The esterolytic activity of poly(1-methyl-4- and -5-vinylimidazole) in water.
The water solubility of poly(1-Me-5-VIm) has made it possible to achieve phenomenal rate enhancements and to gain even greater insight into the mechanism of catalysis by polymeric imidazoles. The poly(1-Me-5-VIm)-catalyzed hydrolysis of S12- exhibited saturation in excess catalyst nad in excess substrate. Inhibition of the poly(1-Me-5-Vim) catalyzed hydrolysis of Sn- type substrates by analog inhibitors was also observed. The saturation apparently did not follow a simple Michaelis-Menten mechanism; however, the results could be rationalized by analogy to certain enzymatic systems. Multisite enzymes have long been known to display kinetic patterns different from that exhibited by enzymes with only one active site, i.e. such phenomena as sigmoidal rate vs [S] plots. These phenomena may arise entirely as a result of the multisite nature of the enzyme. Consequently, a synthetic macromolecular catalyst with multiple sites might also be expected to display such characteristics. The poly(1-Me-5-VIm)-catalyzed hydrolysis of S12- is apparently the first synthetic system in which such phenomena have been observed. The intermediacy of an apolar polymer substrate complex for the poly(1-Me-5-VIm)-catalyzed hydrolysis of S12- in water was given support by studies of the effect of temperature on the rate of hydrolysis. Activation parameters were determined for catalysis by 1,5-DMIm and by poly(1-Me-5-VIm). These results showed that the rate enhancement exhibited by the polymer was due entirely to a favorable entropy term.


Estrogen inhibition of a Mr 39,000 glycoprotein secreted by human breast cancer cells.
We have identified a secreted glycoprotein with an apparent molecular weight of 39,000 that is inhibited by estrogens and stimulated by antiestrogens in the MCF-7 human breast cancer cell line. The protein was detected within 24 h of hormone treatment with inhibition occurring at concentrations as low as 10(-11) M estradiol and stimulation occurring with antiestrogens. When phenol red, which has been found to have estrogenic activity, is removed from the tissue culture medium, no inhibition of cell growth or induction of the Mr 39,000 protein is seen with antiestrogens. A 6-fold decrease in the amount secreted in the presence of estrogens is seen under these conditions. The induction was specific in that growth inhibition by several other means did not induce expression of the Mr 39,000 protein. The Mr 39,000 protein has been identified as a glycoprotein complex that can be resolved into four polypeptides with two major components that migrate in the pH range of 5.5 to 6.3 by two-dimensional gel electrophoresis. This protein is the first evidence that estrogens inhibit a specific protein and it may prove useful as a marker of antiestrogen-induced growth arrest in breast cancer.


Temporal trend of polychlorinated dibenzo-p-dioxin/polychlorinated dibenzofuran and dioxin like-polychlorinated biphenyl concentrations in food from Taiwan markets during 2004-2012.
The levels of polychlorinated dibenzo-p-dioxin (PCDD) and polychlorinated dibenzofuran (PCDF) or polychlorinated biphenyl (PCB) in foodstuffs have decreased over the past decade in many countries. However, the trend for the levels of these compounds in foodstuffs in Taiwan remains unknown. In this study, we compared the distribution of PCDD/F and PCB in nine foodstuff categories acquired from Taiwan markets from 2004 to 2012. The levels expressed as World Health Organization toxic equivalents (WHO-TEQs) in the different foodstuffs tested were as follows: fish, average 0.463 pg WHO98-TEQ/g sample > seafood, 0.163 pg WHO98-TEQ/g > eggs, 0.150 pg WHO98-TEQ/g > oils, 0.126 pg WHO98-TEQ/g > meats, 0.095 pg WHO98-TEQ/g > dairy products, 0.054 pg WHO98-TEQ/g > cereals, 0.017 pg WHO98-TEQ/g > vegetables, 0.013 pg WHO98-TEQ/g > fruits, 0.009 pg WHO98-TEQ/g. Levels were particularly high in crab (average: 0.6 pg WHO98-TEQ/g sample (1.243 pg WHO98-TEQ/g sample) and large marine fish (0.6). In Taiwan, a decreasing trend of PCDD/Fs or dioxin-like PCBs (dl-PCBs) was observed in meat, dairy, eggs, and vegetables, whereas an elevated trend was observed in cereals or the levels were nearly equal in fruits and oils at alternative time shift. Dl-PCBs contributed to 60-65% toxicity equivalence levels in fish and seafood, but only to 13-40% in meat and cereal samples. The decreasing trend was consistent with the results in other countries; however, the trends in cereals, fruits, and oils were in contrast to previous results reported in other countries. Cereals and fruits are important crops in southern Taiwan, and the local pollution generated by industries or incinerators may seriously affect the distribution of PCDD/Fs and dl-PCBs. To ensure food safety, a risk assessment for residents living in different areas should be adopted for all food categories simultaneously in the future.


Functional analysis of the amino-terminal 8-kDa domain of DNA polymerase beta as revealed by site-directed mutagenesis. DNA binding and 5'-deoxyribose phosphate lyase activities.
The amino-terminal 8-kDa domain of DNA polymerase beta functions in binding single-stranded DNA (ssDNA), recognition of a 5'-phosphate in gapped DNA structures, and as a 5'-deoxyribose phosphate (dRP) lyase. NMR and x-ray crystal structures of this domain have suggested several residues that may interact with ssDNA or play a role in the dRP lyase reaction. Nine of these residues were altered by site-directed mutagenesis. Each mutant was expressed in Escherichia coli, and the recombinant protein was purified to near homogeneity. CD spectra of these mutant proteins indicated that the alteration did not adversely affect the global protein structure. Single-stranded DNA binding was probed by photochemical cross-linking to oligo(dT)16. Several mutants (F25W, K35A, K60A, and K68A) were impaired in ssDNA binding activity, whereas other mutants (H34G, E71Q, K72A, E75A, and K84A) retained near wild-type binding activity. The 5'-phosphate recognition activity of these mutants was examined by UV cross-linking to a 5-nucleotide gap DNA where the 5' terminus in the gap was either phosphorylated or unphosphorylated. The results indicate that Lys35 is involved in 5'-phosphate recognition of DNA polymerase beta. Finally, the dRP lyase activity of these mutants was evaluated using a preincised apurinic/apyrimidinic DNA. Alanine mutants of Lys35 and Lys60 are significantly reduced in dRP lyase activity, consistent with the lower ssDNA binding activity. More importantly, alanine substitution for Lys72 resulted in a greater than 90% loss of dRP lyase activity, without affecting DNA binding. Alanine mutants of Lys68 and Lys84 had wild-type dRP lyase activity. The triple alanine mutant, K35A/K68A/K72A, was devoid of dRP lyase activity, suggesting that the effects of the alanine substitution at Lys72 and Lys35 were additive. The results suggest that Lys72 is directly involved in formation of a covalent imino intermediate and are consistent with Lys72 as the predominant Schiff base nucleophile in the dRP lyase beta-elimination catalytic reaction.


Surgical treatment of distal triceps ruptures.
Distal triceps tendon ruptures occur rarely, and the diagnosis is often missed when the injury is acute. The literature provides little guidance regarding treatment or the outcome of treatment of these injuries. The goal of this report was to present our experience with the diagnosis, timing and technique of surgical treatment, and outcome of treatment of distal triceps tendon ruptures in twenty-two patients. None of the ruptures followed joint replacement. Twenty-three procedures were performed in twenty-two patients with an average age of forty-seven years. The average duration of follow-up was ninety-three months (range, seven to 264 months). Data were obtained by a retrospective review of records and radiographs before and after surgery. Also, thirteen patients returned for follow-up and were examined clinically. Six additional patients responded to a telephone questionnaire. One patient was lost to follow-up, and two had died. Formal biomechanical evaluation of isokinetic strength and isokinetic work was performed in eight patients, at an average of eighty-eight months after surgery. Isokinetic strength data were available from the charts of two additional patients. Ten of the triceps tendon ruptures were initially misdiagnosed. At the time of diagnosis, triceps weakness with a decreased active range of motion was found in most patients, and a palpable defect in the tendon was noted after sixteen ruptures. Operative findings revealed a complete tendon rupture in eight cases and partial injuries in fifteen. Fourteen primary repairs and nine reconstructions of various types were performed. Three of the primary repairs were followed by rerupture. At the time of follow-up, the range of elbow motion averaged 10 degrees to 136 degrees. All but two elbows had a functional range of motion; however, the lack of a functional range in the two elbows was probably due to posttraumatic arthritis and not to the triceps tendon rupture. Triceps strength was noted to be 4/5 or 5/5 on manual testing in all examined subjects. Isokinetic testing of ten patients showed that peak strength was, on the average, 82% of that of the untreated extremity. Testing showed the average endurance of the involved extremity to be 99% of that of the uninvolved arm. The results after repair and reconstruction were comparable, but the patients' recovery was slower after reconstruction. The diagnosis of distal triceps tendon rupture is often missed when the injury is acute because of swelling and pain. Primary repair of the ruptured tendon is always possible when it is performed within three weeks after the injury. When the diagnosis is in doubt immediately after an injury, the patient should be followed closely and should be reexamined after the swelling and pain have diminished so that treatment can be instituted before the end of this three-week period. Reconstruction of the tendon is a much more complex, challenging procedure, and the postoperative recovery is slower. Thus, we believe that early surgical repair, within three weeks after the injury, is the treatment of choice for distal triceps tendon ruptures. of evidence.


Blood-based omic profiling supports female susceptibility to tobacco smoke-induced cardiovascular diseases.
We recently reported that differential gene expression and DNA methylation profiles in blood leukocytes of apparently healthy smokers predicts with remarkable efficiency diseases and conditions known to be causally associated with smoking, suggesting that blood-based omic profiling of human populations may be useful for linking environmental exposures to potential health effects. Here we report on the sex-specific effects of tobacco smoking on transcriptomic and epigenetic features derived from genome-wide profiling in white blood cells, identifying 26 expression probes and 92 CpG sites, almost all of which are affected only in female smokers. Strikingly, these features relate to numerous genes with a key role in the pathogenesis of cardiovascular disease, especially thrombin signaling, including the thrombin receptors on platelets F2R (coagulation factor II (thrombin) receptor; PAR1) and GP5 (glycoprotein 5), as well as HMOX1 (haem oxygenase 1) and BCL2L1 (BCL2-like 1) which are involved in protection against oxidative stress and apoptosis, respectively. These results are in concordance with epidemiological evidence of higher female susceptibility to tobacco-induced cardiovascular disease and underline the potential of blood-based omic profiling in hazard and risk assessment.


Rapid (<5 min) identification of pathogen in human blood by electrokinetic concentration and surface-enhanced Raman spectroscopy.
This study reports a novel microfluidic platform for rapid and long-ranged concentration of rare-pathogen from human blood for subsequent on-chip surface-enhanced Raman spectroscopy (SERS) identification/discrimination of bacteria based on their detected fingerprints. Using a hybrid electrokinetic mechanism, bacteria can be concentrated at the stagnation area on the SERS-active roughened electrode, while blood cells were excluded away from this region at the center of concentric circular electrodes. This electrokinetic approach performs isolation and concentration of bacteria in about three minutes; the density factor is increased approximately a thousand fold in a local area of ~5000 μm(2) from a low bacteria concentration of 5 × 10(3) CFU/ml. Besides, three genera of bacteria, S. aureus, E. coli, and P. aeruginosa that are found in most of the isolated infections in bacteremia were successfully identified in less than one minute on-chip without the use of any antibody/chemical immobilization and reaction processes.


Cost-utility analysis of indacaterol in Germany: a once-daily maintenance bronchodilator for patients with COPD.
Indacaterol is a novel inhaled once-daily long-acting beta(2)-agonist (LABA) for the maintenance treatment of COPD that has been compared to existing inhaled monotherapies on a number of symptomatic endpoints in clinical studies. With constrained healthcare budgets, the objective of this analysis was to evaluate the cost-effectiveness of indacaterol 150 μg, the approved starting dose for maintenance therapy, from a German heath service perspective against the most widely used bronchodilator tiotropium, and the twice-daily LABA, salmeterol. A Markov model was developed with the following main health states: Mild, Moderate, Severe, and Very Severe COPD, based on pre-bronchodilator FEV(1) measures reported in the indacaterol clinical trials, and death. Each disease severity health state had two associated health states for severe or non-severe exacerbation. The model considered patients with moderate to severe COPD, with a mean age of 64 years. The base case time horizon was three years, with discounting set at 3% for costs and benefits. Selected clinical inputs and health state utilities were derived from indacaterol clinical trials, while costs were based on publicly available drug prices and tariffs or published sources. Inputs describing disease progression were based on published data on the rate of FEV(1) decline. Point-estimates show that indacaterol 150 μg is dominant (lower total costs and better outcomes) against tiotropium and salmeterol. An alternative analysis comparing indacaterol 300 μg (maximum dose) against tiotropium, showed an incremental cost-effectiveness ratio (ICER) of approximately €28,300 per QALY. Indacaterol is cost-effective compared to tiotropium and salmeterol.


Dual-core photonic crystal fibers for tunable polarization mode dispersion compensation.
A novel type of dual concentric core photonic crystal fiber (PCF) is proposed and theoretically analyzed, aiming at the design of tunable dispersive fiber elements for polarization-mode-dispersion (PMD) compensation. The adjustment of the fiber's geometrical birefringence through the proper selection of structural parameters leads to very high values of differential group-delay (DGD). Moreover, the value of DGD can be dynamically tuned by infiltrating the outer core capillaries of the PCF with an optical liquid, which allows for the thermal control of its refractive index. Such fibers are envisaged as tunable dispersive fiber elements for PMD compensation or emulation modules.


The care span: The importance of transitional care in achieving health reform.
Under the Affordable Care Act of 2010, a variety of transitional care programs and services have been established to improve quality and reduce costs. These programs help hospitalized patients with complex chronic conditions-often the most vulnerable-transfer in a safe and timely manner from one level of care to another or from one type of care setting to another. We conducted a systematic review of the research literature and summarized twenty-one randomized clinical trials of transitional care interventions targeting chronically ill adults. We identified nine interventions that demonstrated positive effects on measures related to hospital readmissions-a key focus of health reform. Most of the interventions led to reductions in readmissions through at least thirty days after discharge. Many of the successful interventions shared similar features, such as assigning a nurse as the clinical manager or leader of care and including in-person home visits to discharged patients. Based on these findings, we recommend several strategies to guide the implementation of transitional care under the Affordable Care Act, such as encouraging the adoption of the most effective interventions through such programs as the Community-Based Care Transitions Program and Medicare shared savings and payment bundling experiments.


Influence of diabetes and mammary artery grafting on survival after coronary bypass.
The effect of diabetes on survival after coronary bypass surgery is uncertain. Also, although the overall clinical benefits of internal mammary artery (IMA) grafting are well established, the survival benefit attributable to IMA grafting in diabetics is not well characterized. To determine the influence of diabetes and IMA grafting on survival after bypass surgery in the current surgical era, characteristics related to subsequent outcome were analyzed in 5,654 consecutive patients undergoing surgery in the decade of the 1980s. The 1,132 diabetic patients (20%) had more extensive coronary disease, had more left ventricular dysfunction, were older, were more frequently female, received a greater number of grafts (mean, 3.5 versus 3.1), and received more IMA grafts (67% versus 58%) than the 4,522 nondiabetic patients (all p less than 0.001). Overall 5-year survival probability was 0.91 in nondiabetic and 0.80 in diabetic patients (p less than 0.0001). Nondiabetic survival exceeded diabetic survival even in high-risk subgroups such as ejection fraction less than or equal to 0.40 (0.80 versus 0.66, p less than 0.02), age greater than or equal to 65 years (0.85 versus 0.73, p less than 0.0003), and, urgent surgery (0.89 versus 0.76, p less than 0.0001). By multivariate analysis, impairment of left ventricular function, advanced age, failure to use an IMA graft, diabetes, female sex, urgent surgery, number of diseased vessels, and mitral insufficiency were incremental risk factors for cardiac mortality (all p less than 0.006). Failure to use an IMA graft and diabetes were equally strong predictors of outcome. Use of an IMA graft conveyed an independent survival benefit to both nondiabetic (p less than 0.0001) and diabetic (p less than 0.02) patients. The magnitude of the survival benefit attributable to IMA grafting in the two groups did not differ (p = 0.4). Diabetes is an important risk factor for late cardiac mortality after bypass surgery and should be included in analyses of the efficacy of therapies for coronary artery disease. IMA grafting conveys a similar benefit to diabetic and nondiabetic patients but does not negate the adverse effect of diabetes on survival.


catena-Poly[aqua-bis-(μ-3-chloro-benzo-ato-κ(2) O:O')zinc].
In the polymeric title compound, [Zn(C7H4ClO2)2(H2O)] n , the Zn(II) cation is located on a twofold rotation axis and is coordinated by carboxylate O atoms of four monodentate chloro-benzoate anions and by one water mol-ecule, located on a twofold rotation axis, in a distorted square-pyramidal geometry. In the anion, the carboxyl-ate group is twisted away from the attached benzene ring by 44.16 (11)°. The chloro-benzoate anion bridges Zn(II) cations, forming polymeric chains running along the c-axis direction. O-H⋯O hydrogen bonds between coordinating water mol-ecules and carboxyl-ate groups link adjacent chains into layers parallel to the bc plane.


Coumarin-BODIPY hybrids by heteroatom linkage: versatile, tunable and photostable dye lasers for UV irradiation.
Linking amino and hydroxycoumarins to BODIPYs through the amino or hydroxyl group lets the easy construction of unprecedented photostable coumarin-BODIPY hybrids with broadened and enhanced absorption in the UV spectral region, and outstanding wavelength-tunable laser action within the green-to-red spectral region (∼520-680 nm). These laser dyes allow the generation of a valuable tunable UV (∼260-350 nm) laser source by frequency doubling, which is essential to study accurately the photochemistry of biological molecules under solar irradiation. The tunability is achieved by selecting the substitution pattern of the hybrid. Key factors are the linking heteroatom (nitrogen vs. oxygen), the number of coumarin units joined to the BODIPY framework and the involved linking positions.


Rad52 function prevents chromosome loss and truncation in Candida albicans.
RAD52 is required for almost all recombination events in Saccharomyces cerevisiae. We took advantage of the heterozygosity of HIS4 in the Candida albicans SC5314 lineage to study the role of Rad52 in the genomic stability of this important fungal pathogen. The rate of loss of heterozygosity (LOH) at HIS4 in rad52-ΔΔ strains was ∼10(-3) , at least 100-fold higher than in Rad52(+) strains. LOH of whole chromosome 4 or truncation of the homologue that carries the functional HIS4 allele was detected in all 80 rad52-ΔΔ His auxotrophs (GLH -GL lab His(-)) obtained from six independent experiments. Isolates that had undergone whole chromosome LOH, presumably due to loss of chromosome, carried two copies of the remaining homologue. Isolates with truncations carried centric fragments of broken chromosomes healed by de novo telomere addition. GLH strains exhibited variable degrees of LOH across the genome, including two strains that became homozygous for all the heterozygous markers tested. In addition, GLH strains exhibited increased chromosomal instability (CIN), which was abolished by reintroduction of RAD52. CIN of GLH isolates is reminiscent of genomic alterations leading to cancer in human cells, and support the mutator hypothesis in which a mutator mutation or CIN phenotype facilitate more mutations/aneuploidies.


Altered adrenergic response in myocytes bordering a chronic myocardial infarction underlies in vivo triggered activity and repolarization instability.
Ventricular arrhythmias are a major complication after myocardial infarction (MI), associated with sympathetic activation. The structurally heterogeneous peri-infarct zone is a known substrate, but the functional role of the myocytes is less well known. Recordings of monophasic action potentials in vivo reveal that the peri-infarct zone is a source of delayed afterdepolarizations (DADs) and has a high beat-to-beat variability of repolarization (BVR) during adrenergic stimulation (isoproterenol, ISO). Myocytes isolated from the peri-infarct region have more DADs and spontaneous action potentials, with spontaneous Ca2+ release, under ISO. These myocytes also have reduced repolarization reserve and increased BVR. Other properties of post-MI remodelling are present in both peri-infarct and remote myocytes. These data highlight the importance of altered myocyte adrenergic responses in the peri-infarct region as source and substrate of post-MI arrhythmias. Ventricular arrhythmias are a major early complication after myocardial infarction (MI). The heterogeneous peri-infarct zone forms a substrate for re-entry while arrhythmia initiation is often associated with sympathetic activation. We studied the mechanisms triggering these post-MI arrhythmias in vivo and their relation to regional myocyte remodelling. In pigs with chronic MI (6 weeks), in vivo monophasic action potentials were simultaneously recorded in the peri-infarct and remote regions during adrenergic stimulation with isoproterenol (isoprenaline; ISO). Sham animals served as controls. During infusion of ISO in vivo, the incidence of delayed afterdepolarizations (DADs) and beat-to-beat variability of repolarization (BVR) was higher in the peri-infarct than in the remote region. Myocytes isolated from the peri-infarct region, in comparison to myocytes from the remote region, had more DADs, associated with spontaneous Ca2+ release, and a higher incidence of spontaneous action potentials (APs) when exposed to ISO (9.99 ± 4.2 vs. 0.16 ± 0.05 APs/min, p = 0.004); these were suppressed by CaMKII inhibition. Peri-infarct myocytes also had reduced repolarization reserve and increased BVR (26 ± 10 ms vs. 9 ± 7 ms, P < 0.001), correlating with DAD activity. In contrast to these regional distinctions under ISO, alterations in Ca2+ handling at baseline and myocyte hypertrophy were present throughout the left ventricle (LV). Expression of some of the related genes was, however, different between the regions. In conclusion, altered myocyte adrenergic responses in the peri-infarct but not the remote region provide a source of triggered activity in vivo and of repolarization instability amplifying the substrate for re-entry. These findings stimulate further exploration of region-specific therapies targeting myocytes and autonomic modulation.


Sustained sleep fragmentation induces sleep homeostasis in mice.
Sleep fragmentation (SF) is an integral feature of sleep apnea and other prevalent sleep disorders. Although the effect of repetitive arousals on cognitive performance is well documented, the effects of long-term SF on electroencephalography (EEG) and molecular markers of sleep homeostasis remain poorly investigated. To address this question, we developed a mouse model of chronic SF and characterized its effect on EEG spectral frequencies and the expression of genes previously linked to sleep homeostasis including clock genes, heat shock proteins, and plasticity-related genes. N/A. Animal sleep research laboratory. Sixty-six C57BL6/J adult mice. Instrumental sleep disruption at a rate of 60/h during 14 days. Locomotor activity and EEG were recorded during 14 days of SF followed by recovery for 2 days. Despite a dramatic number of arousals and decreased sleep bout duration, SF minimally reduced total quantity of sleep and did not significantly alter its circadian distribution. Spectral analysis during SF revealed a homeostatic drive for slow wave activity (SWA; 1-4 Hz) and other frequencies as well (4-40 Hz). Recordings during recovery revealed slow wave sleep consolidation and a transient rebound in SWA, and paradoxical sleep duration. The expression of selected genes was not induced following chronic SF. Chronic SF increased sleep pressure confirming that altered quality with preserved quantity triggers core sleep homeostasis mechanisms. However, it did not induce the expression of genes induced by sleep loss, suggesting that these molecular pathways are not sustainably activated in chronic diseases involving SF.


Approximate Bayesian feature selection on a large meta-dataset offers novel insights on factors that effect siRNA potency.
Short interfering RNA (siRNA)-induced RNA interference is an endogenous pathway in sequence-specific gene silencing. The potency of different siRNAs to inhibit a common target varies greatly and features affecting inhibition are of high current interest. The limited success in predicting siRNA potency being reported so far could originate in the small number and the heterogeneity of available datasets in addition to the knowledge-driven, empirical basis on which features thought to be affecting siRNA potency are often chosen. We attempt to overcome these problems by first constructing a meta-dataset of 6483 publicly available siRNAs (targeting mammalian mRNA), the largest to date, and then applying a Bayesian analysis which accommodates feature set uncertainty. A stochastic logistic regression-based algorithm is designed to explore a vast model space of 497 compositional, structural and thermodynamic features, identifying associations with siRNA potency. Our algorithm reveals a number of features associated with siRNA potency that are, to the best of our knowledge, either under reported in literature, such as anti-sense 5' -3' motif 'UCU', or not reported at all, such as the anti-sense 5' -3' motif 'ACGA'. These findings should aid in improving future siRNA potency predictions and might offer further insights into the working of the RNA-induced silencing complex (RISC).


Memory for emotional picture cues during acute alcohol intoxication.
Memory affects behavior by allowing events to be anticipated and goals to be planned based on previous experiences. Emotional memory, in particular, is thought to play a central role in behavior in general and in drinking behavior in particular. Alcohol intoxication has been shown to disrupt intentional, conscious memory, but not unintentional, implicit memory for neutral stimuli; however, its effects on emotional memory are not well understood. This study examined whether alcohol intoxication affected memory for emotionally valenced stimuli by testing explicit recall and implicit repetition priming of emotional picture cues. Participants were 36 young adults (21-24 years old, 16 women) who received an alcohol, placebo, or no-alcohol beverage. Both cue exposure and memory testing occurred after beverage consumption (i.e., during intoxication for the alcohol group). Alcohol intoxication impaired explicit recall of all cue types but did not impair implicit repetition priming. Emotionally negative and positive cues were more often recalled compared with neutral cues across all beverage groups, and emotionally negative cues demonstrated more priming than emotionally positive or neutral cues in all beverage groups. Alcohol intoxication disrupted effortful recall of all cues, although the relative memory advantage of emotionally valenced over-neutral stimuli remained even after drinking. The effects of alcohol on unintentional memory priming were not statistically significant, but the effects of emotionally negative cues were. Further research is needed to better understand alcohol intoxication and emotional valence effects on memory processes during implicit memory tasks and the possibility that negative mood facilitates memory priming of negative emotional stimuli.


Fatal chytridiomycosis in the tyrrhenian painted frog.
Batrachochytrium dendrobatidis (Bd), the causative agent of the amphibian disease chytridiomycosis, is an important factor in the global decline of amphibians. Within Europe, animals that exhibit clinical signs of the disease have only been reported in Spain despite the pathogen's wide, but patchy, distribution on the continent. Recently, another occurrence of chytridiomycosis was reported in Euproctus platycephalus, the Sardinian brook newt, on the Mediterranean island of Sardinia, but without any evidence of fatal disease. We report further evidence of the emergence of Bd on Sardinia and the first evidence of lethal chytridiomycosis outside of Spain. Unusual mortalities of the Tyrrhenian painted frog (Discoglossus sardus) were found at three sites in the Limbara mountains of northern Sardinia. Molecular and histological screens of corpses, frogs, and tadpoles from these sites revealed infection with Bd. Infection and mortality occurred at locations that are unusual in terms of the published habitat requirements of the pathogen. Given the endemicity, the IUCN Red List status of the amphibian species on Sardinia, and the occurrence of infection and mortality caused by chytridiomycosis, there is serious reason for concern for the impact that disease emergence may have on the conservation of the amphibians of the island.


Association of ACE2 receptor and ACEIs/ARBs with disease severity in COVID-19.
Coronavirus disease 2019 (COVID-19) is found to be associated with various comorbidities which include cardiovascular diseases, hypertension, and diabetes. The impaired regulation of renin-angiotensin-aldosterone system (RAAS) has been seen in COVID-19 patients, but whether RAAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs), are responsible for worsening of clinical conditions remains unknown. Herein, we review the role of angiotensin-converting enzyme 2 (ACE2) expression in disease progression, its association with comorbidities and COVID-19, and summarize the clinical evidence for several potential directions for future research work on ACEIs/ARBs in COVID-19 patients.


An unusual metabolite of testosterone. 17 beta-Hydroxy-4,6-androstadiene-3-one.
A testosterone metabolite, 17 beta-hydroxy-4,6-androstadiene-3-one, possessing an absorbance maximum at 284 nm, was formed during incubation of testosterone with liver microsomes from dexamethasone-treated rats. The metabolite was identified by HPLC, UV spectroscopy, and thermospray liquid chromatography/mass spectrometry. The formation of this metabolite by rat liver microsomes required NADPH and oxygen and was inhibited markedly by SKF 525-A, 2,4-dichloro-6-phenylphenoxyethylamine, or CO/O2 (8:2, v/v), but not by cyanide, an inhibitor for stearyl-CoA desaturase. Pretreatment of rats with phenobarbital, pregnenolone 16 alpha-carbonitrile, and dexamethasone enhanced the formation of this metabolite in parallel with the increase in formation of 6 beta-hydroxytestosterone (r2 = 0.99). Although 16-methylprogesterone, a known 6 beta-hydroxylase inhibitor, competitively inhibited the formation of the metabolite and 6 beta-hydroxytestosterone by liver microsomes from dexamethasone-treated rats, the metabolite was not formed from either 6 beta-hydroxytestosterone or 7-hydroxytestosterone during incubation with liver microsomes. These findings are consistent with the view that cytochrome P-450 isozymes that catalyze 6 beta-hydroxylation of steroids in rat liver microsomes also catalyze the dehydrogenation of testosterone to form a double bond between the C-6 and C-7 positions.


Retirement patterns and bridge jobs in the 1990s.
During most of the post-World War II period, American men have been leaving the labor force at earlier and earlier ages. Evidence suggests that this trend has been under way for more than a century. However, in the mid-1980s, this trend came to an abrupt halt. Male labor force participation rates have been flat since 1985, and have actually increased over the past several years. Understanding these issues is especially important given the looming increase in the Social Security normal retirement age to 67 and the possibility of even more increases in the ages of eligibility under Social Security and Medicare reform. Because of the influx of married women into the labor market in the post-World War II period, older women's participation rates did not decline as men's did. In contrast, their rates were relatively steady, rising or falling very slowly. Since the mid-1980s, however, older women's participation rates have increased significantly. Many more older men and women are working today than the pre-1986 trends would have suggested. Many older Americans leave the labor force gradually, utilizing "bridge jobs" between employment on a full-time career job and complete labor force withdrawal. These bridge jobs are often part-time, often in a new line of work, and sometimes involve a switch from wage and salary work to self-employment. Estimates suggest that between one-third and one-half of older Americans will work on a bridge job before retiring completely, and for these workers retirement is best viewed as a process, not as a single event. These changes in retirement behavior are consistent with societal changes that have altered the relative attractiveness of work and leisure late in life. Mandatory retirement has been outlawed for most American workers. Social Security has become more age-neutral, no longer penalizing the average worker who wants to continue working after age 65. An increasing proportion of employer pension coverage has been in defined contribution plans, which do not contain the age-specific retirement incentives that many defined benefit plans do. The composition of jobs has shifted from manufacturing to service occupations. Americans are living longer and healthier lives, and many look forward to years to productive activity after age 65. These structural changes have been accompanied by an important cyclical factor: the strength of the American economy over the past decade. This has increased the demand for all types of labor, including older workers. Evidence suggests that there is more than this cyclical factor at work, however, and that new attitudes about work late in life are developing. Labor supply decisions late in life are correlated in expected ways with the individual's health (measured in several ways), age, and pension and health insurance status. Retirement patterns in America are much richer and more varied than the stereotypical one-step view of retirement suggests. Public policy is changing in ways that make continued work late in life more likely. If employers are willing to provide flexible job opportunities to meet the needs of these potential employees, then society can tap a growing pool of older, experienced, and willing workers for years to come.


Curved FtsZ protofilaments generate bending forces on liposome membranes.
We have created FtsZ-YFP-mts where an amphipathic helix on the C-terminus tethers FtsZ to the membrane. When incorporated inside multi-lamellar tubular liposomes, FtsZ-YFP-mts can assemble Z rings that generate a constriction force. When added to the outside of liposomes, FtsZ-YFP-mts bound and produced concave depressions, bending the membrane in the same direction as the Z ring inside liposomes. Prominent membrane tubules were then extruded at the intersections of concave depressions. We tested the effect of moving the membrane-targeting sequence (mts) from the C-terminus to the N-terminus, which is approximately 180 degrees from the C-terminal tether. When mts-FtsZ-YFP was applied to the outside of liposomes, it generated convex bulges, bending the membrane in the direction opposite to the concave depressions. We conclude that FtsZ protofilaments have a fixed direction of curvature, and the direction of membrane bending depends on which side of the bent protofilament the mts is attached to. This supports models in which the FtsZ constriction force is generated by protofilament bending.


Ameliorative effect of thymoquinone on ovalbumin-induced allergic conjunctivitis in Balb/c mice.
Thymoquinone (TQ) is an active and potent compound in the oil of Nigella sativa, which has anti-inflammatory properties. The aim of this study was to evaluate the effects of TQ on ovalbumin (OVA)-induced allergic conjunctivitis (AC) in Balb/c. The mice were divided into seven experimental groups; PBS Con, OVA Con, Conj, 0.05%TQ, 0.1%TQ, 0.5%TQ and Dex group. The mice were immunized and exposed to OVA, and eyes were treated with TQ and dexamethasone. Ocular symptoms were observed after last exposure to OVA. Eosinophils count in blood and Ophthalmic lavage fluid (OLF), recruitment of inflammatory cells in conjunctiva, serum IgE and OVA-specific IgE were evaluated by Giemsa and HE staining, and Enzyme-Linked Immunosorbent Assay (ELISA) respectively. High Performance Liquid Chromatography (HPLC) was used to determine the histamine level in OLF. The mRNA expression and protein level of cytokines were examined by real time RT-PCR and ELISA respectively. Ocular symptoms of AC and other characteristics of allergic inflammation including IgE and OVA-specific immunoglobulin E (IgE) level, recruitment of eosinophils, histamine level, mRNA expressions and protein level of cytokines were remarkably increased in OVA-exposed mice compared with the control groups. Administration of TQ suppressed the ocular symptoms, inflammatory cell infiltration in conjunctiva, blood and OLF, increased level of serum IgE and OVA-specific IgE, and OLF histamine level in OVA-exposed mice. Furthermore, TQ abrogated the mRNA expression and serum level of interleukin including 1L-4, IL-5, IL-13 and transforming growth factor beta (TGF-β) in mice immunized and exposed to OVA. Administration of TQ significantly reduced the ocular symptoms in AC by attenuating the recruitment of eosinophils, level of IgE, histamine and cytokines. Our findings suggest that TQ might be a useful intimation for the treatment and future research for AC.


A comprehensive approach uncovers hidden diversity in freshwater mussels (Bivalvia: Unionidae) with the description of a novel species.
Major geological processes have shaped biogeographical patterns of riverine biota. The Edwards Plateau of central Texas, USA, exhibits unique aquatic communities and endemism, including several species of freshwater mussels. Lampsilis bracteata (Gould, 1855) is endemic to the Edwards Plateau region; however, its phylogenetic relationship with other species in the Gulf coastal rivers and Mississippi River basin is unknown. We evaluated phylogenetic relationships, shell morphologies and soft anatomy characters of L. bracteata and a closely related congener, Lampsilis hydiana (Lea, 1838) throughout their ranges. Our results showed the presence of an undescribed species: Lampsilis bergmanni sp.n. Lampsilis bracteata and L. bergmanni sp.n. share similar shell morphologies and soft anatomy characters; however, they are genetically distinct. Geological processes, such as faulting and sea-level changes during the Miocene to Pliocene, are likely to have facilitated diversification of Lampsilis species, resulting in isolation of L. bracteata on the Edwards Plateau and diversification between L. bergmanni sp.n. and L. hydiana. We conclude that L. bracteata range is restricted to the Colorado River basin, whereas L. bergmanni sp.n. occurs only in upstream reaches of the Guadalupe River basin. Conservation actions are warranted for both species due to their restricted distributions and potential anthropogenic threats.


Food insecurity and its sociodemographic correlates among Afghan immigrants in Iran.
The study determined the prevalence of food insecurity and its sociodemographic determinants among Afghan immigrants in two major cities of Iran. This cross-sectional study was conducted on a sample of 310 adult females from immigrant Afghan households in Tehran (n=155) and Mashhad (n=155), who were recruited through multistage sampling. Data were collected through face-to-face interviews, using a questionnaire. Food security was measured by a locally-adapted Household Food Insecurity Access Scale. More than 60% suffered from moderate-to-severe food insecurity, 37% were mildly food-insecure while about 23% were food-secure. Food insecurity was significantly more prevalent in female-headed households, households whose head and spouse had lower level of education, belonged to the Sunni sect, and those with illegal residential status, unemployment/low job status, not owning their house, low socioeconomic status (SES), and living in Mashhad. Prevalence of food insecurity was relatively high among Afghan immigrants in Iran. This calls for the need to develop community food security strategies for ensuring their short- and long-term health.


Ethanol-induced impairment in the biosynthesis of N-linked glycosylation.
Deficiency in N-linked protein glycosylation is a long-known characteristic of alcoholic liver disease and congenital disorders of glycosylation. Previous investigations of ethanol-induced glycosylation deficiency demonstrated perturbations in the early steps of substrate synthesis and in the final steps of capping N-linked glycans in the Golgi. The significance of the biosynthesis of N-glycan precursors in the endoplasmic reticulum, however, has not yet been addressed in alcoholic liver disease. Ethanol-metabolizing hepatoma cells were treated with increasing concentrations of ethanol. Transcript analysis of genes involved in the biosynthesis of N-glycans, activity assays of related enzymes, dolichol-phosphate quantification, and analysis of dolichol-linked oligosaccharides were performed. Upon treatment of cells with ethanol, we found a decrease in the final N-glycan precursor Dol-PP-GlcNAc(2) Man(9) Glc(3) and in C95- and C100-dolichol-phosphate levels. Transcript analysis of genes involved in N-glycosylation showed a 17% decrease in expression levels of DPM1, a subunit of the dolichol-phosphate-mannose synthase, and an 8% increase in RPN2, a subunit of the oligosaccharyl transferase. Ethanol treatment decreases the biosynthesis of dolichol-phosphate. Consequently, the formation of N-glycan precursors is affected, resulting in an aberrant precursor assembly. Messenger RNA levels of genes involved in N-glycan biosynthesis are slightly affected by ethanol treatment, indicating that the assembly of N-glycan precursors is not regulated at the transcriptional level. This study confirms that ethanol impairs N-linked glycosylation by affecting dolichol biosynthesis leading to impaired dolichol-linked oligosaccharide assembly. Together our data help to explain the underglycosylation phenotype observed in alcoholic liver disease and congenital disorders of glycosylation.


A phenomenology of meditation-induced light experiences: traditional buddhist and neurobiological perspectives.
The scientific study of Buddhist meditation has proceeded without much attention to Buddhist literature that details the range of psychological and physiological changes thought to occur during meditation. This paper presents reports of various meditation-induced light experiences derived from American Buddhist practitioners. The reports of light experiences are classified into two main types: discrete lightforms and patterned or diffuse lights. Similar phenomena are well documented in traditional Buddhist texts but are virtually undocumented in scientific literature on meditation. Within Buddhist traditions, these phenomena are attributed a range of interpretations. However, because it is insufficient and problematic to rely solely upon the textual sources as a means of investigating the cause or significance of these phenomena, these qualitative reports are also considered in relation to scientific research on light-related experiences in the context of sensory deprivation, perceptual isolation, and clinical disorders of the visual system. The typologies derived from these studies also rely upon reports of experiences and closely match typologies derived from the qualitative study of contemporary practitioners and typologies found in Buddhist literary traditions. Taken together, these studies also provide evidence in support of the hypothesis that certain meditative practices - especially those that deliberately decrease social, kinesthetic, and sensory stimulation and emphasize focused attention - have perceptual and cognitive outcomes similar to sensory deprivation. Given that sensory deprivation increases neuroplasticity, meditation may also have an enhanced neuroplastic potential beyond ordinary experience-dependent changes. By providing and contextualizing these reports of meditation-induced light experiences, scientists, clinicians, and meditators gain a more informed view of the range of experiences that can be elicited by contemplative practices.


[Tissue concentration of intravesically instilled (2"R)-4'-o-tetrahydropyranyl-adriamycin or adriamycin in superficial bladder cancer].
Twenty-one patients with superficial bladder cancer entered an analysis of single dose (2'R)-4'-O-tetrahydropyranyladriamycin (THP) or adriamycin (ADM) administration. The patients in each group that have been or not have been treated previously with anti-cancer drugs were randomized into two groups, one was given THP and the other ADM. Thirty-mg of THP or ADM dissolved in 30 ml of physiologic saline was instilled into the bladder, and retained for 1 hour. After 1 hour retention of the drugs, tumor tissues and normal mucosas were removed by punch biopsy forceps transurethrally. The tissue concentrations of THP and ADM were estimated by high performance liquid chromatography. The tissue concentrations of THP and ADM in the tumors were significantly greater (p < 0.05) than those in the normal bladder mucosas. The tissue concentration of THP in the tumors were greater than that of ADM. The tissue concentrations of THP and ADM in the tumor of patients who have been treated with anti-cancer drugs previously were less than those of patients who have not. This results demonstrated that prior therapy with anti-cancer drug may cause a resistance for intravesical instillation chemotherapy. However in patients with prior therapy, the tissue concentration of THP in the tumors were greater than that of ADM. Based on these findings, THP has been shown to be were effective as an intravesical instillating agent especially, in cases with prior chemotherapy.


Human circulatory and thermoregulatory adaptations with heat acclimation and exercise in a hot, dry environment.
1. Heat acclimation was induced in eight subjects by asking them to exercise until exhaustion at 60% of maximum oxygen consumption rate (VO2) for 9-12 consecutive days at an ambient temperature of 40 degrees C, with 10% relative humidity (RH). Five control subjects exercised similarly in a cool environment, 20 degrees C, for 90 min for 9-12 days; of these, three were exposed to exercise at 40 degrees C on the first and last day. 2. Acclimation had occurred as seen by the increased average endurance from 48 min to 80 min, the lower rate of rise in the heart rate (HR) and core temperature and the increased sweating. 3. Cardiac output increased significantly from the first to the final heat exposure from 19.6 to 21.4 l min-1; this was possibly due to an increased plasma volume and stroke volume. 4. The mechanism for the increased plasma volume may be an isosmotic volume expansion caused by influx of protein to the vascular compartment, and a sodium retention induced by a significant increase in aldosterone. 5. The exhaustion coincided with, or was elicited when, core temperature reached 39.7 +/- 0.15 degrees C; with progressing acclimation processes it took progressively longer to reach this level. However, at this point we found no reduction in cardiac output, muscle (leg) blood flow, no changes in substrate utilization or availability, and no recognized accumulated 'fatigue' substances. 6. It is concluded that the high core temperature per se, and not circulatory failure, is the critical factor for the exhaustion during exercise in heat stress.


Giant pelvic retroperitoneal epidermoid cyst: a rare case report.
Epidermoid cyst is a frequent benign cutaneous tumor. The pelvic localization does not occur very often. The literature that taps into such cases is very limited in scope. Here is a report of a 27-year-old woman with a giant pelvic retroperitoneal epidermoid cyst. The use of ultrasound exploration and computed tomography has indicated ovarian origins. The surgery also revealed a retroperitoneal epidermoid cyst, uterus and ovaries were all intact. The evacuation of a cyst was found to contain lamellas of keratin. Histology permitted us to confirm the diagnosis. The patient was faring well after two years of followup.


Neutral and adaptive genomic signatures of rapid poleward range expansion.
Many species are expanding their range polewards, and this has been associated with rapid phenotypic change. Yet, it is unclear to what extent this reflects rapid genetic adaptation or neutral processes associated with range expansion, or selection linked to the new thermal conditions encountered. To disentangle these alternatives, we studied the genomic signature of range expansion in the damselfly Coenagrion scitulum using 4950 newly developed genomic SNPs and linked this to the rapidly evolved phenotypic differences between core and (newly established) edge populations. Most edge populations were genetically clearly differentiated from the core populations and all were differentiated from each other indicating independent range expansion events. In addition, evidence for genetic drift in the edge populations, and strong evidence for adaptive genetic variation in association with the range expansion was detected. We identified one SNP under consistent selection in four of the five edge populations and showed that the allele increasing in frequency is associated with increased flight performance. This indicates collateral, non-neutral evolutionary changes in independent edge populations driven by the range expansion process. We also detected a genomic signature of adaptation to the newly encountered thermal regimes, reflecting a pattern of countergradient variation. The latter signature was identified at a single SNP as well as in a set of covarying SNPs using a polygenic multilocus approach to detect selection. Overall, this study highlights how a strategic geographic sampling design and the integration of genomic, phenotypic and environmental data can identify and disentangle the neutral and adaptive processes that are simultaneously operating during range expansions.


Transcriptomic response of Escherichia coli O157 isolates on meat: Comparison between a typical Australian isolate from cattle and a pathogenic clinical isolate.
The majority of foodborne illnesses associated with E. coli O157 are attributed to the consumption of foods of bovine origin. In this study, RNA-Seq experiments were undertaken with E. coli O157 to identify genes that may be associated with growth and survival on meat and the beef carcass at low temperature. In addition, the response of an E. coli O157 isolate representative of the general genetic 'type' found in Australia (E. coli O157:H- strain EC2422) was compared to that of a pathogenic clinical isolate (E. coli O157:H7 strain Sakai) not typically found in Australia. Both strains up-regulated genes involved in the acid stress response, cold shock response, quorum sensing, biofilm formation and Shiga toxin production. Differences were also observed, with E. coli O157:H7 Sakai up-regulating genes playing a critical role in the barrier function of the outer membrane, lipopolysaccharide biosynthesis, extracellular polysaccharide synthesis and curli production. In contrast, E. coli O157:H- EC2422 down-regulated genes involved in peptidoglycan biosynthesis and of the primary envelope stress response Cpx system. The unique gene expression profiles of the strains, indicate that these genotypes may differ in their ability to persist in the meat production environment and therefore also in their ability to cause disease.


Delivery of RALA/siFKBPL nanoparticles via electrospun bilayer nanofibres: An innovative angiogenic therapy for wound repair.
FK506-binding protein-like (FKBPL) has previously been shown to inhibit angiogenesis viain vitro and in vivo experimentation. Thus, it was proposed that the delivery of a siRNA targeting FKBPL could hold great potential in promoting angiogenesis for advanced wound healing applications. An effective delivery system has been utilised to encapsulate the siFKBPL to form nanoparticles, thereby improving cellular entry and eliciting a potent angiogenic response. In this study, nanoparticles were formed via condensation of siFKBPL with RALA; a novel, cationic 30 mer amphipathic peptide. Nanoparticles prepared at a N:P ratio of 6 demonstrated an average particle size of 76.6nm with a zeta potential of +16.5mV. Treatment of HMEC-1 cells at N:P 6 resulted in a transfection efficiency of 33.7%, negligible cytotoxicity, and significant knockdown of endogenous FKBPL expression. Functionally, treatment with RALA/siFKBPL resulted in significant improvements in cell migration and endothelial tubule formation in vitro. The process of electrospinning was employed to fabricate a nanofibrous wound patch to facilitate the controlled delivery of the RALA/siFKBPL nanoparticles. Alginate/poly-(vinyl alcohol) was electrospun following electrospinning of Chitosan/poly-(vinyl alcohol) to form a bilayered wound patch. Subsequently, the nanofibres were crosslinked to improve stability, before nanoparticle incorporation via soak loading. In vivo wound healing studies using C57BL/6J mice demonstrated a significant increase in angiogenesis when the RALA/siFKBPL nanoparticles were delivered from the bilayered wound patch; a 326% increase in blood vessel density was observed compared to untreated wounds. Taken together, this data demonstrates that delivery of RALA/siFKBPL nanoparticles from the bilayered wound patch represents an innovative wound healing therapy.


SU-E-T-445: A Dosimetric Comparison of Gamma Knife Plans with Measurement Based and Image Based Skull Definitions.
To compare gamma knife treatment plans that use skull scaling instrument measurements for skull definition vs. CT based skull definition. Eight previously treated patients who had head CT scans were randomly selected. Their CT images were imported into Leksell GammaPlan. For each patient, three dose plans were developed: 1. the reference plan. It was planned based on the standard clinical treatment planning guidelines. Measurements were used for skull definition and TMR10 for dose calculation algorithm. 2. CT TMR10 plan, a recalculation of the reference plan with CT images used for skull definition 3. CT Convolution plan, a recalculation of the TMR10 plan using convolution algorithm. The treatment times for CT TMR10 plan and CT convolution plan were set to be the same as the reference plan by adjusting the prescription dose level. Prescription dose and shots were left unchanged. Plan comparisons were carried out using minimum dose, target coverage, gradient index and selectivity. On average, the minimum dose for CT TMR10 and CT Convolution plans are 1.8% and 6.5% lower than that of the reference plan. The target coverage, gradient index are comparable for these three plans. The selectivity indices for CT TMR10 and CT Convolution plans were found to be 3.1% and 9.8% higher than that of reference plan. This work indicates the measurement based skull definition could Result in inaccurate calculation in minimum dose to the target. The target coverage and gradient index are however uncompromised. The selectivity index was actually underestimated.


Magneto-optic polar Kerr and Faraday effects in periodic multilayers.
Magnetooptic (MO) effects in magnetic multilayers with periodically stratified regions are analyzed for the case of normal light wave incidence and polar magnetization (Faraday and polar Kerr effects). From the universal 4 x 4-matrix formalism simplified analytical representations restricted to terms linear in the off-diagonal permittivity tensor elements are obtained with no loss in accuracy. The MO effects are expressed as weighted sums of contributions from individual layers. Approximate expressions useful for the evaluation of trends in MO effects are given for periodic multilayers consisting of blocks with ultrathin magnetic films. The procedure is illustrated on periodic systems built of symmetric units. Limits on the ultrathin approximation are discussed.


Protein Delivery in the Intensive Care Unit: Optimal or Suboptimal?
Emerging evidence suggests that exogenous protein/amino acid supplementation has the potential to improve the recovery of critically ill patients. After a careful review of the published evidence, experts have concluded that critically ill patients should receive up to 2.0-2.5 g/kg/d of protein. Despite this, however, recent review of current International Nutrition Survey data suggests that protein in critically ill patients is underprescribed and grossly underdelivered. Furthermore, the survey suggests that most of protein administration comes from enteral nutrition (EN) despite the availability of products and protocols that enhance the delivery of protein/amino acids in the intensive care unit (ICU) setting. While future research clarifies the dose, timing, and composition for exogenous protein administration, as well as identification of patients who will benefit the most, ongoing process improvement initiatives should target a concerted effort to increase protein intake in the critically ill. This assertion follows from the notion that current patients are possibly being harmed while we wait for confirmatory evidence. Further research should also develop better tools to enable bedside practitioners to monitor optimal or adequate protein intake for individual patients. Finally, exploring the effect of combining adequate protein delivery with early mobility and/or resistance exercise in the ICU setting has the greatest potential for improving the functional outcomes of survivors of critical illness and warrants further study.


Migratory animals couple biodiversity and ecosystem functioning worldwide.
Animal migrations span the globe, involving immense numbers of individuals from a wide range of taxa. Migrants transport nutrients, energy, and other organisms as they forage and are preyed upon throughout their journeys. These highly predictable, pulsed movements across large spatial scales render migration a potentially powerful yet underappreciated dimension of biodiversity that is intimately embedded within resident communities. We review examples from across the animal kingdom to distill fundamental processes by which migratory animals influence communities and ecosystems, demonstrating that they can uniquely alter energy flow, food-web topology and stability, trophic cascades, and the structure of metacommunities. Given the potential for migration to alter ecological networks worldwide, we suggest an integrative framework through which community dynamics and ecosystem functioning may explicitly consider animal migrations.


Human peripheral blood basophils primed by interleukin 3 (IL-3) produce IL-4 in response to immunoglobulin E receptor stimulation.
In contrast to most cytokines, interleukin 4 (IL-4) expression is restricted to T lymphocytes, with the exception of mast cell lines and mast cells, as more recently demonstrated in rodents. Little is known, however, about the capacity of human nonlymphoid cells to produce IL-4. In this study we show that mature human basophils are capable of expressing IL-4 and examine the regulation of IL-4 production in comparison with the lipid mediator leukotriene C4. IL-4 was produced upon immunoglobulin E receptor (IgER) activation of basophils cultured with IL-3, a cytokine previously shown to prime these cells for enhanced release of inflammatory mediators. In some experiments, IL-3 or IgER activation alone also induced IL-4 production close to the detection limit. The effect of IL-3 on IgER-dependent IL-4 expression was dose and time dependent: maximal IL-4 production occurred between 18 and 48 h preexposure of basophils to 3-10 ng/ml IL-3. IgER-induced IL-4 synthesis and release by basophils cultured with IL-3 was rapid and complete after 6 h. In contrast to IL-3, other cytokines (IL-5, granulocyte/macrophage colony-stimulating factor, and nerve growth factor) that also prime basophils for enhanced histamine and leukotriene C4 release did not promote IgER-induced IL-4 synthesis. Basophils appear to secrete a "TH2-like" cytokine profile since no detectable IL-2 or interferon gamma was produced upon IgER activation. Mononuclear cells (depleted of basophils), cultured in parallel, did not release IL-4 in response to IL-3 and/or IgER activation, and produced approximately ten times less IL-4 than basophils upon nonspecific activation by phorbol ester and calcium ionophore. Thus, human basophils are an important cellular source of IL-4, and may, therefore, in addition to their inflammatory effector functions, also regulate the differentiation of T helper cells and B cells, in particular in allergic diseases.


Hepatocellular organic anion-transporting polypeptides (OATPs) and multidrug resistance-associated protein 2 (MRP2) are inhibited by silibinin.
Silibinin has been reported to be a promising compound for hepatitis C treatment of nonresponders to standard treatment. Although administered silibinin is well tolerated, increased serum bilirubin levels have been observed during high-dose i.v. silibinin therapy. The mechanism of silibinin-induced hyperbilirubinemia in humans, however, has not been identified so far. The aim of this study was to investigate the effect of silibinin on hepatocellular uptake and efflux transport systems for organic anions to elucidate the cause of silibinin-induced hyperbilirubinemia. Therefore, the effect of silibinin on transport activity of the hepatocellular uptake transporters organic anion-transporting polypeptides (OATPs) OATP1B1, OATP1B3, and OATP2B1, as well as Na(+)-taurocholate cotransporting polypeptide (NTCP) and of the efflux transporters multidrug resistance-associated protein 2 (MRP2) and bile-salt export pump (BSEP) was studied. The effect of silibinin on OATPs and NTCP function was studied in stable transfected Chinese hamster ovary cells using the radiolabeled model substrates estrone-3-sulfate and dehydroepiandrosteronesulfate for OATPs and taurocholate for NTCP. Interaction of silibinin with MRP2 and BSEP was measured in vesicles isolated from Sf21 or Sf9 insect cells expressing these transporters using either estradiol-17β-glucuronide or taurocholate as substrates. OATP1B1, OATP1B3, and OATP2B1 were inhibited by silibinin, with OATP1B1 being inhibited by (a) complex mechanism(s). An inhibitory effect was also seen for MRP2. In contrast, the bile acid transporters NTCP and BSEP were not affected by silibinin. We concluded that silibinin-induced hyperbilirubinemia may be caused by an inhibition of the bilirubin-transporting OATPs and the efflux-transporter MRP2.


THE FUNCTION OF THE SPLEEN IN THE EXPERIMENTAL INFECTION OF ALBINO MICE WITH BACILLUS TUBERCULOSIS : SECOND PAPER.
The resistance to an infection with the tubercle bacillus which can be given to mice by the removal of the spleen is lost when fresh spleen, either of mouse or sheep, is added to the diet. The logical conclusion that splenic function in its relation to the specific infection is restored by feeding spleen cannot, however, be drawn; because, in the first place, the character of the disease in the splenectomized spleen-fed animals differs somewhat from that in intact animals; and, secondly, because fresh spleen when fed to splenectomized animals apparently gives rise to an acute intoxication. This intoxication occurs quite regularly in mice. It is manifested in the infected animals and in those not inoculated. It has been seen in one of two splenectomized dogs experimented upon. Up to the present it can hardly be definitely characterized, but it seems to be best marked out by the specific anorexia associated with it.


cis-preferential stimulation of alfalfa mosaic virus RNA 3 accumulation by the viral coat protein.
RNA 3 of alfalfa mosaic virus (AIMV) encodes the movement protein P3 and the viral coat protein (CP) which is translated from the subgenomic RNA 4. RNA 3 is able to replicate in tobacco plants transformed with the AIMV replicase genes P1 and P2 (P12 plants). Frameshifts or deletions in the P3 gene have little effect on RNA 3 accumulation in P12 protoplasts whereas such mutations in the CP gene result in a 100-fold reduction of plus-strand RNA 3 accumulation. When P12 protoplasts were inoculated with a mixture of a RNA 3 mutant with a deletion in the P3 gene and a mutant with a deletion in the CP gene, CP expressed by the P3 mutant was unable to upregulate plus-strand RNA accumulation of the CP mutant. However, when a wild-type CP gene and subgenomic promoter were inserted in a RNA 3 mutant with a defective CP gene, the mutant accumulated at wild-type levels. It is concluded that the function of CP in plus-strand RNA 3 accumulation acts in cis and cannot be complemented in trans. In P12 plants, P3 and CP mutants were able to complement each other at low and variable levels. This complementation in plants appeared to be correlated with the occurrence of recombination to wild-type RNA 3.


Risk of stroke in adults with cyanotic congenital heart disease.
Adults with cyanotic congenital heart disease and elevated hematocrit levels are often phlebotomized because of an assumed risk of cerebral arterial thrombotic stroke. Whether a relation exists between hematocrit level, symptomatic erythrocytosis (hyperviscosity), and stroke remains to be established in this patient population. Accordingly, 112 cyanotic patients 19-74 years old (mean, 36 +/- 11.7 years) in the UCLA Adult Congenital Heart Disease Center Registry were selected for study by virtue of continuous observation for 1-12 years (total, 748 patient-years). Patients with independent risk factors for embolic or vasospastic stroke were excluded. The study patients were then divided into two groups: 1) compensated erythrocytosis (stable hematocrit levels of 46.0-72.7% [mean, 57.5 +/- 7.2%], iron replete, absent or mild hyperviscosity symptoms), and 2) decompensated erythrocytosis (unstable rising hematocrit levels of 61.5-75.0% [mean, 69.5 +/- 10.6%], iron deficiency, marked-to-severe hyperviscosity symptoms). No patient with either compensated or decompensated erythrocytosis, irrespective of hematocrit level, iron stores, or the presence, degree, or recurrence of cerebral hyperviscosity symptoms, progressed to clinical evidence of a complete stroke (cerebral arterial thrombosis with brain infarction). Because a risk of stroke caused by cerebral arterial thrombosis was not demonstrated, because the circulatory effects of phlebotomy are transient, and because of the untoward sequelae of phlebotomy-induced iron deficiency, we recommend phlebotomy for the temporary relief of significant, intrusive hyperviscosity symptoms but not for the hematocrit level per se. According to our data, phlebotomy is not warranted to reduce an assumed risk of stroke because that risk did not materialize.


Community and facility-level engagement in planning and budgeting for the government health sector--a district perspective from Kenya.
Health systems reform processes have increasingly recognized the essential contribution of communities to the success of health programs and development activities in general. Here we examine the experience from Kilifi district in Kenya of implementing annual health sector planning guidelines that included community participation in problem identification, priority setting, and planning. We describe challenges in the implementation of national planning guidelines, how these were met, and how they influenced final plans and budgets. The broad-based community engagement envisaged in the guidelines did not take place due to the delay in roll out of the Ministry of Health-trained community health workers. Instead, community engagement was conducted through facility management committees, though in a minority of facilities, even such committees were not involved. Some overlap was found in the priorities highlighted by facility staff, committee members and national indicators, but there were also many additional issues raised by committee members and not by other groups. The engagement of the community through committees influenced target and priority setting, but the emphasis on national health indicators left many local priorities unaddressed by the final work plans. Moreover, it appears that the final impact on budgets allocated at district and facility level was limited. The experience in Kilifi highlights the feasibility of engaging the community in the health planning process, and the challenges of ensuring that this engagement feeds into consolidated plans and future implementation.


Review of the species of the genus Serrapinnus Malabarba, 1998 (Teleostei: Characidae: Cheirodontinae) from the rio Tocantins-Araguaia basin, with description of three new species.
Species of the genus Serrapinnus from the rio Tocantins-Araguaia basin are revised and three new species are described. Serrapinnus aster new species is diagnosed by the presence of scimitar-shaped ventral procurrent caudal-fin rays of mature males forming a semicircle and by the presence of 7-9 cusps on the premaxillary teeth; S. lucindai new species is distinguished from its congeners by the presence of a higher number of ventral procurrent caudal-fin rays (17 to 19); and S. tocantinensis new species differs from the remaining species of the genus by the elongation of the unbranched dorsal and pelvic-fin rays into filaments in mature males. Serrapinnus sterbai is recognized as broadly distributed in the Tocantins-Araguaia basin and is redescribed based on specimens from across its entire distribution. A key for the cheirodontines occurring in the Atlantic drainages of northeastern Brazil, from the rio Tocantins-Araguaia to the rio Paraguaçú is provided.


Visualization of Seifert surfaces.
The genus of a knot or link can be defined via Seifert surfaces. A Seifert surface of a knot or link is an oriented surface whose boundary coincides with that knot or link. Schematic images of these surfaces are shown in every text book on knot theory, but from these it is hard to understand their shape and structure. In this paper, the visualization of such surfaces is discussed. A method is presented to produce different styles of surface for knots and links, starting from the so-called braid representation. Application of Seifert's algorithm leads to depictions that show the structure of the knot and the surface, while successive relaxation via a physically based model gives shapes that are natural and resemble the familiar representations of knots. Also, we present how to generate closed oriented surfaces in which the knot is embedded, such that the knot subdivides the surface into two parts. These closed surfaces provide a direct visualization of the genus of a knot. All methods have been integrated in a freely available tool, called SeifertView, which can be used for educational and presentation purposes.


The transcriptional regulator JAZ8 interacts with the C2 protein from geminiviruses and limits the geminiviral infection in Arabidopsis.
Jasmonates (JAs) are phytohormones that finely regulate critical biological processes, including plant development and defense. JASMONATE ZIM-DOMAIN (JAZ) proteins are crucial transcriptional regulators that keep JA-responsive genes in a repressed state. In the presence of JA-Ile, JAZ repressors are ubiquitinated and targeted for degradation by the ubiquitin/proteasome system, allowing the activation of downstream transcription factors and, consequently, the induction of JA-responsive genes. A growing body of evidence has shown that JA signaling is crucial in defending against plant viruses and their insect vectors. Here, we describe the interaction of C2 proteins from two tomato-infecting geminiviruses from the genus Begomovirus, tomato yellow leaf curl virus (TYLCV) and tomato yellow curl Sardinia virus (TYLCSaV), with the transcriptional repressor JAZ8 from Arabidopsis thaliana and its closest orthologue in tomato, SlJAZ9. Both JAZ and C2 proteins colocalize in the nucleus, forming discrete nuclear speckles. Overexpression of JAZ8 did not lead to altered responses to TYLCV infection in Arabidopsis; however, knock-down of JAZ8 favors geminiviral infection. Low levels of JAZ8 likely affect the viral infection specifically, since JAZ8-silenced plants neither display obvious developmental phenotypes nor present differences in their interaction with the viral insect vector. In summary, our results show that the geminivirus-encoded C2 interacts with JAZ8 in the nucleus, and suggest that this plant protein exerts an anti-geminiviral effect.


Oxidative stress signalling: a potential mediator of tumour necrosis factor alpha-induced genomic instability in primary vascular endothelial cells.
Studying the potential role of tumour necrosis factor (TNF)alpha in the initiation of genomic instability is necessary to understand whether TNFalpha can serve as a signalling mediator of radiation-induced genomic instability in non-irradiated bystander cells. In this study, we examined whether TNFalpha could initiate processes through oxidative stress signalling that lead to DNA damage and genomic instability in primary vascular endothelium. In these cells, low linear energy transfer (LET) radiation (0.1-2 Gy) induced the secretion of TNFalpha into the culture medium. When added ectopically, TNFalpha at concentrations ranging from 0.1 ng ml(-1) to 10 ng ml(-1) increased (twofold to threefold) intracellular oxidative stress. Next, to examine whether TNFalpha induces genetic damage, cells were treated with TNFalpha for 5 h and analysed immediately using the single cell gel electrophoresis assay or after 3 days, 12 days and 20 days using solid stain chromosomal analysis. Cells exposed to 0.1 Gy, 1 Gy or 2 Gy or treated with 100 microM H2O2 were used as positive controls. The results showed that TNFalpha as low as 0.1 ng ml(-1) could initiate increased DNA damage compared with untreated controls. When examined in the progeny cells after several generations, the chromosomal instability appeared to be carried over even after day 12 and day 20. The increased genetic damage is inhibited in cells that are pre-incubated with the antioxidant enzyme catalase, the antioxidant N-acetyl-L-cysteine or the metal chelator pyrrolidine dithiocarbamate. These results clearly indicate that TNFalpha at concentrations at which no cytotoxicity is observed could induce genetic damage through free radical generation, which could, in turn, lead to the delayed events associated with genomic instability.


Generic selection criteria for safety and patient benefit [X]: Water-vapor permeability and peel force properties of brand-name and generic ketoprofen tapes.
Tape products containing ketoprofen have transdermal analgesic and anti-inflammatory effects. We compared the physicochemical properties (water-vapor permeability, peel force, peel force-time curve) between one brand-name product and eight generic products. Regarding the measurement of water-vapor permeability, the formulations using methacrylic acid n-butyl acrylate copolymer (MBA) adhesives showed higher water-vapor permeability than those using styrene isopropyl styrene block copolymer (SIS) adhesives. In the case of the formulation using SIS adhesive, the central part of the formulation had higher water-vapor permeability than both ends. In the 90-degree peel test using the methods of adhesion testing, significant differences were observed between the products, especially as the various application times (5 min, 30 min, 9 h and 24 h) increased. This may be because the longer the time of attachment to the adherend, the more the adhesive force with the adherend increased due to the "anchoring effect" of the adhesive. The measurement of the peel force-time curve showed different curves among the products, especially in the peel force curve of Teikoku after 24 h, which showed two characteristic peak curves. Furthermore, when the peel forces at 25°C and 40°C were compared, Mohrus and Toko showed significantly higher values at 40°C compared to 25°C. This study showed that there are many generic drugs with formulation characteristics different from those of brand-name drugs, and that there is a large difference among the products in terms of adhesion and detachment.


Small differences in arrival time influence composition and productivity of plant communities.
'Who comes first' is decisive for plant community assembly and ecosystem properties. Early arrival or faster initial development of a species leads to space occupancy both above and below ground and contributes to species success. However, regular disturbance (e.g. biomass removal) might permit later-arriving or slower-developing species to catch up. Here, artificial communities of grassland species belonging to the plant functional types (PFTs) herb, grass and legume were used to test the effect of stepwise arrival (sowing) of PFTs. Dramatic effects were found as a result of a 3 wk arrival difference on composition and above-ground biomass that persisted over four harvests and two seasons. Priority effects, such as unequal germination time (arrival), and thus differences in community age structure, had lasting effects on PFT biomass contribution and associated ecosystem functioning. These effects were robust against above-ground disturbance. Benefits of earlier root formation outweighed above-ground species interaction. Earlier space occupancy and bigger reserve pools are the likely causes. Natural populations commonly exhibit age diversity and asynchrony of development among taxa. In experiments, artificial synchrony of arrival (sowing) may thus induce assembly routes favouring faster-establishing taxa, with consequences for ecosystem functioning (e.g. productivity). Founder effects, such as those observed here, could be even greater in communities of slow-growing species or forests, given their longer generation time and minor disturbance.


Extreme resistance to Potato virus Y in potato carrying the Rysto gene is mediated by a TIR-NLR immune receptor.
Potato virus Y (PVY) is a major potato (Solanum tuberosum L.) pathogen that causes severe annual crop losses worth billions of dollars worldwide. PVY is transmitted by aphids, and successful control of virus transmission requires the extensive use of environmentally damaging insecticides to reduce vector populations. Rysto , from the wild relative S. stoloniferum, confers extreme resistance (ER) to PVY and related viruses and is a valuable trait that is widely employed in potato resistance breeding programmes. Rysto was previously mapped to a region of potato chromosome XII, but the specific gene has not been identified to date. In this study, we isolated Rysto using resistance gene enrichment sequencing (RenSeq) and PacBio SMRT (Pacific Biosciences single-molecule real-time sequencing). Rysto was found to encode a nucleotide-binding leucine-rich repeat (NLR) protein with an N-terminal TIR domain and was sufficient for PVY perception and ER in transgenic potato plants. Rysto -dependent extreme resistance was temperature-independent and requires EDS1 and NRG1 proteins. Rysto may prove valuable for creating PVY-resistant cultivars of potato and other Solanaceae crops.


[Thyroid dysfunction in pregnant women: clinical dilemmas].
Hypothyroidism and hyperthyroidism are associated with maternal and neonatal pregnancy complications. Hypothyroidism should be treated with levothyroxine. Hyperthyroidism requires treatment with propylthiouracil or thiamazole. Subclinical hypothyroidism and thyroid auto-immunity are also associated with maternal and neonatal pregnancy complications. For both subclinical hypothyroidism and thyroid auto-immunity, treatment with levothyroxine has not yet been proven to be effective in preventing complications during pregnancy. For the Dutch population the following reference values for TSH levels during pregnancy may be used: 0.01-4.00 mU/l in the first and second trimesters. Reference values for the third trimester have not reported for this population, but are probably comparable with those of the second trimester.


Effects of gradual volume loading on left ventricular diastolic function in dogs: implications for the optimisation of cardiac output.
Volume loading is commonly used to adjust preload and optimise cardiac output. It is difficult to monitor preload at the bedside because filling affects ventricular diastolic function and consequently end diastolic pressure, which is the variable used to monitor preload. To assess the effects of gradual volume loading on the different components of left ventricular diastolic function---filling velocities, relaxation, and chamber compliance---to identify how excessive loading produces diastolic dysfunction. Eight mongrel dogs, anaesthetised and mechanically ventilated with both the chest and the pericardium closed, were studied during basal conditions (B), during gradual volume loading with physiological saline---5 ml/kg (VL5), 10 ml/kg (VL10), and 15 ml/kg (VL15)---and during infusion of isosorbide dinitrate (10 g/kg/min) started after the VL15 load was achieved. Dogs were monitored haemodynamically and by transthoracic Doppler echocardiography to assess peak modal velocities of the E and A waves, E/A ratios, and the deceleration time of the E wave. M mode recordings of aligned mitral and aortic valve motion were also obtained to calculate the isovolumic relaxation time. Effects of volume loading on ventricular diastolic function seemed to occur in two phases. Small and moderate volume loads (VL5 and VL10) promoted early ventricular filling, increasing E wave velocities, improving the mean (SD) E/A ratio from 1.95 (0.3) (B) to 2.0 (0.27) (VL5) and 2.6 (0.3) (VL10) (P < 0.00005), prolonging the E wave deceleration time, and only slightly increasing ventricular diastolic pressures. These changes suggest an improvement in ventricular compliance. Extreme volume loads (VL15) produced an abrupt reduction in early ventricular filling, which was transfered to late in diastole, by decreasing E wave velocity, by increasing A wave velocity, and by decreasing E/A ratio from 2.6 (0.3) (VL10) to 0.8 (0.05) (VL15) (P < 0.00005). The E wave deceleration time was shortened and left ventricular diastolic pressures were much increased, all suggesting a deterioration in chamber compliance. All these restrictive changes were promptly reversed by the perfusion of isosorbide dinitrate. The isovolumic relaxation time steadily increased with volume loading. Small and moderate volume loads improved ventricular diastolic function by promoting early ventricular filling and increasing ventricular compliance. Extreme volume loads promptly induced a diastolic restrictive pattern, transferring filling to the second part of diastole (increasing dependence on atrial contraction) and reducing ventricular compliance. These changes in ventricular diastolic function were independent of simultaneously measured haemodynamic systolic performance and were promptly reversed by isosorbide dinitrate, which after extreme loading promoted early filling, myocardial relaxation, and improved chamber compliance.


Cooking fuel choices and garbage burning practices as determinants of birth weight: a cross-sectional study in Accra, Ghana.
Effect of indoor air pollution (IAP) on birth weight remains largely unexplored but yet purported as the most important environmental exposure for pregnant women in developing countries due to the effects of second-hand smoke. We investigated the associations between the determinants of indoor air quality in households and birth weight. A cross-sectional study of 592 mothers and their newborns using postnatal services at the Korle Bu Teaching Hospital located in Accra, Ghana was conducted in 2010 to collect information on characteristics of indoor environment and other potential determinants of fetal growth. Birth weight was recorded from hospital records. Household cooking fuel choices and garbage burning practices were determinants of birth weight. Multivariate linear regression analysis adjusting for age, social class, marital status and gravidity of mothers, and sex of neonate resulted in a 243 g (95% CI: 496, 11) and 178g (95% CI: 421, 65) reduction in birth weight for use of charcoal, and garbage burning respectively compared with use of LPG only. The estimated reductions in birth weight was not statistically significant. Applying the ordinal scale exposure parameter nonetheless revealed a significant exposure-response relationship between maternal exposures from charcoal use and garbage burning, and birth weight. Generalized linear models adjusting for confounders resulted in a 41% (risk ratio [RR] = 1.41; 95% CI: 0.62, 3.23) and 195% (RR=2.95; 95% CI: 1.10, 7.92) increase in the risk of low birth weight (LBW) for use of charcoal, and garbage burning respectively compared with use of LPG only. A combination of charcoal use and household garbage burning during pregnancy on fetal growth resulted in a 429 g (95% CI: 259, 599) reduction in birth weight and 316% (RR=4.16; 95% CI: 2.02, 8.59) excess risk of LBW. Sensitivity analysis performed by restricting the analysis to term births produced similar results. Maternal use of charcoal as a cooking fuel during pregnancy and burning of garbage at home are strong determinants of average fetal growth and risk of LBW. Efforts to reduce maternal exposures to IAP are thus important to improve birth outcomes.


Evaluation of trypanocidal activity of combinations of anti-sleeping sickness drugs with cysteine protease inhibitors.
Chemotherapy of human African trypanosomiasis (HAT) is unsatisfactory because only a few drugs, with serious side effects and poor efficacy, are available. As drug combination regimes often achieve greater therapeutic efficacy than monotherapies, here the trypanocidal activity of the cysteine protease inhibitor K11777 in combination with current anti-HAT drugs using bloodstream forms of Trypanosoma brucei was investigated. Isobolographic analysis was used to determine the interaction between cysteine protease inhibitors (K11777, CA-074Me and CAA0225) and anti-HAT drugs (suramin, pentamidine, melarsoprol and eflornithine). Bloodstream forms of T. brucei were incubated in culture medium containing cysteine protease inhibitors or anti-HAT drugs alone or in combination at a 1:1 fixed-dose ratio. After 48 h incubation, live cells were counted, the 50% growth inhibition values determined and combination indices calculated. The general cytotoxicity of drug combinations was evaluated with human leukaemia HL-60 cells. Combinations of K11777 with suramin, pentamidine and melarsoprol showed antagonistic effects while with eflornithine a synergistic effect was observed. Whereas eflornithine antagonises with CA-074Me, an inhibitor inactivating the targeted TbCATL only under reducing conditions, it synergises with CAA0255, an inhibitor structurally related to CA-074Me which inactivates TbCATL independently of thiols. These findings indicate an essential role of thiols for the synergistic interaction between K11777 and eflornithine. Encouragingly, the K11777/eflornithine combination displayed higher trypanocidal than cytotoxic activity. The results of this study suggest that the combination of the cysteine protease inhibitor K11777 and eflornithine display promising synergistic trypanocidal activity that warrants further investigation of the drug combination as possible alternative treatment of HAT.


Osteoarthritis year in review: outcome of rehabilitation.
This review highlights seminal publications of rehabilitation interventions for osteoarthritis (OA) since April 2012. Medline in process, Embase, CINAHL and Cochrane databases were searched from April 2012 through February 2013 for English language publications using key words osteoarthritis, rehabilitation, physiotherapy, physical therapy, and exercise. Rehabilitation intervention studies included randomized trials or systematic reviews/meta-analyses or pre-post studies. Pilot randomized trials, feasibility studies and studies of surgical interventions unless they included evaluation of a rehabilitation intervention were excluded. Twenty-five studies were identified for inclusion and grouped thematically. The short-term benefits (i.e., to 3 months) of variable types and dosages of exercise were demonstrated for a number of outcomes including pain, stiffness, function, balance, biomarkers, and executive function and dual task performance (related to falling) in people with knee OA. Modalities such as 890-nm radiation, interferential current, short wave diathermy, ultrasound and neuromuscular functional electrical stimulation did not demonstrate benefit over sham controls in those with knee OA. Spa therapy improved pain over the period of treatment in those with knee and hand OA. Supervised self-management based on cognitive therapy principles resulted in improved outcomes for people with knee OA. Shock absorbing insoles compared to normal footwear minimally improved knee pain and but not function and did not decrease knee load. Neuromuscular and motor training improved function in those with total hip replacement. Accelerated weight-bearing and rehabilitation (8 versus 11 weeks) was demonstrated to be safe and effective at 5 years following matrix autologous chondrocyte implantation for cartilage defects in the knee. Exercise remains a mainstay of conservative management although most studies report only short-term outcomes. Self-management strategies also are beneficial in knee OA. There seems to be a placebo effect with most trials of physical modalities although spa therapy demonstrated very short-term effects.


Perceptions and Health-Seeking Behaviour for Mental Illness Among Syrian Refugees and Lebanese Community Members in Wadi Khaled, North Lebanon: A Qualitative Study.
This is a qualitative exploration of the perceptions of mental health (MH) and their influence on health-seeking behaviour among Syrian refugees and the Lebanese population in Wadi Khaled, a rural area of Lebanon bordering Syria. Eight focus group discussions and eight key informant interviews were conducted with male and female Syrian refugees and Lebanese community members from March to April 2018. MH illness was associated with stigma, shame and fear among both populations. Beliefs surrounding mental illness were strongly linked to religious beliefs, including Jinn. Religious healers were considered the first line of help for people with mental illnesses, and were perceived as culturally acceptable and less stigmatizing than MH professionals. It is essential for MH professionals to build trust with the communities in which they work. Collaboration with religious healers is key to identifying MH symptoms and creating referral pathways to MH professionals in this context.


Interleukin-6 secretion in vitro is up-regulated in ectopic and eutopic endometrial stromal cells from women with endometriosis.
An in vitro model developed to compare human endometrial and endometriosis stromal cells was used to examine basal and stimulated expression of interleukin (IL-6). Stromal cells isolated from normal endometrium (NE) exhibited the lowest level of IL-6 secretion (84 pg/10(6) cells-48 h), whereas those cells isolated from endometriosis implants (EI) secreted the highest concentration of this inflammatory cytokine (46,284 pg/10(5) cells-48 h; P < 0.01). Eutopic endometrial stromal cells from women with endometriosis (EE) expressed an intermediate concentration of IL-6 (831 pg/10(6) cells-48 h). Stimulation of the various cultures with IL-1 beta dramatically augmented stromal cell production of IL-6. The mean concentrations of stimulated IL-6 secretion were 16,257, 37,800, and 264,290 pg/10(5) cells-48 h for NE, EE, and EI cells, respectively (P < 0.03). Exposure of the cell cultures to 10 nmol/L estradiol had little direct effect on IL-6 production. The results indicate that endometrial stromal cells isolated from tissues of women with and without endometriosis express IL-6 under basal and cytokine-stimulated conditions. Differential responsiveness among the three cell sources indicates that NE, EE, and EI cells have intrinsic quantitative differences in cytokine regulation.


The active straight leg raising test and mobility of the pelvic joints.
Objective signs to assess impairment in patients who are disabled by peripartum pelvic girdle pain hardly exist. The purpose of this study was to develop a clinical test to quantify and qualify disability in these patients. The study examined the relationship between impaired active straight leg raising (ASLR) and mobility of pelvic joints in patients with peripartum pelvic girdle pain, focusing on (1) the reduction of impairment of ASLR when the patient was wearing a pelvic belt, and (2) motions between the pubic bones measured by X-ray examination when the patient was standing on one leg, alternating left and right. Twenty-one non-pregnant patients with peripartum pelvic girdle pain in whom pain and impairment of ASLR were mainly located on one side were selected. ASLR was performed in the supine position, first without a pelvic belt and then with a belt. The influence of the belt on the ability to actively raise the leg was assessed by the patient. Mobility of the pelvic joints was radiographically visualized by means of the Chamberlain method. Assessment was blinded. Ability to perform ASLR was improved by a pelvic belt in 20 of the 21 patients (binomial two-tailed P = 0.0000). When the patient was standing on one leg, alternating the symptomatic side and the reference side, a significant difference between the two sides was observed with respect to the size of the radiographically visualized steps between the pubic bones (binomial two-tailed P = 0.01). The step at the symptomatic side was on average larger when the leg at that side was hanging down than when the patient was standing on the leg at that side. Impairment of ASLR correlates strongly with mobility of the pelvic joints in patients with peripartum pelvic girdle pain. The ASLR test could be a suitable instrument to quantify and qualify disability in diseases related to mobility of the pelvic joints. Further studies are needed to assess the relationship with clinical parameters, sensitivity, specificity and responsiveness in various categories of patients. In contrast with the opinion of Chamberlain, that a radiographically visualized step between the pubic bones is caused by cranial shift of the pubic bone at the side of the standing leg, it is concluded that the step is caused by caudal shift of the pubic bone at the side of the leg hanging down. The caudal shift is caused by an anterior rotation of the hip bone about a horizontal axis near the sacroiliac joint.


Quality of life in maltreated children and adult survivors of child maltreatment: a systematic review.
To review data on health-related quality of life (HRQoL) in individuals with childhood trauma, including psychological maltreatment, physical maltreatment, sexual abuse, and neglect. The literature search was conducted with pre-defined keywords using the following electronic bibliographic databases: EMBASE, PubMed, MEDLINE, CINAHL, PsyINFO, PSYNDEX, and Cochrane Database of Systematic Reviews. Further databases were searched for relevant dissertations. Study selection and data extraction were completed by two independent reviewers. The literature search yielded 1568 entries. Nineteen articles met all inclusion criteria and were retained for further analysis. Findings quite consistently showed significant negative associations between child maltreatment and both self- and proxy-rated HRQoL. Effect sizes range from small to large. Number of types of maltreatment and HRQoL were found to be negatively related. Data on HRQoL for maltreated children are still rare. Studies often investigate adult survivors of child maltreatment. Considering HRQoL in children and adolescents who suffered maltreatment would allow the planning of effective interventions and the evaluation of treatments to improve HRQoL of these children.