at www.clinicaltrials.gov as #NCT00412984.


Does cerebellar injury in premature infants contribute to the high prevalence of long-term cognitive, learning, and behavioral disability in survivors?
Although cerebellar hemorrhagic injury is increasingly diagnosed in infants who survive premature birth, its long-term neurodevelopmental impact is poorly defined. We sought to delineate the potential role of cerebellar hemorrhagic injury in the long-term disabilities of survivors of prematurity. We compared neurodevelopmental outcome in 3 groups of premature infants (N = 86; 35 isolated cerebellar hemorrhagic injury, 35 age-matched controls, 16 cerebellar hemorrhagic injury plus supratentorial parenchymal injury). Subjects underwent formal neurologic examinations and a battery of standardized developmental, functional, and behavioral evaluations (mean age: 32.1 +/- 11.1 months). Autism-screening questionnaires were completed. Neurologic abnormalities were present in 66% of the isolated cerebellar hemorrhagic injury cases compared with 5% of the infants in the control group. Infants with isolated cerebellar hemorrhagic injury versus controls had significantly lower mean scores on all tested measures, including severe motor disabilities (48% vs 0%), expressive language (42% vs 0%), delayed receptive language (37% vs 0%), and cognitive deficits (40% vs 0%). Isolated cerebellar hemorrhagic injury was significantly associated with severe functional limitations in day-to-day activities. Significant differences were noted between cases of cerebellar hemorrhagic injury versus controls on autism screeners (37% vs 0%) and internalizing behavioral problems (34% vs 9%). Global developmental, functional, and social-behavioral deficits were more common and profound in preterm infants with injury to the vermis. Preterm infants with cerebellar hemorrhagic injury and supratentorial parenchymal injury were not at overall greater risk for neurodevelopmental disabilities, although neuromotor impairment was more severe. Cerebellar hemorrhagic injury in preterm infants is associated with a high prevalence of long-term pervasive neurodevelopment disabilities and may play an important and underrecognized role in the cognitive, learning, and behavioral dysfunction known to affect survivors.


Structural implications into dsRNA binding and RNA silencing suppression by NS3 protein of Rice Hoja Blanca Tenuivirus.
Rice Hoja Blanca Tenuivirus (RHBV), a negative strand RNA virus, has been identified to infect rice and is widely transmitted by the insect vector. NS3 protein encoded by RHBV RNA3 was reported to be a potent RNAi suppressor to counterdefense RNA silencing in plants, insect cells, and mammalian cells. Here, we report the crystal structure of the N-terminal domain of RHBV NS3 (residues 21-114) at 2.0 Å. RHBV NS3 N-terminal domain forms a dimer by two pairs of α-helices in an anti-parallel mode, with one surface harboring a shallow groove at the dimension of 20 Å × 30 Å for putative dsRNA binding. In vitro RNA binding assay and RNA silencing suppression assay have demonstrated that the structural conserved residues located along this shallow groove, such as Arg50, His51, Lys77, and His85, participate in dsRNA binding and RNA silencing suppression. Our results provide the initial structural implications in understanding the RNAi suppression mechanism by RHBV NS3.


Cadherin sequences that inhibit beta-catenin signaling: a study in yeast and mammalian cells.
Drosophila Armadillo and its mammalian homologue beta-catenin are scaffolding proteins involved in the assembly of multiprotein complexes with diverse biological roles. They mediate adherens junction assembly, thus determining tissue architecture, and also transduce Wnt/Wingless intercellular signals, which regulate embryonic cell fates and, if inappropriately activated, contribute to tumorigenesis. To learn more about Armadillo/beta-catenin's scaffolding function, we examined in detail its interaction with one of its protein targets, cadherin. We utilized two assay systems: the yeast two-hybrid system to study cadherin binding in the absence of Armadillo/beta-catenin's other protein partners, and mammalian cells where interactions were assessed in their presence. We found that segments of the cadherin cytoplasmic tail as small as 23 amino acids bind Armadillo or beta-catenin in yeast, whereas a slightly longer region is required for binding in mammalian cells. We used mutagenesis to identify critical amino acids required for cadherin interaction with Armadillo/beta-catenin. Expression of such short cadherin sequences in mammalian cells did not affect adherens junctions but effectively inhibited beta-catenin-mediated signaling. This suggests that the interaction between beta-catenin and T cell factor family transcription factors is a sensitive target for disruption, making the use of analogues of these cadherin derivatives a potentially useful means to suppress tumor progression.


Probing the anticancer mechanism of prospective herbal drug Withaferin A on mammals: a case study on human and bovine proteasomes.
The UPP (ubiquitin proteasome pathway) is the major proteolytic system in the cytosol and nucleus of all eukaryotic cells which regulates cellular events, including mitotis, differentiation, signal transduction, apoptosis, and inflammation. UPP controls activation of the transcriptional factor NF-κB (nuclear factor κB), which is a regulatory protein playing central role in a variety of cellular processes including immune and inflammatory responses, apoptosis, and cellular proliferation. Since the primary interaction of proteasomes occurs with endogenous proteins, the signalling action of transcription factor NF-κB can be blocked by inhibition of proteasomes. A great variety of natural and synthetic chemical compounds classified as peptide aldehydes, peptide boronates, nonpeptide inhibitors, peptide vinyl sulfones and epoxyketones are now widely used as research tools for probing their potential to inhibit proteolytic activities of different proteasomes and to investigate the underlying inhibition mechanisms. The present work reports a bio-computational study carried out with the aim of exploring the proteasome inhibition capability of WA (withaferin A), a steroidal lactone, by understanding the binding mode of WA as a ligand into the mammalian proteasomes (X-ray crystal structure of Bos taurus 20S proteasome and multiple template homology modelled structure of 20S proteasome of Homo sapiens) using molecular docking and molecular dynamics simulation studies. One possible mode of action which is proposed here for WA to act as a proteasome inhibitor is by suppression of the proteolytic activity which depends on the N-terminal threonine (Thr1) residue hydroxyl group. Docking studies carried out with herbal ligand WA into the structures of bovine and human proteasomes substantiate that WA has the ability to inhibit activity of mammalian 20S proteasomes by blocking the nucleophilic function of N-terminal Thr1. Results from molecular dynamics simulations in water show that the trajectories of both the native human 20S proteasome and the proteasome complexed with WA are stable over a considerably long time period of 4 ns suggesting the dynamic structural stability of human 20S proteasome/WA complex. Inhibition of proteasomal activity are promising ways to retard or block degradation of specific proteins to correct diverse pathologies. Though quite a number of selective and efficient proteasomal inhibitors exist nowadays, their toxic side effects limit their potential in possible disease treatment. Thus there is an indispensable need for exploration of novel natural products as antitumor drug candidates. The present work supports the mammalian proteasomes inhibiting activity of WA along with elucidation of its possible mode of action. Since WA is a small herbal molecule, it is expected to provide one of the modest modes of inhibition along with added favours of ease in oral administration and decreased immunogenicity. The molecular docking results suggest that WA can inhibit the mammalian proteasomes irreversibly and with a high rate through acylation of the N-terminal Thr1 of the β-5 subunit.


Transport of treosulfan and temozolomide across an in-vitro blood-brain barrier model.
In vitro, treosulfan (TREO) has shown high effectiveness against malignant gliomas. However, a first clinical trial for newly diagnosed glioblastoma did not show any positive effect. Even though dosing and timing might have been the reasons for this failure, it might also be that TREO does not reach the brain in sufficient amount. Surprisingly, there are no published data on TREO uptake into the brain of patients, despite extensive research on this compound. An in-vitro blood-brain barrier (BBB) model consisting of primary porcine brain capillary endothelial cells was used to determine the transport of TREO across the cell monolayer. Temozolomide (TMZ), the most widely used cytotoxic drug for malignant gliomas, served as a reference. An HPLC-ESI-MS/MS procedure was developed to detect TREO and TMZ in cell culture medium. Parallel to the experimental approach, the permeability of TREO and the reference substance across the in-vitro BBB was estimated on the basis of their physicochemical properties. The detection limit was 30 nmol/l for TREO and 10 nmol/l for TMZ. Drug transport was measured in two directions: influx, apical-to-basolateral (A-to-B), and efflux, basolateral-to-apical (B-to-A). For TREO, the A-to-B permeability was lower (1.6%) than the B-to-A permeability (3.0%). This was in contrast to TMZ, which had higher A-to-B (13.1%) than B-to-A (7.2%) permeability values. The in-vitro BBB model applied simulated the human BBB properly for TMZ. It is, therefore, reasonable to assume that the values for TREO are also meaningful. Considering the lack of noninvasive, significant alternative methods to study transport across the BBB, the porcine brain capillary endothelial cell model was efficient to collect first data for TREO that explain the disappointing clinical results for this drug against cerebral tumors.


Healthcare waste management during disasters and its effects on climate change: Lessons from 2010 earthquake and cholera tragedies in Haiti.
Despite growing effects of human activities on climate change throughout the world, and global South in particular, scientists are yet to understand how poor healthcare waste management practices in an emergency influences the climate change. This article presents new findings on climate change risks of healthcare waste disposal during and after the 2010 earthquake and cholera disasters in Haiti. The researchers analysed quantities of healthcare waste incinerated by the United Nations Mission in Haiti for 60 months (2009 to 2013). The aim was to determine the relationship between healthcare waste incinerated weights and the time of occurrence of the two disasters, and associated climate change effects, if any. Pearson product-moment correlation coefficient indicated a weak correlation between the quantities of healthcare waste disposed of and the time of occurrence of the actual emergencies (r (58) = 0.406, p = 0.001). Correspondingly, linear regression analysis indicated a relatively linear data trend (R2 = 0.16, F (1, 58) = 11.42, P = 0.001) with fluctuating scenarios that depicted a sharp rise in 2012, and time series model showed monthly and yearly variations within 60 months. Given that the peak healthcare waste incineration occurred 2 years after the 2010 disasters, points at the need to minimise wastage on pharmaceuticals by improving logistics management. The Government of Haiti had no data on healthcare waste disposal and practised smoky open burning, thus a need for capacity building on green healthcare waste management technologies for effective climate change mitigation.


[Hemodynamic and anti-ischemic effects of moexipril in patients having postinfarction heart dysfunction and moderate left ventricular heart failure].
The purpose of the study was to evaluate hemodynamic and anti-ischemic effects of moexipril in patients with postinfarction left ventricular dysfunction (PL VD) and moderate left ventricular heart failure (NYHA functional class II-III). The subjects of the study were 21 male patients (aged 52.4 +/- 1.1 years) with CHD and PLVD, related to old large-focal anterior myocardial Q-wave infarction. 4-week treatment with ACF-inhibitor moexipril in an average dose of 10.7 +/- 0.4 mg per day clinically improved the patients' condition, which was characterized by 32.2% reduction of stenocardia attack frequency (p < 0.01) and 36.4% decrease in nitroglycerin demand (p < 0.01). Activity tolerance increased by 39.2% (p < 0.001), and echoCG found a 16.5% increase of LV ejection fraction (p < 0.05). Conjunctival biomicroscopy showed that moexipril substantially improved microcirculation (MC); total conjunctival index significantly decreased by 21.7%. The results of the 4-week moexipril administration demonstrate hemodynamic and anti-ischemic effects of the new ACF inhibitor, its positive influence on transcapillary oxygen exchange and MC in patients with PLVD, associated with NYHA functional class II-III heart failure.


Vesicular stomatitis virus growth in Drosophila melanogaster cells. II. Modifications of viral protein phosphorylation.
The phosphoproteins of vesicular stomatitis virus released from infected Drosophila melanogaster cells were examined. The membrane (M) protein was more phosphorylated than after multiplication in chicken embryo cells, even in Drosophila cell cytoplasm before its association with cellular membranes. Analysis of phosphopeptides generated after partial proteolysis and of phosphoamino acids obtained after complete acid hydrolysis showed that M phosphorylation was quantitatively and qualitatively changed, while NS protein phosphorylation was only slightly modified.


How to track and assess genotyping errors in population genetics studies.
Genotyping errors occur when the genotype determined after molecular analysis does not correspond to the real genotype of the individual under consideration. Virtually every genetic data set includes some erroneous genotypes, but genotyping errors remain a taboo subject in population genetics, even though they might greatly bias the final conclusions, especially for studies based on individual identification. Here, we consider four case studies representing a large variety of population genetics investigations differing in their sampling strategies (noninvasive or traditional), in the type of organism studied (plant or animal) and the molecular markers used [microsatellites or amplified fragment length polymorphisms (AFLPs)]. In these data sets, the estimated genotyping error rate ranges from 0.8% for microsatellite loci from bear tissues to 2.6% for AFLP loci from dwarf birch leaves. Main sources of errors were allelic dropouts for microsatellites and differences in peak intensities for AFLPs, but in both cases human factors were non-negligible error generators. Therefore, tracking genotyping errors and identifying their causes are necessary to clean up the data sets and validate the final results according to the precision required. In addition, we propose the outline of a protocol designed to limit and quantify genotyping errors at each step of the genotyping process. In particular, we recommend (i) several efficient precautions to prevent contaminations and technical artefacts; (ii) systematic use of blind samples and automation; (iii) experience and rigor for laboratory work and scoring; and (iv) systematic reporting of the error rate in population genetics studies.


Zika Virus-associated Ocular and Neurologic Disorders: The Emergence of New Evidence.
It has been approximately 70 years since the discovery of the Zika virus (ZIKV). It had been established that the virus causes mild infections and is confined to Africa and Asia; however, major changes in the clinical and epidemiologic patterns of ZIKV infection have occurred in recent years. The virus has attracted intense interest because of the possible association of several autoimmune and neurodevelopmental disorders. We present a summary of the articles that attempt to explain the ZIKV unknowns and strengthen the association with some disorders that are thought to be related to ZIKV, by describing the discovery milestones from the initial identification of the virus to the present day. New evidence strengthens the association between ZIKV infections and Guillain-Barré syndrome (GBS), microcephaly and various neurodevelopmental and ophthalmologic disorders as a result of numerous new clinical and experimental studies. The World Health Organization declared the end of the "Public Health Emergency of International Concern" in December 2016, but ZIKV and associated consequences remain a significant enduring public health challenge.


An Investigation of Processes for Glass Micromachining.
This paper presents processes for glass micromachining, including sandblast, wet etching, reactive ion etching (RIE), and glass reflow techniques. The advantages as well as disadvantages of each method are presented and discussed in light of the experiments. Sandblast and wet etching techniques are simple processes but face difficulties in small and high-aspect-ratio structures. A sandblasted 2 cm × 2 cm Tempax glass wafer with an etching depth of approximately 150 µm is demonstrated. The Tempax glass structure with an etching depth and sides of approximately 20 μm was observed via the wet etching process. The most important aspect of this work was to develop RIE and glass reflow techniques. The current challenges of these methods are addressed here. Deep Tempax glass pillars having a smooth surface, vertical shapes, and a high aspect ratio of 10 with 1-μm-diameter glass pillars, a 2-μm pitch, and a 10-μm etched depth were achieved via the RIE technique. Through-silicon wafer interconnects, embedded inside the Tempax glass, are successfully demonstrated via the glass reflow technique. Glass reflow into large cavities (larger than 100 μm), a micro-trench (0.8-μm wide trench), and a micro-capillary (1-μm diameter) are investigated. An additional optimization of process flow was performed for glass penetration into micro-scale patterns.


No longer an innocent bystander: epithelial toll-like receptor signaling in the development of mucosal inflammation.
Diseases of mucosal inflammation represent important causes of morbidity and mortality, and have led to intense research efforts to understand the factors that lead to their development. It is well accepted that a breakdown of the normally impermeant epithelial barrier of the intestine, the lung, and the kidney is associated with the development of inflammatory disease in these organs, yet significant controversy exists as to how this breakdown actually occurs, and how such a breakdown may lead to inflammation. In this regard, much work has focused upon the role of the epithelium as an "innocent bystander," a target of a leukocyte-mediated inflammatory cascade that leads to its destruction in the mucosal inflammatory process. However, recent evidence from a variety of laboratories indicates that the epithelium is not merely a passive component in the steps that lead to mucosal inflammation, but is a central participant in the process. In addressing this controversy, we and others have determined that epithelial cells express Toll-like receptors (TLRs) of the innate immune system, and that activation of TLRs by endogenous and exogenous ligands may play a central role in determining the balance between a state of "mucosal homeostasis," as is required for optimal organ function, and "mucosal injury," leading to mucosal inflammation and barrier breakdown. In particular, activation of TLRs within intestinal epithelial cells leads to the development of cellular injury and impairment in mucosal repair in the pathogenesis of intestinal inflammation, while activation of TLRs in the lung and kidney may participate in the development of pneumonitis and nephritis respectively. Recent work in support of these concepts is extensively reviewed, while essential areas of further study that are required to determine the significance of epithelial TLR signaling during states of health and disease are outlined.


Dynamic physiological and molecular changes in gastric ulcer healing achieved by melatonin and its precursor L-tryptophan in rats.
Following induction of gastric ulcer in rats by serosal application of acetic acid, local mucosal necrosis ensues accompanied by a reduction in mucosal microcirculation and by almost immediate expression of inducible nitric oxide (NO) synthase (iNOS) and proinflammatory cytokines. Daily application of melatonin (20 mg/kg) or l-tryptophan (100 mg/kg) accelerates ulcer healing by affecting the cyclooxygenase-2 (COX-2)-prostaglandin (PG) system with excessive production of protective PG, especially in later period of ulcer healing. Furthermore, expression of hypoxia inducible factor, vascular-endothelial growth factor, an activation of cNOS-NO system and the stimulation of sensory nerves with the expression and release of calcitonin gene related peptide (CGRP) appear to aid the restoration of mucosal repair and microcirculation in the ulcer bed. The enhanced expression of the melatonin MT(2) receptors (MT(2)-R) combined with overexpression of key enzymes involved in biosynthesis of melatonin such as N-acetyltransferase and hydroxyindole-O-methyltransferase contribute to the acceleration of ulcer healing by this indole. Melatonin-induced acceleration of ulcer healing is also mediated by release of gastrin and ghrelin, the most potent stimulants of gastric mucosal cell proliferation and mucosal repair. These sequential steps in ulcer healing accelerated by melatonin can be interfered with by the blockade of MT(2)R, COX-2/PG and cNOS/NO systems, and by reduction in the inflammatory iNOS/NO system. Thus, melatonin and its precursor l-tryptophan, trigger the cascade of molecular events leading to the functional improvement in ulcer healing.


Emotional conditioning to masked stimuli: expectancies for aversive outcomes following nonrecognized fear-relevant stimuli.
The role of conscious awareness in human Pavlovian conditioning was examined in 2 experiments using masked fear-relevant (snakes and spiders; Experiments 1 and 2) and fear-irrelevant (flowers and mushrooms; Experiment 1) pictures as conditioned stimuli, a mild electric shock as the unconditioned stimulus, and skin conductance responses as the primary dependent variable. The conditioned stimuli were presented briefly (30 ms) and were effectively masked by an immediately following masking stimulus. Experiment 1 demonstrated nonconscious conditioning to fear-relevant but not to fear-irrelevant stimuli. Even though the participants could not recognize the stimuli in Experiment 2, they differentiated between masked stimuli predicting and not predicting shocks in expectancy ratings. However, expectancy ratings were not related to the conditioned autonomic response.


Practical methods using boronic acid compounds for identification of class C beta-lactamase-producing Klebsiella pneumoniae and Escherichia coli.
Detection of the resistance mediated by class C beta-lactamases remains a challenging issue, considering that transferable plasmid-mediated class C beta-lactamases are of worldwide concern. Methods for the identification of strains that produce extended-spectrum beta-lactamases (ESBLs) or metallo-beta-lactamases (MBLs) have been developed and applied for routine use in clinical microbiology laboratories, but no practical methods for identification of plasmid-mediated class C producers have been established to date. We therefore developed three simple methods for clinical microbiology laboratories that allow identification of plasmid-mediated class C beta-lactamase-producing bacteria using a boronic acid derivative, 3-aminophenylboronic acid (APB), one of the specific inhibitors of class C beta-lactamases. Detection by the disk potentiation test was based on the enlargement of the growth-inhibitory zone diameter (by greater than or equal to 5 mm) around a Kirby-Bauer disk containing a ceftazidime (CAZ) or a cefotaxime (CTX) disk in combination with APB. In a double-disk synergy test, the discernible expansion of the growth-inhibitory zone around the CAZ or the CTX disk toward a disk containing APB was indicative of class C beta-lactamase production. A greater than or equal to eightfold decrease in the MIC of CAZ or CTX in the presence of APB was the criterion for detection in the microdilution test. By using these methods, Escherichia coli and Klebsiella pneumoniae isolates producing plasmid-mediated class C beta-lactamases, ACT-1, CMY-2, CMY-9, FOX-5, LAT-1, and MOX-1, were successfully distinguished from those producing other classes of beta-lactamases, such as ESBLs and MBLs. These methods will provide useful information needed for targeted antimicrobial therapy and better infection control.


The expression of viral and cellular genes in papillomas of the choroid plexus induced in transgenic mice.
A line of transgenic mice that carry the SV40 gene for the large Tumor antigen express this protein during the first two weeks of life in brain tissue. By 30-40 days after birth, independently derived multiple foci of abnormal cells appear throughout the choroid plexus. After 90 days, higher levels of T antigen and rapid tumor growth are detected and all these animals die in a narrow time span, between 100-120 days. In situ hybridization with tissue sections and Northern blot analysis have been employed to follow the steady state levels of SV40 RNA and the p53 oncogene RNA levels in normal and tumor tissues. The level of SV40 RNA is quite variable between tumor cells in a section. This heterogeneity of T antigen mRNA levels could permit the selection of cells (from the multiple foci) expressing higher levels of T antigen and growing more rapidly. The increased levels of p53 RNA observed in tumor cells could then result from the active growth state of these cells or a more direct transcriptional activation. Two cellular genes, transthyretin and the 5-HT1C serotonin receptor, both of which are preferentially expressed in normal choroid plexus cells, were also examined for RNA production in these tumors of the choroid plexus. Both of these genes produced high levels of RNA in tumor tissue indicating the retention of well differentiated gene expression in these tumor tissues. This reflects, at the level of gene expression, the well differentiated morphology of these papillomas of the choroid plexus. Interestingly, as cell lines have been derived from these tumors, both the choroid plexus specific RNA species (for 5-HT1C receptor) and characteristic morphology were lost and an increase in T antigen levels was observed.


A comparison of infarct mass by cardiac magnetic resonance and real time myocardial perfusion echocardiography as predictors of major adverse cardiac events following reperfusion for ST elevation myocardial infarction.
Infarct mass as assessed by myocardial-delayed enhancement imaging on cardiac magnetic resonance (CMR) and myocardial blood flow as assessed by real time myocardial perfusion echocardiography (RT-MPE) have been shown to predict adverse events following ST elevation myocardial infarction (STEMI). There has been no published comparison of quantitative assessment using these modalities as predictors of clinical outcomes to date. We compared RT-MPE with CMR for prediction of cardiac events in reperfused STEMI patients. Consecutive STEMI patients with early reperfusion were studied. RT-MPE and CMR were performed. Perfusion score indices (PSIRT-MPE and PSICMR ) were calculated [sum of segmental perfusion scores/number of segments]. CMR infarct mass (g) and RT-MPE myocardial blood flow (MBF dB/s) were quantified. Patients were followed for cardiac events (death, nonfatal MI, revascularization, angina, and heart failure). All 27 patients (age 62±14; follow-up 3.5±2.6 years) had thrombolysis in myocardial infarction (TIMI) grade 3 flow of infarct vessel. Cardiac events occurred in 17 (63%). Cardiac event patients had higher PSIRT-MPE , PSICMR , infarct mass, and lower MBF. PSIRT-MPE cutoff of 0.3 had an AUC of 0.856 (82% sensitivity, 70% specificity), while a PSICMR cutoff of 0.2 had an AUC of 0.765 (76% sensitivity, 60% specificity). Infarct mass and MBF were independent predictors of cardiac events after adjusting for risk factors (hazard ratios: 20.9 [95% CI 1.8-256] P=.02 and 8.1 [95% CI 1.5-78] P=.01, respectively). Quantitative RT-MPE performed comparably to CMR for prediction of MACE in STEMI patients supporting a prognostic role for this noninvasive, bedside imaging method.


OKN-Fast: Objective visual acuity threshold measurement using the optokinetic response.
Visual acuity (VA) is the gold-standard measure for the assessment of visual function, but it is challenging to obtain in non-verbal adults and young children. We present OKN-Fast, an objective, automated method for estimation of VA using a reflexive eye movement called optokinetic nystagmus (OKN) that does not require a verbal response from the patient (VA-OKN). We tested the method in a cohort of healthy adults (n=12) with good vision, who were also blurred using a lens. On average OKN-Fast reduced the number of trials needed to determine threshold by half, as compared to a gold standard trial-by-trial assessment. The VAs determined by OKN and ETDRS were similar when blurred (no statistically significant difference). However, a significant bias of logMAR 0.2 was observed for the good vision condition. VA-OKN was highly repeatable with limits of agreement (LOA) similar to those found for ETDRS charts when blurred. However, this VA-OKN was only moderately correlated with VA measured using a ETDRS chart (r2 = 0.55). These results suggest that further optimization is warranted.Clinical Relevance- This work provides an automated approach for the estimation of visual acuity in non-verbal populations such as young children or non-verbal adults.


Prognostic role of on-line vectorcardiography as regards repeat revascularization after successful coronary angioplasty.
This study evaluated the prognostic significance of continuous on-line vectorcardiography (VCG) during elective coronary angioplasty (percutaneous transluminal coronary angioplasty, PTCA). Patients (n = 192, mean age 58 +/- 10), treated with elective and initially successful PTCA, were included. VCG monitoring was started before start of the PTCA procedure and was carried out during the entire procedure. ST vector magnitude (ST-VM) was monitored. A 6-month follow-up was obtained. Main outcome measures were the frequency of cardiac events and revascularization during follow-up. During follow-up, 1 patient died, 6 suffered a nonfatal myocardial infarction and 50 were revascularized. Angiography revealed restenosis in 88% of the patients who had a revascularization. In the total patient group, the VCG predictor of revascularization was the total ischemic time of all ST-VM episodes (p = 0.05). Clinical predictors of revascularization were diabetes mellitus (p < 0.01), a more severe type of lesion (type B; p < 0.01), percent post-PTCA stenosis (p < 0.05), nominal balloon size (p < 0.01), maximum balloon pressure (p < 0.05) and no stent implanted (p < 0.001). In a multivariate analysis all the above significant univariate variables of revascularization were entered. Total ischemic time of ST-VM (p < 0.01) was the best variable giving independent prognostic information. In the nonstent group, total ischemic time of ST-VM (p < 0.01) was the only independent predictor of a further revascularization. In conclusion, VCG monitoring during elective PTCA gives on-line information that identifies patients at an increased risk of a revascularization during 6 months after the initial procedure.


The management of iron deficiency in inflammatory bowel disease--an online tool developed by the RAND/UCLA appropriateness method.
Iron deficiency is a common and undertreated problem in inflammatory bowel disease (IBD). To develop an online tool to support treatment choice at the patient-specific level. Using the RAND/UCLA Appropriateness Method (RUAM), a European expert panel assessed the appropriateness of treatment regimens for a variety of clinical scenarios in patients with non-anaemic iron deficiency (NAID) and iron deficiency anaemia (IDA). Treatment options included adjustment of IBD medication only, oral iron supplementation, high-/low-dose intravenous (IV) regimens, IV iron plus erythropoietin-stimulating agent (ESA), and blood transfusion. The panel process consisted of two individual rating rounds (1148 treatment indications; 9-point scale) and three plenary discussion meetings. The panel reached agreement on 71% of treatment indications. 'No treatment' was never considered appropriate, and repeat treatment after previous failure was generally discouraged. For 98% of scenarios, at least one treatment was appropriate. Adjustment of IBD medication was deemed appropriate in all patients with active disease. Use of oral iron was mainly considered an option in NAID and mildly anaemic patients without disease activity. IV regimens were often judged appropriate, with high-dose IV iron being the preferred option in 77% of IDA scenarios. Blood transfusion and IV+ESA were indicated in exceptional cases only. The RUAM revealed high agreement amongst experts on the management of iron deficiency in patients with IBD. High-dose IV iron was more often considered appropriate than other options. To facilitate dissemination of the recommendations, panel outcomes were embedded in an online tool, accessible via http://ferroscope.com/.


Aglycosylation and disposition of doxorubicin in isolated rat liver nuclei and microsomes.
Although the chromatographic profile of fluorescent metabolites of doxorubicin was indistinguishable from that generated with microsomes, the rate of aglycosylation of the drug by isolated nuclei was substantially slower. Whereas microsomes consumed 90% of the doxorubicin, nuclei failed to metabolize more than 25% of the drug, even at extended incubation times. A time-dependent decrease in total measurable fluorescence recovered in butanol extracts of microsomes was accompanied by a progressive increase in drug associated with the residual pellet, suggesting the accumulation of metabolic adducts. In contrast, a large portion of the drug-related fluorescence was not extracted in butanol from nuclear reactions at all times examined, which may reflect the rapid partitioning of unmetabolized doxorubicin into nuclear DNA. The time-dependent decrease in fluorescence recovered from the reaction mixtures was dependent on metabolism and correlated with the appearance of drug-related color in the acid-insoluble precipitate following anaerobic incubation of nuclei or microsomes. The data indicate that, mechanistically, the anaerobic aglycosylation of doxorubicin by isolated nuclei resembles that catalyzed by microsomes. However, a major distinction is the association of a large portion of the drug with acid-soluble components of isolated nuclei which may restrict the accessibility of doxorubicin to the nuclear drug-metabolizing enzymes.


Use of an inducible promoter for antibiotic production in a heterologous host.
The biosynthetic gene cluster of the aminocoumarin antibiotic novobiocin comprises 20 coding sequences. Sixteen of them code for essential enzymes for novobiocin formation, transcribed in the form of a single 18-kb polycistronic mRNA. In the present study, we replaced the genuine promoter of this operon by the tetracycline-inducible promoter tcp830 and at the same time deleting the two pathway-specific positive regulator genes of novobiocin biosynthesis. The heterologous producer Streptomyces coelicolor M512 harboring the modified gene cluster produced, upon addition of 2 mg L(-1) of the inducer compound anhydrotetracyline, 3.4-fold more novobiocin than strains carrying the unmodified cluster. A second tcp830 promoter was inserted in the middle of the 18-kb operon in order to ensure adequate transcription of the rearmost genes. However, this did not lead to a further increase of novobiocin formation, showing that a single tcp830 promoter was sufficient to achieve high transcription of all 16 genes of the operon. A high induction of novobiocin formation was achieved within a wide range of anhydrotetracyline concentrations (0.25-2.0 mg L(-1)). Growth of the strains was not affected by these concentrations. The inducer compound could be added either at the time of inoculation or at any other time up to mid-growth phase, always achieving a similar final antibiotic production. Therefore, the tcp830 promoter presents a robust, easy-to-use system for the inducible expression of biosynthetic gene clusters in heterologous hosts, independent from the genuine regulatory network.


RGS13 acts as a nuclear repressor of CREB.
Cyclic AMP-induced phosphorylation of the transcription factor CREB elicits expression of genes mediating diverse biological functions. In lymphoid organs, the neurotransmitter norepinephrine stimulates beta(2)-adrenergic receptors on B lymphocytes to promote CREB-dependent expression of genes like the B cell Oct 2 coactivator (OCA-B). Although CREB phosphorylation recruits cofactors such as CBP/p300 to stimulate transcription, bona fide endogenous inhibitors of CREB-coactivator or CREB-DNA interactions have not emerged. Here, we identified RGS13, a member of the Regulator of G protein Signaling (RGS) protein family, as a nuclear factor that suppresses CREB-mediated gene expression. cAMP or Ca(2+) signaling promoted RGS13 accumulation in the nucleus, where it formed a complex with phosphorylated CREB and CBP/p300. RGS13 reduced the apparent affinity of pCREB for both the CRE and CBP. B lymphocytes from Rgs13(-/-) mice had more beta(2)-agonist-induced OCA-B expression. Thus, RGS13 inhibits CREB-dependent transcription of target genes through disruption of complexes formed at the promoter.


Temporal target integration underlies performance at Lag 1 in the attentional blink.
When two targets follow each other directly in rapid serial visual presentation (RSVP), they are often identified correctly but reported in the wrong order. These order reversals are commonly explained in terms of the rate at which the two targets are processed, the idea being that the second target can sometimes overtake the first in the race toward conscious awareness. The present study examined whether some of these order reversals might alternatively be due to a mechanism of temporal integration whereby targets appearing closely in time may be merged into a single representation. To test this integration account, we used an attentional blink task in which the two targets could be combined perceptually in a meaningful way such that the conjunction of the two target elements constituted a possible target stimulus itself. The results showed that when targets appeared at Lag 1, observers frequently reported seeing only a single merged target stimulus, and these reports occurred up to approximately three times as often as (real) order reversals. When the possibility to report the integrated percept was removed, order reversals consequently tripled. These results suggest that integration may actually be the primary cause of order reversals in dual-target RSVP tasks.


Clinical application of multidisciplinary teams in tumor therapy.
Multidisciplinary team (MDT) model is a diagnostic and treatment model characterized by interdisciplinarity, integration, centralism, individualization, and precision and is becoming more common in the management of complex malignancies. MDT emphasizes team spirit and a personalized treatment strategy according to the actual condition of each patient. A cooperative and effective multidisciplinary team is an important guarantee for delivering high-quality services to patients. Under the guidance of a medical humanistic concept, MDT provides reasonable, effective, convenient, and a full range of excellent quality medical service to patients. The MDT maximizes patient benefits, and it is the developmental direction for large-scale general hospitals. At the same time, the MDT is also an important measure to strengthen the core competitiveness of hospitals. Here, we introduce the clinical application of the model in tumor therapy as well as the current state and development in our hospital.


Thyroid hormone inhibits purified taste bud membrane adenosine 3',5'-monophosphate phosphodiesterase activity.
Thyroid hormone inhibited purified taste bud membrane adenosine 3'5'-monophosphate (cAMP) phosphodiesterase (PDE) activity in a dose-dependent manner. Taste bud membrane cAMP PDE was inhibited most effectively by thyroxine (T4) followed in order by triiodothyionine (T3), diiodotyrosine (DIT) and monoiodotyrosine (MIT). Concentrations required for 50% inhibition (IC50) of enzyme activity were about 1 x 10(-6), 1 x 10(-5), 6 x 10(-4) M and greater than 1 x 10(-3) M for T4, T3, DIT and MIT, respectively. Addition of zinc at physiological concentrations found in serum greatly augmented the inhibitory effects of T4 and T3 at lower concentrations (10(-7) and 10(-6) M, respectively) resulting in further inhibition of cAMP PDE by 40-50%. Inhibition of cAMP PDE by T4 appears to be relatively tissue selective as indicated by the IC50 of 1 x 10(-6) M for the taste bud but only 7 x 10(-6) M, 3 x 10(-5) M, and 4 x 10(-5) M, for heart, kidney and brain cAMP PDE, respectively. Inhibition of taste bud membrane cAMP PDE by T4 was competitive with substrate cAMP with a Ki of 4 microM. These results suggest that inhibition of cAMP PDE, which increases taste bud membrane intracellular cAMP, may participate in the action of thyroid hormone in the taste process.


Diabetes at the front door. A guideline for dealing with glucose related emergencies at the time of acute hospital admission from the Joint British Diabetes Society (JBDS) for Inpatient Care Group.
People with diabetes account for nearly one-fifth of all inpatients in English and Welsh hospitals; of these, up to 90% are admitted as an emergency. Most are admitted for a reason other than diabetes with only 8% requiring admission for a diabetes-specific cause. Healthcare professionals working in emergency departments experience numerous clinical challenges, notwithstanding the need to know whether each individual with diabetes requires urgent admission. This document has been developed and written by experts in the field, and reviewed by the parent organizations of the Joint British Diabetes Societies for Inpatient Care-Diabetes UK, the Diabetes Inpatient Specialist Nurse Group and the Association of British Clinical Diabetologists. The document aims to support staff working in emergency departments and elsewhere by offering practical advice and tools for effective, appropriate and safe triage. Each section relates to the commonest diabetic specific emergencies and algorithms can be printed off to enable ease of access and use.


Plasticity of a colloidal polycrystal under cyclic shear.
We use confocal microscopy and time-resolved light scattering to investigate plasticity in a colloidal polycrystal, following the evolution of the network of grain boundaries as the sample is submitted to thousands of shear deformation cycles. The grain boundary motion is found to be ballistic, with a velocity distribution function exhibiting nontrivial power law tails. The shear-induced dynamics initially slow down, similarly to the aging of the spontaneous dynamics in glassy materials, but eventually reach a steady state. Surprisingly, the crossover time between the initial aging regime and the steady state decreases with increasing probed length scale, hinting at a hierarchical organization of the grain boundary dynamics.


The Toxoplasma gondii peptide AS15 elicits CD4 T cells that can control parasite burden.
The apicomplexan parasite Toxoplasma gondii can cause severe disease in immunocompromised individuals. Previous studies in mice have focused largely on CD8(+) T cells, and the role of CD4 T cells is relatively unexplored. Here, we show that immunization of the C57BL/6 strain of mice, in which the immunodominant CD8 T cell response to the parasite dense-granule protein GRA6 cannot be generated, leads to a prominent CD4 T cell response. To identify the CD4 T cell-stimulating antigens, we generated a T. gondii-specific, lacZ-inducible, CD4 T cell hybridoma and used it as a probe to screen a T. gondii cDNA library. We isolated a cDNA encoding a protein of unknown function that we call CD4Ag28m and identified the minimal peptide, AS15, which was presented by major histocompatibility complex (MHC) class II molecules to the CD4 T cells. Immunization of mice with the AS15 peptide provided significant protection against subsequent parasite challenge, resulting in a lower parasite burden in the brain. Our findings identify the first CD4 T cell-stimulating peptide that can confer protection against toxoplasmosis and provide an important tool for the study of CD4 T cell responses and the design of effective vaccines against the parasite.


A Mycobacterium marinum TesA mutant defective for major cell wall-associated lipids is highly attenuated in Dictyostelium discoideum and zebrafish embryos.
Infection of the zebrafish with Mycobacterium marinum is regarded as a well-established experimental model to study the pathogenicity of Mycobacterium tuberculosis. Herein, a M. marinum transposon mutant library was screened for attenuated M. marinum phenotypes using a Dictyostelium discoideum assay. In one attenuated mutant, the transposon was located within tesA, encoding a putative type II thioesterase. Thin-layer chromatography analyses indicated that the tesA::Tn mutant failed to produce two major cell wall-associated lipids. Mass spectrometry and nuclear magnetic resonance clearly established the nature of missing lipids as phthioglycol diphthioceranates and phenolic glycolipids, respectively, indicating that TesA is required for the synthesis of both lipids. When injected into the zebrafish embryo bloodstream, the mutant was found to be highly attenuated, thus validating the performance and relevance of the Dictyostelium screen. Consistent with these in vivo findings, tesA::Tn exhibited increased permeability defects in vitro, which may explain its failure to survive in host macrophages. Unexpectedly, virulence was retained when bacteria were injected into the notochord. Histological and ultrastructural studies of the infected notochord revealed the presence of actively proliferating mycobacteria, leading to larval death. This work presents for the first time the notochord as a compartment highly susceptible to mycobacterial infection.


Sequencing complex polysaccharides.
Although rapid sequencing of polynucleotides and polypeptides has become commonplace, it has not been possible to rapidly sequence femto- to picomole amounts of tissue-derived complex polysaccharides. Heparin-like glycosaminoglycans (HLGAGs) were readily sequenced by a combination of matrix-assisted laser desorption ionization mass spectrometry and a notation system for representation of polysaccharide sequences. This will enable identification of sequences that are critical to HLGAG biological activities in anticoagulation, cell growth, and differentiation.


Snapshot of an integrated psychosocial gastroenterology service.
To characterize the patients utilizing a gastroenterology behavioral medicine service and examine the effect of treatment on health care utilization. Patients were referred by their gastroenterologists for psychological treatment during a 15 mo period. Patients seen for an intake with a psychologist completed the Brief Symptom Inventory (BSI) and a checklist of psychosocial concerns. A subset of patients with functional bowel disorders also completed a disease specific quality of life measure. Chart review was conducted to obtain information on type and frequency of sessions with the psychologist, the number of outpatient gastroenterology visits, and number of gastroenterology-related medical procedures during the 6 mo following psychological intake. Of 259 patients referred for treatment, 118 (46%) completed an intake with a psychologist. Diagnoses included: irritable bowel syndrome (42%), functional dyspepsia (20%), inflammatory bowel diseases (20%), esophageal symptoms (10%), and "other" (8%). Demographic variables and disease type did not differentiate between those who did and did not schedule an intake. Mean t-scores for the BSI global score index and the depression, anxiety, and somatization subscales fell below the cutoff for clinical significance (t = 63). Treatments were predominantly gut-directed hypnosis (48%) and cognitive behavioral therapy (44%). Average length of treatment was 4 sessions. Among functional gastrointestinal (GI) patients, those patients who initiated treatment received significantly fewer GI-related medical procedures during the 6 mo following the referral than patients who did not schedule an intake [t (197) = 2.69, P < 0.01]. Patients are receptive to psychological interventions for GI conditions and there is preliminary evidence that treatment can decrease health-care utilization among patients with functional GI conditions.


Proteomic analysis of cellular response to novel proapoptotic agents related to atypical retinoids in human IGROV-1 ovarian carcinoma cells.
Novel agents characterized by the scaffold of the atypical retinoid ST1926, but containing different chemical functions (carboxylic or hydroxamic acid), exhibit potent proapoptotic activity. In the present paper, we show that the treatment of the IGROV-1 ovarian cancer cell line with compounds sharing structural features with ST1926 (ST1898, ST3595, ST3056) determines a strong inhibition of proliferation mainly due to apoptotic cell death. In an effort to understand the mechanism of action of these compounds, we performed a proteomics analysis of IGROV-1 total lysates and nuclear extracts. Using this approach, we found that deregulation of calcium homeostasis, oxidative stress, cytoskeleton reorganization, and deregulation of proteasome function may represent important pathways involved in response of IGROV-1 cells to the studied compounds. The most prominent effect was down-regulation of factors involved in protein degradation, an event more marked in cells treated with ST3595. In addition, we identified proteins specifically modulated by each treatment, including prohibitin and cochaperone P23 (ST1898), pre-mRNA splicing factor SF2p32 and clathrin light chain (ST3595), as well as Far upstream element (FUSE) binding protein 1 and DNA-binding protein B (ST3056). By identifying proteins modulated by novel proapoptotic agents, this study provides insights into critical aspects of their mechanism of action.


Luminescent Gold Nanocluster-Methylcellulose Composite Optical Fibers with Low Attenuation Coefficient and High Photostability.
Because of their lightweight structure, flexibility, and immunity to electromagnetic interference, polymer optical fibers (POFs) are used in numerous short-distance applications. Notably, the incorporation of luminescent nanomaterials in POFs offers optical amplification and sensing for advanced nanophotonics. However, conventional POFs suffer from nonsustainable components and processes. Furthermore, the traditionally used luminescent nanomaterials undergo photobleaching, oxidation, and they can be cytotoxic. Therefore, biopolymer-based optical fibers containing nontoxic luminescent nanomaterials are needed, with efficient and environmentally acceptable extrusion methods. Here, such an approach for fibers wet-spun from aqueous methylcellulose (MC) dispersions under ambient conditions is demonstrated. Further, the addition of either luminescent gold nanoclusters, rod-like cellulose nanocrystals or gold nanocluster-cellulose nanocrystal hybrids into the MC matrix furnishes strong and ductile composite fibers. Using cutback attenuation measurement, it is shown that the resulting fibers can act as short-distance optical fibers with a propagation loss as low as 1.47 dB cm-1 . The optical performance is on par with or even better than some of the previously reported biopolymeric optical fibers. The combination of excellent mechanical properties (Young's modulus and maximum strain values up to 8.4 GPa and 52%, respectively), low attenuation coefficient, and high photostability makes the MC-based composite fibers excellent candidates for multifunctional optical fibers and sensors.


Improving resource utilization in the intensive care units. A challenge for Saudi Hospitals.
In the face of increasing demand of intensive care services in the Kingdom of Saudi Arabia, as well as the high cost of delivering such services, systematic steps must be undertaken in order to ensure optional utilization and fair allocation of resources. Strategies start prior to intensive care units (ICU) admission by the proper selection of patients who are likely to benefit from ICU. Less resource-demanding alternatives, such as intermediate care units, should be used for low-risk patients. Do-not-resuscitate status in patients with no meaningful chance of recovery will prevent futile admissions to ICUs. Measures known to improve the efficiency of care in the ICU must be implemented, including hiring full-time qualified intensivists, switching open units to closed ones and the introduction of certain evidence-base driven management protocols. On discharge, the intermediate care units again play a role as less expensive alternative transitional area for patients who are not stable enough to go to general ward. Measures to reduce re-admissions to ICU must also be implemented. Improving ICU resource utilization requires teamwork not only the intensivists but also the administrators and other health care providers.


Pharmacokinetic/LDL-C and exposure-response analysis of tafolecimab in Chinese hypercholesterolemia patients: Results from phase I, II, and III studies.
Tafolecimab, a novel fully human monoclonal antibody targeting PCSK9, has been assessed in Chinese healthy volunteers and patients with hypercholesterolemia. This analysis is to develop and qualify a population pharmacokinetics (PopPKs)/LDL-C model to characterize tafolecimab PK and LDL-C profiles, evaluate the impact of potential covariates on tafolecimab, estimate individual predicted exposure, and LDL-C decreasing, furthermore, explore exposure-response relationship to support clinical use. Data from six clinical trials in China were used to develop the PopPK/LDL-C model. A Michaelis-Menten approximation of the target-mediated drug disposition (TMDD) model was used to describe PK data and indirect response (IDR) model was developed to estimate the LDL-C profile. A stochastic approximation expectation maximization algorithm was applied to estimate PopPK/LDL-C parameters. The PK/LDL-C time course data for tafolecimab were well described by TMDD/IDR model. Baseline covariates resulting in statistically significant changes in PK/LDL-C parameters included: body weight and sex on absorption rate constant; body weight, sex, and unbound PCSK9 on central volume; body weight and sex on clearance; baseline LDL-C on first-order rate constants for the removal of an effect); and disease and sex on maximum effect. However, the magnitudes of changes associated with these covariates do not necessitate dose adjustment. Exposure-efficacy relationship indicated that the nadir of LDL-C reduction achieved with the steady-state trough plasma concentration (Ctrough ) of tafolecimab at 5 μg/mL, and no further LDL-C decreasing with the increasing Ctrough . There was no exposure dependency observed in exposure-safety exploration. The PopPK/LDL-C model was successfully developed, validated, and predicted tafolecimab/LDL-C concentrations and individual exposures.


Longitudinal adherence to maternal antiretroviral therapy and infant Nevirapine prophylaxis from 6 weeks to 18 months postpartum amongst a cohort of mothers and infants in South Africa.
Despite improved policies to prevent mother-to-child HIV transmission (MTCT), adherence to maternal antiretroviral therapy (ART) and infant Nevirapine prophylaxis (NVP) is low in South Africa. We describe ART adherence amongst a cohort of HIV-positive mothers and HIV-exposed but uninfected infants from 6 weeks until 18 months post-delivery and identify risk factors for nonadherence. Data were collected in 2012-2014 through a nationally representative survey of PMTCT effectiveness. Mother-infant pairs were enrolled during the infant's first immunization visit at 6 weeks. Mothers and HIV-exposed infants (2811 pairs) were followed to 18 months at 3-month intervals. Mothers who self-reported being on ART at 6 weeks postpartum (N = 1572 (55.9%)) and infants on NVP at 6 weeks (N = 2370 (84.3%)) were eligible for this analysis and information about their adherence was captured at each interview they attended thereafter. We defined nonadherence within each 3-month interval as self-report of missing > 5% of daily ART/NVP doses, estimated adherence using a Cox survival curve with Andersen & Gill setup for recurring events, and identified risk factors for nonadherence with an extended Cox regression model (separately for mothers and infants) in Stata 13. Results are not nationally representative as this is a subgroup analysis of the follow-up cohort. Amongst mothers on ART at 6 weeks postpartum, cumulative adherence to maternal ART until 18 months was 63.4%. Among infants on NPV at 6 weeks postpartum, adherence to NVP was 74.5%.. Risk factors for nonadherence to maternal ART, controlling for other factors, included mother's age (16-24 years vs. ≥34 years, adjusted Hazard Ratio (aHR): 1.9, 95% CI: 1.4-2.5), nondisclosure of HIV status to anyone (nondisclosure vs. disclosure: aHR: 1.7, 95% CI: 1.3-2.1), and timing of ART initiation (initiated ART after delivery vs. initiated ART before delivery: aHR: 1.6, 95% CI: 1.3-2.0). Provincial variation was seen in nonadherence to infant NVP, controlling for other factors. Maintaining ART adherence until 18 months postpartum remains a crucial challenge, with maternal ART adherence among the six week maternal ART cohort below 65% and infant NVP adherence among breastfeeding infants in this cohort below 75%.This is gravely concerning, given the global policy shift to lifelong ART amongst pregnant and lactating women, and the need for extended infant prophylaxis amongst mothers who are not virally suppressed. Our findings suggest that young mothers and mothers who do not disclose their status should be targeted with messages to improve adherence, and that late maternal ART initiation (after delivery) increases the risk of maternal nonadherence.


[Procedure for preliminary rapid estimation of bacteria susceptibility to chemotherapeutics].
Principles and procedure for rapid estimation of bacteria susceptibility to antibiotics on a glucose-tryptone medium with an indicator are described. The results of the tests with 50 microbial strains of 17 species showed practically complete identity to the results of the antibiograms when the data were estimated in 3-6 hours according to the described procedure in comparison to the findings estimated in 18-24 hours on the standard media.


Insomnia in survivors 8.5 years after the Utøya Island terrorist attack: transition from late adolescence to early adulthood - the Utøya study.
Insomnia is a global health concern, associated with many mental and physical health conditions. Prevalence of insomnia is reported to increase during adolescence and early adulthood. High levels of insomnia are also reported in adolescents up to 2.5 years after a traumatic event. What is less well understood is the prevalence of insomnia in a trauma exposed population transitioning from adolescence to adulthood. To assess insomnia in the survivors in the 2011 Utøya Island terrorist attack, 2.5 years and 8.5 years after the attack when the majority of survivors were transitioning from late adolescence to early adulthood. Participants were 336 survivors of the Utøya Island attack who completed the Utøya Study 2.5 years (T3) and 8.5 years (T4) after the attack. Participants completed a face-to-face interview including the Bergen Insomnia Scale (BIS), which was used to assess insomnia symptoms and prevalence of meeting diagnostic criteria for insomnia. Insomnia was indicated in 47.7% of survivors 8.5 years after the attack. Insomnia prevalence did not significantly change from 2.5 to 8.5 years after the attack, though insomnia symptoms (BIS sum score) were found to increase. Age was negatively associated with insomnia at T4, with older age being associated with less insomnia. No significant sex difference was found in insomnia prevalence at T4. Almost a decade after the Utøya Island terrorist attack, nearly a half of the young survivors in our study reported insomnia and typical age- and sex-related differences in sleep were not always seen. This rate is almost double what is reported in the general population (20-30%) indicating a high level of unmet need in this population. The implications of such sleep disruption during a critical time for physical, mental, social and cognitive development are far reaching.


Delivering umbilical cord mesenchymal stem cell exosomes through hydrogel ameliorates vaginal atrophy in ovariectomized rats.
Menopausal and postmenopausal women often experience vaginal atrophy due to estrogen deficiency. Mesenchymal stem cell exosomes have emerged as potential therapeutic agents, capable of promoting tissue regeneration and repair. This study aimed to explore the benefits of exosomes on VK2 cells and the therapeutic effect of topical exosomal hydrogel on atrophic vaginas. Exosomes were extracted using the high-speed centrifugation method, and their effects on VK2 cell proliferation, migration, and differentiation were observed through co-culture. The menopause model was induced by ovariectomy in rats, followed by the injection of exosome-loaded hydrogel into their vaginas. The treatment's effectiveness was evaluated by measuring vaginal epithelium thickness using HE staining, and assessing vaginal mucosa proliferation and lamina propria angiogenesis using Ki67 and anti-CD31 staining, respectively. Exosomes significantly promoted VK2 cell proliferation and migration, but had no significant effect on differentiation. The exosome hydrogel increased the expression of Ki67 and CD31, leading to a significant improvement in epithelial thickness. UcMSC- ex can stimulate the proliferation and migration of VK2 cells, but do not appear to promote differentiation. Topical application of exosome hydrogel enhances vaginal epithelium thickness to a certain degree, offering a promising non-hormonal therapeutic strategy to alleviate vaginal atrophy in postmenopausal women.


Solvent effect on thermally activated delayed fluorescence by 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene.
Thermally activated delayed fluorescence (TADF) is fluorescence arising from a reverse intersystem crossing (RISC) from the lowest triplet (T1) to the singlet excited state (S1), where these states are separated by a small energy gap (ΔEst), followed by a radiative transition to the ground state (S0). Rate constants relating TADF processes in 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) were determined at four different solvent polarities (toluene, dichloromethane, ethanol, and acetonitrile). We revealed that the rate constant of RISC, kRISC, which is the most important factor for TADF, was significantly enhanced by a reduced ΔEst in more polar solvents. The smaller ΔEst was mainly attributable to a stabilization of the S1 state. This stabilization also induced a Stokes shift in fluorescence through a relatively large change of the dipole moment between S1 and S0 states (17 D). Despite of this factor, we observed a negative correlation between ΔEst and efficiency of the delayed fluorescence (φd). This was ascribed to a lower intersystem crossing rate, kISC, and increased nonradiative decay from S1, k(s)nrs, in polar solvents.


The reliability and concurrent validity of the Scoliosis Research Society-22r patient questionnaire compared with the Child Health Questionnaire-CF87 patient questionnaire for adolescent spinal deformity.
This is a clinic-based cross-sectional study involving 2 health-related quality-of-life (HRQL) questionnaires. To compare the score distribution and reliability of the spinal deformity specific Scoliosis Research Society-22r (SRS-22r) questionnaire and the established generic Child Health Questionnaire-CF87 (CHQ-CF87), and to assess the concurrent validity of the SRS-22r using the CHQ-CF87 in an adolescent spine deformity population. Different questionnaires are commonly thought to be necessary to assess the HRQL of adolescent and adult populations. But since spinal deformities usually begin in the second decade of life, longitudinal follow-up with the same HRQL is desirable. The SRS-22r HRQL has recently been validated for score distribution and internal consistency in a spinal deformity population ranging in age from 7 to 78 years. The SRS-22r and CHQ-CF87 HRQLs were completed by 70 orthopedic spinal deformity outpatients 8 to 18 years of age, of whom 54 returned mailed retest questionnaires at an average of 24 days later. The ceiling effect averaged 27% for the SRS-22r and 36% for the CHQ-CF87. Respective values for internal consistency (Cronbach alpha) were 0.81 and 0.82, and for test-retest reproducibility the intraclass correlations (ICC) were 0.73 and 0.61. Concurrent validity was r > or = 0.68 or more for relevant function, pain, and mental health domains. The SRS Self-Image and particularly the Satisfaction/Dissatisfaction with Management domains did not correlate well with any CHQ-CF87 domains (r = 0.50 and 0.30, respectively). In a spinal deformity population 8 to 18 years of age, the score distribution and reliability, internal consistency, and reproducibility of the SRS-22r were at least as good as the CHQ-CF87. The SRS-22r function, pain, and mental health domains were concurrently valid in comparison to relevant CHQ-CF87 domains, but the SRS-22r self-image and satisfaction/dissatisfaction domains were not, thereby providing health-related quality-of-life information not provided for by the CHQ-CF87.


Cholelithiasis in children with congenital spherocytosis.
Cholelithiasis was diagnosed in two children with congenital spherocytosis of 7 and 9 years of age. Surgery was performed at age 10 and 14, respectively. The presence of gallstones should be considered in patients with congenital spherocytosis even under the age of 10. Various radiologic methods and ultrasonography are useful in the diagnosis of cholelithiasis in children as well as in adults. Once the diagnosis of cholelithiasis is established the treatment of choice is cholecystectomy and splenectomy at the same operation. To perform both procedures an upper midline incision proved to be satisfactory.


Stent-assisted coiling of intracranial bifurcation aneurysms leads to immediate and delayed intracranial vascular angle remodeling.
Wide-neck bifurcating aneurysms are increasingly treated with intracranial stent-assisted coiling by using shape-memory alloy microstents. We sought to investigate the short- and long-term effects of intracranial stent implantation on the geometry and angular conformation of the stent-coiled vascular bifurcation. Thirty patients underwent stent-mediated coiling for 31 bifurcation aneurysms by using 31 self-expanding Neuroform (n = 14) and Enterprise (n = 17) stents (17 women; mean age, 56 years). The angle (δ) between the stented mother and daughter vessels at the bifurcation was measured by using multiplanar imaging of reconstructed rotational conventional angiography volumes and was compared by using matched-pair statistics. Neuroform and Enterprise longitudinal stent stiffness was measured in vitro at an increasing bending angle θ (θ = 180°-δ). Stent deployment increased the bifurcation angle δ from 101.5° to 119.8° postprocedurally and to 137.3° (P < .0001) at latest follow-up, resulting in effective straightening; the angular remodeling was greater in distal-versus-proximal arteries (anterior cerebral > MCA > BA > ICA), inversely proportional to mother-vessel diameter and proportional to pretreatment bending angle θ. At follow-up, angle δ continued to significantly expand, with remodeling being greater in the early period (1-6 versus >7 months) and more pronounced with the longitudinally stiffer closed-cell Enterprise compared with the open-cell Neuroform stent. Stent placement across bifurcation aneurysms leads to a significant biphasic angular remodeling related to stent type and vessel caliber, altering morphology to mimic sidewall lesions, a phenomenon needing consideration during procedural planning. Future work is needed to uncover the hemodynamic implications of this structural change and any possible effect on aneurysm-recurrence rates.


Effectiveness of Multimodal Training on Functional Capacity in Frail Older People: A Meta-Analysis of Randomized Controlled Trials.
In this meta-analysis, we investigated the effect of resistance training (RT) alone or included in a multimodal training on physical frailty outcomes, and whether different variables of RT prescription affect these outcomes. We identified 15 relevant studies searching through MEDLINE, Cochrane Central Register of Controlled Trials, SPORTDiscus, and PEDro database. Postintervention standardized mean difference scores were computed and combined using fixed effects meta-analysis. Analyses have shown positive effects of interventions on maximum strength, gait speed, and Timed Up and Go test. Further analyses have shown significant greater effect of shorter periods on maximum strength. Regarding RT prescription, percentage of one-repetition maximum showed significant effect on physical variables, whereas RT based on rate of perceived effort presented lower effect in the Timed Up and Go test. Although multimodal training is an effective intervention to increase physical capacity, caution should be taken regarding the period and the method to control RT intensity to optimize enhancements in frail older people.


Hck inhibitors as potential therapeutic agents in cancer and HIV infection.
Hematopoietic cell kinase (Hck) is a member of the Src-family of non-receptor tyrosine kinases, which plays many roles in signalling pathways involved in the regulation of cell processes. Hck is expressed in cells of hematopoietic origin, specifically myelomonocytic cells and B lymphocytes. It participates in phagocytosis, adhesion, migration, regulation of protrusion formation on cell membrane, lysosome exocytosis, podosome formation and actin polymerization. More importantly from a medicinal chemistry point of view, high levels of Hck are involved in chronic myeloid leukemia and other hematologic tumors. Furthermore, Hck activity has been associated with virus infections including HIV-1. In particular, Hck is activated by the HIV-1 accessory protein Nef, a multifunctional HIV-1 protein that accelerates progression to AIDS and enhances the infectivity of progeny viruses. Nef binding to Hck leads to kinase activation which is important in AIDS pathogenesis. For these reasons, Hck represents a potentially good therapeutic target for the treatment of both specific cancers and HIV infection. This article summarizes Hck biological activities connected with malignancies and HIV infection, many of which have been only recently reported, and presents an overview of the compounds endowed with Hck inhibitory activity, especially focusing on the medicinal chemistry aspect.


An Increased Plasma Level of ApoCIII-Rich Electronegative High-Density Lipoprotein May Contribute to Cognitive Impairment in Alzheimer's Disease.
High-density lipoprotein (HDL) plays a vital role in lipid metabolism and anti-inflammatory activities; a dysfunctional HDL impairs cholesterol efflux pathways. To understand HDL's role in patients with Alzheimer's disease (AD), we analyzed the chemical properties and function. HDL from AD patients (AD-HDL) was separated into five subfractions, H1-H5, using fast-protein liquid chromatography equipped with an anion-exchange column. Subfraction H5, defined as the most electronegative HDL, was increased 5.5-fold in AD-HDL (23.48 ± 17.83%) in comparison with the control HDL (4.24 ± 3.22%). By liquid chromatography mass spectrometry (LC/MSE), AD-HDL showed that the level of apolipoprotein (apo)CIII was elevated but sphingosine-1-phosphate (S1P)-associated apoM and anti-oxidative paraoxonase 1 (PON1) were reduced. AD-HDL showed a lower cholesterol efflux capacity that was associated with the post-translational oxidation of apoAI. Exposure of murine macrophage cell line, RAW 264.7, to AD-HDL induced a vibrant expression of ganglioside GM1 in colocalization with apoCIII on lipid rafts alongside a concomitant increase of tumor necrosis factor-α (TNF-α) detectable in the cultured medium. In conclusion, AD-HDL had a higher proportion of H5, an apoCIII-rich electronegative HDL subfraction. The associated increase in pro-inflammatory (apoCIII, TNF-α) components might favor Amyloid β assembly and neural inflammation. A compromised cholesterol efflux capacity of AD-HDL may also contribute to cognitive impairment.


Clinical feasibility of 90Y digital PET/CT for imaging microsphere biodistribution following radioembolization.
The purpose of this study was to evaluate the clinical feasibility of next generation solid-state digital photon counting PET/CT (dPET/CT) technology and imaging findings in patients following 90Y microsphere radioembolization in comparison with standard of care (SOC) bremsstrahlung SPECT/CT (bSPECT/CT). Five patients underwent SOC 90Y bremsstrahlung imaging immediately following routine radioembolization with 3.5 ± 1.7 GBq of 90Y-labeled glass microspheres. All patients also underwent dPET/CT imaging at 29 ± 11 h following radioembolization. Matched pairs comparison was used to compare image quality, image contrast and 90Y biodistribution between dPET/CT and bSPECT/CT images. Volumetric assessments of 90Y activity using different isocontour thresholds on dPET/CT and bSPECT/CT images were also compared. Digital PET/CT consistently provided better visual image quality and 90Y-to-background image contrast while depicting 90Y biodistribution than bSPECT/CT. Isocontour volumetric assessment using a 1% threshold precisely outlined 90Y activity and the treatment volume on dPET/CT images, whereas a more restrictive 20% threshold on bSPECT/CT images was needed to obtain comparable treatment volumes. The use of a less restrictive 10% threshold isocontour on bSPECT/CT images grossly overestimated the treatment volume when compared with the 1% threshold on dPET/CT images. Digital PET/CT is clinically feasible for the assessment of 90Y microsphere biodistribution following radioembolization, and provides better visual image quality and image contrast than routine bSPECT/CT with comparable acquisition times. With further optimization and clinical validation, dPET technology may allow faster and more accurate imaging-based assessment of 90Y microsphere biodistribution.


Using chemical derivatization and mass spectrometric analysis to characterize the post-translationally modified Staphylococcus aureus surface protein G.
The Staphylococcus aureus surface protein G (SasG) is an important mediator of biofilm formation in virulent S. aureus strains. A detailed analysis of its primary sequence has not been reported to date. SasG is highly abundant in the cell wall of the vancomycin-intermediate S. aureus strain HIP5827, and was purified and subjected to sequence analysis by MS. Data from MALDI-TOF and LC-MS/MS experiments confirmed the predicted N-terminal signal peptide cleavage site at residue A(51) and the C-terminal cell wall anchor site at residue T(1086). The protein was also derivatized with N-succinimidyloxycarbonyl-methyl-tris(2,4,6-trimethoxyphenyl) phosphonium bromide (TMPP-Ac-OSu) to assess the presence of additional N-terminal sites of mature SasG. TMPP-derivatized SasG peptides featured m/z peaks with a 572 Da mass increase over the equivalent underivatized peptides. Multiple N-terminal peptides, all of which were observed in the 150 amino acid segment following the signal peptide cleavage at the residue A(51), were characterized from MS and MS/MS data, suggesting a series of successive N-terminal truncations of SasG. A strategy combining TMPP derivatization, multiple enzyme digestions to generate overlapping peptides and detailed MS analysis will be useful to determine and understand functional implications of PTMs in bacterial cell wall-anchored proteins, which are frequently involved in the modulation of virulence-associated bacterial surface properties.


The importance of thinking styles in predicting binge eating.
Impulsivity, Body Mass Index, negative emotions and irrational food beliefs are often reported as predictors of binge eating. In the current study we explored the role played by two thinking styles, namely food thought suppression and desire thinking, in predicting binge eating among young adults controlling for established predictors of this condition. A total of 338 university students (268 females) participated in this study by completing a battery of questionnaires measuring the study variables. Path analysis revealed that impulsivity was not associated with binge eating, that Body Mass Index and negative emotions predicted binge eating, and that irrational food beliefs only influenced binge eating via food thought suppression and desire thinking. In conclusion, thinking styles appear an important predictor of binge eating and they should be taken into consideration when developing clinical interventions for binge eating.