Intracranial Atherosclerosis and Stage 1 Hypertension Defined by the 2017 ACC/AHA Guideline.
In 2017, the American College of Cardiology (ACC)/American Heart Association (AHA) released a new, stricter definition of stage 1 hypertension which was previously considered prehypertension. However, impacts of the novel stage 1 hypertension on deleterious target-organ outcomes are still controversial. In this study, we evaluated the relationship between this newly defined stage 1 hypertension and the presence of intracranial atherosclerosis (ICAS) lesions in neurologically healthy participants. We assessed consecutive participants in routine health checkups between January 2006 and December 2013. Blood pressure (BP) was classified according to the 2017 ACC/AHA hypertension guideline, and ICAS was defined as occlusion or ≥50% stenosis of intracranial vessels on flight magnetic resonance angiography. Among 3,111 healthy participants (mean age: 56 years, sex: 54% men), 85 (3%) had ICAS lesions. In multivariate analysis, stage 1 hypertension (adjusted odds ratio: 2.46, 95% confidence interval: 1.10-5.51, P = 0.029) remained an independent predictor of ICAS after adjustment for confounders. Stage 2 hypertension showed a higher odds ratio and a lower P value, indicating a dose-response effect. Age and HbA1c level were also significantly associated with ICAS, independent of the BP categories. The ICAS lesion burden showed a dose-response effect across the BP categories (P for trend <0.001), whereas ICAS lesion location did not (P for trend = 0.699). We demonstrated that stage 1 hypertension, defined according to the 2017 ACC/AHA guideline, was associated with a higher prevalence and burden of ICAS lesions in a neurologically healthy population.


Biotransformations of prenylated hop flavonoids for drug discovery and production.
In this review we aim to present current knowledge on biotransformation of flavonoids from hop cones with respect to type of product, catalyst and conversion. Subsequently, a comparative analysis of biological activity of prenylated hop flavonoids and their biotransformation products has been performed in order to indicate these research efforts that have good potential for application in pharmaceutical industry. There is increasing evidence that the products of biotransformation of hop prenylflavonoids, which have been little studied until recently, can be used as drugs or drug ingredients and also as standards of human drug metabolites. They can also serve as an inspiration for the design and chemical synthesis of new derivatives with higher or different biological activity. Nevertheless, much additional work, among others on determining the mechanism of action in in vivo systems, is needed to open up the way to biomedical application of these compounds.


Deep subwavelength interference lithography with tunable pattern period based on bulk plasmon polaritons.
Interference lithography based on surface plasmon polaritons has been proven to break the diffraction limit and deliver the high imaging resolution. However, most previously reported studies suffer from the inflexible pattern pitch for a certain structure ascribed to fixed excitation mode, which limits the applications in micro-/nano- fabrications. In this work, the large area deep subwavelength interference lithography with tunable pattern period based on bulk plasmon polaritons (BPPs) is proposed. By simply tuning the incident angle, the spatial frequencies of the selected BPPs modes squeezed through hyperbolic metamaterial changes correspondingly. As a result, the pitch of the interference pattern is continuously altered. The results demonstrate that one-dimensional and two-dimensional periodic patterns with pitch resolution ranging from 45 nm (~λ/10) to 115 nm (~λ/4) can be generated under 436 nm illumination. Additionally, the general method of designing such an interference lithography system is also discussed, which can be used for nanoscale fabrication in this fashion.


Calreticulin reveals a critical Ca(2+) checkpoint in cardiac myofibrillogenesis.
Calreticulin (crt) is an ubiquitously expressed and multifunctional Ca(2+)-binding protein that regulates diverse vital cell functions, including Ca(2+) storage in the ER and protein folding. Calreticulin deficiency in mice is lethal in utero due to defects in heart development and function. Herein, we used crt(-/-) embryonic stem (ES) cells differentiated in vitro into cardiac cells to investigate the molecular mechanisms underlying heart failure of knockout embryos. After 8 d of differentiation, beating areas were prominent in ES-derived wild-type (wt) embryoid bodies (EBs), but not in ES-derived crt(-/-) EBs, despite normal expression levels of cardiac transcription factors. Crt(-/-) EBs exhibited a severe decrease in expression and a lack of phosphorylation of ventricular myosin light chain 2 (MLC2v), resulting in an impaired organization of myofibrils. Crt(-/-) phenotype could be recreated in wt cells by chelating extracellular or cytoplasmic Ca(2+) with EGTA or BAPTA, or by inhibiting Ca(2+)/calmodulin-dependent kinases (CaMKs). An imposed ionomycin-triggered cystolic-free Ca(2+) concentration ([Ca(2+)](c)) elevation restored the expression, phosphorylation, and insertion of MLC2v into sarcomeric structures and in turn the myofibrillogenesis. The transcription factor myocyte enhancer factor C2 failed to accumulate into nuclei of crt(-/-) cardiac cells in the absence of ionomycin-triggered [Ca(2+)](c) increase. We conclude that the absence of calreticulin interferes with myofibril formation. Most importantly, calreticulin deficiency revealed the importance of a Ca(2+)-dependent checkpoint critical for early events during cardiac myofibrillogenesis.


16S rRNA phylogenetic analysis and quantification of Korarchaeota indigenous to the hot springs of Kamchatka, Russia.
The candidate archaeal division Korarchaeota is known primarily from deeply branching sequences of 16S rRNA genes PCR-amplified from hydrothermal springs. Parallels between the phylogeny of these genes and the geographic locations where they were identified suggested that Korarchaeota exhibit a high level of endemism. In this study, the influence of geographic isolation and select environmental factors on the diversification of the Korarchaeota was investigated. Fourteen hot springs from three different regions of Kamchatka, Russia were screened by PCR using Korarchaeota-specific and general Archaea 16S rRNA gene-targeting primers, cloning, and sequencing. Phylogenetic analyses of these sequences with Korarchaeota 16S rRNA sequences previously identified from around the world suggested that all Kamchatka sequences cluster together in a unique clade that subdivides by region within the peninsula. Consistent with endemism, 16S rRNA gene group-specific quantitative PCR of all Kamchatka samples detected only the single clade of Korarchaeota that was found by the non-quantitative PCR screening. In addition, their genes were measured in only low numbers; small Korarchaeota populations would present fewer chances for dispersal to and colonization of other sites. Across the entire division of Korarchaeota, common geographic locations, temperatures, or salinities of identification sites united sequence clusters at different phylogenetic levels, suggesting varied roles of these factors in the diversification of Korarchaeota.


Fe(III) Complexes Based on Mono- and Bis-pyrazolyl-s-triazine Ligands: Synthesis, Molecular Structure, Hirshfeld, and Antimicrobial Evaluations.
The self-assembly of iron(III) chloride with three pyrazolyl-s-triazine ligands, namely 2,4-bis(3,5-dimethyl-1H-pyrazol-1-yl)-6-(piperidin-1-yl)-1,3,5-triazine (PipBPT), 4-(4,6-bis(3,5-dimethyl-1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)morpholine (MorphBPT), and 4,4'-(6-(3,5-dimethyl-1H-pyrazol-1-yl)-1,3,5-triazine-2,4-diyl)dimorpholine (bisMorphPT) afforded [Fe(PipBPT)Cl2][FeCl4] (1), [Fe(MorphBPT)Cl2][FeCl4] (2), and [H(bisMorphPT)][FeCl4]. bisMorphPT.2H2O (3), respectively, in good yield. In complexes 1 and 2, the Fe(III) is pentacoordinated with three Fe-N interactions from the pincer ligand and two coordinated chloride anions in the inner sphere, and FeCl4¯ in the outer sphere. Complex 3 is comprised of one protonated ligand as cationic part, one FeCl4¯ anion, and one neutral bisMorphPT molecule in addition to two crystallized water molecules. Analysis of molecular packing using Hirshfeld calculations indicated that H…H and Cl…H are the most important in the molecular packing. They comprised 40.1% and 37.4%, respectively in 1 and 32.4% and 37.8%, respectively in 2. Complex 1 exhibited the most bioactivity against the tested microbes while 3 had the lowest bioactivity. The bisMorphPT and MorphBPT were inactive towards the tested microbes while PipBPT was active. As a whole, the Fe(III) complexes have enhanced antibacterial and antifungal activities as compared to the free ligands.


Novel strategies using DNA for the induction of mucosal immunity.
The mucosal surfaces are the primary sites for transmission of most infectious diseases. However, most conventional vaccines are administered parenterally [e.g., by intramuscular (IM) or intradermal (ID) injection] and induce systemic but rarely mucosal immunity. Novel vaccination strategies capable of inducing both systemic and mucosal immune responses could greatly reduce infection and morbidity worldwide. One of the most exciting advances in vaccine technology in recent years has been the development of DNA vaccines, through which the antigen is synthesized in vivo after direct introduction of its encoding sequences. The vast majority of DNA vaccines have been delivered parenterally; however, in recent years a number of studies have reported successful mucosal immunization with DNA vaccines. The induction of strong immune responses following the introduction of DNA appears to be partly due to the potent adjuvant effect of unmethylated immunostimulatory CpG motifs present in the DNA backbone. Synthetic oligodeoxynucleotides (ODN) containing such immunostimulatory CpG motifs are potent adjuvants systemically and mucosally in mice, and have synergistic action with other adjuvants, such as alum and cholera toxin (CT). This article highlights the recent advances in vaccination strategies using DNA delivered to mucosal surfaces either as an antigen-encoding plasmid or as an adjuvant.


Non-invasive vocal biomarker is associated with pulmonary hypertension.
Emerging data suggest that noninvasive voice biomarker analysis is associated with coronary artery disease. We recently showed that a vocal biomarker was associated with hospitalization and heart failure in patients with heart failure. We evaluate the association between a vocal biomarker and invasively measured indices of pulmonary hypertension (PH). Patients were referred for an invasive cardiac hemodynamic study between January 2017 and December 2018, and had their voices recorded on three separate occasions to their smartphone prior to each study. A pre-established vocal biomarker was determined based on each individual recording. The intra-class correlation co-efficient between the separate voice recording biomarker values for each individual participant was 0.829 (95% CI 0.740-0.889) implying very good agreement between values. Thus, the mean biomarker was calculated for each patient. Patients were divided into two groups: high pulmonary arterial pressure (PAP) defined as ≥ 35 mmHg (moderate or greater PH), versus lower PAP. Eighty three patients, mean age 61.6 ± 15.1 years, 37 (44.6%) male, were included. Patients with a high mean PAP (≥ 35 mmHg) had on average significantly higher values of the mean voice biomarker compared to those with a lower mean PAP (0.74 ± 0.85 vs. 0.40 ± 0.88 p = 0.046). Multivariate logistic regression showed that an increase in the mean voice biomarker by 1 unit was associated with a high PAP, odds ratio 2.31, 95% CI 1.05-5.07, p = 0.038. This study shows a relationship between a noninvasive vocal biomarker and an invasively derived hemodynamic index related to PH obtained during clinically indicated cardiac catheterization. These results may have important practical clinical implications for telemedicine and remote monitoring of patients with heart failure and PH.


Differential response to contact-based stigma reduction programs: Perceived quality and personal experience matter.
The aim of this study was to examine two under-studied factors integral to the theoretical underpinnings of contact-based mental illness stigma reduction programs: the quality of the contact and prior personal experience with persons with mental health problems. This study utilized pre- and post-survey data collected from 4122 individuals participating in a diverse set of contact-based educational programs implemented as part of California's statewide initiative to reduce mental illness stigma. Multi-level mixed regression models were used to determine whether pre-post changes in a variety of stigma-related measures varied depending on perceived quality of contact and prior personal experience with mental illness. Significant pre-post reductions in stigma were observed, but individual perceptions of contact quality strongly moderated program effects. Mean contact quality across all attendees at a presentation was rarely a moderator. Though effective for all participants, on average, contact-based educational programs were more effective for those without prior personal or family experience of mental illness. Program organizers may wish to target recruitment efforts to reach more individuals without such experience, given the greater effectiveness of contact among these individuals. More research should explore the factors underlying individual variation in perceived quality of contact-based stigma reduction programs.


Characterization of Inhibitory Effectiveness in Hyperpolarization-Activated Cation Currents by a Group of ent-Kaurane-Type Diterpenoids from Croton tonkinensis.
Croton is an extensive flowering plant genus in the spurge family, Euphorbiaceae. Three croton compounds with the common ent-kaurane skeleton have been purified from Croton tonkinensis. We examined any modifications of croton components (i.e., croton-01 [ent-18-acetoxy-7α-hydroxykaur-16-en-15-one], croton-02 [ent-7α,14β-dihydroxykaur-16-en-15-one] and croton-03 [ent-1β-acetoxy-7α,14β-dihydroxykaur-16-en-15-one] on either hyperpolarization-activated cation current (Ih) or erg-mediated K+ current identified in pituitary tumor (GH3) cells and in rat insulin-secreting (INS-1) cells via patch-clamp methods. Addition of croton-01, croton-02, or croton-03 effectively and differentially depressed Ih amplitude. Croton-03 (3 μM) shifted the activation curve of Ih to a more negative potential by approximately 11 mV. The voltage-dependent hysteresis of Ih was also diminished by croton-03 administration. Croton-03-induced depression of Ih could not be attenuated by SQ-22536 (10 μM), an inhibitor of adenylate cyclase, but indeed reversed by oxaliplatin (10 μM). The Ih in INS-1 cells was also depressed effectively by croton-03. Our study highlights the evidence that these ent-kaurane diterpenoids might conceivably perturb these ionic currents through which they have high influence on the functional activities of endocrine or neuroendocrine cells.


Antitumor function and mechanism of phycoerythrin from Porphyra haitanensis.
The anti-tumor effect of R-Phycoerythrin (R-PE) from Porphyra haitanensis was studied using cell line HeLa as an in vitro model and Sarcoma-180 (S180) tumor-bearing mice as an in vivo model. The results showed that the combination treatment of R-PE and photodynamic therapy PDT) significantly inhibited the growth of HeLa cells up to 81.5%, with a fair dose-effect relationship, but did not inhibit endothelial cells. The annexin v-fitc/PI fluorescence staining experiments demonstrated that at doses between 0~60µg/mL, apoptosis cells and later stage apoptosis cells or necrosis cells increased significantly as the R-PE dosage increased. DNA electrophoresis showed that after R-PE+PDT treatment of HeLa cells for 24 hours, a light "smear" band between 100~400bp appeared to indicate the degradation of genomic DNA. The QRT-PCR results showed that R-PE+PDT treatment increased caspase-3 and caspase-10 gene expression and decreased the Bcl-2 gene expression level significantly as the R-PE dose increased, implying that R-PE promoted HeLa cell apoptosis. Compared with untreated S180 tumor-bearing mice, R-PE injection significantly inhibited the growth of S180 in tumor-bearing mice up to 41.3% at a dose of 300mg-kg⁻¹. Simultaneously, the significant increase of superoxide dismutase (SOD) activity in serum (p < 0.01) and the decrease of the malondialdehyde (MDA) level in liver suggests that R-PE improved the anti-oxidant ability of the S180 tumor-bearing mice, which may related to its antitumor effect. In addition, the R-PE caused a significant increase (p < 0.05) in the spleen index and thymus index, and a significant increase (p < 0.01) in lymphocyte proliferation, NK cell kill activity and the TNF-α level in the serum of S180 tumor-bearing mice. These results strongly suggest that the antitumor effect of R-PE from Porphyra haitanensis functioned by increasing the immunity and antioxidant ability of S180 tumor-bearing mice, promoting apoptosis by increasing protease gene expression and TNF-α secretion.


Usability Study of the User-Interface of Intensive Care Ventilators Based on User Test and Eye-Tracking Signals.
BACKGROUND The aim of this study was to evaluate the ergonomics of the user-interface for 3 intensive care ventilators, and identify usability problems leading to user errors. MATERIAL AND METHODS Sixteen respiratory therapists were recruited to perform 6 specific user-interface operational tasks on ventilators. Data (task completion time, pupil diameter, average slope of pupil diameter change, and subjective evaluation) were collected through objective measurement, questionnaires, and an eye-tracking instrument. RESULTS For task completion time, there were significant differences among ventilators in recognition tasks of ventilator mode and settings (P<0.05), modification of ventilator modes and recognizing (P<0.05) and changing alarm settings (P<0.05). A mean of 15±2 task failures was observed for each ventilator. For the change of pupil diameter, a significant difference was observed between ventilators (except task 2, P<0.05). For average slope of pupil diameter change, a significant difference was also observed between ventilators (except task 2, P<0.05). The Servo I showed a better correlation between task completion time and pupil diameter change. The subjective evaluation results were clear: Evital 4 received worst scores in terms of friendliness of user-interface, information display and safety (respectively, P<0.05). CONCLUSIONS The present study provided valuable evidence to indicate the ergonomic of ventilators now used in China. With the result of this study, we can infer that the Evital 4 were poorly ergonomic designed. Furthermore, the study also demonstrated that eye-tracking can be a promising tool to evaluate the ergonomics of the user-interface.


Evidence-based behavioral interventions for repetitive behaviors in autism.
Restricted and repetitive behaviors (RRBs) are a core symptom of autism spectrum disorders (ASD). There has been an increased research emphasis on repetitive behaviors; however, this research primarily has focused on phenomenology and mechanisms. Thus, the knowledge base on interventions is lagging behind other areas of research. The literature suggests there are evidence-based practices to treat "lower order" RRBs in ASD (e.g., stereotypies); yet, there is a lack of a focused program of intervention research for "higher order" behaviors (e.g., insistence on sameness). This paper will (a) discuss barriers to intervention development for RRBs; (b) review evidence-based interventions to treat RRBs in ASD, with a focus on higher order behaviors; and (c) conclude with recommendations for practice and research.


[Relationship of acromial morphology and rotator cuff tears].
To evaluate the effect of acromial morphology, as assessed on radiographs, on rotator cuff tears. A total of 200 patients surgically treated for shoulder disorders were enrolled. All were older than 40 years and had good quality shoulder radiographs. Two groups were composed: First, a clinical model group of 136 patients to be investigated for three parameters of rotator cuff injury that was divided into two subgroups. One included 68 patients, with an average age of 53.5 years, in whom surgery revealed no injury to the rotator cuff; the other subgroup of 68 patients, with an average age of 58 years, had a ruptured supraspinatus tendon. Subsequently, a control group of 64 patients (32 with rotator cuff injury and 32 without it) was used to verify the results of the model group. Three parameters describing the acromion, i.e., acromion index (AI), lateral acromion angle and acromial slope, were measured on standard radiographs. Tangential antero-posterior and scapular "Y" (supraspinatus outlet) views were taken, the images were digitalised and evaluated using a TomoCon 3.0 Viewer programme, and the results of the two groups were statistically analysed and compared. The difference between the patients with rotator cuff injury and those without it was best shown, in both groups, by significant differences in the acromion index. This was true for both the men and women. The AI values for the patients with rotator cuff injury were 0.66 and 0.65 in the model and control groups, respectively. The same AI value of 0.76 was found for uninjured rotator cuffs in both groups. The two other parameters investigated did not appear to be of any significant validity for assessment of rotator cuff tears. The aetiology of injury to the rotator cuff has not been fully understood yet but, undoubtedly, the causes will be many. The shape of the acromion is regarded as one of the important factors. We agree with Nyffeler et al. that a lateral extension of the acromion is most often associated with rotator cuff tears and that the acromion index proposed by these authors is a good parameter to assess this morphological change. A lateral extension of the acromion plays an important role in the aetiology of degenerative tears of the supraspinatus tendon. The acromion index appears to be the best instrument for assessing this morphological change.


Kinetics of the interaction of chymotrypsin with eglin c.
The kinetics of binding of recombinant eglin c to bovine pancreatic chymotrypsin was studied by conventional and stopped-flow techniques. With nanomolar enzyme and inhibitor concentrations, the inhibition was fast and pseudo-irreversible (k(assoc.) = 4 x 10(6) m-1.s-1 at 7.4 and 25 degrees C). Reaction of the enzyme-inhibitor complex with alpha 1-proteinase inhibitor, an irreversible chymotrypsin ligand, resulted in a slow release of free eglin c, which was monitored by electrophoresis (k(dissoc.) approximately 1.6 x 10(-6) s-1, t1/2 approximately 5 days). The proflavin displacement method and a stopped-flow apparatus were used to monitor the association of chymotrypsin with eglin c under a wide range of inhibitor concentration and under pseudo-first-order conditions. At pH 7.4 and 25 degrees C or 5 degrees C, or at pH 5.0 and 25 degrees C, the pseudo-first-order rate constant of proflavin displacement increased linearly with eglin c up to the highest concentration tested, suggesting a one-step bimolecular association reaction: E + I in equilibrium with EI. However, kassoc. is much lower than the rate constant for a bimolecular reaction and its activation energy (66 kJ.mol-1 at pH 7.4 and 78 kJ.mol-1 at pH 5.0) is far too high for a diffusion-controlled step. The enzyme-inhibitor association may therefore occur via a loose pre-equilibrium complex EI* (Ki* much greater than 5 x 10(-4) M) that rapidly isomerizes (k2 much greater than 2 x 10(3) s-1) into an extremely stable final complex (Ki approximately 4 x 10(-13) M). Unlike other proteinase-inhibitor systems, the chymotrypsin-eglin association is virtually pH-independent.


[Microcalorimetric study of human serum].
It was established that albumin of donor blood serum denatures in two temperature ranges. It is shown that the first stage of denaturation with Td = 61.5 degrees C is dominant and corresponds to melting of regions not bound to fatty acids. The second stage with Td = 80 degrees C corresponds to melting of regions bound to fatty acids. Serum denaturation heat is equal to 20.2 J/g dry protein. A change in denaturation heat capacity is 0.21 J/(g.K). Analysis of thermal parameters of deconvolution peaks showed that albumin of donor blood serum is in a fatless state and its multiple binding centers are essentially free as compared with freshly isolated albumin and may play an important role in binding of ligands in vivo. The thermal parameters of denaturation of some important human blood serum proteins including gamma-globulins, transferrin ceruloplasmin and protease inhibitors were also determined.


Increased baseline sway contributes to increased losses of balance in older people following triazolam.
Although it has been stated frequently that older people are more sensitive to benzodiazepines, the relative roles of impaired baseline performance, impaired elimination, and altered responsiveness have not been defined. We evaluated postural sway and plasma triazolam concentrations after administration of placebo and triazolam 0.375 mg in both young and older healthy subjects. Double-blind placebo-controlled trial. Nine young and nine older healthy men. All subjects received triazolam 0.375 mg or placebo on different study days, which were separated by at least 48 hours. Postural sway, visual analog scale of drowsiness, and plasma triazolam levels. The older subjects swayed more during triazolam than did the younger subjects, and this resulted in an increased number of losses of balance. This difference appeared to be caused by greater baseline sway in the older subjects rather than higher concentrations or increased responsiveness. A subset of older people had a much greater number of losses of balance during triazolam than did the rest of the subjects, and these individuals could be identified from their baseline sway. In this study, the increase in drug effect seen in the older subjects was of similar magnitude to that of the young, but it resulted in greater postural sway after drug administration than was seen in the young. The higher postural sway and the corresponding increased instability seen in the older subjects may put these older persons at increased risk of drug-related falls. This study also suggests that it should be possible to develop techniques that will identify individuals at particular risk of drug-induced postural instability.


Development and external validation of a nomogram predicting overall survival for Gastric adenocarcinoma patients with radical gastrectomy.
The aim of this study was to develop and externally validate a nomogram to accurately predict the overall survival (OS) of patients with gastric adenocarcinoma who underwent radical gastrectomy. A total of 3492 patients with gastric adenocarcinoma who underwent radical gastrectomy from 2012 to 2017 were included as the training cohort. Survival analysis was performed via Kaplan Meier method and log-rank test. Independent postoperative prognostic factors in patients with gastric adenocarcinoma were analyzed using univariate and multifactorial COX analysis methods. The prognosis nomogram was established in the training cohort and verified externally in the Surveillance, Epidemiology and End Results (SEER) database. According to the univariate and multifactorial COX analyses, metastatic lymph node ratio (MLNR) and five other independent prognostic factors (age at surgery, type of gastrectomy, tumor size, T stage, and pathological grade) were included in the prognostic nomogram. The nomogram had better prognostic predictive ability than the American Joint Committee on Cancer (AJCC) TNM staging in both the training (C-index: 0.736 VS. 0.668) and external validation cohort (C-index: 0.712 VS. 0.627). The calibration plots showed that the predicted survival rate was in good agreement with the actual survival rate. And the decision curve analysis (DCA) curves revealed that nomogram showed stronger ability in predicting 1-year, 3-year, and 5-year OS. This study estimated the excellent prognostic predictive power and clinical application potential of the MLNR-based nomogram, which may be used to facilitate postoperative clinical treatment decisions and potentially improve patient survival outcomes.


Karyopherin Kap114p-mediated trans-repression controls ribosomal gene expression under saline stress.
Nuclear accessibility of transcription factors controls gene expression, co-regulated by Ran-dependent nuclear localization and a competitive regulatory network. Here, we reveal that nuclear import factor-facilitated transcriptional repression attenuates ribosome biogenesis under chronic salt stress. Kap114p, one of the karyopherin-βs (Kap-βs) that mediates nuclear import of yeast TATA-binding protein (yTBP), exhibits a yTBP-binding affinity four orders of magnitude greater than its counterparts and suppresses binding of yTBP with DNA. Our crystal structure of Kap114p reveals an extensively negatively charged concave surface, accounting for high-affinity basic-protein binding. KAP114 knockout in yeast leads to a high-salt growth defect, with transcriptomic analyses revealing that Kap114p modulates expression of genes associated with ribosomal biogenesis by suppressing yTBP binding to target promoters, a trans-repression mechanism we attribute to reduced nuclear Ran levels under salinity stress. Our findings reveal that Ran integrates the nuclear transport pathway and transcription regulatory network, allowing yeast to respond to environmental stresses.


The new bioabsorbable sheet for the sling method in immediate breast reconstruction with expander-implant: a study protocol for interventional prospective study.
The popularity of a sling method using biomaterial sheets for immediate breast reconstruction based on prosthesis has been increasing in western countries. However, acellular dermal matrix, which is representative of the biomaterial sheet, is not available and the sling method also has not been accepted in Japan. We focused on a new bioabsorbable sheet (NEOVEIL sheet) as a substitute for the sling method and report a prospective study protocol to assess the safety and effectiveness of this material. This was an ongoing, single center, open-label, single-arm study. Inclusion criteria and exclusion criteria are defined restrictively. If the surgeon determined that the perfusion of skin envelope after mastectomy is poor, the surgical procedure can be modified and that patient was excluded from the study. The primary outcome was the incidence of tissue expansion or implant explantation occurring within 1 month after surgery. The secondary outcomes are as follows: (1) aesthetic outcome using a rating scale; (2) symmetry of the nipple areolar complex position; (3) patient reported outcomes using BREAST-Q; (4) pain intensity using the Visual Analog Scale; (5) histology of the capsule around the tissue expander; (6) inflation volume at the first stage and overall inflation time of expansion; and (7) other adverse events regarding the surgery. This study will determine the safety and effectiveness of the sling method using a NEOVEIL sheet in Japanese women.


[Diagnostics and treatment of cholangiocarcinoma].
--Cholangiocarcinoma is a rare malignancy originating from the biliary epithelium. The disease can arise anywhere in the biliary tract: intrahepatic, perihilar or distal. The overall prognosis for cholangiocarcinoma is poor. --The treatment necessitates a multidisciplinary approach. --Radical resection of the extrahepatic bile ducts, usually in combination with concomitant partial liver resection, remains the only curative treatment. --Liver transplantation in combination with neoadjuvant chemoradiation therapy seems to be promising in a highly selected group of patients. --Palliative treatment should be targeted at adequate biliary drainage, preferably by stenting. --Radiotherapy and systemic chemotherapy are not standard treatment and should be applied in an experimental setting only. --New options such as photodynamic therapy and tyrosine kinase inhibitors are promising, but still experimental treatments.


Mechanism of chaperone function in small heat-shock proteins. Fluorescence studies of the conformations of T4 lysozyme bound to alphaB-crystallin.
To further develop the mechanistic understanding of small heat-shock protein (sHSP) chaperone activity, we investigate the nature of the intermediate states recognized by alpha-crystallin and the conformations that are stably bound. The model substrates consist of a set of well characterized, destabilized T4 Lysozyme (T4L) mutants that have been shown to differentially bind alpha-crystallin in a manner that reflects their free-energy of unfolding. A new approach for the detection of complex formation is introduced based on the conformational sensitivity of the fluorescent probe bimane, site-specifically introduced in T4L. Emission spectra of bimane-labeled T4L reveal two distinct patterns of intensity changes upon binding that depend on the molar ratio of alpha-crystallin to T4L. This directly demonstrates the two-mode nature of the binding process by the alpha-crystallins. Biphasic binding isotherms, obtained and analyzed over a wide range of T4L concentrations, demonstrate a substantially quenched bimane fluorescence in the low affinity-bound T4L that is similar to the quenching level observed due to denaturant unfolding. Furthermore, the pattern of intensity changes that occur upon binding of a T4L variant, bimane-labeled at an alternative solvent-exposed site, establishes a direct correlation between the quenching level observed in binding and unfolding. The results can be interpreted in terms of a model where alpha-crystallin binds at least two conformationally distinct non-native states of T4L, one of which is substantially unfolded and is bound with low affinity. A high affinity binding mode to compact states may be relevant to chaperone function in the lens, where protein damage is unlikely to cause global unfolding.


Increased Caveolin-2 Expression in Brain Endothelial Cells Promotes Age-Related Neuroinflammation.
Aging is a major risk factor for common neurodegenerative diseases. Although multiple molecular, cellular, structural, and functional changes occur in the brain during aging, the involvement of caveolin-2 (Cav-2) in brain ageing remains unknown. We investigated Cav-2 expression in brains of aged mice and its effects on endothelial cells. The human umbilical vein endothelial cells (HUVECs) showed decreased THP-1 adhesion and infiltration when treated with Cav-2 siRNA compared to control siRNA. In contrast, Cav-2 overexpression increased THP-1 adhesion and infiltration in HUVECs. Increased expression of Cav-2 and iba-1 was observed in brains of old mice. Moreover, there were fewer iba-1-positive cells in the brains of aged Cav-2 knockout (KO) mice than of wild-type aged mice. The levels of several chemokines were higher in brains of aged wild-type mice than in young wild-type mice; moreover, chemokine levels were significantly lower in brains of young mice as well as aged Cav-2 KO mice than in their wild-type counterparts. Expression of PECAM1 and VE-cadherin proteins increased in brains of old wild-type mice but was barely detected in brains of young wild-type and Cav-2 KO mice. Collectively, our results suggest that Cav-2 expression increases in the endothelial cells of aged brain, and promotes leukocyte infiltration and age-associated neuroinflammation.


Stress, Coping Style and Nursing Needs for Hospitalized Pregnant Women due to Preterm Labor.
The purpose of this descriptive study was to assess levels of stress, coping style, and nursing needs for hospitalized pregnant women diagnosed with preterm labor. Data were collected from 125 pregnant women aged between 20 and 40 years and diagnosed with preterm labor by OBGY units at 3 hospitals. Data were analyzed by frequency, percentage, t-test, and ANOVA with Scheffe test. The level of stress among women was an average of 2.13 out of 4 points, the level of coping style was an average of 2.66, and nursing needs was an average of 2.83 out of 4 points. The level of stress was significantly different by job, length of hospital stay, type of hospital, and history of admission at obstetric unit. The level of coping style was significantly different by age and monthly income. The level of nursing needs was significantly different by type of hospital. Higher level of stress and coping style were related to higher level of nursing needs. There was no significant correlation between stress and coping style. The result showed the importance of nursing intervention dealing with stress, coping style and nursing needs for women with preterm labor. Nurses need to provide nursing interventions to reduce the stress, to strengthen the coping style, and to satisfy the nursing needs for pregnant women hospitalized due to preterm labor.


Low-energy laser irradiation reduces formation of scar tissue after myocardial infarction in rats and dogs.
Low-energy laser irradiation (LELI) has been found to attenuate various biological processes in tissue culture and experimental animal models. The aim of the present study was to investigate the effect of LELI on the formation of scar tissue in experimentally induced chronic infarct in rats and dogs. Myocardial infarction (MI) was induced in 50 dogs and 26 rats by ligation of the left anterior descending coronary artery. After induction of MI, the laser-irradiated (LI) group received laser irradiation (infrared laser, 803-nm wavelength) epicardially. Control MI-induced non-laser irradiated (NLI) dogs were sham-operated, and laser was not applied. All dogs were euthanized at 5 to 6 weeks after MI. Infarct size was determined by TTC staining and histology. The laser treatment (P:<0.05) lowered mortality significantly, from 30% to 6.5%, after induction of MI. The infarct size in the LI dogs was reduced significantly (P:<0.0001) (52%) compared with NLI dogs. Histological observation of the infarct revealed a typical scar tissue in NLI dogs and cellularity in most of the LI dogs. Only 14+/-3% of the mitochondria in the cardiomyocytes in the ischemic zone (4 hours after MI) of LI MI-induced rats were severely damaged, compared with 36+/-1% in NLI rats. Accordingly, ATP content in that zone was 7.6-fold (significantly) higher in LI than in NLI rats. Our observations indicate that epicardial LELI of rat and dog hearts after chronic MI caused a marked reduction in infarct size, probably due to a cardioprotective effect of the LELI.


Direct antigonadal activity of cannabinoids: suppression of rat granulosa cell functions.
The direct effects of delta 9-tetrahydrocannabinol (THC) and related cannabinoids on ovarian granulosa cells were studied in vitro. Granulosa cells from immature, hypophysectomized, estrogen-treated rats were cultured for 2 days in an androstenedione-supplemented medium in the presence or absence of follicle-stimulating hormone (FSH) (10 ng/ml) with or without cannabinoids. FSH treatment increased progesterone and estrogen biosynthesis, whereas concomitant treatment with THC led to a dose-dependent inhibition of the FSH-stimulated accumulation of progesterone and estrogen with ED50 values of 3.5 +/- 0.3 X 10(-7) and 1.8 +/- 0.2 X 10(-6) M, respectively. Treatment with related but nonpsychoactive cannabinoids (cannabidiol, cannabinol, cannabigerol, or cannabichromene) was equally effective. The THC-induced inhibition of progesterone production was reversible and was associated with an inhibition of pregnenolone biosynthesis and a decrease of 3 beta-hydroxysteroid dehydrogenase activity. In addition, treatment with THC brought about a dose-dependent inhibition of the FSH-induced increase in luteinizing hormone (LH) receptors. The inhibitory effects of THC were not associated with changes in cell number, protein content, or cell viability. Thus, THC exerts direct inhibitory effects on FSH-dependent functions related to steroidogenesis and the acquisition of LH receptors, all of which are essential to follicular maturation. Because plasma concentrations of THC similar to those used in this study have been reported in human beings, repeated exposure of female users to THC may lead to ovarian dysfunction, due in part, to the direct antigonadal activity to THC.


Seasonal changes in background levels of deuterium and oxygen-18 prove water drinking by harp seals, which affects the use of the doubly labelled water method.
The aim of this study was to monitor seasonal changes in stable isotopes of pool freshwater and harp seal (Phoca groenlandica) body water, and to study whether these potential seasonal changes might bias results obtained using the doubly labelled water (DLW) method when measuring energy expenditure in animals with access to freshwater. Seasonal changes in the background levels of deuterium and oxygen-18 in the body water of four captive harp seals and in the freshwater pool in which they were kept were measured over a time period of 1 year. The seals were offered daily amounts of capelin and kept under a seasonal photoperiod of 69°N. Large seasonal variations of deuterium and oxygen-18 in the pool water were measured, and the isotope abundance in the body water showed similar seasonal changes to the pool water. This shows that the seals were continuously equilibrating with the surrounding water as a result of significant daily water drinking. Variations in background levels of deuterium and oxygen-18 in freshwater sources may be due to seasonal changes in physical processes such as precipitation and evaporation that cause fractionation of isotopes. Rapid and abrupt changes in the background levels of deuterium and oxygen-18 may complicate calculation of energy expenditure by use of the DLW method. It is therefore strongly recommended that analysis of seasonal changes in background levels of isotopes is performed before the DLW method is applied on (free-ranging) animals, and to use a control group in order to correct for changes in background levels.


Indinavir impairs protein synthesis and phosphorylations of MAPKs in mouse C2C12 myocytes.
Anti-retroviral therapy promotes clinical, immunologic, and virologic improvement in human immunodeficiency virus-infected patients. Whereas this therapy adversely affects carbohydrate and lipid metabolism, the effects of anti-retroviral drugs on muscle protein synthesis and degradation have not been reported. To examine these processes, we treated C2C12 myocytes with increasing concentrations of the protease inhibitor indinavir for 1 or 2 days. Treatment of myocytes with a therapeutic concentration of indinavir (20 microM) for 24 h decreased basal protein synthesis by 18%, whereas a 42% decline was observed after 48 h. A similar decrement, albeit quantitatively smaller, was detected with other protease inhibitors. Indinavir did not alter the rate of proteolysis. Likewise, indinavir did not impair the anabolic effect of insulin-like growth factor-I on protein synthesis. Mechanistically, indinavir decreased the phosphorylation of the S6 ribosomal protein (rpS6), and this reduction was associated with a decreased phosphorylation of p70S6 kinase and p90rsk as well as the upstream regulators ERK1/2 and MEK1/2. Indinavir also decreased the phosphorylation of Mnk1 and its upstream effectors, p38 MAPK and ERK1/2. Indinavir did not affect the phosphorylation of mTOR or 4E-BP1, but it did decrease the amount of the active eukaryotic initiation factor eIF4G-eIF4E complex. In conclusion, indinavir decreased protein synthesis in myocytes. This decrease was associated with the disruption of the ERK1/2 and p38 MAPK pathways and a reduction in both the level of functional eIF4F complex and rpS6 phosphorylation.


Site-specific familial risk and survival of familial and sporadic head and neck cancer.
The vast majority of head and neck cancers (HNCs) are sporadic squamous cell carcinomas, smoking and heavy drinking being the main risk factors. However, little is known about the possible role of family history and the importance of inherited factors versus shared environment. We used Swedish population-based registries to study the family history of HNC. In order to estimate the risk for family members to get the same cancer, and the risk for cancer-specific death in patients with a family history of HNC compared with patients without a family history, multivariate Cox proportional hazards analyses were performed. A 1.43-fold increased risk for developing HNC in the first-degree relatives (FDRs) of HNC patients [hazard ratio (HR), 1.43; 95% CI, 1.28-1.61] was found, when compared with relatives of healthy controls. In spouses of patients with HNC, the risk for developing any HNC was moderately increased (HR, 1.25; 95% CI, 1.01-1.53), compared with spouses of healthy controls. In addition, a 1.34-fold increased risk for death of HNC was found in HNC patients with a family history of HNC (HR, 1.34; 95% CI, (1.03-1.73) compared with HNC patients without a family history. We found an increased risk for HNC in relatives and spouses of HNC patients, when compared with family members of healthy controls. This suggests that in addition to inherited factors, shared environmental factors have a significant role in the development of the cancer. Family history of HNC was associated with worse survival in a newly diagnosed HNC patient.


Quantifying the effects of anagenetic and cladogenetic evolution.
An ongoing debate in evolutionary biology is whether phenotypic change occurs predominantly around the time of speciation or whether it instead accumulates gradually over time. In this work I propose a general framework incorporating both types of change, quantify the effects of speciational change via the correlation between species and attribute the proportion of change to each type. I discuss results of parameter estimation of Hominoid body size in this light. I derive mathematical formulae related to this problem, the probability generating functions of the number of speciation events along a randomly drawn lineage and from the most recent common ancestor of two randomly chosen tip species for a conditioned Yule tree. Additionally I obtain in closed form the variance of the distance from the root to the most recent common ancestor of two randomly chosen tip species.


Competitive binding kinetics in ligand-receptor-competitor systems. Rate parameters for unlabeled ligands for the formyl peptide receptor.
We describe the real-time kinetics of the competition of different ligands for the same receptor and use the computer routine SAAM to simulate this competition. Based on the simulation, we have developed two experimental approaches whereby the parameters of the interaction of nonlabeled ligands with their receptor can be detected; briefly, the analysis of the nonlabeled ligands depends on the perturbation of the kinetics of interaction of labeled ligands with the receptor with which they are in competition. The approach relies primarily upon an analysis of the kinetics of the competition between fluorescent and nonfluorescent ligands using a real-time, homogeneous binding assay in the fluorescence flow cytometer. A secondary approach depends upon an examination of the kinetic impact of antagonists on the responses of cells stimulated by agonists at the same receptor. Experimental verification of these approaches has been obtained using the N-formyl peptides (and their antagonists) which bind to receptors on human neutrophils and produce rapid cell stimulation. We find that agonistic N-formyl peptides have residence times of minutes while nonstimulatory antagonists have residence periods of, at most, a few seconds at these receptors. The limitations and general range of applicability of these procedures are discussed. The main advantage of these approaches is that they permit the evaluation of kinetic parameters of unlabeled ligands, even those which bind weakly or which have brief residence times--properties which make analyses by conventional methods difficult.


A descriptive evaluation of transfusion practices in patients receiving mechanical ventilation.
To characterize and compare transfusion practices in a broad sample of patients receiving mechanical ventilation (MV) and not receiving MV in the ICU. Retrospective subgroup analysis from the prospective, multicenter, observational CRIT study. Two hundred eighty-four medical, surgical, or medical/surgical ICUs. Critically ill adults. Of the 4,892 patients enrolled in the CRIT study, 60% were receiving MV on ICU admission or within 48 h after admission for a median of 4 days. Patients receiving MV had higher baseline APACHE (acute physiology and chronic health evaluation) II scores than patients not receiving MV (22.8 +/- 7.8 and 14.9 +/- 6.4, respectively [mean +/- SD]; p < 0.0001). Despite similar baseline hemoglobin levels (11.0 +/- 2.3 g/dL and 10.9 +/- 2.5 g/dL, p = 0.17), more patients receiving MV underwent transfusions (49% vs 33%, p < 0.0001), and they received significantly more RBCs than patients not receiving MV (p < 0.0001). The principal reason for transfusion in both groups was low hemoglobin level (78.4% and 84.6%, respectively); however, patients receiving MV had higher pretransfusion hemoglobin levels (8.7 +/- 1.7 g/dL) than patients not receiving MV (8.2 +/- 1.7 g/dL, p < 0.0001). Notably, 40.1% of all transfusions in patients receiving MV were administered after day 3 of the ICU stay, compared to 21.2% in patients not receiving MV (p < 0.0001), and a higher percentage of patients receiving MV remaining in the ICU after day 3 underwent transfusions (33.4% vs 18.3%, p < 0.0001). Mortality was higher (17.2% vs 4.5%, p < 0.0001) and mean hospital (15 days vs 10 days, p < 0.0001) and ICU stays (9 days vs 4 days, p < 0.0001) were longer in the subgroup receiving MV. Mechanical ventilation appears to be an easily identifiable early marker for allogeneic blood exposure risk in ICU patients. While the longer ICU stays account for much of this risk, patients receiving MV also appear to undergo transfusions at higher hemoglobin thresholds than patients not receiving MV, at least early in the ICU stay. Justification of this relatively liberal transfusion practice in patients receiving MV will require further study.


Impact of Hyperinsulinemia on Long-Term Clinical Outcomes of Percutaneous Coronary Intervention in Patients without Diabetes Who Have Acute Myocardial Syndrome.
Hyperinsulinemia plays a key role in the development of cardiovascular impairment in patients with metabolic syndrome. The aim of this study was to evaluate the influence of hyperinsulinemia on long-term clinical outcomes of percutaneous coronary intervention (PCI) in patients without diabetes mellitus who have acute myocardial syndrome (ACS). Between March 2016 and January 2019, we enrolled 468 patients with ACS and without diabetes mellitus who received primary PCI. Patients were divided into a low-insulin group (n = 157), medium-insulin group (n = 154), and high-insulin group (n = 157) according to tertiles of fasting insulin level. The primary endpoint was major adverse cardiac events (MACE; all-cause death, non-fatal myocardial infarction, target vessel revascularization [TVR]) at 24 months. The secondary endpoint was angina hospitalization. Patients in the high-insulin group had an unfavorable prognosis, with a higher rate of MACE (34.39%) than the low-insulin group (22.29%) and medium-insulin group (23.37%) at 24 months (P < 0.05). This difference was mainly driven by the increase in TVR. The high-insulin group also had a higher rate of angina hospitalization than the low-insulin group. Cox proportional hazards regression showed that high-insulin level (hazard ratio [HR] 1.870, 95% confidence interval [CI] 1.202-2.909), small-vessel lesion (HR 1.713, 95% CI 1.111-2.642), bifurcation lesion (HR 3.394, 95% CI 2.033-5.067), SYNTAX score (HR 1.084, 95% CI 1.039-1.130), and stent length (HR 1.017, 95% CI 1.002-1.032) increased the incidence of MACE in patients with ACS and without diabetes who underwent PCI. Hyperinsulinemia might be a valid predictor of clinical outcomes in patients with ACS undergoing PCI.


Effect of anesthetics on pathogenesis of experimentally induced murine pneumococcal pneumonia.
To define the effects of three commonly used anesthetic agents--sodium pentobarbital given intraperitoneally, and inhaled halothane and methoxyflurane--on the pathogenesis of pneumococcal pneumonia and bacteremia in an experimental murine model. Swiss outbred mice were anesthetized with either sodium pentobarbital, halothane, or methoxyflurane before intranasal infection with Streptococcus pneumonia. At defined times after infection, bacterial numbers in lungs and blood, markers of acute lung injury, and lung cytokine levels were compared. Mice anesthetized with inhaled halothane or methoxyflurane prior to intranasal inoculation with type-2 Streptococcus pneumoniae developed pneumonia and bacteremia distinctly different from that in mice anesthetized by intraperitoneal (IP) administration of sodium pentobarbital. Mice having brief exposure to inhaled halothane or methoxyflurane had significantly greater numbers of bacteria in lungs and blood 48 hours after inoculation, compared with mice anesthetized by IP administration of pentobarbital. Also, mice inhaling halothane had significantly decreased activities of pro-inflammatory cytokines interleukin 6 and tumor necrosis factor-alpha in lung homogenates at 24 hours after inoculation, compared with those given pentobarbital IP. Effects of anesthesia on murine models of pneumonia should be considered in the design and interpretation of studies of pneumococcal pathogenesis.


Protocol for the Prognostication of Consciousness Recovery Following a Brain Injury.
Individuals who have suffered a severe brain injury typically require extensive hospitalization in intensive care units (ICUs), where critical treatment decisions are made to maximize their likelihood of recovering consciousness and cognitive function. These treatment decisions can be difficult when the neurological assessment of the patient is limited by unreliable behavioral responses. Reliable objective and quantifiable markers are lacking and there is both (1) a poor understanding of the mechanisms underlying the brain's ability to reconstitute consciousness and cognition after an injury and (2) the absence of a reliable and clinically feasible method of tracking cognitive recovery in ICU survivors. Our goal is to develop and validate a clinically relevant EEG paradigm that can inform the prognosis of unresponsive, brain-injured patients in the ICU. This protocol describes a study to develop a point-of-care system intended to accurately predict outcomes of unresponsive, brain-injured patients in the ICU. We will recruit 200 continuously-sedated brain-injured patients across five ICUs. Between 24 h and 7 days post-ICU admission, high-density EEG will be recorded from behaviorally unresponsive patients before, during and after a brief cessation of pharmacological sedation. Once patients have reached the waking stage, they will be asked to complete an abridged Cambridge Brain Sciences battery, a web-based series of neurocognitive tests. The test series will be repeated every day during acute admission (ICU, ward), or as often as possible given the constraints of ICU and ward care. Following discharge, patients will continue to complete the same test series on weekly, and then monthly basis, for up to 12 months following injury. Functional outcomes will also be assessed up to 12 months post-injury. We anticipate our findings will lead to an increased ability to identify patients, as soon as possible after their brain injury, who are most likely to survive, and to make accurate predictions about their long-term cognitive and functional outcome. In addition to providing critically needed support for clinical decision-making, this study has the potential to transform our understanding of key functional EEG networks associated with consciousness and cognition.


A defect in renal calcium conservation may contribute to the pathogenesis of postmenopausal osteoporosis.
Although all postmenopausal women are estrogen deficient, women who have postmenopausal osteoporosis may have a defect, in addition to estrogen deficiency, that accounts for their higher rates of bone resorption and greater bone loss, relative to those who do not. To test the hypothesis that one defect is an impairment in renal calcium conservation, we measured renal calcium transport in 19 osteoporotic and 19 normal postmenopausal women, whose ages (median and 25th-75th percentile range) were 70 yr (range, 67-72) and 72 yr (range, 69-74), respectively. There was no difference between groups in values for serum ionized calcium and PTH concentrations or in renal filtered load of calcium. However, before PTH infusion, the osteoporotic women had lower (P = 0.0046) values for tubular reabsorption of calcium (TRCa) of 96.8% (range, 96.0-97.1) vs. 98.0% (range, 97.2-98.3) and higher (P = 0.0154) urinary calcium excretion of 0.194 mg/dL of glomerular filtrate (GF) (0.154-0.239) vs. 0.125 mg/dL of GF (0.103-0.173) than the normal women. After infusion of 200 U of synthetic PTH (synthetic 1-34 analog of human PTH), TRCa increased and calcium excretion decreased comparably in both groups, so that the differences between groups after intervention remained: for TRCa, 98.3% (97.7-98.6) vs. 98.9% (98.4-99.3; P = 0.0042); and for calcium excretion, 0.099 mg/dL of GF (0.080-0.138) vs. 0.066 mg/dL of GF, (0.045-0.097, P = 0.0180). In conclusion, postmenopausal women with osteoporosis have a PTH-independent defect in renal calcium conservation. This defect is of sufficient magnitude to contribute to the greater negative calcium balance in post-menopausal women with osteoporosis vs. their postmenopausal peers.


Role of stereoelectronic features of imine and enamine in (S)-proline catalyzed Mannich reaction of acetaldehyde: an in silico study.
A detailed mechanistic investigation of sixteen possible diastereomeric pathways for the C-C bond formation step in (S)-proline catalyzed Mannich reaction of acetaldehyde with N-acetyl protected benzaldimine in acetonitrile solvent has been carried out to understand how stereoelectronic features invoke enantioselectivity of the final product. Both kinetic and thermodynamic factors of the reaction obtained using various density functional theory methods point out that si-enantiofacial nucleophilic attack of anti-enamine on the iminium carbon of the E, s-cis N-acetyl protected imine is the stereoselective pathway. Structural features of the transition states predicted that enamine in anti conformation attacks the imine through a Burgi-Dunitz trajectory to yield the stereocenter. Computations at B3LYP-PCM/6-311++G(3df,2p)//B3LYP-PCM/6-31G(d,p) level showed a strong linear correlation between Burgi-Dunitz angle and activation energy when anti-enamine is used as nucleophile to react with all the configurations of the imine. Further, energy decomposition analysis has been carried out at B3LYP/TZ2P+ level for all the transition states, which revealed that the most dominant factor that control the enantioselectivity of the (S)-proline catalyzed Mannich reaction is steric effect. Though the less favored transition states showed high amount of stabilizing orbital interaction, the destabilizing steric effects from both Pauli repulsion and preparation energy for the reactant molecules are very high and overshadowed the stabilizing effects. However, in the most favored transition state, a balanced outcome of electronic and steric effects was observed. Solvation effect was nearly same for all the transition states and electrostatic effects showed no correlation to the rank order of the energy of the transition states.


Effect of transferrin on hypomyelination induced by iron deficiency.
We have used a model of iron deficiency in the rat to analyze the effects of a disruption in iron availability on oligodendroglial cell (OLGc) maturation and myelinogenesis and to explore the possible beneficial influence of an intracranial injection (ICI) of apotransferrin (aTf) at 3 days of age on this process. Studies carried out on postnatal days 17 and 24 showed that iron deficiency produced a decrease in myelin proteins and lipids at 24 days of age. Immunohistochemistry showed that in untreated iron-deficient (ID) rats, the immunoreactivity of anti-adenomatous polyposis coli (APC) and anti-MBP antibodies decreased markedly with reference to normal controls, whereas in ID rats treated with an ICI of aTf, the immunoreactivity of these markers increased. A similar situation occurred with the immunoreactivity of H-ferritin. In primary OLGc cultures from ID rats, there was a high number of cells positive to the antibody against the polysialylated form of the cell surface glycoprotein NCAM (PSA-NCAM) compared with in OLGc cultures prepared from normal controls or from ID animals treated with aTf. The number of MBP+ cells in cultures from ID rats increased after treatment with aTf. The presence of lipid rafts evaluated with a specific anti-protein prion cellular (PrPc) antibody showed a smaller number of PrPc-positive structures in ID rat cultures. Treatment of the ID animals with a single ICI of aTf stimulated myelination, producing a significant correction in the different biochemical parameters affected by ID.


Potentiation of human immunodeficiency virus type 1 Tat by human cellular proteins.
The Tat protein is a potent activator of human immunodeficiency virus type 1 transcription. Tat has been shown to act by increasing both transcription initiation and elongation, but a detailed understanding of its interaction with the transcriptional machinery is lacking. With the aim of isolating cellular proteins that interact with Tat and play a role in transactivation, we have reexamined its function in a cell-free transcription assay. Monitoring the appearance of transactivation after addition of purified Tat at intervals to the reaction mix revealed a lag of approximately 10 min before Tat is able to effect transactivation. Incubation of Tat in nuclear or cytoplasmic extracts of human cells was sufficient to eliminate the lag, but nuclear extract from a rodent cell line was inactive. The accelerating effect of the human cell extract could be abrogated by dilution, heat inactivation, or chromatographic depletion. We infer that Tat is potentiated for transactivation through interaction with a protein factor(s) that is specific to human cells.


Outcomes of simultaneous liver/kidney transplants are equivalent to kidney transplant alone: a preliminary report.
With adoption of Model for End-Stage Liver Disease, the number of simultaneous liver-kidney transplants (SLK) has greatly increased. A recent registry study questioned the equity of allocating kidney transplants (KTx) simultaneously with liver transplantation due to poor outcomes (Locke et al., Transplantation 2008; 85: 935). To investigate outcome of KTx in SLK, all SLK (n=36) performed at our center from January 2000 to December 2007 were reviewed and KTx outcomes compared with those of kidney transplant alone (KTA) performed during that period (n=1283). We also reviewed whether pretransplant panel reactive antibody and donor-specific antibody affected KTx outcome in SLK. One- and 3-year KTx and patient survival were not different between KTA and SLK regardless of sensitization level. There were 348 (27%) KTx failures in KTA vs. 6 (17%) in SLK (NS). Overall freedom from acute cellular rejection (ACR) and antibody-mediated rejection (AMR) in SLK was 93 and 96% at 3 years, compared with 72 and 78% in KTA (P=0.0105 and P=0.0744, respectively). Sensitized KTx recipients had more ACR and AMR (32 and 38%) at 3 years compared with nonsensitized recipients (28 and 20%) (P=0.23 and 0.0001, respectively). No differences in ACR and AMR were observed when SLK was divided and level of sensitization compared (P=0.17 and 0.65, respectively). SLK is a life-saving procedure with excellent patient and graft survival. AMR incidence in the KTx appears reduced in SLK compared with KTA regardless of level of preoperative panel reactive antibody. A high level of donor-specific antibody should not preclude simultaneous transplantation when clinically indicated.


Genetic Control of Genomic Alterations Induced in Yeast by Interstitial Telomeric Sequences.
In many organisms, telomeric sequences can be located internally on the chromosome in addition to their usual positions at the ends of the chromosome. In humans, such interstitial telomeric sequences (ITSs) are nonrandomly associated with translocation breakpoints in tumor cells and with chromosome fragile sites (regions of the chromosome that break in response to perturbed DNA replication). We previously showed that ITSs in yeast generated several different types of instability, including terminal inversions (recombination between the ITS and the "true" chromosome telomere) and point mutations in DNA sequences adjacent to the ITS. In the current study, we examine the genetic control of these events. We show that the terminal inversions occur by the single-strand annealing pathway of DNA repair following the formation of a double-stranded DNA break within the ITS. The point mutations induced by the ITS require the error-prone DNA polymerase ζ. Unlike the terminal inversions, these events are not initiated by a double-stranded DNA break, but likely result from the error-prone repair of a single-stranded DNA gap or recruitment of DNA polymerase ζ in the absence of DNA damage.


[In vivo degradation of PDLLA membrane made in China:a study on rats]
OBJECTIVE:The possibility of absorbable membrane materials poly PDLLA using in guided tissue regeneration(GTR)was evaluated through degradation in vivo. METHODS: membranes were implanted in the drosal subcutis of rats for periods of 1,2,4,8,12weeks.The surface morphology was observed,the mass loss was measured and molecular weight was determined with gel permeation chromatography(GPC). RESULTS: The mass loss were similar to those in virto,and molecular weight changes were the same to those in vitro,but the number average molecular weight did not fit the Pitt's model. CONCLUSION: The surface morphology of PDLLA membrane remained relatively unaltered,its integrity kept more than 12 weeks,which could meet the requirements of GTR.


Natural products in agarwood and Aquilaria plants: chemistry, biological activities and biosynthesis.
Covering: Up to the end of 2019.Agarwood is a resinous portion of Aquilaria trees, which is formed in response to environmental stress factors such as physical injury or microbial attack. It is very sought-after among the natural incenses, as well as for its medicinal properties in traditional Chinese and Ayurvedic medicine. Interestingly, the chemical constituents of agarwood and healthy Aquilaria trees are quite different. Sesquiterpenes and 2-(2-phenethyl)chromones with diverse scaffolds commonly accumulate in agarwood. Similar structures have rarely been reported from the original trees that mainly contain flavonoids, benzophenones, xanthones, lignans, simple phenolic compounds, megastigmanes, diterpenoids, triterpenoids, steroids, alkaloids, etc. This review summarizes the chemical constituents and biological activities both in agarwood and Aquilaria trees, and their biosynthesis is discussed in order to give a comprehensive overview of the research progress on agarwood.


Identification of a novel cell type in peripheral lymphoid organs of mice. 3. Functional properties in vivo.
Several properties of lymphoid dendritic cells in situ have been determined, and contrasted to information previously established for lymphocytes and mononuclear phagocytes. Dendritic cells are not found in newborn mice, and their concentration in both spleen and mesenteric lymph node does not reach adult levels until 3-4 wk of age. Dendritic cells largely disappear from adherent populations following administration of steroids (2.5 mg hydrocortisone acetate s.c.) and ionizing radiation (D(o) of 100 rads for Co(60)). Splenic dendritic cells can originate from precursors located in both bone marrow and spleen itself, probably the red pulp. The mature splenic population does not actively divide (pulse labeling index with [(3)H]thymidine of 1.5-2.5%), but does turnover at substantial rate, 10+% of the total pool per day. The influx of new cells appears to be derived from a proliferating precursor compartment, but the mechanism for efflux or turnover is not known. Dendritic cells in spleen and node undergo little or moderate increase in numbers during development of a primary immune response. These in vivo characteristics, taken together, further distinguish dendritic cells as a novel cell type, distinct from mononuclear phagocytes and lymphocytes.


Body Mass Index From Early-, Mid-, and Older-Adulthood and Risk of Heart Failure and Atherosclerotic Cardiovascular Disease: MESA.
Background Obesity contributes significantly to risk of atherosclerotic cardiovascular disease (ASCVD) and especially for heart failure (HF). An elevated body mass index (BMI) in older adults might not carry the same risk as in younger adults, but measured weights at other lifetime points are often not available. We determined the associations of self-reported weights from early- and mid-adulthood, after accounting for measured weight at older age, with incident HF/ASCVD risk. Methods and Results We studied 6437 MESA (Multi-Ethnic Study of Atherosclerosis) participants (aged 45-84, free of baseline HF/ASCVD) with self-reported weights at ages 20 and 40 years (by questionnaire), measured weights at up to 5 in-person examinations (2000-2012), and follow-up for adjudicated HF/ASCVD events. Participant mean±SD age at the baseline examination was 62.2±10.2 years. Over median follow-up of 13 years, 290 HF and 828 ASCVD events occurred. After adjustment for cardiovascular risk factors and baseline BMI, higher self-reported weights at ages 20 and 40 years were independently associated with increased risk of incident HF with hazard ratios (95% confidence interval) of 1.27 (1.07-1.50) and 1.36 (1.18-1.57), respectively, per 5-kg/m2 higher BMI. For incident ASCVD, only higher BMI at age 20 years was associated after accounting for current BMI (1.13 [1.01-1.26] per 5 kg/m2). Obesity during follow-up examinations was also associated with incident HF (1.72 [1.21-2.45]) but not ASCVD. Conclusions Self-reported lifetime weight is a low-tech tool easily utilized in any clinical encounter. Although subject to recall bias, self-reported weights may provide prognostic information about future HF risk, incremental to current BMI, in a multiethnic cohort of middle-aged to older adults. Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT00005487.


High-Performance Near-Infrared Chlorinated Rylenecarboximide Fluorophores via Consecutive C-N and C-C Bond Formation.
A new class of near-infrared (NIR) fluorophores, PAI, is obtained by consecutive C-N/C-C bond formation between diphenylamines and 9,10-dibromoperylenecarboximide. Owing to the rigid structure, extended π-conjugation and pronounced push-pull substitution, these fluorophores show emission maxima up to 804 nm and large Stokes shifts. The extraordinarily high fluorescence quantum yields from 47 % to 70 % are attributed to chloro substitution in the bay positions of the perylene core. These characteristics, together with high photostability, qualify them as useful NIR emitters for applications as biomarkers and security inks.


The visual speech head start improves perception and reduces superior temporal cortex responses to auditory speech.
Visual information about speech content from the talker's mouth is often available before auditory information from the talker's voice. Here we examined perceptual and neural responses to words with and without this visual head start. For both types of words, perception was enhanced by viewing the talker's face, but the enhancement was significantly greater for words with a head start. Neural responses were measured from electrodes implanted over auditory association cortex in the posterior superior temporal gyrus (pSTG) of epileptic patients. The presence of visual speech suppressed responses to auditory speech, more so for words with a visual head start. We suggest that the head start inhibits representations of incompatible auditory phonemes, increasing perceptual accuracy and decreasing total neural responses. Together with previous work showing visual cortex modulation (Ozker et al., 2018b) these results from pSTG demonstrate that multisensory interactions are a powerful modulator of activity throughout the speech perception network.


Human sedative self-administration: effects of interingestion interval and dose.
In a residential hospital ward setting, either sodium pentobarbital, diazepam or ethanol was made availabe for oral ingestion to volunteer human subjects with documented histories of drug abuse. During specified portions of the day, tokens could be earned by riding an exercise bicycle and exchanged for doses of a drug. Increases in the required minimum interingestion interval from 0 to 30 minutes produced decreases in the number of ingestions of sodium pentobarbital and diazepam. In another experiment, increases in the dose per ingestion (30-90 mg of sodium pentobarbital, 2-10 mg of diazepam, or 1.86-11.14 g of ethanol) produced increases in the number of ingestions. In both experiments, the effects of the manipulated variable were similar for all of the drugs studied. The study demonstrates the feasibility of human self-administration research with the sedative drugs, sodium pentobarbital and diazepam, for which substantive experimental data have not previously been reported. In addition, the results indicate that both dose and minimum interingestion interval bear a systematic controlling relationship to the occurrence of drug self-administration behavior.


Metabolomic Effects of Folic Acid Supplementation in Adults: Evidence from the FACT trial.
Folic acid (FA) is the oxidized form of folate found in supplements and FA-fortified foods. Most FA is reduced by dihydrofolate reductase to 5-methyltetrahydrofolate (5mTHF); the latter is the form of folate naturally found in foods. Ingestion of FA increases plasma levels of both 5mTHF and unmetabolized FA (UMFA). Limited information is available on downstream metabolic effects of supplemental FA intake, including potential effects associated with UMFA. We aimed to assess the metabolic effects of FA-supplementation, and the associations of plasma 5mTHF and UMFA with the metabolome in FA-naïve Bangladeshi adults. Sixty participants were selected from the Folic Acid and Creatine Trial (FACT); half received 800 μg FA/day for 12 weeks and half placebo. Plasma metabolome profiles were measured by high-resolution mass spectrometry, including 170 identified metabolites and 26,541 metabolic features. Penalized regression methods were used to assess the associations of targeted metabolites with FA-supplementation, 5mTHF, and UMFA. Pathway analyses were conducted using Mummichog. In penalized models of identified metabolites, FA-supplementation was associated with higher choline. Changes in 5mTHF concentrations were positively associated with metabolites involved in amino acid metabolism (5-hydroxyindoleacetic acid, acetylmethionine, creatinine, guanidinoacetate, hydroxyproline/n-acetylalanine) and two fatty acids (docosahexaenoic acid and linoleic acid). Changes in 5mTHF concentrations were negatively associated with acetylglutamate, acetyllysine, carnitine, propionyl carnitine, cinnamic acid, homogentisate, arachidonic acid and nicotine. UMFA concentrations were associated with lower levels of arachidonic acid. Together, metabolites selected across all models were related to lipids, aromatic amino acid metabolism, and the urea cycle. Analyses of nontargeted metabolic features identified additional pathways associated with FA supplementation. In addition to the recapitulation of several expected metabolic changes associated with 5mTHF, we observed additional metabolites/pathways associated with FA-supplementation. Further studies are needed to confirm these associations and assess their potential implications for human health. This trial was registered at https://clinicaltrials.gov as NCT01050556.


Audiovestibular symptoms as predictors of prolonged sports-related concussion among NCAA athletes.
We looked to determine the rates of audiovestibular symptoms following sports-related concussions among collegiate athletes. Further, we assessed the correlation between these symptoms and the time to return to participation in athletic activity. Retrospective analysis of the National Collegiate Athletic Association Injury Surveillance System (NCAA-ISS). The NCAA-ISS was queried from 2009 through 2014 for seven men's sports and eight women's sports across divisions 1, 2, and 3. Injuries resulting in concussions were analyzed for audiovestibular symptoms, duration of symptoms, and return to participation times. From 2009 to 2014, there were 1,647 recorded sports-related concussions, with athletes reporting dizziness (68.2%), imbalance (35.8%), disorientation (31.4%), noise sensitivity (29.9%), and tinnitus (8.5%). Concussion symptoms resolved within 1 day (17.1%), within 2 to 7 days (50.0%), within 8 to 30 days (25.9%), or persisted over 1 month (7.0%). Return to participation occurred within 1 week (38.3%), within 1 month (53.0%), or over 1 month (8.7%). Using Mann-Whitney U testing, overall symptom duration and return to competition time were significantly increased when any of these symptoms were present (P < 0.05). Duration of concussion symptom correlated with dizziness (P = 0.043) and noise sensitivity (P = 0.000), whereas return to participation times correlated with imbalance (P = 0.011) and noise sensitivity (P = 0.000). Dizziness and imbalance (odds ratio: 4.15, confidence interval: 3.20-5.38, P < 0.001) were the two symptoms with the strongest association. Audiovestibular symptoms are common complaints among collegiate athletes sustaining concussions. Dizziness and noise sensitivity correlated with the duration of concussive symptoms, whereas imbalance and noise sensitivity was correlated with prolonged return to competition time. 4. Laryngoscope, 127:2850-2853, 2017.


Investigation of potential RNA bulge stabilizing elements.
As a part of our interest in recognition and cleavage of RNA we carried out thermal melting studies with the aim of screening a number of simple oligonucleotide modifications for their potential as modifying elements for RNA bulge stabilizing oligonucleotides. A specific model system from our studies on oligonucleotide-based artificial nuclease (OBAN) systems was chosen and the bulge size was varied from one to five nucleotides. Introduction of single 2'-modified nucleoside moieties (2'-O-methyl, 2'-deoxy and 2'-deoxy-2'-amino) with different conformational preferences adjacent to the bulge revealed that a higher preference for the north conformers gave more stable bulges across the whole range of bulge sizes. Changing a bulge closing a G-U wobble base pair to a G-C pair resulted in the interesting observation that, although the fully complementary complex and small bulges were highly stabilized, there was little difference in the stability of the larger bulges. The wobble base pair even gave a slight stabilization of the 5 nt bulge system. Introduction of a uridine C-5 linker with a single ammonium group was clearly bulge stabilizing (DeltaT(m) + 4.6 to + 5.4 degrees C for the three most stabilized bulges), although with limited selectivity for different bulge sizes since the fully complementary duplex was also stabilized. Introduction of a naphthoyl group on a 2'-aminolinker mostly gave a destabilizing effect, while introduction of a 5-aminoneocuproine moiety on the same linker resulted in stabilization of all bulges, in particular those with two or four unpaired nucleotides (DeltaT(m) + 3.6 and + 2.9 degrees C respectively). The aromatic groups destabilize the fully complementary duplex, resulting in higher selectivity towards stabilization of bulges. A combination of the studied partial element should be suitable for future designs of modified oligonucleotides that, apart from standard base pairing, can also provide additional non-Watson-Crick recognition of RNA.


Near-infrared spectroscopy for prediction of extubation success after neonatal cardiac surgery.
Reliable predictors of extubation readiness are needed and may reduce morbidity related to extubation failure. We aimed to examine the relationship between changes in pre-extubation near-infrared spectroscopy measurements from baseline and extubation outcomes after neonatal cardiac surgery. In this retrospective cross-sectional multi-centre study, a secondary analysis of prospectively collected data from neonates who underwent cardiac surgery at seven tertiary-care children's hospitals in 2015 was performed. Extubation failure was defined as need for re-intubation within 72 hours of the first planned extubation attempt. Near-infrared spectroscopy measurements obtained before surgery and before extubation in patients who failed extubation were compared to those of patients who extubated successfully using t-tests. Near-infrared spectroscopy measurements were available for 159 neonates, including 52 with single ventricle physiology. Median age at surgery was 6 days (range: 1-29 days). A total of 15 patients (9.4 %) failed extubation. Baseline cerebral and renal near-infrared spectroscopy measurements were not statistically different between those who were successfully extubated and those who failed, but pre-extubation cerebral and renal values were significantly higher in neonates who extubated successfully. An increase from baseline to time of extubation values in cerebral oximetry saturation by ≥ 5 % had a positive predictive value for extubation success of 98.6 % (95%CI: 91.1-99.8 %). Pre-extubation cerebral near-infrared spectroscopy measurements, when compared to baseline, were significantly associated with extubation outcomes. These findings demonstrate the potential of this tool as a valuable adjunct in assessing extubation readiness after paediatric cardiac surgery and warrant further evaluation in a larger prospective study.


Dissociative chemisorption of O2 on Agn and Agn-1Ir (n = 3-26) clusters: a first-principle study.
Understanding the interactions between O2 and small metal clusters is of great importance in exploring heterogeneous catalysis particularly involving an oxidation reaction. We herein present the dissociative chemisorption of O2 on Agn and Agn-1Ir clusters (n = 3-26) by using density functional theory calculations. Combining a particle swarm optimization algorithm and a minima hopping method, we have optimized and obtained stable geometric structures of Agn and Agn-1Ir clusters without and with O2 adsorption. Some important physical parameters, including bond length, adsorption energy, dissociation barriers and bader charge, have been systematically calculated for appraising the stability and reactivity of Agn and Agn-1Ir clusters. It is found that the dopant Ir atom can largely enhance the stability and promote the O2 dissociation, especially on small Agn-1Ir clusters (n = 3-10). It is mainly attributed to the dopant Ir atom being completely exposed outside the Ag atoms. For O2 adsorption and dissociation on large Agn-1Ir clusters (n = 11-26), the dissociation barriers are much higher due to the dopant Ir emerging into the core of Agn-1Ir clusters, which is very similar to those on large Agn (n = 11-26). Microkinetic simulation results provide direct evidence for high reaction temperature and pressure effects on improving O2 dissociation on Agn and Agn-1Ir clusters especially for small clusters (n < 10). It is found that the Ag5Ir cluster is the most suitable nanocluster for promoting O2 dissociation at the given reaction temperatures and pressures. Our theoretical work is helpful for the rational design of doped silver nanocluster catalysts in future experiments.


Seeking knowledge, discovering learning: uncovering the impetus for baccalaureate nursing studies in Malaysian Borneo.
Changes to the nursing profession over recent decades have provoked an increasing migration of nursing education into the tertiary sector. For nurses who live and work in developing nations, such as Malaysia, opportunities for further study might be limited, particularly for those located in more remote regions. This paper reports on a research study of registered nurses who undertook baccalaureate degree studies in off-campus mode in Malaysian Borneo. A grounded theory methodology was employed in this research, which is part of a larger study into the nature and outcomes of change experienced as a result of postregistration degree studies. This paper explores the reasons why nurses in this location enrolled in one such course and the extent to which completion of their studies addressed their motivational goals. The findings indicate that the experience of learning and acquisition of knowledge was well beyond what was expected, resulting in a sense of achievement that was similarly unanticipated.


Biosynthesis of vitamin B12: factor IV, a new intermediate in the anaerobic pathway.
The structure of a novel tetradehydrocorrin, factor IV, isolated from Propionibacterium shermanii has been established by multidimensional NMR spectroscopy. Incorporation of radiolabeled factor IV into cobyrinic acid established the biointermediacy of this cobalt complex, whose structure has implications for the mechanisms of the anaerobic pathway to B12.


Can realistic dolls protect body satisfaction in young girls?
Ultra-thin fashion dolls may represent a risk factor for thin-ideal internalisation and body dissatisfaction amongst young girls. We asked thirty one 5- to 9-year-old girls to engage in interactive play with commercially available dolls which were either ultra-thin (Barbie and Monster High) or represented a putative realistic childlike shape (Lottie and Dora) and to indicate their perceived own-body size and ideal body size on an interactive computer task both before and after play. There was a significant interaction between testing phase and doll group such that playing with the ultra-thin dolls led to the girls' 'ideal self' becoming thinner. A further 46 girls played with the ultra-thin dolls and then played with either the same dolls again, the realistic childlike dolls, or with cars. Initial play with the ultra-thin dolls again produced a drop in perceived ideal own body size; however, no group showed any significant change in their body ideals during the additional play phase. These data indicate the potential benefit of dolls representing a realistic child body mass to young girls' body satisfaction and do not support the hypothesis that the negative impacts of ultra-thin dolls can be directly countered by other toys.


Assessment of body composition and impact of sarcopenia and sarcopenic obesity in patients with gastric cancer.
Malnutrition is a critical problem in patients with gastric cancer (GC); however, no universally accepted marker that is convenient for clinical use has been defined. Recently, body composition has attracted considerable attention as a means to assess nutrition status in patients with cancer. The clinical role of skeletal muscle mass has also been increasingly recognized. In patients with GC, sarcopenia, which is the loss of skeletal muscle mass, was found to be significantly associated with increased post-surgical complications including hospital stay, healthcare costs, and poor survival. In addition, sarcopenic obesity, which combines the health risks of obesity and sarcopenia, is recognized as a strong risk factor for poor short- and long-term outcomes following gastrectomy. The mechanism linking sarcopenia to worse postoperative outcomes remains unclear; however, skeletal muscle has been found to act as an endocrine organ that produces substances affecting the immune system. In addition, sarcopenia was reported to be associated with toxicity and termination of chemotherapy. Patients with sarcopenia may be unable to react appropriately to the stress of gastrectomy and perioperative chemotherapy. To improve the short- and long-term outcomes of patients with GC and sarcopenia, adequate energy and protein intake are necessary during resistance training. In the present study, we performed a literature review and presented a method to evaluate body composition, the relationship between skeletal muscle mass and GC, and perioperative nutrition and exercise therapy for patients with sarcopenia.


Longer-term Baerveldt to Trabectome glaucoma surgery comparison using propensity score matching.
To apply propensity score matching to compare Baerveldt glaucoma drainage implant (BGI) to Trabectome-mediated ab interno trabeculectomy (AIT). Recent data suggests that AIT can produce results similar to BGI which is traditionally reserved for more severe glaucoma. BGI and AIT patients with at least 1 year of follow-up were included. The primary outcome measures were intraocular pressure (IOP), number of glaucoma medications, and a Glaucoma Index (GI) score. GI reflected glaucoma severity based on visual field, the number of preoperative medications, and preoperative IOP. Score matching used a genetic algorithm consisting of age, gender, type of glaucoma, concurrent phacoemulsification, baseline number of medications, and baseline IOP. Patients with neovascular glaucoma, with prior glaucoma surgery, or without a close match were excluded. Of 353 patients, 30 AIT patients were matched to 29 BGI patients. Baseline characteristics including, IOP, the number of glaucoma medications, type of glaucoma, the degree of VF loss and GI were not significantly different between AIT and BGI. BGI had a preoperative IOP of 21.6 ± 6.3 mmHg compared to 21.5 ± 7.4 for AIT on 2.8 ± 1.1 medications and 2.5 ± 2.3 respectively. At 30 months, the mean IOP was 15.0 ± 3.9 mmHg for AIT versus 15.0 ± 5.7 mmHg for BGI (p > 0.05), while the number of drops was 1.5 ± 1.3 for AIT (change: p = 0.001) versus 2.4 ± 1.2 for BGI (change: p = 0.17; AIT vs BGI: 0.007). Success, defined as IOP < 21 mmHg, < 20% reduction and no reoperation, was achieved at 1 year in 56% of AIT versus 55% of BGI (p > 0.05) and 50% versus 52% at 2.5 years. A propensity score matched comparison of AIT and BGI demonstrated a similar IOP reduction through 1 year. AIT required fewer medications.


Implementing QA programs in managed care health plans: factors contributing to success.
The purpose of this paper is to identify the factors that contribute to the success or failure of quality assurance programs implemented by Israeli managed care health plans. An in-depth study of seven quality assurance programs was conducted, comparing successful with unsuccessful ones using the comparative "case study" method. Employing a semi-structured questionnaire, 42 program directors and professionals in the field were interviewed. A number of factors associated with the programs' success emerged. Those external to the program included: ongoing management support, resource allocation, information system support and perceived financial benefit for the organization. Internal factors included: leadership, perceived problem's importance, laying the groundwork in the field, involving field staff in planning and implementation and staff motivation. The study provides insights into ways to encourage the implementation of successful quality assurance programs in the special organizational context of managed care health plans. As the implementation relies heavily on data, one important precondition is the development of computerized information systems to facilitate ongoing data collection. It is also necessary from the planning stage to take into account organizational factors that affect success.


Periosteal transection of the proximal phalanx in foals with angular limb deformities of the metacarpo/metatarsophalangeal area.
Bilateral angular limb deformities of the metacarpo/metatarsophalangeal regions in 2 foals are discussed. Periosteal transection was used to correct the deformity in both foals. In one foal, only the right forelimb was treated because the deformity in the left forelimb did not appear to warrant surgery. Subsequently, an angular limb deformity, which could have been prevented, developed in the left forelimb. A third foal developed a deformity in the proximal phalanx after periosteal transection of the distal third metatarsal bone.


Role of histone deacetylase 2 in epigenetics and cellular senescence: implications in lung inflammaging and COPD.
Histone deacetylase 2 (HDAC2) is a class I histone deacetylase that regulates various cellular processes, such as cell cycle, senescence, proliferation, differentiation, development, apoptosis, and glucocorticoid function in inhibiting inflammatory response. HDAC2 has been shown to protect against DNA damage response and cellular senescence/premature aging via an epigenetic mechanism in response to oxidative stress. These phenomena are observed in patients with chronic obstructive pulmonary disease (COPD). HDAC2 is posttranslationally modified by oxidative/carbonyl stress imposed by cigarette smoke and oxidants, leading to its reduction via an ubiquitination-proteasome dependent degradation in lungs of patients with COPD. In this perspective, we have discussed the role of HDAC2 posttranslational modifications and its role in regulation of inflammation, histone/DNA epigenetic modifications, DNA damage response, and cellular senescence, particularly in inflammaging, and during the development of COPD. We have also discussed the potential directions for future translational research avenues in modulating lung inflammaging and cellular senescence based on epigenetic chromatin modifications in diseases associated with increased oxidative stress.


Ligand-based receptor identification on living cells and tissues using TRICEPS.
Physiological responses to ligands such as peptides, proteins, pharmaceutical drugs or whole pathogens are generally mediated through interactions with specific cell surface protein receptors. Here we describe the application of TRICEPS, a specifically designed chemoproteomic reagent that can be coupled to a ligand of interest for the subsequent ligand-based capture of corresponding receptors on living cells and tissues. This is achieved by three orthogonal functionalities in TRICEPS-one that enables conjugation to an amino group containing ligands, a second for the ligand-based capture of glycosylated receptors on gently oxidized living cells and a biotin tag for purifying receptor peptides for analysis by quantitative mass spectrometry (MS). Specific receptors for the ligand of interest are identified through quantitative comparison of the identified peptides with a sample generated by a control probe with known (e.g., insulin) or no binding preferences (e.g., TRICEPS quenched with glycine). In combination with powerful statistical models, this ligand-based receptor capture (LRC) technology enables the unbiased and sensitive identification of one or several specific receptors for a given ligand under near-physiological conditions and without the need for genetic manipulations. LRC has been designed for applications with proteins but can easily be adapted for ligands ranging from peptides to intact viruses. In experiments with small ligands that bind to receptors with comparatively large extracellular domains, LRC can also reveal approximate ligand-binding sites owing to the defined spacer length of TRICEPS. Provided that sufficient quantities of the ligand and target cells are available, LRC can be carried out within 1 week.


Validation of a questionnaire to assess self-reported colorectal cancer screening status using face-to-face administration.
The aim of this study was to assess the accuracy of a National Cancer Institute (NCI)-developed colorectal cancer screening questionnaire. We conducted 36 cognitive interviews and made iterative changes to the questionnaire to improve comprehension. The revised questionnaire was administered face-to-face to 201 participants. The primary outcome was agreement between questionnaire responses and medical records for whether or not a participant was up-to-date for any colorectal cancer screening test. Comprehension of descriptions and questions was generally good; however, the barium enema description required several revisions. The sensitivity of the questionnaire for up-to-date screening status was 94%, specificity 63%, and concordance 88%. The modified questionnaire was highly sensitive for determining if a person was up-to-date for any colorectal cancer screening test, although the specificity was low. Given the difficulty of obtaining all relevant records, self-report using this questionnaire is a reasonable option for identifying people who have undergone testing.


Polypyrimidine tract-binding protein positively regulates inclusion of an alternative 3'-terminal exon.
Polypyrimidine tract-binding protein (PTB) is an abundant vertebrate hnRNP protein. PTB binding sites have been found within introns both upstream and downstream of alternative exons in a number of genes that are negatively controlled by the binding of PTB. We have previously reported that PTB binds to a pyrimidine tract within an RNA processing enhancer located adjacent to an alternative 3'-terminal exon within the gene coding for calcitonin and calcitonin gene-related peptide. The enhancer consists of a pyrimidine tract and CAG directly abutting on a 5' splice site sequence to form a pseudoexon. Here we show that the binding of PTB to the enhancer pyrimidine tract is functional in that exon inclusion increases when in vivo levels of PTB increase. This is the first example of positive regulation of exon inclusion by PTB. The binding of PTB was antagonistic to the binding of U2AF to the enhancer-located pyrimidine tract. Altering the enhancer pyrimidine tract to a consensus sequence for the binding of U2AF eliminated enhancement of exon inclusion in vivo and exon polyadenylation in vitro. An additional PTB binding site was identified close to the AAUAAA hexanucleotide sequence of the exon 4 poly(A) site. These observations suggest a dual role for PTB in facilitating recognition of exon 4: binding to the enhancer pyrimidine tract to interrupt productive recognition of the enhancer pseudoexon by splicing factors and interacting with the poly(A) site to positively affect polyadenylation.