The economy of the enterohepatic circulation of bile acids in the baboon. 2. Regulation of bile acid synthesis by enterohepatic circulation of bile acids.
Isotope dilution within bile acid pools and radiochemical assessment of cholesterol oxidation to bile acids were methods used to measure short-term feedback regulation of bile acid synthesis in baboons with controlled enterohepatic circulations. Intraduodenal infusion of labeled endogenous bile acid pools into bile acid-depleted animals with enhanced bile acid synthesis showed that the rate of bile acid returned to the liver affected the degree of inhibition of bile acid synthesis. Infusion of prepared bile acid pools of varying composition resulted in a specific pattern of feedback inhibition of bile salt synthesis related to pool composition and mass. Individual bile salts inhibited their own synthesis more than that of other bile salts, and chenodeoxycholic and deoxycholic acids were found to have greater inhibitory effects than cholic acid. Glycine-conjugated cholic and chenodeoxycholic acids had greater inhibitory effects than did the respective free bile salts. Infusion of mixed bile acid pools showed that dihydroxy bile acids (chenodeoxycholic or deoxycholic) enhanced feedback inhibition of cholic acid. In all studies, inhibition of bile acid synthesis occurred twice as fast as its derepression.


Development and Application of Spin Traps, Spin Probes, and Spin Labels.
This chapter focuses on major achievements of the last decade in the synthesis and applications of spin traps, spin probes, and spin labels. Our discussion on spin trapping is mainly concerned with novel aspects of nitrones used as spin traps and with the kinetics caused by bioreductants. The second part of the chapter deals with recent developments in site-directed spin labeling (SDSL) for studying structure and functions of proteins and nucleic acids. We focus on SDSL EPR distance measurements using advanced trityl and nitroxide labels, on new approaches for incorporation of spin labels in biomolecules, and finally, on recent room/physiological temperature measurements made feasible by these novel spin labels.


Production of granulocyte-macrophage (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) by rat clonal osteoblastic cell population CRP 10/30 and the immortalized cell line IRC10/30-myc1 stimulated by tumor necrosis factor alpha.
Previously, we have shown that primary cultures of murine calvarial cells produce both granulocyte macrophage (GM) and granulocyte (G) colony stimulating factor (CSF). Because of the heterogeneity of cell types in these cultures the osseous origin of these cytokines was not certain. Thus a non-transformed rat clonal osteoblastic cell population CRP 10/30 and the immortalized cell line IRC10/30-myc1 derived from it, which both express the osteoblastic phenotype, were now investigated. Both produced hemopoietic growth activity after treatment with recombinant murine tumor necrosis factor alpha. This activity eluted from diethylaminoethyl Sephacel at 0.2-0.3 M NaCl, and migrated on Sephacryl S-200 at a mol wt of around 30 k, as described for murine GM- and G-CSF. On a Phenyl Sepharose CL-4B column, it was separated into two peaks appearing at position where GM (peak I) and G-CSF (peak II) are expected to be eluted. Antisera against GM-CSF inhibited the activity of peak I. In the colony assay in semisolid medium, peak I induced colonies of the GM-type and peak II of the G-type. These data indicate that cloned osteoblasts produce GM- and G-CSF. Through CSF production, osteoblasts might regulate osteoclast formation, influence hemopoiesis and/or participate in local inflammatory reactions of bone.


[Correlation between cerebrovascular hemodynamic index accumulative score and subclinical arteriosclerosis indicators].
To explore the correlation between cerebrovascular hemodynamic index (CVHI)accumulative score and subclinical arteriosclerosis indicators. Methods: A total of 27 184 cases were collected from the Health Management Center, the Third Xiangya Hospital, Central South University. Linear regression analysis was carried out to confirm the correlations between CVHI accumulative score and the modified Framingham stroke profile (FSP), as well as between CVHI accumulative score and cerebrovascular diseases (ICVD) scale. The correlation between CVHI accumulative score and brachial-ankle pulse wave velocity (baPWV), carotid plaque orcarotid intima-media thickness (CIMT) was analyzed by multifactor logistic regression model in 11 580 cases. Moreover, the correlation between CVHI accumulative score and microalbuminuria or serum cystatin C was performed by multifactor logistic regression model in 9 860 cases. Results: In this study, the people whose CVHI accumulative score was less than 75 accounted for 12.98%. The CVHI accumulative score was negatively related with the modified FSP score (r=-0.484, P<0.01) or ICVD score (r=-0.455, P<0.01). The multifactor logistic regression model found that the baPWV, carotid plaque, microalbuminuria and serum cystatin C were independent predictors for CVHI accumulative score. Conclusion: The CVHI accumulative score is correlated with the modified FSP score, ICVD score and indexes of subclinical arteriosclerosis (baPWV, carotid plaque, microalbuminuria and serum cystatin C). The CVHI accumulative score could be used as a tool for zero-level and primary prevention of cerebral stroke.


Role of α₁-adrenoceptor subtypes in pupil dilation studied with gene-targeted mice.
The α₁A-adrenoceptor (α₁A-AR) subtype was suggested to mediate contraction and trophic effects in the iris dilator muscle, and thus its pharmacological blockade may be involved in intraoperative floppy iris syndrome. We tested the hypothesis that the α₁A-AR mediates pupil dilation and trophic effects in the mouse iris. The α₁-AR subtype mRNA expression was quantified in iris tissue by real-time PCR. To assess the role of individual α₁-ARs for mediating pupil dilation, the α₁-AR agonist phenylephrine was topically applied to the ocular surface of mice deficient in one of the three α₁-AR subtypes (α₁A-AR(-/-), α₁B-AR(-/-), α₁D-AR(-/-), respectively) and wild-type controls. Changes in pupil diameter were measured under a microscope in restrained mice. Moreover, iris and iris muscle thickness were determined in cryosections. Messenger RNA for all three α₁-AR subtypes was detected the iris of wild-type mice with a rank order of abundance of α₁A ≥ α₁B > > α₁D. The lack of a single α₁-AR gene did not affect mRNA expression of the remaining two receptor subtypes. Phenylephrine induced pupil dilation in wild-type mice that was reduced in extent and duration in α₁A-AR(-/-) and, less so, in α₁B-AR(-/-) but not in α₁D-AR(-/-) mice. The lack of a single α₁-AR subtype had no effect on iris or iris muscle thickness. The α₁-AR-induced mydriasis in mice is mediated mainly by the α₁A-AR, with a smaller contribution of the α₁B-AR, matching the relative abundance of these subtypes at the mRNA level. The lack of a single α₁-AR subtype does not appear to cause atrophy in the mouse iris.


Clinical Importance of Left Atrial Infiltration in Cardiac Transthyretin Amyloidosis.
The aim of this study was to characterize left atrial (LA) pathology in explanted hearts with transthyretin amyloid cardiomyopathy (ATTR-CM); LA mechanics using echocardiographic speckle-tracking in a large cohort of patients with ATTR-CM; and to study the association with mortality. The clinical significance of LA involvement in ATTR-CM is of great clinical interest. Congo red staining and immunohistochemistry was performed to assess the presence, type, and extent of amyloid and associated changes in 5 explanted ATTR-CM atria. Echo speckle tracking was used to assess LA reservoir, conduit, contractile function, and stiffness in 906 patients with ATTR-CM (551 wild-type (wt)-ATTR-CM; 93 T60A-ATTR-CM; 241 V122I-ATTR-CM; 21 other). There was extensive ATTR amyloid infiltration in the 5 atria, with loss of normal architecture, vessels remodeling, capillary disruption, and subendocardial fibrosis. Echo speckle tracking in 906 patients with ATTR-CM demonstrated increased atrial stiffness (median [25th-75th quartile] 1.83 [1.15-2.92]) that remained independently associated with prognosis after adjusting for known predictors (lnLA stiff: HR: 1.23; 95% CI: 1.03-1.49; P = 0.029). There was substantial impairment of the 3 phasic functional atrial components (reservoir 8.86% [5.94%-12.97%]; conduit 6.5% [4.53%-9.28%]; contraction function 4.0% [2.29%-6.56%]). Atrial contraction was absent in 22.1% of patients whose electrocardiograms showed sinus rhythm (SR) "atrial electromechanical dissociation" (AEMD). AEMD was associated with poorer prognosis compared with patients with SR and effective mechanical contraction (P = 0.0018). AEMD conferred a similar prognosis to patients in atrial fibrillation. The phenotype of ATTR-CM includes significant infiltration of the atrial walls, with progressive loss of atrial function and increased stiffness, which is a strong independent predictor of mortality. AEMD emerged as a distinctive phenotype identifying patients in SR with poor prognosis.


Current barriers and potential strategies to increase the use of long-acting reversible contraception (LARC) to reduce the rate of unintended pregnancies in Australia: An expert roundtable discussion.
Australia's abortion rates are among the highest in the developed world. Efficacy of the most commonly used form of contraception (oral contraceptives and condoms) relies on regular user compliance. Long-acting reversible contraception (LARC) virtually eradicates contraceptive failure as it is not user-dependent; however, its uptake has been low. To provide an overview of barriers to LARC use in Australia and potential strategies to overcome these barriers. A roundtable of Australian experts was convened to share clinical perspectives and to explore the barriers and potential strategies to increase LARC use. Three broad barriers to LARC uptake were identified. (i) A paucity of Australian research exists that impedes closure of evidence gaps regarding contraceptive prescription and use. Systematic data collection is required. (ii) Within primary care, lack of familiarity with LARC and misperceptions about its use, lack of access to general practitioners (GPs) trained in LARC insertion/removal and affordability impede LARC uptake. Potential strategies to encourage LARC use include, GP education to promote informed choice by women, training in LARC insertions/removals, effective funding models for nurses to perform LARC insertions/removals, and rapid referral pathways. (iii) At the health system level, primary care incentives to provide LARC to women and health economic analyses to inform government policy changes are required. Although LARC decreases unintended pregnancies by eliminating user compliance issues, its uptake is low in Australia. Strategies that promote LARC uptake by targeting specific barriers may effectively reduce Australia's high unintended pregnancy rate.


Peroxisomal oxidation of thiazolidine carboxylates in firefly fat body, frog retina, and rat liver and kidney.
D-amino acid oxidase is a widely distributed peroxisomal enzyme whose principal natural substrates are still unknown. Thiazolidine carboxylates, their derivatives and relatives, and the intermediates in their metabolism are among the more plausible substrate candidates. Using a cytochemical procedure, we have explored the distribution of peroxide-generating enzymatic activity against two thiazolidine carboxylates. We find that these compounds are effective substrates for peroxisomal oxidation in a variety of tissues that contain peroxisomal D-amino acid oxidase. Reaction was seen in the "classical" peroxisomes of rat liver and kidney, the peroxisomes of the fat body of firefly and of Drosophila and the peroxisomes of frog retina. Interestingly, both with the thiazolidine compounds and with more traditional D-amino acid oxidase substrates, the fireflies' photocyte granules, which are peroxisomes, lack activity.


Clinical cut scores for the Persian version of the personality inventory for DSM-5.
The cut points of psychological tools to diagnose clinical conditions are not universal and depend on the region and prevalence of the disorder. Thus, we aimed to identify the cutoff points of the Persian original version of the personality inventory for DSM-5 (PID-5; 220 items) that would optimally distinguish nonclinical from clinical groups. Both nonclinical (N = 634, 73% female, 34.0 ± 10.8 years) and clinical (N = 454, 29% female, 29.5 ± 7.4 years) samples from the West of Iran participated in the study. Data were analyzed using receiver operating characteristic (ROC) and Youden's index was used to determine the cutoff scores across the PID-5 domains and facets. The means and standard deviations of both the clinical male and female were compared with the nonclinical group using Cohen's d and independent t-tests. All the PID-5 algorithms and facets significantly distinguished clinical from nonclinical samples with some unique findings for male and female samples. The mean score of all the PID-5 algorithms and facets in the clinical male and female samples were respectively 1.0-2.0 SD and 0.5-1.0 SD above the mean for the nonclinical counterparts. A score higher than 1.5 on ranging from 0 to 3 in each domain or facet indicated clinical status. Raw cutting scores throughout the PID-5 algorithms can be well used to diagnose any pathology of personality and the severity of the disorder in clinical patients. The cut scores provide a useful tool for the clinical use of the original version of PID-5 in Iran.


Retinoblastoma protein function and p16INK4a expression in actinic keratosis, squamous cell carcinoma in situ and invasive squamous cell carcinoma of the skin and links between p16INK4a expression and infiltrative behavior.
p16INK4a is involved in many important regulatory events in the cell and the expression and function is closely associated with the retinoblastoma protein (Rb). Earlier, we have in colorectal cancer and in basal cell carcinoma showed that p16INK4a is upregulated at the invasive front causing cell cycle arrest in infiltrative tumor cells via a functional Rb. This role for p16INK4a as a regulator of proliferation when tumor cells infiltrate might besides a general cyclin-dependent kinase (cdk) inhibitory effect explain why p16INK4a is deregulated in many tumor forms. The expression pattern of p16INK4a in relation to Rb-function in squamous cancer and precancerous forms of the skin has not been fully detailed. We therefore characterized the expression of p16INK4a, Rb-phosphorylation and proliferation in actinic keratosis, squamous cell carcinoma in situ and invasive squamous cell carcinoma with special reference to infiltrative behavior. The expression of p16INK4a varied between the lesions, with weak and cytoplasmic p16INK4a expression and functional Rb in actinic keratosis. Strong nuclear and cytoplasmic p16INK4a expression was observed in all carcinomas in situ in parallel with lack of Rb-phosphorylation but high proliferation indicating a nonfunctional Rb. Invasive squamous carcinoma showed a mixed p16INK4a expression pattern where some tumors had strong cytoplasmic p16INK4a expression, large fraction of Rb-phosphorylated cells and high proliferation. Interestingly, despite this disability of p16INK4a to inhibit proliferation there was an upregulation of cytoplasmic p16INK4a in infiltrative cells compared to tumor cells towards the tumor center. A similar scenario but strong and combined nuclear and cytoplasmic p16INK4a expression in infiltrative cells, was observed in other invasive squamous cancers. This suggests that the p16INK4a upregulation in infiltrative cells is governed independently of the subcellular localization or of the potential to affect proliferation via Rb, and suggests a potentially proliferation independent function for p16INK4a in infiltrative behavior.


Clinical outcomes after endoscopic submucosal dissection for colorectal neoplasia: a systematic review and meta-analysis.
Endoscopic submucosal dissection (ESD) is an endoscopic resection technique for lesions suspicious of superficial malignancy. It is performed using an ESD knife on its own (standard technique) or by the sequential use of a knife and a snare (hybrid technique). The experience with these techniques is different in Asian and non-Asian countries. We performed a systematic review and meta-analysis of available evidence on colorectal ESD. Electronic databases were searched up to August 2016 for studies evaluating R0, en bloc resection, and adverse event rates of both techniques for the treatment of colorectal lesions. Proportions were pooled by a random effects model. Ninety-seven studies (71 performed in Asia) evaluated the standard technique and 12 studies (7 in Asia) the hybrid technique. The R0 resection rate of the standard technique was 82.9%, and it was significantly lower in non-Asian versus Asian countries: 71.3% versus 85.6%. The en bloc resection rate was 91% and was significantly lower in non-Asian versus Asian countries (81.2% vs 93%, respectively). Surgery was needed in 1.1% of the ESD-related adverse events, with a significant difference between non-Asian and Asian countries (3.1% vs 0.8%). The R0 and en bloc resection rates with the hybrid technique were significantly lower than those achieved with the standard technique: 60.6% and 68.4%, respectively, with similar adverse event rates. In non-Asian countries the standard ESD technique is still failing to achieve acceptable levels of performance. The hybrid technique showed low R0 resection rates and should not be considered as an adequate alternative to the standard technique.


Rapid and in vivo quantification of cellular lipids in Chlorella vulgaris using near-infrared Raman spectrometry.
A rapid and noninvasive quantification method for cellular lipids in Chlorella vulgaris is demonstrated in this study. This method applied near-infrared Raman spectroscopy to monitor the change of signal intensities at 1440 cm(-1) and 2845-3107 cm(-1) along the nitrogen depletion period, and calibration curves relating signal intensity and cellular lipid abundance were established. The calibration curves show that signal intensity at 2845-3107 cm(-1) and cellular lipid abundance were highly correlated. When the calibration curve was applied on the lipid quantification of two unknown samples, the differences between lipid abundances estimated by the calibration curve and measured by gas chromatography were less than 2 wt %. Carotenoids produced a strong and broad peak near 1440 cm(-1), and it weakened the correlation between signal intensity and lipid abundance. The consistency of detection and effects of cellular contents and water on the Raman spectrogram of Chlorella vulgaris were also addressed. The sample pretreatment only involved centrifugation, and the time required for lipid quantification was shortened to less than 1.5 h. The rapid detection has great potential in high-throughput screening of microalgae and also provides valuable information for monitoring the quality of microalgae culture and determining parameters for the mass production of biodiesel from microalgae.


Does the Australasian "Health Star Rating" Front of Pack Nutritional Label System Work?
This article describes an experiment to measure the impact of the Australasian "Health Star Rating" front of pack nutritional label system on consumer choice behaviour. This system presents a one-half to five star rating of nutritional quality via the front facings of food product packages. While this system has been recently rolled out across Australasia, no test of its impact on food choice has been conducted. A sample of 1200 consumers was recruited on exit from supermarkets in New Zealand. A 2 × 2 factorial design was used with two levels of cold cereal product nutritional status (high, five star/low, two star) and two levels of the Health Star Rating label (present/absent). The dependent variable was revealed choice behaviour. The results indicated that the presence of the label had a significant depressive effect on consumer preference, but that this impact was not moderated in any way by the nutritional status expressed by the label. The result represents a significant functional failure of the Health Star Rating label in this research environment. The nature of the failure is consistent with the consumers processing the label in much the same way as the nominal brand cues that dominate the retail food packaging.


Comparative evaluation of in vitro cytotoxic effects among parent abietyl alcohol and novel fatty acid ester derivatives against MCF7 and hepatocellular carcinoma cell lines.
Synthesis of twelve hitherto unreported esters of abietyl alcohol and screening of these esters against four cancer cell lines including one breast cancer line MCF7 and four hepatocellular carcinoma cell lines (HCC) Huh7, Hep3B, Snu449 and Plc has been determined using SRB assay. The Cell cycle progression showed changes in cellular behaviour after 48 and 72 hours in MCF7 and Huh7 cell lines. Abietyl alcohol was obtained from the reduction of abietic acid, a tricyclic diterpene, isolated from oleoresin of Pinus longifolia Roxberghii.


Comparative clinical pharmacokinetics of dipeptidyl peptidase-4 inhibitors.
Dipeptidyl peptidase-4 (DPP-4) inhibitors collectively comprise a presently unique form of disease management for persons with type 2 diabetes mellitus. The aim of this review is to compare the clinical pharmacokinetics of available DPP-4 inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin) for the purpose of identifying potential selection preferences according to individual patient variables and co-morbidities. DPP-4 inhibitors are readily absorbed orally. Following oral ingestion, absorption occurs mainly in the small intestine, with median times to maximum (peak) plasma concentration ranging from 1 to 3 hours. The fraction of each dose absorbed ranges from approximately 30% with linagliptin to 75-87% for all others. Numerical differences in maximum (peak) plasma drug concentrations and areas under the plasma concentration-time curve among the DPP-4 inhibitors vary by an order of magnitude. However, functional capacity measured in terms of glucose-lowering ability remains comparable among all available DPP-4 inhibitors. Distribution of DPP-4 inhibitors is strongly influenced by both lipophilicity and protein binding. Apparent volumes of distribution (V(d)) for most agents range from 70 to 300 L. Linagliptin exhibits a V(d) of more than 1000 L, indicating widespread distribution into tissues. Binding to target proteins in plasma and peripheral tissues exerts a major influence upon broadening linagliptin distribution. DPP-4 inhibitor metabolism is widely variable, with reported terminal half-lives ranging from approximately 3 to more than 200 hours. Complex relationships between rates of receptor binding and dissociation appear to strongly influence the durations of action of those DPP-4 inhibitors with comparatively shorter half-lives. Durations of activity often are not reflective of clearance and, with the exception of vildagliptin which may be administered either once daily in the evening or twice daily, these medications are effective when used with a once-daily dosing schedule. Saxagliptin and, to a lesser extent, sitagliptin are largely metabolized by hepatic cytochrome P450 (CYP) 3A4 and 3A5 isoforms. With the exception of the primary hydroxylated metabolite of saxagliptin, which is 2-fold less potent than its parent molecule, metabolic products of hepatic biotransformation are minimally active and none appreciably contribute to either the therapeutic or the toxic effects of DPP-4 inhibitors. No DPP-4 inhibitor has been shown to inhibit or to induce hepatic CYP-mediated drug metabolism. Accordingly, the number of clinically significant drug-drug interactions associated with these agents is minimal, with only saxagliptin necessitating dose adjustment if administered concurrently with medications that strongly inhibit CYP3A4. Linagliptin undergoes enterohepatic cycling with a large majority (85%) of the absorbed dose eliminated in faeces via biliary excretion. Other DPP-4 inhibitors predominantly undergo renal excretion, with 60-85% of each dose eliminated as unchanged parent compound in the urine. Systematic reviews of clinical trials suggest that the overall efficacy of DPP-4 inhibitors in patients with type 2 diabetes generally is similar. Apart from these generalizations, pharmacokinetic distinctions that potentially influence product selection are tentative. When considered in total, data reviewed in this report suggest that the best overall balance between potency and the clinical pharmacokinetic characteristics of distribution, metabolism and elimination may be observed with linagliptin followed closely by vildagliptin, saxagliptin, sitagliptin and alogliptin.


Pulmonary Arterial Hypertension-Specific Drug Therapy in COPD Patients with Severe Pulmonary Hypertension and Mild-to-Moderate Airflow Limitation.
Patients with severe pulmonary hypertension (PH) associated with chronic obstructive pulmonary disease (COPD) present a poor outcome. Specific PH treatment could improve the clinical and hemodynamic status of these patients but may worsen arterial blood gases. Our study retrospectively included 28 patients with severe precapillary PH (mean pulmonary arterial pressure >35 mm Hg) associated with mild-to-moderate COPD [forced expiratory volume in 1 s (FEV1) >50% predicted]. All patients underwent specific pulmonary arterial hypertension (PAH) treatment as mono-, bi- or triple therapy. Our single-center study was conducted based on retrospective data of 537 right heart catheterizations (RHCs) performed on patients with COPD from January 2004 to June 2014. An echocardiography, comprehensive blood tests, pulmonary function tests, and a high-resolution computed tomography were performed before the RHCs. All patients underwent RHC with a Swan-Ganz catheter. Compared to baseline, patients treated with specific PAH drugs showed a significant increase in cardiac index at long term (2.5 ± 0.7 liters/min/m2 at baseline vs. 3.2 ± 0.6 liters/min/m2 at 6/12 months; p = 0.003) as well as a decrease in pulmonary vascular resistance in the long term (8.4 ± 4.2 Wood units at baseline vs. 5 ± 1.7 Wood units at 6/12 months; p = 0.008). There was a slight decrease in arterial oxygen tension (PaO2) after 3 months of treatment (-2.4 ± 7.21 mm Hg; p = 0.066). During a median follow-up of 3 years, 12 patients (42.8%) died (including all causes of death). This preliminary report suggests that the use of specific PH therapy in severe PH associated with mild-to-moderate COPD can improve pulmonary hemodynamic parameters, with worsening of PaO2, which had no clinical significance and did not lead to specific PAH therapy withdrawal in any patient.


Mothers' differential treatment of their adolescent childbearing and nonchildbearing children: contrasts between and within families.
This study examined mothers' differential treatment of adolescent sibling pairs in 2 family contexts: families with and without an adolescent childbearing daughter. Results based on mothers' ratings and children's ratings revealed that the mothers of childbearing daughters treated all of their children less affectionately than did the mothers of nonchildbearing adolescents. In families with a childbearing daughter, mothers expected a brighter future for and treated their never-pregnant daughter(s) more favorably than their childbearing daughter, and mothers' harsh treatment toward their children was correlated with high financial stress, excessive time spent caring for their daughter's child, and younger children's sexual behavior and drug and alcohol use. Findings highlight the preferential parenting that occurs within the families of childbearing teens and suggest its ramifications.


Controlling Intramolecular and Intermolecular Electronic Coupling of Radical Ligands in a Series of Cobaltoviologen Complexes.
Controlling electronic coupling between multiple redox sites is of interest for tuning the electronic properties of molecules and materials. While classic mixed-valence (MV) systems are highly tunable, e.g., via the organic bridges connecting the redox sites, metal-bridged MV systems are difficult to control because the electronics of the metal cannot usually be altered independently of redox-active moieties embedded in its ligands. Herein, this limitation was overcome by varying the donor strengths of ancillary ligands in a series of cobalt complexes without directly perturbing the electronics of viologen-like redox sites bridged by the cobalt ions. The cobaltoviologens [1X-Co]n+ feature four 4-X-pyridyl donor groups (X = CO2Me, Cl, H, Me, OMe, NMe2) that provide gradual electronic tuning of the bridging CoII centers, while a related complex [2-Co]n+ with NHC donors supports exclusively CoIII states even upon reduction of the viologen units. Electrochemistry and IVCT band analysis indicate that the MV states of these complexes have electronic structures ranging from fully localized ([2-Co]4+; Robin-Day Class I) to fully delocalized ([1CO2Me-Co]3+; Class III) descriptions, demonstrating unprecedented control over electronic coupling without changing the identity of the redox sites or bridging metal. Additionally, single-crystal XRD characterization of the homovalent complexes [1H-Co]2+ and [1H-Zn]2+ revealed radical-pairing interactions between the viologen ligands of adjacent complexes, representing a type of through-space electronic coupling commonly observed for organic viologen radicals but never before seen in metalloviologens. The extended solid-state packing of these complexes produces 3D networks of radical π-stacking interactions that impart unexpected mechanical flexibility to these crystals.


Differences in circadian photosensitivity between retinally degenerate CBA/J mice (rd/rd) and normal CBA/N mice (+/+).
Using the magnitude of phase shift of circadian locomotor rhythms induced by a single pulse of white fluorescent light, we compared the sensitivity of the circadian system to light in retinally degenerate mice and in normal mice. In the first experiment, phase response curves (PRCs) for 10-lux white light were generated in CBA/J mice with retinal degeneration (rd/rd) and CBA/N mice with normal retinas (+/+). Although large phase delays early in the subjective night and small phase advances in the late subjective night were observed in CBA/N mice, CBA/J mice showed only small phase delays early in the subjective night. In the second experiment, we found that the magnitude of phase shifts at circadian time (CT) 16 for delays and CT 24 for advances in CBA/J mice became larger with increasing light intensity, and that CBA/J mice could show the same amount of phase shift as CBA/N mice when higher intensities were used. These findings indicate that the differences in the shapes of PRCs are not due to differences in the nature of the oscillating system, but to differences in circadian photosensitivity between these strains. Because the genetic background for the rd loci was not completely identical in the CBA/N and CBA/J mice, it was possible that genes other than the rd gene might have caused different photosensitivity in these mice. Therefore, in the last experiment, we studied the circadian photosensitivity in F1 hybrids between CBA/N and CBA/J mice and in the backcross progeny with different genotypes (+/rd and rd/rd) obtained from the crossing between F1 hybrids between CBA/N and CBA/J mice and in the backcross progeny with different genotypes (+/rd and rd/rd) obtained from the crossing between F1 and CBA/J mice. In these mice with heterogeneous genetic backgrounds as well, mice with retinal degeneration were always less sensitive to light, suggesting that reduced circadian photosensitivity is caused by retinal degeneration. These results are discussed in relation to recent findings in retinally degenerate C57BL mice, which have been found to have normal circadian sensitivity to light.


Regulation of extracellular matrix synthesis by mechanical stress.
The extracellular matrix (ECM) provides mechanical support to tissues and is a substrate for cell adhesion and differentiation. Cells bind to ECM via specific cell surface receptors such as integrins. When engaging with ECM ligands, these receptors can activate signal transduction pathways within the cells and may act as mechanochemical transducers. Thus, interaction of cells with ECM can modulate gene expression although the exact mechanisms are not known. Among the genes that are, in part, controlled by cell-ECM interactions are those for certain ECM components themselves. Bone cells, for example, remodel their matrix and reorient bone trabeculae in response to mechanical strain. Recently, we found that fibroblasts attached to a strained collagen matrix produce more of the ECM glycoproteins tenascin and collagen XII than cells in a relaxed matrix. In vivo, these two proteins are specifically expressed in places where mechanical strain is high. We also showed that the chick tenascin gene promoter contains a novel cis-acting, "strain-responsive" element that causes enhanced transcription in cells attached to a strained collagen matrix. Similar enhancer elements might be present in the promoters of other genes induced by mechanical stress. It can be speculated that connective tissue cells sense force vectors in their ECM environment and react to altered mechanical needs by regulating the transcription of specific ECM genes; this process is a prerequisite for matrix remodeling.


Anxious arousal predicts within-person changes in hippocampal volume in adults with a history of childhood maltreatment: A CAN-BIND4 report.
Childhood maltreatment (CM) is a strong transdiagnostic risk factor for future psychopathology. This risk is theorized to emerge partly because of glucocorticoid-mediated atrophy in the hippocampus, which leaves this area sensitive to further volume loss even through adulthood in the face of future stress and the emergence of psychopathology. This proof-of-principle study examines which specific dimensions of internalizing psychopathology in the context of a CM history are associated with decreases in hippocampal volume over a 6-month period. This study included 80 community-recruited adults (ages 18-66 years, 61.3% women) oversampled for a lifetime history of internalizing psychopathology. At baseline and a naturalistic 6-month follow-up, the symptom dimensions of the tripartite model (anxious arousal, anhedonic depression, and general distress) were assessed by self-report. Hippocampal volume was derived through T1-weighted magnetic resonance imaging scanning segmented via the volBrain HIPS pipeline. CM severity was determined via a semistructured, contextual interview with independent ratings. We found that higher levels of anxious arousal predicted decreases in hippocampal volume over time in those with greater severity of CM but were associated at a trend with increases in hippocampal volume over time in those with lower severity of maltreatment. Findings were specific to anxious arousal and the CA1 subregion of the hippocampus. These novel results suggest that for individuals with a history of CM, transdiagnostic interventions that target and reduce psychological and physiological arousal may result in the preservation of hippocampal structure and, thus, improvements in cognitive and emotional regulation in the face of stress. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Evaluating the Quality of Systematic Reviews and Meta-Analyses About Breast Augmentation Using AMSTAR.
Breast augmentation is one of the most commonly performed cosmetic surgeries worldwide. Therefore, it is imperative to have evidence with high methodological quality to guide clinical decision making. To evaluate the methodological quality of the systematic reviews (SRs) focused on breast augmentation. A comprehensive search of MEDLINE, Embase, and the Cochrane Library of Systematic Reviews was performed. SRs that have a particular focus on breast augmentation and were published in the top 15 plastic and reconstructive surgery journals were included. Quality assessment was performed using a measurement tool to assess systematic reviews (AMSTAR). Study characteristics were extracted including journal and impact factor, year of publication, country affiliation of the corresponding author, reporting adherence to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, number of citations, and number of studies included. Among the 22 studies included for analysis, the mean AMSTAR score was moderate (5.55), with no SR achieving good quality (AMSTAR score of ≥9). There were no significant associations between AMSTAR score and journal impact factor, number of citations, year of publication, or number of included studies. Studies that reported adherence to PRISMA guidelines on average scored higher on the AMSTAR tool (P = 0.03). The methodological quality of reviews about breast augmentation was found to be moderate, with no significant increase in studies or quality over time. Adherence to PRISMA guidelines and increased appraisal of SRs about breast augmentation using methodological assessment tools would further strengthen methodological quality and confidence in study findings.


Exploration of the meaning of connectedness for older people in long-term care in context of their quality of life: a review and commentary.
A link between 'quality of life' and 'connectedness' is emerging in the literature. However, there has been little debate on what 'connectedness' means and how it can be fostered in long-term care settings. This review examines the meaning of 'connectedness' in long-term care. This paper critically examines the meaning of 'connectedness' in the context of its contribution to the quality of life of older people living in long-term care settings. Key databases (CINAHL, PsychInfo and Medline) were searched systematically. Fourteen papers and two book chapters met the inclusion criterion of papers exploring 'connectedness for older people in residential care'. The experience of connectedness for older people in long-term care settings is linked with quality of life and successful ageing. Fundamental prerequisites of connectedness for older people are: self-awareness, meaningful relationships with family and friends, involvement in meaningful activities and connections with wider society. However, barriers to these prerequisites are evident for many residents in long-term care settings. Register and Herman (Advances in Nursing Science, 33, 2010, 53) identify six connections that combine to generate connectedness for older people. These connections are representative of the factors associated with increased quality of life for residents living in long-term care settings. The six connections are helpful in identifying areas to focus on when planning person-centred care.


The dentinogenic effect of mineral trioxide aggregate (MTA) in short-term capping experiments.
The objective of the present experiment was to study the early pulpal cell response and the onset of reparative dentine formation after capping application of MTA in mechanically exposed pulps. Thirty-three teeth from three dogs, 12-18 months of age were mechanically exposed via class V cavities. Light pressure was applied to control haemorrhage. ProRoot MTA (Dentsply Simfra, Paris) was placed at the exposure site and light pressure was applied with a wet cotton pellet. The cavities were restored with amalgam and the pulpal tissue reactions were assessed by light and electron microscopy (transmission and scanning) after healing intervals of 1, 2 or 3 weeks. A homogenous zone of crystalline structures was initially found along the pulp-MTA interface, whilst pulpal cells showing changes in their cytological and functional state were arranged in close proximity to the crystals. Deposition of hard tissue of osteotypic form was found in all teeth in direct contact with the capping material and the associated crystalline structures. Formation of reparative dentine (tubular matrix formation in a polar predentine-like pattern by elongated polarized cells) was consistently related to a firm osteodentinal zone. The present experiments indicate that MTA is an effective pulp-capping material, able to stimulate reparative dentine formation by the stereotypic defensive mechanism of early pulpal wound healing.


The genetics of Leigh syndrome and its implications for clinical practice and risk management.
Leigh syndrome, also referred to as subacute necrotizing encephalomyelopathy, is a severe, early-onset neurodegenerative disorder that is relentlessly progressive and devastating to both the patient and the patient's family. Attributed to the ultimate failure of the mitochondrial respiratory chain, once it starts, the disease often results in the regression of both mental and motor skills, leading to disability and rapid progression to death. It is a mitochondrial disorder with both phenotypic and genetic heterogeneity. The cause of death is most often respiratory failure, but there are a whole host of complications, including refractory seizures, that may further complicate morbidity and mortality. The symptoms may develop slowly or with rapid progression, usually associated with age of onset. Although the disease is usually diagnosed within the first year of life, it is important to note that recent studies reveal phenotypic heterogeneity, with some patients having evidence of in utero presentation and others having adult-onset symptoms.


Genome characterization of a porcine circovirus type 3 in South China.
Porcine circovirus type 3 (PCV3) is a novel circovirus that was associated with porcine dermatitis and nephropathy syndrome, reproductive failure, and multisystemic inflammation. Recently, a PCV3 strain was identified from pyretic and pneumonic piglets in Guangdong province, China. This virus strain was sequenced and designated PCV3-China/GD2016. The complete genome of PCV3-China/GD2016 is 2,000 bp in length and shared 99.1% and 99.1% nucleotide identities with PCV3/29160 and PCV3/2164, respectively. [Corrections added after initial online publication on 13 March 2017: The numbers '98.5%' and '97.4%' has been changed to '99.1%' and '99.1%' in the previous sentence.] Phylogenetic analysis based on the complete genome showed that PCV3-China/GD2016 clustered with the emerging PCV3 and separated with other virus in genus Circovirus. The results of this study suggest that PCV3 has existed within the pigs of China. It is urgent to investigate the pathogenicity and epidemiology of this novel circovirus China.


Effectiveness of an educational program on improving healthcare providers' knowledge of acute stroke: A randomized block design study.
Stroke is a time-sensitive neurological disease and a life-threatening medical condition. Providing timely management for stroke patients is a crucial issue in healthcare settings. The primary objective of this study is to evaluate the effectiveness of an evidence-based educational program on healthcare providers' (HCPs) overall knowledge of stroke. A randomized block design with post-test only was used. A total of 189 HCPs (physicians, registered nurses, and paramedics) involved with treating stroke patients in the emergency were recruited. Participants were randomly assigned to either the intervention or waiting list control group. A one-session, stroke educational program was offered to the HCPs followed by a post-test designed to assess knowledge about stroke. A significant main effect on the profession type was found, with physicians having higher mean scores of stroke knowledge compared with nurses and paramedics (F [2, 183]=48.55, P<0.001). The implemented educational program had a positive effect on increasing the level of stroke knowledge among HCPs (F [1, 183]=43.31, P<0.001). The utilization of any evidence-based assessment tools for patients with suspected stroke was denied by 36% of the total sample. The implemented intervention can increase HCP's knowledge regarding stroke. Stroke education should be considered as one of the essential requirements for professional development for all HCPs in the emergency.


Towards an assessment of the accuracy of density functional theory for first principles simulations of water.
A series of Car-Parrinello (CP) molecular dynamics simulations of water are presented, aimed at assessing the accuracy of density functional theory in describing the structural and dynamical properties of water at ambient conditions. We found negligible differences in structural properties obtained using the Perdew-Burke-Ernzerhof or the Becke-Lee-Yang-Parr exchange and correlation energy functionals; we also found that size effects, although not fully negligible when using 32 molecule cells, are rather small. In addition, we identified a wide range of values of the fictitious electronic mass (micro) entering the CP Lagrangian for which the electronic ground state is accurately described, yielding trajectories and average properties that are independent of the value chosen. However, care must be exercised not to carry out simulations outside this range, where structural properties may artificially depend on micro. In the case of an accurate description of the electronic ground state, and in the absence of proton quantum effects, we obtained an oxygen-oxygen correlation function that is overstructured compared to experiment, and a diffusion coefficient which is approximately ten times smaller.


Hypotension after spinal anesthesia for cesarean section: how to approach the iatrogenic sympathectomy.
Hypotension during cesarean section remains a frequent complication of spinal anesthesia and is associated with adverse maternal and fetal events. Despite ongoing research, no single measure for sufficient treatment of spinal-induced hypotension was identified so far. Current literature discusses the efficacy of low-dose spinal anesthesia, timing and solutions for adequate fluid therapy and various vasopressor regimens. Present guidelines favor the use of phenylephrine over ephedrine because of decreased umbilical cord pH values, while norepinephrine is discussed as a probable superior alternative with regard to maternal bradycardia, although supporting data is limited. Alternative pharmacological approaches, such as 5HT3-receptor antagonists and physical methods may be taken into consideration to further improve hemodynamic stability. Current evidence favors a combined approach of low-dose spinal anesthesia, adequate fluid therapy and vasopressor support to address maternal spinal-induced hypotension. As none of the available vasopressors is associated with relevantly impaired maternal and fetal outcomes, none of them should be abandoned from obstetric practice. Rapid crystalloid co-loading is of equivalent efficacy as compared with colloids and should be preferred because of a more favorable risk profile.


Acylation of aspartate aminotransferase.
1. Acetylation of aspartate aminotransferase from pig heart inhibits completely the enzymic activity when the coenzyme is in the amino form (pyridoxamine phosphate) or when the coenzyme has been removed, but not when the coenzyme is in the aldehyde form (pyridoxal phosphate). 2. The group the acylation of which is responsible for the inhibition has been identified with the in-amino group of a lysine residue at the coenzyme-binding site. Moreover, in the pyridoxamine-enzyme the amino group of the coenzyme is also acetylated. 3. The reactivity of the coenzyme-binding lysine residue is greatly different in the pyridoxamine-enzyme and in the apoenzyme, suggesting the possibility of an interaction of its in-amino group with pyridoxamine or with other groups on the protein.


[Smuggling of narcotics in body cavities].
Smuggling of narcotics by internal concealment has increased considerably worldwide, including in the Scandinavian countries. During the period 1988-92, Norwegian custom officials reported 245 seizures where packets of narcotics had been inserted into the rectum or vagina, or had been swallowed. Based on two fatal cases as a result of intestinal obstruction and cocaine intoxication respectively, this report summarizes the main features of the "body packer" syndrome.


Prognostic significance of selected immunohistochemical parameters in patients with invasive breast carcinoma concomitant with ductal carcinoma in situ.
The purpose of the present study was to carry out multivariate analysis of the effect of the expression of estrogen and progesterone receptors, p53, proliferative antigen (Ki67) and c-erbB-2 on 5-year survival in patients with invasive breast carcinoma concomitant with ductal carcinoma in situ. Material for study consisted of tissue specimens obtained from 48 patients undergoing modified Patey's mastectomy between 1991 and 1998. Univariate analysis revealed that the variables significantly affecting survival were tumour size on gross examination and the level of estrogen and progesterone receptors in the cells of invasive ductal carcinoma of the breast (for the level of significance p = 0.05). The Cox regression model revealed that the only independent variable having a significant effect on survival was the level of estrogen receptors in invasive cancer cells.


Quantitating MHC class I ligand production and presentation using TCR-like antibodies.
Accurately determining the number of peptide-MHC class I complexes on the cell surface is necessary when evaluating cellular processes or pharmaceuticals that alter the antigen presentation machinery. Here I describe a quantitative flow cytometry application for determining the number of peptide-MHC complexes on the surface of cells grown in tissue culture that express an endogenous protein from which the peptide is derived. The procedure requires a monoclonal antibody with the ability to distinguish MHC class I molecules presenting the peptide of interest from other peptide-MHC complexes. Fluorescence signal measured on antibody-labeled cells can be compared to fluorescent-calibrated beads to determine the relative number of antibodies bound to the cell surface and hence the number of specific peptide-MHC complexes expressed by the cell. As new monoclonal antibodies with TCR-like specificity for peptide-MHC complexes are created, this method will be helpful in quantifying the exact numbers of complexes generated by cell types and relating these numbers to physiological outcomes of T cell activation.


St. John's wort formulations induce rat CYP3A23-3A1 independent of their hyperforin content.
The pregnane X receptor (PXR) is a ligand activated regulator of cytochrome P450 (CYP)3A enzymes. Among the ligands of human PXR is hyperforin, a constituent of St John's wort (SJW) extracts and potent inducer of human CYP3A4. It was the aim of this study to compare the effect of hyperforin and SJW formulations controlled for its content on CYP3A23-3A1 in rats. Hyperiplant® was used as it contains a high hyperforin content and Rebalance® because it is controlled for a low hyperforin content. In silico analysis revealed a weak hyperforin-rPXR binding affinity, which was further supported in cell-based reporter gene assays showing no hyperforin-mediated reporter activation in presence of rPXR. However, cellular exposure to Hyperiplant® and Rebalance® transactivated the CYP3A-reporter 3.8 fold and 2.8 fold, respectively, and they induced Cyp3a23-3a1 mRNA expression in rat hepatoma cells compared to control 48-fold and 18-fold, respectively. In Wistar rats treated for 10 days with 400 mg/kg of Hyperiplant® we observed 1.8-times the Cyp3a23-3a1 mRNA expression, a 2.6-fold higher CYP3A23-3A1 protein amount and a 1.6-fold increase in activity compared to control. For Rebalance® we only observed a 1.8-fold hepatic increase of CYP3A23-3A1 protein compared to control animals. Even though there are differing effects on rCyp3a23-3a1/CYP3A23-3A1 in rat liver reflecting the hyperforin content of the SJW extracts, the modulation is most likely not linked to an interaction of hyperforin with rPXR. Significance Statement Treatment with St John's wort (SJW) has been reported to affect CYP3A expression and activity in rats. Our comparative study further supports this finding but shows that the PXR-ligand hyperforin is not the driving force for changes in rat CYP3A23-3A1 expression and function in vivo and in vitro Importantly, CYP3A induction mimics findings in humans but our results suggest that another so far unknown constituent of SJW is responsible for the expression and function modifying effects in rat liver.


BAG3: An enticing therapeutic target for idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a dreadful and fatal disease of unknown etiology, for which no cure exists. Autophagy, a lysosomal cellular surveillance pathway is insufficiently activated in both alveolar epithelial type II cells and fibroblasts of IPF patient lungs. Fine-tuning this pathway may result in the degradation of the accumulated cargo and influence cell fate. Based on our previous data, we here present our view on modulating autophagy via a unique co-chaperone, namely Bcl2-associated athanogene3 (BAG3) in IPF and discuss about how repurposing drugs that modulate this pathway may emerge as a promising novel therapeutic approach for IPF.


Variation of canine vertebral bone architecture in computed tomography.
Focal vertebral bone density changes were assessed in vertebral computed tomography (CT) images obtained from clinically healthy dogs without diseases that affect bone density. The number, location, and density of lesions were determined. A total of 429 vertebral CT images from 20 dogs were reviewed, and 99 focal vertebral changes were identified in 14 dogs. Focal vertebral bone density changes were mainly found in thoracic vertebrae (29.6%) as hyperattenuating (86.9%) lesions. All focal vertebral changes were observed at the vertebral body, except for a single hyperattenuating change in one thoracic transverse process. Among the hyperattenuating changes, multifocal changes (53.5%) were more common than single changes (46.5%). Most of the hypoattenuating changes were single (92.3%). Eight dogs, 40% of the 20 dogs in the study and 61.6% of the 13 dogs showing focal vertebral changes in the thoracic vertebra, had hyperattenuating changes at the 7th or 8th thoracic vertebra. Our results indicate that focal changes in vertebral bone density are commonly identified on vertebral CT images in healthy dogs, and these changes should be taken into consideration on interpretation of CT images.


Initial experience with a new balloon-on-a-wire catheter: the Bijou.
This paper presents our initial experience with a new low-profile balloon "on-a-wire" catheter, the Bijou. The concept of this balloon is to provide an additional side lumen with the advantages of (1) the ability to measure pressure gradient, (2) the possibility of drug infusion, and (3) the ability to advance a steerable guidewire through this side lumen. The balloon has been tested in 15 patients; 14 underwent an elective procedure for stable angina pectoris (with 2 cases of restenosis) and one an emergency angioplasty in a case of acute myocardial infarction. The stenosis was located on the left anterior descending artery in 11 procedures, on the right in 3, on a marginal branch in 2, on the circumflex and a saphenous vein graft in 1. All stenoses could be dilated successfully (residual stenosis < 25%). The transstenotic pressure gradient felt from 49 +/- 13 mmHg to 7 +/- 4 mm Hg after angioplasty. Except for an uncomplicated dissection in 3 patients, no other complication was noted. With this new catheter, the double-lumen configuration adds the advantages of an "over-the-wire" to an "on-a-wire" system.


Statistical Methods for Predicting Malaria Incidences Using Data from Sudan.
Malaria is the leading cause of illness and death in Sudan. The entire population is at risk of malaria epidemics with a very high burden on government and population. The usefulness of forecasting methods in predicting the number of future incidences is needed to motivate the development of a system that can predict future incidences. The objective of this paper is to develop applicable and understood time series models and to find out what method can provide better performance to predict future incidences level. We used monthly incidence data collected from five states in Sudan with unstable malaria transmission. We test four methods of the forecast: (1) autoregressive integrated moving average (ARIMA); (2) exponential smoothing; (3) transformation model; and (4) moving average. The result showed that transformation method performed significantly better than the other methods for Gadaref, Gazira, North Kordofan, and Northern, while the moving average model performed significantly better for Khartoum. Future research should combine a number of different and dissimilar methods of time series to improve forecast accuracy with the ultimate aim of developing a simple and useful model for producing reasonably reliable forecasts of the malaria incidence in the study area.


The African American Study of Kidney Disease: do these results indicate that 140/90 mm hg is good enough?
Current national guidelines recommend aggressive lowering of blood pressure (< 130/80 mm Hg) in patients with chronic kidney disease (CKD). In this paper, we summarize recent clinical trial data evaluating the effect of lower blood pressure goals on renal outcomes. The epidemiologic data relating blood pressure to progression of kidney disease, the Modification of Diet in Renal Disease (MDRD) study (in patients with > 1 g proteinuria/d), and meta-analyses of angiotensin-converting enzyme (ACE) inhibitor clinical trials all support lower blood pressure goals in CKD patients, particularly those with proteinuria. The African American Study of Kidney Disease and Hypertension (AASK) supports lower blood pressure goals in terms of reduction of proteinuria, but demonstrates no additional benefit for clinical renal outcomes. Similarly, the second Ramipril Efficacy in Nephropathy study (REIN-2) shows that in patients with proteinuric nondiabetic renal disease who are receiving ACE inhibitors, a lower than usual blood pressure goal does not improve renal outcomes. However, there are limited clinical trial data evaluating the effects of low blood pressure on the increased cardiovascular risk seen in patients with CKD. Pending further clinical studies, current recommendations to target tight blood pressure control (< 130/80 mm Hg) in patients with CKD appear reasonable.


Exercise rehabilitation for patients with critical illness: a randomized controlled trial with 12 months of follow-up.
The purpose of this trial was to investigate the effectiveness of an exercise rehabilitation program commencing during ICU admission and continuing into the outpatient setting compared with usual care on physical function and health-related quality of life in ICU survivors. We conducted a single-center, assessor-blinded, randomized controlled trial. One hundred and fifty participants were stratified and randomized to receive usual care or intervention if they were in the ICU for 5 days or more and had no permanent neurological insult. The intervention group received intensive exercises in the ICU and the ward and as outpatients. Participants were assessed at recruitment, ICU admission, hospital discharge and at 3-, 6- and 12-month follow-up. Physical function was evaluated using the Six-Minute Walk Test (6MWT) (primary outcome), the Timed Up and Go Test and the Physical Function in ICU Test. Patient-reported outcomes were measured using the Short Form 36 Health Survey, version 2 (SF-36v2) and Assessment of Quality of Life (AQoL) Instrument. Data were analyzed using mixed models. The a priori enrollment goal was not reached. There were no between-group differences in demographic and hospital data, including acuity and length of acute hospital stay (LOS) (Acute Physiology and Chronic Health Evaluation II score: 21 vs 19; hospital LOS: 20 vs 24 days). No significant differences were found for the primary outcome of 6MWT or any other outcomes at 12 months after ICU discharge. However, exploratory analyses showed the rate of change over time and mean between-group differences in 6MWT from first assessment were greater in the intervention group. Further research examining the trajectory of improvement with rehabilitation is warranted in this population. The trial was registered with the Australian New Zealand Clinical Trials Registry ACTRN12605000776606.


International staging system for multiple myeloma.
There is a need for a simple, reliable staging system for multiple myeloma that can be applied internationally for patient classification and stratification. Clinical and laboratory data were gathered on 10,750 previously untreated symptomatic myeloma patients from 17 institutions, including sites in North America, Europe, and Asia. Potential prognostic factors were evaluated by univariate and multivariate techniques. Three modeling approaches were then explored to develop a staging system including two nontree and one tree survival assessment methodologies. Serum beta2-microglobulin (Sbeta2M), serum albumin, platelet count, serum creatinine, and age emerged as powerful predictors of survival and were then used in the tree analysis approach. A combination of Sbeta2M and serum albumin provided the simplest, most powerful and reproducible three-stage classification. This new International Staging System (ISS) was validated in the remaining patients and consists of the following stages: stage I, Sbeta2M less than 3.5 mg/L plus serum albumin > or = 3.5 g/dL (median survival, 62 months); stage II, neither stage I nor III (median survival, 44 months); and stage III, Sbeta2M > or = 5.5 mg/L (median survival, 29 months). The ISS system was further validated by demonstrating effectiveness in patients in North America, Europe, and Asia; in patients less than and > or = 65 years of age; in patients with standard therapy or autotransplantation; and in comparison with the Durie/Salmon staging system. CONCLUSION) The new ISS is simple, based on easy to use variables (Sbeta2M and serum albumin), and recommended for early adoption and widespread use.


Male drug abuse, criminality and subcultural affiliation in a career perspective.
Degree of connection to the criminal underworld was the basis for typologic research on 698 male drug abusers; interviews as well as official records were used. Four types were distinguished: The addicted criminals seemed to resemble the groups dominant in Sweden from the 1950s to the 1970s. An early crime debut and criminal offenses in youthful years characterized their deviant careers. Drugs and criminal activities coexisted with an often very high intake of alcohol and the most difficult childhood and adolescence conditions compared to the other types. The criminal addicts had fewer recorded acts of juvenile delinquency. Their drug abuse was severe and occurred later in life, as criminality did, but tended to accelerate very rapidly. Their subcultural affiliation was probably as strong as that of the addicted criminals. A large group called low-crime addicts had a weak subgroup affiliation. The "normal" abuse pattern, with cannabis as the first substance used and a gradual shift to more severe opioid and CNS stimulant abuse, was most true of this type. Probably the drug abuse played a role in the development of the criminal pattern. Emotionally unstable addicts with little or no criminality had the best education, job situation and social relations. Multiple drug abuse and abuse of legal drugs were common. Mental ill-health was characteristic for this group. The results show that drug abusers in Sweden cannot be seen as a homogeneous group of individuals, that they do not commit crimes only in order to finance their habit, and that the history of narcotics use in Sweden, with its strong connection to a criminal subculture, is highly relevant to this sample.


Causes and control of sow losses.
Pigs weaned/sow/year increases after the first litter to a maximum at about the third litter, after which it declines such that the sixth litter size is the same as the first, with a gradual decline thereafter. The cost of producing a weaned pig decreases with increasing numbers of litters weaned up to the third, then gradually increases. Average sow culling rates on commercial farms are 24-40% annually. The average time from weaning of pigs to culling of sows is 50-60 days. Sow mortality ranges between 2% and 14%, with a 6-8% average.


The Virtues of Scientific Practice: MacIntyre, Virtue Ethics, and the Historiography of Science.
"Practice" has become a ubiquitous term in the history of science, and yet historians have not always reflected on its philosophical import and in particular on its potential connections with ethics. This essay draws on the work of the virtue ethicist Alasdair MacIntyre to develop a theory of "communal practices" and explore how such an approach can inform the history of science, including allegations about the corruption of science by wealth or power, consideration of scientific ethics or "moral economies," the role of values in science, the ethical distinctiveness (or not) of scientific vocations, and the relationship between history of science and the practice of science itself.


Generation and characterization of infectious chimeric clones between human immunodeficiency virus type 1 and simian immunodeficiency virus from an African green monkey.
A series of chimeric clones of human immunodeficiency virus type 1 and simian immunodeficiency virus isolated from an African green monkey was constructed in vitro. In transient transfection experiments, all clones produced virion-associated reverse transcriptase, gag proteins, and env proteins. Eight out of 10 chimeric viruses clearly grew in the human CD4+ cell line C8166. Susceptibility of other CD4+ cell lines, MT-4, A3.01, and Molt4 clone 8, to infection with these viruses was also demonstrated.


Lipid raft-mediated entry is not required for Chlamydia trachomatis infection of cultured epithelial cells.
Using pharmacologic and biochemical criteria, we evaluated whether uptake of four different Chlamydia trachomatis serovars, D, E, K, and L2, was dependent upon lipid rafts. Our data suggest that lipid raft-mediated entry is not required for C. trachomatis infection of cultured epithelial cells.


Excited state dynamics of meso-tetra(sulphonatophenyl) metalloporphyrins.
The excited state dynamics of Zn2+, Fe3+, and Mn3+ meso-tetra(sulfonatophenyl) porphyrin complexes were investigated with a Z-scan technique at 532 nm using 70 ps and 120 fs single pulses and 200 ns pulse trains of a Q-switched and mode locked laser. We determined the characteristic interconversion and intersystem crossing times, quantum yields of the excited S1 state, and S1 --> Sn and T1 --> Tn transition cross-sections. The ground state cross-sections were obtained using UV-vis absorption spectroscopy, and a five-energy-level diagram was used to yield the photophysical parameters mentioned previously.


Mode of binding of quercetin to DNA.
The difference spectrum of the quercetin--DNA complex versus quercetin alone was characterized by a peak at 395 nm. An increase in the magnitude of difference spectrum was seen with increased ionic strength. Spectrophotometric changes in absorbance and fluorescence of quercetin showed that ethidium bromide is able to displace quercetin from the quercetin--DNA complex. These results indicate that the binding of quercetin to DNA does not involve electrostatic interactions but may be intercalative in nature. Experiments using DNase I footprinting technique showed that the flavonoid does not possess any preferred sites of binding in DNA. Strand scission in DNA by the quercetin--Cu(II) system gave a generally uniform cutting pattern of internucleotide bonds. This led to the observation that the quercetin--Cu(II) cleavage reaction has the potential of being used as preferred DNA footprinting reagent.


Sarcoidal foreign-body granulomatous dermatitis associated with ophthalmic drops.
Sarcoidal granulomas are found in sarcoidosis and in reactions to foreign materials. We report the case of an 81-year-old woman with glaucoma who presented with multiple brown-black asymptomatic papules over the chin and involving nasal mucosa and columella of 1-year duration. Biopsy of the nasal mucosa and cutaneous papules showed sarcoidal granulomas associated with brown-black intracellular pigment within multinucleated giant cells. Electron-probe x-ray microanalysis demonstrated high sulfur content. Clinical studies showed no evidence of systemic sarcoidosis. Two of three ophthalmologic drops contained sodium bisulfite; bisulfite is known to cause allergic reactions. Although the exact substance causing the granulomatous reaction is unknown, the distribution of the lesions--nasal mucosa and columella (via the nasal lacrimal duct) and the underlying chin--implicate the eyedrops in the production of the pigmented granulomatous nodules.


Tempe fermentation: some aspects of formation of gamma-linolenic acid, proteases and vitamins.
During a tempe fermentation the concentrations of linoleic, and alpha-linolenic acids (ALA) decreased while the concentration of oleic acid increased. During fatty acid synthesis Rhizopus sp. produced only gamma-linolenic acid (GLA) instead of ALA. The amount of GLA in tempe were influenced by varying external parameters. The proteolytic capacity of 36 strains of the genus Rhizopus isolated from Indonesian tempe or tempe inocula was examined. There was a distinct increase in the amount of free amino acids during tempe fermentation. Fermentations with mixed populations of bacteria and Rhizopus yielded a lower level of free amino acids, but an increase in total amount of amino acids. In comparison to intracellular, and extracellular proteases the proteases of the cell wall fraction are most responsible for proteolytic capacity of the different Rhizopus strains. Two isolated strains of Citrobacter freundii were found to be the best vitamin B(12) producers during the soaking of soybeans. In the solid substrate fermentation the Rhizopus molds formed vitamin B(6), riboflavin, and nicotinic acid. The addition of bacteria to the solid substrate fermentation resulted in a strong increase of active vitamin B(12) in tempe. In the presence of the Rhizopus mold, the vitamin B(12) formation by C. freundii was three times higher than that of a fermentation without the mold.


Broad-spectrum antiviral activity of the deubiquitinase inhibitor HBX against human adenoviruses
Human adenoviral (HAdV) infections are usually mild and self-limited, however, some infections from species A, B, C, D and E, can cause severe illnesses, which have raised public health concerns over the past few years. Current available antiviral therapies have limited efficacy and severe toxicity; therefore, finding new targets for specific anti-adenoviral drug design is urgently needed. Our previous work showed that the small molecule compound, HBX, inhibits HAdV type 5 (species C, HAdV-C5) replication and oncogenic transformation through inhibition of the cellular pro-viral factor ubiquitin-specific protease 7 (USP7). Here, we have tested the ability of HBX to inhibit other HAdV species, as well as different clinical isolates that are the cause of severe infections. We treated HAdV-infected A549 cells with different concentrations of HBX and analysed the antiviral efficacy of the drug by determining the half maximal inhibitory concentration (IC50) necessary to decrease both viral genome copies and virus progeny production at different time points after infection. In addition to its effect on HAdV-C5, HBX was able to significantly inhibit virus genome replication and progeny release of all adenovirus types tested, with the exception of types 12 and 31, from species A. Of note, clinical isolates were more sensitive to HBX treatment than their prototype strains. These results point to HBX as a promising broad-spectrum anti-adenoviral drug, opening new opportunities to prevent severe adenoviral infections and to improve their treatment.


A Study to Identify the Optimum Forearm Floss Band Intensity in 29 Young Adults Performing Blood Flow Restriction Training.
BACKGROUND A floss band is used in resistance training and consists of a heavy-duty rubber resistance band to compress a joint or muscle group while performing a range of motion. Blood flow restriction (BFR) training combines low-intensity exercise with occlusion of blood flow, resulting in the effects of high-intensity training. This study aimed to identify the optimum forearm floss band intensity in 29 young adults while performing BFR training. MATERIAL AND METHODS Twenty-nine young and healthy adults voluntarily participated in this experiment. One of 4 types of floss bands with different intensities was randomly selected from the subjects and wound around their forearms. The tension of the floss band was calculated to be the length of the participant's forearm when stretched by 105%, and then wound around the forearm. Blood flow was measured 4 times at regular intervals (pretest: 1 min, during: 2 min, posttest [1]: 1 min, posttest [2]: 2 min) using laser Doppler imaging. RESULTS We found that the application of floss bands resulted in a significant interaction between the intensity (colors) and time (pre/during/post) with regard to the hemodynamic changes (P<0.05). The hemodynamic evaluation revealed a reduction in the blood flow (P<0.05). CONCLUSIONS This preliminary study shows that the use of blood flow restriction training requires support from guidelines for optimal floss band intensity, particularly with the increasing clinical use of this method.


Transversus abdominis and core stability: has the pendulum swung?
In the past decade there has been a focus on isolated transversus abdominis activation and how it contributes to lumbo-pelvic stability. This rationale has not only influenced the management of chronic low back pain (LBP); it has also been included in exercises for many other pathologies of the lower and upper limb and also for prophylaxis in pain-free subjects.


Activin receptor-like kinase-2 inhibits activin signaling by blocking the binding of activin to its type II receptor.
Activin receptor-like kinase-2 (Alk2) has been shown to be a promiscuous type I receptor for the transforming growth factor beta (TGFbeta) family of growth and differentiation factors, such as activin, bone morphogenetic proteins, and Müllerian inhibiting substance (MIS). We have studied the putative role of Alk2 in activin signaling using MA-10 cells, a mouse transformed Leydig cell line, in which endogenous expression of cytochrome P450 c17 hydroxylase/C17-20 lyase mRNA is inhibited by both MIS and activin A. Overexpression of Alk2 in MA-10 cells inhibited the activation of the activin-responsive CAGA-luciferase reporter and, conversely, transfection of siRNA for Alk2 increased the response. In contrast, overexpression of the MIS type II receptor in MA-10 cells increased the activin-mediated induction of CAGA-luciferase approximately fivefold, which we hypothesized occurs by MIS type II receptor sequestering endogenous Alk2. Binding experiments with (125)I-labeled activin show that the underlying mechanism of Alk2-mediated inhibition of activin signaling involves Alk2 blocking the access of activin to its type II receptor, which we show can bind Alk2 in the absence of ligand. These results show that the complement of other type I receptors in addition to the ligand-specific type I receptor can provide an important mechanism for modulating cell-specific responses to members of the TGFbeta family.


Vibration analysis of an isotropic elastic sphere contacting a semi-infinite cubic solid.
Vibration analysis of an isotropic elastic-sphere oscillator contacting a semi-infinite cubic solid is investigated by considering dynamic deformation at the contact interface. Assuming sufficiently small oscillation amplitude of the sphere compared with the static indentation deformation, the dynamic maximum contact pressure and the variable contact radius yield a dynamic-contact pressure distribution of constant contact radius. The combination of the sphere oscillation and the solid motion at the contact interface through contact-displacement conditions gives resonance frequencies of the elastic sphere. Unlike the conventional quasi-static model, this dynamic contact model agrees well with the measurements, which will benefit the quantitative evaluation of the local Young's modulus and the orientation of micro-scaled anisotropic grains by the resonance-frequency shifts of a vibrating oscillator in resonance ultrasound microscopy and the efficient removal of micron or sub-micron particles from the substrate in the dry laser cleaning technique.


[Biocompatibility studies on bioactive glass ceramics and polylactic acid combined with cultured bone marrow stromal cells in vitro].
To study the biocompatibility on bioactive glass ceramics (BGC) and polylactic acid (PLA) combined with cultured bone marrow stromal cells (BMSCs) in bone tissue engineering. BMSCs were cultured combined with BGC and PLA in vitro, and the morphological characters, cell proliferation, protein content, and alkaline phosphatase activity were detected. BMSCs could be attached to and extended on both BGC and PLA, and normally grown, proliferated, had active function. BGC could promote cell proliferation. The results show that both BGC and PLA have good biocompatibility with BMSCs, they can be used as biomaterials for cell transplantation in tissue engineering.


Macroscopic frictional properties of poly(1-(2-methacryloyloxy)ethyl-3-butyl imidazolium bis(trifluoromethanesulfonyl)-imide) brush surfaces in an ionic liquid.
Poly(1-(2-methacryloyloxy)ethyl-3-butylimidazolium bis(trifluoromethanesulfonyl)imide) (PMIS) and poly(n-hexyl methacrylate) (PHMA) brushes were prepared on initiator-immobilized silicon wafers by surface-initiated atom transfer radical polymerization. The macroscopic frictional properties of the brushes were determined using a ball-on-flat type tribotester under reciprocating motion in a dry nitrogen atmosphere, water, methanol, and 1-ethyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide (EMImTFSI). When the PMIS and PHMA brushes were exposed to EMImTFSI, the friction coefficient of the former was lower than that of the latter. It is thought that the high affinity of the PMIS brush to EMImTFSI led to a reduction in the interaction between the brush and the friction probe, which resulted in a low friction coefficient. The friction force of the PMIS brush in EMImTFSI was proportional to a normal load in the range of 0.2-0.98 N. The friction coefficient gradually decreased to 0.01 with an increase in the sliding velocity from 1 x 10(-4) to 1 x 10(-1) m s(-1). The friction coefficient of the PMIS brush exhibited low magnitude until 800 friction cycles in the dry nitrogen atmosphere, whereas the PHMA brush was abraded away within 150 friction cycles. The XPS spectra of the worn surfaces on the PMIS brush suggested that the brush was gradually abraded by friction.


Usefulness of concomitant nitrate administration for the enhancement of viability detection with myocardial perfusion imaging.
Myocardial viability assessment is crucial in the evaluation of patients who had prior myocardial infarction for revascularisation procedures. Conventional methods include nuclear myocardial perfusion imaging, dobutamine stress echocardiography and positron emission tomography. Utility of nitrate in assessment of viability was assessed. Twenty-five patients with prior myocardial infarction underwent 99mTc-sestamibi single photon emission computed tomography protocol of stress, rest and post 5 mg sublingual isorbide dinitrate. The mean age of the patients was 51.28 years. Eight (32%) had reduction in perfusion defect and increased tracer uptake following nitrate administration. It is concluded that addition of nitrate adds to utility of conventional perfusion imaging in the assessment of myocardial viability.


Dietary fat and cholesterol and serum cholesterol in the gerbil.
Groups of gerbils were fed purified diets containing either 10 or 20% of safflower, olive, or coconut oil. Each diet was fed without cholesterol and with 0.1 and 0.2% of added cholesterol. The animals were bled after 2, 4, and 8 wk for the determination of the level of serum cholesterol. The major factors affecting the level of serum cholesterol were the kind of dietary oil, the amount of dietary cholesterol, and the length of time the diet was fed. The level of safflower oil had a statistically significant effect but the level of olive or coconut oil had no significant effect. Various other statistically significant interactions were observed which make simple interpretations of the data difficult. The levels of serum cholesterol achieved in the gerbils fed the different oils with no or very low levels of dietary cholesterol were similar to those seen in men fed the same oils. Although the gerbil is apparently resistant to the development of atherosclerosis, it may be a useful model for studying the effect of dietary fats upon cholesterol metabolism.


Perfluorocarbon Enhanced Glasgow Oxygen Level Dependent (GOLD) Magnetic Resonance Metabolic Imaging Identifies the Penumbra Following Acute Ischemic Stroke.
The ability to identify metabolically active and potentially salvageable ischaemic penumbra is crucial for improving treatment decisions in acute stroke patients. Our solution involves two complementary novel MRI techniques (Glasgow Oxygen Level Dependant (GOLD) Metabolic Imaging), which when combined with a perfluorocarbon (PFC) based oxygen carrier and hyperoxia can identify penumbra due to dynamic changes related to continued metabolism within this tissue compartment. Our aims were (i) to investigate whether PFC offers similar enhancement of the second technique (Lactate Change) as previously demonstrated for the T2*OC technique (ii) to demonstrate both GOLD metabolic imaging techniques working concurrently to identify penumbra, following administration of Oxycyte® (O-PFC) with hyperoxia. Methods: An established rat stroke model was utilised. Part-1: Following either saline or PFC, magnetic resonance spectroscopy was applied to investigate the effect of hyperoxia on lactate change in presumed penumbra. Part-2; rats received O-PFC prior to T2*OC (technique 1) and MR spectroscopic imaging, which was used to identify regions of tissue lactate change (technique 2) in response to hyperoxia. In order to validate the techniques, imaging was followed by [14C]2-deoxyglucose autoradiography to correlate tissue metabolic status to areas identified as penumbra. Results: Part-1: PFC+hyperoxia resulted in an enhanced reduction of lactate in the penumbra when compared to saline+hyperoxia. Part-2: Regions of brain tissue identified as potential penumbra by both GOLD metabolic imaging techniques utilising O-PFC, demonstrated maintained glucose metabolism as compared to adjacent core tissue. Conclusion: For the first time in vivo, enhancement of both GOLD metabolic imaging techniques has been demonstrated following intravenous O-PFC+hyperoxia to identify ischaemic penumbra. We have also presented preliminary evidence of the potential therapeutic benefit offered by O-PFC. These unique theranostic applications would enable treatment based on metabolic status of the brain tissue, independent of time from stroke onset, leading to increased uptake and safer use of currently available treatment options.


Differences in treatment regimes, consultation frequency and referral patterns of diabetes mellitus in general practice in five European countries.
In many European countries, maturity onset diabetes mellitus (DM) is to a large extent managed in general practice. Our aim was to compare management of DM in general practice in five European countries in order to contribute to international guidelines on the management of DM by GPs. Routine monitoring of patients presenting with DM was performed during a 12 month period (1999-2000) to GPs in established sentinel practice surveillance networks in five European countries (Belgium, Croatia, England, Spain and The Netherlands). Results were stratified by age and country. The proportion of patients treated by diet only varied from 13% (The Netherlands) to 25% (Spain); diet and oral antidiabetics from 51% (England) to 62% (Belgium); a combination of diet and insulin varied from 15% (Belgium and Croatia) to 26% (The Netherlands); and a combination of diet, oral antidiabetics and insulin was <10% in all countries. In the older age groups, insulin is prescribed most frequently in The Netherlands. Spain and Croatia show high consultation rates for DM; England and The Netherlands show low rates. Referral percentages vary considerably between countries (highest in Croatia). National differences found included the use of insulin in the elderly, the consultation frequency in general practice and the referral rate to ophthalmologist and diabetic specialists. Further quantitative and qualitative studies are needed to explore the needs for support in diabetes management in general practice in Europe.


Flexural Strength Comparison of Silorane- and Methacrylate-Based Composites with Pre-impregnated Glass Fiber.
Sufficient adhesion between silorane/methacrylate-based composites and methacrylate impregnated glass fiber increases the benefits of fibers and enhances the mechanical and clinical performance of both composites. The aim of this study was to evaluate the compatibility of silorane and methacrylate-based composites with pre-impregnated glass fiber by using flexural strength (FS) test. A total of 60 bar specimens were prepared in a split mold (25×2×2 mm) in 6 groups (n=10). In groups 1 and 4 (control), silorane-based (Filtek P90) and nanohybrid (Filtek Z350) composites were placed into the mold and photopolymerized with a high-intensity curing unit. In groups 2 and 5, pre-impregnated glass fiber was first placed into the mold and after two minutes of curing, the mold was filled with respective composites. Prior to filling the mold in groups 3 and 6, an intermediate adhesive layer was applied to the glass fiber. The specimens were stored in distilled water for 24 hours and then their flexural strength was measured by 3 point bending test, using universal testing machine at the crosshead speed of 1 mm/min. Two-way ANOVA and post-hoc test were used for analyzing the data (p< 0.05). A significant difference was observed between the groups (p< 0.05). The highest FS was registered for combination of Z350 composite, impregnated glass fiber, and application of intermediate adhesive layer .The lowest FS was obtained in Filtek P90 alone. Cohesive failure in composite was the predominant failure in all groups, except group 5 in which adhesive failure between the composite and fiber was exclusively observed. Significant improvement in FS was achieved for both composites with glass fiber. Additional application of intermediate adhesive layer before composite build up seems to increase FS. Nanohybrid composite showed higher FS than silorane-based composite.


Circulating sperm antibodies: indications for testing in infertile couples.
Sperm antibody titers were evaluated in the serum of 73 infertile couples by the F-D and Kibrick agglutination tests, to study the relationship of the quality of post-coital tests and semen analysis. Thirty-eight couples had poor post-coital tests, fifteen couples had normal post-coital tests, and twenty couples revealed abnormal semen pictures of the males. In the first two groups, semen analysis was normal. The incidence of sperm antibodies was 10.5%, 6.6% in men, and 18.4%, 20.0% in women, with poor and normal post-coital tests, respectively. This suggests that sperm antibody testing is equally indicated in infertile couples with poor post-coital tests. In addition, there was no difference in the incidence of sperm antibodies in men with poor semen pictures and those with normal semen analysis in this infertile population. This suggests the significance of sperm antibody testing in infertile men with abnormal and normal semen pictures after correcting other infertility factors, in order to detect those patients who could benefit from treatment of such immunologic problems.


Mucosal healing in Crohn's disease: relevance for clinical outcomes.
The clinical management of Crohn's disease (CD) has evolved in recent years from symptom control to healing of mucosal lesions. Mucosal healing, induced and maintained by immunomodulators and/or biologicals, has been shown to alter the disease course in patients with CD. As a consequence, long-term disease outcomes have been dramatically improved, in particular since the introduction of anti-tumor necrosis factor (TNF) agents. CD patients with active inflammation (ileocolonic ulcers and/or increased C-reactive protein levels) benefit most from treatment with TNF antagonists. Since healing of the inflamed mucosa is now considered an important treatment goal, endoscopic monitoring is gradually entering routine practice. Therefore, the mucosal appearance will more and more influence the therapeutic decision making process. Mucosal healing has also become an end-point in therapeutic trials. We will summarize some of the fundamental issues regarding mucosal healing and discuss data to support its clinical relevance in the management of CD.


Complete Versus Incomplete Angiography Prior to Percutaneous Coronary Intervention in ST-Elevation Myocardial Infarction.
Shorter reperfusion times in ST-elevation myocardial infarction (STEMI) are associated with improved survival. Prehospital strategies have been developed to minimize door-to-balloon (DTB) time, but few strategies within the catheterization laboratory itself have been evaluated. Incomplete angiography (IA) prior to percutaneous coronary intervention (PCI) is undertaken in clinical practice as a means to further reduce DTB time. We sought to determine whether or not those with STEMI who underwent IA prior to PCI had different preprocedural characteristics or post-PCI outcomes. We retrospectively reviewed patients presenting to our institution between March 2013 and December 2015. Clinical, demographic, and angiographic data were reviewed. The frequency, predictors, and outcomes among those who received IA vs complete angiography (CA) prior to PCI were compared with analysis of variance. Two hundred fifty-six patients were identified; 68 patients (26.6%) underwent IA and 188 patients (73.4%) had CA prior to PCI. Patients who received IA were younger, but no other preprocedural factors were predictive of IA. The practice of IA did vary by operator (range, 0%-47%; P<.01). DTB times were shorter in the IA group (28.1 min vs 37.3 min; P<.01). Overall outcomes, including peak troponin values, length of stay, in-hospital mortality, and discharge ejection fraction did not differ between the groups. IA is associated with shorter DTB times, although in this population was not associated with improvements in short-term outcomes.


Myxoma virus oncolytic efficiency can be enhanced through chemical or genetic disruption of the actin cytoskeleton.
Myxoma virus (MYXV) is one of many animal viruses that exhibit oncolytic properties in transformed human cells. Compared to orthopoxviruses like vaccinia (VACV), MYXV spreads inefficiently, which could compromise its use in treating tumors and their associated metastases. The VACV F11 protein promotes virus exit and rapid spread by inhibiting Rho signalling, which results in a disruption of cortical actin. We have previously shown that although MYXV lacks an F11 homolog, the F11L gene can be introduced into MYXV promoting the spread of this Leporipoxvirus in natural host cells. Here we show that the F11-encoding (F11L(+)) MYXV strain replicates to higher levels in a number of human cancer cells. We also show that F11L(+) MYXV induces better tumor control and prolonged survival of mice bearing MDA-MB-231 cancer cells. Furthermore, we show that this virus also spreads more efficiently from the site of growth in one injected tumor, to a second untreated tumor. While we focused mostly on the use of a modified MYXV we were able to show that the effects of F11 on MYXV growth in cancer cells could be mimicked through the use of pharmacological inhibition or siRNA-mediated silencing of key regulators of cortical actin (RhoA, RhoC, mDia1, or LIMK2). These data suggest that it may be possible to increase the oncolytic efficacy of wild-type MYXV using chemical inhibitors of RhoA/C or their downstream targets. Furthermore, since all viruses must overcome barriers to exit posed by structures like cortical actin, these findings suggest that the oncolytic activity of other viruses may be enhanced through similar strategies.


Negligible differences in metabolism and thermal tolerance between diploid and triploid Atlantic salmon (Salmo salar).
The mechanisms that underlie thermal tolerance in aquatic ectotherms remain unresolved. Triploid fish have been reported to exhibit lower thermal tolerance than diploids, offering a potential model organism to better understand the physiological drivers of thermal tolerance. Here, we compared triploid and diploid juvenile Atlantic salmon (Salmo salar) in freshwater to investigate the proposed link between aerobic capacity and thermal tolerance. We measured specific growth rates (SGR) and resting (aerobic) metabolic rates (RMR) in freshwater at 3, 7 and 9 weeks of acclimation to 10, 14 and 18°C. Additionally, maximum metabolic rates (MMR) were measured at 3 and 7 weeks of acclimation, and critical thermal maxima (CTmax) were measured at 9 weeks. Mass, SGR and RMR differed between ploidies across all temperatures at the beginning of the acclimation period, but all three metrics were similar across ploidies by week 7. Aerobic scope (MMR-RMR) remained consistent across ploidies, acclimation temperatures and time. At 9 weeks, CTmax was independent of ploidy, but correlated positively with acclimation temperature despite the similar aerobic scope between acclimation groups. Our findings suggest that acute thermal tolerance is not modulated by aerobic scope, and the altered genome of triploid Atlantic salmon does not translate to reduced thermal tolerance of juvenile fish in freshwater.


Identification of ocular and auditory manifestations of congenital rubella syndrome in mbingo.
Purpose. Congenital rubella syndrome (CRS) is a global cause of preventable hearing impairment, blindness, and intellectual impairment. The present study sought to identify ocular and auditory manifestations of CRS in school-aged children in Mbingo, Cameroon. Design. Cross sectional study. Subjects. Students at two schools, one for children with hearing impairment, were screened for cataract, congenital glaucoma, and pigmentary retinopathy. Methods. Students underwent seven-field digital fundus photography through a dilated pupil using a Topcon NW200 nonmydriatic camera. Images were assessed by retina specialists in Canada via teleophthalmology. Clinical evidence was integrated to form case definitions for CRS based on Center for Disease Control and Prevention guidelines. Serological evidence of rubella infection was obtained using standardized IgG antibody titers. Main Outcome Measure. Number of probable and suspicious cases of CRS. Results. Between September 2009 and May 2010, 320 students participated. There were 28 (10.2%) probable cases, 104 (37.8%) suspects, and 143 (52.0%) unaffected. Rubella IgG serology was positive in 79 (48.7%) of children with hearing impairment and 11 (7.4%) of children with normal hearing. Conclusions. The present study identified 28 probable cases of CRS. Furthermore, 92.6% of students with normal hearing did not possess rubella IgG antibodies making future cases of CRS likely without intervention.


Effects of prostacyclin on tumor cell-induced platelet aggregation.
Prostacyclin has been evaluated for its ability to inhibit tumor cell-induced platelet aggregation (TCIPA) induced by several rodent tumor lines: B16a (melanoma); 3LL (carcinoma); 15091A (adenocarcinoma); and W256 (carcinosarcoma). Aggregation of human platelets by all four lines was inhibited by prostaglandin I2 (PGI2) in a dose-dependent manner, with complete inhibition observed at 10 ng/ml. However, higher PGI2 concentrations were required to inhibit aggregation of homologous rat platelets induced by W256 cells. Prostacyclin was compared to other icosanoids known to inhibit platelet aggregation and was found to be 100-fold more potent than either prostaglandin E1 or prostaglandin D2 and 1000-fold more potent than its stable nonenzymatic metabolite (6-ketoprostaglandin F1 alpha). Prostaglandin E2 in contrast to prostaglandin E1 and prostaglandin D2, did not inhibit TCIPA; however, both prostaglandin E2 and its enzymatic metabolite (13,14-dihydro-15-ketoprostaglandin E2) prevented PGI2 inhibition of TCIPA. The addition of prostaglandin I2 (100 ng/ml) after initiation of TCIPA (50% of maximum response) resulted in immediate arrest of TCIPA followed by reversal of platelet aggregation. Prostacyclin partially reversed platelet aggregation when added at 100% of maximum response. Platelets enhanced the adhesion of [125I]uridine-labeled W256 cells to plastic culture dishes under both aggregatory and nonaggregatory conditions. Prostacyclin in vitro inhibited platelet-facilitated tumor cell adhesion. These in vitro results demonstrated that PGI2 is a potent inhibitor of TCIPA and of tumor cell adhesion; we suggest that these are possible mechanisms to explain the antimetastatic effects of PGI2 in vivo [Honn, K. V., Cicone, B., and Skoff, A. Science (Wash. D.C.), 212: 1270-1272, 1981].