The structural mechanism of the inhibition of archaeal RelE toxin by its cognate RelB antitoxin.
The archaeal toxin, aRelE, in the hyperthermophilic archaeon Pyrococcus horikoshii OT3 inhibits protein synthesis, whereas its cognate antitoxin, aRelB, neutralizes aRelE activity by forming a non-toxic complex, aRelB-aRelE. The structural mechanism whereby aRelB neutralizes aRelE activity was examined by biochemical and biophysical analyses. Overexpression of aRelB with an aRelE mutant (ΔC6), in which the C-terminal residues critical for aRelE activity were deleted, in Escherichia coli allowed a stable complex, aRelB-ΔC6, to be purified. Isothermal titration of aRelE or ΔC6 with aRelB indicated that the association constant (Ka) of wild-type aRelB-aRelE is similar to that of aRelB-ΔC6, demonstrating that aRelB makes little contact with the C-terminal active site of aRelE. Overexpression of deletion mutants of aRelB with aRelE indicated that either the N-terminal (pos. 1-27) or C-terminal (pos. 50-67) fragment of aRelB is sufficient to counteract the toxicity of aRelE in E. coli cells and the second α-helix (α2) in aRelB plays a critical role in forming a stable complex with aRelE. The present results demonstrate that aRelB, as expected from its X-ray structure, precludes aRelE from entering the ribosome, wrapping around the molecular surface of aRelE.


Dental anxiety and behavioral problems: a study of prevalence and related factors among a group of Iranian children aged 6-12.
The aims of this study were to assess the prevalence and also some related demographic and dental factors of dental anxiety and behavioral problems in school-aged children. A total of 150 children of 6-12 years old were selected according to the inclusion criteria. Prior to the dental visit, the mothers were asked to answer a questionnaire of dental and demographic background and a Corah dental anxiety scale (CDAS). At the same time, a faces version of the modified child dental anxiety scale (MCDAS) was completed by the child. Next, the child was guided to the operating room. According to the treatment plan, local anesthesia solution was injected and the child's cooperative behaviors were quantified based on the Frankle index duration the injection stage. Analysis of Variance and Linear regression models were used for the statistical analysis. The mean scores of the child's dental anxiety and cooperative behavior were 20.81 (±6.97) and 3.04 (±0.86), respectively. Forty four children (29.33%) had severe dental anxiety. Child's age and regular dental visit are predictive factors for the child's dental anxiety (P<0.05). Dental behavioral problems had been identified in 43 children (28.67%). Unpleasant previous dental experience is an important factor affecting the child's cooperative behaviors (P<0.05). High prevalence of severe dental anxiety may be seen in early years of school. It seems that general factors such as family factors have less impact on behavior of school aged children in a dental visit.


The effects of compression upon conduction in myelinated axons of the isolated frog sciatic nerve.
1. Action potential conduction along frog sciatic nerve fibres has been monitored during compression of a mid-portion of the nerve. 2. The effects of compressing a 24 mm length of nerve with a pressure of 250 mmHg applied pneumatically were investigated by recording unitary action potentials. A plot of time before conduction failure (survival time) against initial conduction velocity revealed that the faster myelinated axons tend to fail before the slower myelinated axons. A large degree of scatter was evident in the pooled data as well as in the data from individual experiments. 3. When the compression was made more severe by increasing the applied pressure to 750 mmHg, the order of block was reversed, i.e. the slower myelinated axons tended to block first. Similar scatter in the order of conduction block was observed. 4. The average survival time of units following application of compression was considerably different between these two series of experiments. When 750 mmHg pressure was applied, units survived for, on average, 10.9 min (n = 246). When 250 mmHg pressure was applied units survived for, on average, 50.4 min (n = 148). 5. The results are discussed in relation to the underlying causes of conduction failure as a result of compression and in relation to results from previous investigations.


The E2F transcription factor activates a replication-dependent human H2A gene in early S phase of the cell cycle.
Histone gene expression is restricted to the S phase of the cell cycle. Control is mediated by a complex network of sequence-specific DNA-binding factors and protein-protein interactions in response to cell cycle progression. To further investigate the regulatory functions that are associated at the transcriptional level, we analyzed the regulation of a replication-dependent human H2A.1-H2B.2 gene pair. We found that transcription factor E2F binds specifically to an E2F recognition motif in the H2A.1 promoter region. Activation of the H2A.1 promoter by E2F-1 was shown by use of luciferase reporter constructs of the intergenic promoter region. Overexpression of the human retinoblastoma suppressor gene product RB suppressed E2F-1 mediated transcriptional activation, indicating an E2F-dependent regulation of promoter activity during the G1-to-S-phase transition. Furthermore, the activity of the H2A.1 promoter was also downregulated by overexpression of the RB-related p107, a protein that has been detected in S-phase-specific protein complexes of cyclin A, E2F, and cdk2. In synchronized HeLa cells, expression of luciferase activity was induced at the beginning of DNA synthesis and was dependent on the presence of an E2F-binding site in the H2A.1 promoter. Together with the finding that E2F-binding motifs are highly conserved in H2A promoters of other species, our results suggest that E2F plays an important role in the coordinate regulation of S-phase-specific histone gene expression.


Composition and natural history notes of the coastal snake assemblage from Northern Bahia, Brazil.
Information about the snake diversity and their natural history from the Atlantic forest domain in Brazil refer mostly to inland forests than to coastal region. Within the state of Bahia, this knowledge is concentrated to the southeastern coastal stretch. Herein we report on the diversity of snakes from the restinga, ombrophilous forest and anthropogenic environment from the northern Atlantic coast of Bahia. We sampled nine sites for three years and visited four museum collections. Furthermore, we provide anecdotal natural history information, voucher analyses, literature complements, and a key to fascilitate species identification. We report a total of 774 snakes belonging to 50 species and 23 new distribution records for northeastern coast of Bahia, supplemented by new data on feeding and reproduction. The number of detected species is similar to numbers obtained in comparable studies from other Brazilian ecoregions. This study reports and focuses for the first time on all known species of snakes from the northeastern coast of Bahia.


Genistein in Sanfilippo disease: a randomized controlled crossover trial.
Sanfilippo disease (mucopolysaccharidosis type III [MPS III]) is a rare neurodegenerative metabolic disease caused by a deficiency of 1 of the 4 enzymes involved in the degradation of heparan sulfate (HS), a glycosaminoglycan (GAG). Genistein has been proposed as potential therapy but its efficacy remains uncertain. We aimed to determine the efficacy of genistein in MPS III. Thirty patients were enrolled. Effects of genistein were determined in a randomized, crossover, placebo-controlled intervention with a genistein-rich soy isoflavone extract (10mg/kg/day of genistein) followed by an open-label extension study for patients who were on genistein during the last part of the crossover. Genistein resulted in a significant decrease in urinary excretion of total GAGs (p = 0.02, slope -0.68 mg GAGs/mmol creatinine/mo) and in plasma concentrations of HS (p = 0.01, slope -15.85 ng HS/ml/mo). No effects on total behavior scores or on hair morphology were observed. Parents or caregivers could not predict correctly during which period of the crossover a patient was on genistein. Genistein at 10mg/kg/day effectively reduces urinary excretion of GAGs and plasma HS concentration in patients with MPS III. However, the absolute reduction in GAGs and in HS is small and values after 12 months of treatment remain within the range as observed in untreated patients. No clinical efficacy was detected. Substantially higher doses of genistein might be more effective as suggested by recent studies in animal models.


An alpha-cardiac myosin heavy chain gene mutation impairs contraction and relaxation function of cardiac myocytes.
Left Ventricular (LV) myocytes were isolated from 15-wk-old male mice bearing the Arg403 --> Gln alpha-cardiac myosin heavy chain missense mutation (alpha-MHC403/+), a model of familial hypertrophic cardiomyopathy. LV myocytes were classified morphologically: type I, rod shaped with parallel myofibrils; type II, irregularly shaped, shorter and wider than wild-type (WT) control cells, with parallel myofibrils; and type III, irregularly shaped with disoriented myofibrils. Compared with WT myocytes, alpha-MHC403/+ myocytes had fewer type I cells (WT = 74 +/- 3%, alpha-MHC403/+ = 41 +/- 4%, P < 0.01) and more type III cells (WT= 12 +/- 3%, alpha-MHC403/+ = 49 +/- 7%, P < 0.01). In situ histology also demonstrated marked myofibrillar disarray in the alpha-MHC403/+ hearts. With the use of video edge detection, myocytes were paced at 1 Hz (37 degrees C) to determine the effects of the mutation on myocyte function. End-diastolic length was reduced in mutant myocytes, but fractional shortening (% contraction) and sarcomere length were not. Velocity of contraction (-dL/dtmax) was depressed in mutant cells, but more in type II and III cells (-31%) than in type I cells (-18%). Velocity of relaxation (+dL/dt) was also depressed more in type II and III cells (-38%) than in type I cells (-16%). Using fura 2 dye with intracellular Ca2+ transients, we demonstrated that in alpha-MHC403/+ myocytes, the amplitude of the Ca2+ signal during contraction was unchanged but that the time required for decay of the signal to decrease 70% from its maximum was delayed significantly (WT = 159 +/- 8 ms; alpha-MHC403/+ = 217 +/- 14 ms, P < 0.01). Sarco(endo)plasmic reticulum Ca2+-ATPase mRNA levels in alpha-MHC403/+ and WT mice were similar. These data indicate that the altered cardiac dysfunction of alpha-MHC403/+ myocytes is directly due to defective myocyte function rather than to secondary changes in global cardiac function and/or loading conditions.


Higher order exceptional points in infinite lattices.
One of the hallmarks of non-Hermitian photonics is the existence of unique degeneracies, the so-called higher order exceptional points (HEPs). So far, HEPs have been examined mostly in finite coupled systems. In this paper, we present a systematic way to construct infinite optical waveguide lattices that exhibit exceptional points of higher order. The spectral properties and the sensitivity of these lattices around such points are investigated by employing the method of pseudospectra.


Effect of dietary (n--3) fatty acids on platelet function and lipid metabolism in rats.
Six groups of rats were fed diets containing 40% (by weight) lipids, mostly as saturated fatty acids (from 78 to 90%), with a basic amount of linoleic acid (18:2) (1.9%). In four groups, 5% of the saturated fats were substituted with an oil (vegetable: corn, rapeseed; or fish: cod liver, maxepa) and in one group 0.6% of the saturated fats was replaced by eicosapentaenoic acid ethyl ester. The diets supplied different amounts of 18:2 (1.9 to 10%), 18:3 (0.2 to 1.2%), 20:5 (n--3) (eicosapentaenoic acid) (0 to 1.3%) and 22:6(n--3) (0 to 1.6%). After 3-8 months on diets, platelet aggregation, plasma and platelet cholesterol, fatty acids and incorporation of [14C]acetate and [14C]arachidonate into platelet lipids were investigated. The three diets supplying eicosapentaenoic acid (1.3%) induced an approximately 80-fold increase in this fatty acid in plasma and platelet phospholipids, mainly at the expense of arachidonic acid. This was associated with an increase of the incorporation of arachidonic acid into platelet PE and PS. The incorporation of acetate in the (n--3) fatty-acid-fed animals was markedly increased into 22:5 and 22:6(n--3) at the expense of 22:4(n--6). Platelet aggregation induced by ADP was similar in the six groups. The response to thrombin was lower in animals fed corn and maxepa oils. Collagen aggregation tended to be lower in the fish-oil groups. Platelet aggregation to collagen was significantly negatively correlated to the level of eicosapentaenoic acid in platelet phospholipids, while the aggregation to thrombin was related to the level of 20:3(n--9). In the present study in rat, the (n--3) fatty acids added in small amounts to a saturated fat diet over a period of several months induced drastic changes in platelet lipid metabolism and composition without comparable effects on platelet behaviour.


Transcriptome sequencing revealed the inhibitory mechanism of ketoconazole on clinical Microsporum canis.
Microsporum canis is a zoonotic disease that can cause dermatophytosis in animals and humans. In clinical practice, ketoconazole (KTZ) and other imidazole drugs are commonly used to treat M. canis infection, but its molecular mechanism is not completely understood. The antifungal mechanism of KTZ needs to be studied in detail. In this study, one strain of fungi was isolated from a canine suffering with clinical dermatosis and confirmed as M. canis by morphological observation and sequencing analysis. The clinically isolated M. canis was treated with KTZ and transcriptome sequencing was performed to identify differentially expressed genes in M. canis exposed to KTZ compared with those unexposed thereto. At half-inhibitory concentration (½MIC), compared with the control group, 453 genes were significantly up-regulated and 326 genes were significantly down-regulated (p < 0.05). Quantitative reverse transcription polymerase chain reaction analysis verified the transcriptome results of RNA sequencing. Gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that the 3 pathways of RNA polymerase, steroid biosynthesis, and ribosome biogenesis in eukaryotes are closely related to the antifungal mechanism of KTZ. The results indicated that KTZ may change cell membrane permeability, destroy the cell wall, and inhibit mitosis and transcriptional regulation through CYP51, SQL, ERG6, ATM, ABCB1, SC, KER33, RPA1, and RNP genes in the 3 pathways. This study provides a new theoretical basis for the effective control of M. canis infection and the effect of KTZ on fungi.


Effects of the 2011 Tohoku earthquake and tsunami on the abundance and composition of anthropogenic marine debris on the continental slope off the Pacific coast of northeastern Japan.
The abundance and composition of anthropogenic marine debris from 2012 to 2014 was assessed according to three bottom trawl surveys conducted on the upper continental slope between 198 m and 501 m off the Pacific coast of northeastern Japan. The surveys quantitated marine debris as follows: 33.52-164.62 items km-2 (January to July 2012), 91.68-215.11 items km-2 (November 2012 to May 2013), and 160.13-178.19 items km-2 (November 2013 to May 2014). Plastic bags or household materials mainly dominated terrestrial sources of debris. Principal component analysis latitudinally divided the study area according to debris abundance caused by geographical and hydrodynamic features. The long-term effect of tsunami-associated debris on the seafloor environment was recognized, because terrestrial sources such as heavy household materials were most abundant throughout the study period, with the additional accumulation of fishing gear and plastic bags.


Clinical, electrophysiological and morphological changes in a case of hereditary retinal degeneration in the Papillon dog.
An autosomal recessive retinal disease with a late onset in Swedish Papillon dogs has recently been described. A 7-year-old Papillon dog showed no obvious signs of visual impairment and only minor ophthalmoscopic changes. Cone ERG b-wave amplitudes were within normal limits, while rod responses were nonrecordable or severely abnormal. Ultrastructural examination showed a generalized retinal degenerative disease, most prominent in the peripheral areas. The inferior retina was more severely affected than the superior areas. Both rods and cones showed morphological changes. The Papillon dog is another dog breed affected by progressive rod-cone degeneration, with similarities to the canine retinal disease given the gene symbol prcd.


[Endarterium injury and the related pathway in chronic intermittent hypoxia rats].
To examine the pathological change and intima thickness of thoracic aorta, detect the serum concentration of hypoxia-inducible factor-1α (HIF-1α), oxidized LDL (ox-LDL), and pentraxin 3 (PTX3) in the rat model of chronic intermittent hypoxia (CIH), and to determine the effect of CIH on endarterium injury and its possible pathway. Twenty-four male Sprague-Dawley (SD) rats were divided into 4 groups: a CIH+Nacetylcysteine (NAC) group, a CIH+normal saline (NS) group, a CIH control group and a control group. CIH rats were subjected to alternating cycles of hypoxia (6%-8% O2 in N2 for 20-25 s) and normoxia (21% O2 in N2 for 2 min) every 180 s for 7 h/d. Rats in the control group were not treated. Rats in the CIH+NAC group were treated with NAC [800 mL/(kg.d)] intraperitoneal injection, and rats in the CIH+NS group were treated with NS [5 mL/(kg.d)] intraperitoneal injection. After 42 day treatment, the rats were sacrificed, blood taken, and thoracic aorta cut off. The serum concentration of HIF-1α, ox-LDL, and PTX3 were detected by ELISA. The thickness of intima was taken by computer digital image analysis. Vascular endothelial cell injury and detachment were found in the thoracic aorta in the CIH and the CIH+NS group. The intima in the CIH and the CIH+NS group was thicker than that in the control and the CIH+NAC group (P<0.001). The serum concentration of HIF-1α, ox-LDL, and PTX3 in the CIH and the CIH+NS group was higher than that in the control and the CIH+NAC group (P<0.001). The serum concentration of HIF-1α, ox-LDL, and PTX3 was pairwise positive correlation, and the serum concentration of ox-LDL and PTX3 was positively correlated with the thickness of intina (P<0.001). The vascular endothelial cell injury and endarterium thickening can be induced by CIH. It is an important pathway that CIH activates oxidative stress and elevates the levels of HIF- 1α, ox-LDL, and PTX3.


The inequalities in health debate: a critical review of the issues.
There has been an ongoing dispute about inequalities in health ever since the suppressed publication of the Black Report in 1980. It has recently been given a new edge by three publications: the proceedings of an SSRC Workshop held in November 1983 and the Registrar General's Decennial Supplement for 1979-1983, and another half-suppressed report, this time from Health Education Council. The first and third broadly claim that inequalities in health are widening; the second that they are irrelevant. This paper reviews the debate since 1980 around the issues of measurement (how to assess differences between social groups and how to compare across time) and the four kinds of explanation examined by the Black Report. The concluding discussion emphasises the essentially political nature of the debate over the 'trends' but concludes that, whilst most agree on the importance of materialist/structuralist variables, there are differences in the policy implications of the different explanatory positions. However, on the whole these will not be resolved by 'further research': the time is long overdue for a redistribution of resources to eradicate poverty.


Idiopathic edema and eating disorders: evidence for an association.
Using a computerized self-report questionnaire format incorporating the Eating Attitudes Test-26 (EAT-26) and a modification of the McKendry criteria for the diagnosis of idiopathic edema (IE), the authors surveyed a population of women students to determine the prevalence of IE symptoms and their relationship to abnormal eating attitudes and behaviors (AEAB). The mean age of 177 respondents was 20.8 years. IE symptoms were reported by 12.4% of respondents, and AEAB by 16.4%. The prevalence of IE symptoms was 37.9% in respondents with AEAB and 7.4% in normal respondents (p = .0001). A score of 11 or greater on the modified McKendry IE criteria had a sensitivity of .37, specificity of .93, positive predictive value of .5, and a negative predictive value of .89 for an abnormal EAT-26 score. Body mass index (BMI) scores were similar for all respondent groups.


Karyotype and genome size variation in white-flowered Eranthis sect. Shibateranthis (Ranunculaceae).
Comparative karyomorphological analyses of six out of the eight white-flowered species of Eranthissect.Shibateranthis have been carried out. All studied specimens of E.byunsanensis, E.lobulata, E.pinnatifida, and E.stellata had a somatic chromosome number 2n = 16 with basic chromosome number x = 8. On the contrary, E.tanhoensis and E.sibirica had a basic chromosome number x = 7. The specimens of E.tanhoensis were diploid with 2n = 14, while the specimens of E.sibirica were polyploid with 2n = 42. Monoploid chromosome sets of the investigated diploid species had 4-5 metacentric chromosomes and 2-4 submetacentric/subtelocentric/acrocentric chromosomes. The highest level of interchromosomal asymmetry, estimated via CVCL, was found in E.byunsanensis and E.pinnatifida. The highest levels of intrachromosomal asymmetry (MCA) and heterogeneity in centromere position (CVCI) were found in E.lobulata and E.byunsanensis, while E.sibirica had the most symmetric karyotype. A multivariate PCoA analysis of basic karyotype parameters (2n, x, THL, CVCL, MCA, and CVCI) highlighted no overlap among species accessions, which was also confirmed by LDA. The average absolute monoploid DNA content (1Cx) of the 23 investigated samples of six Eranthis species varied from 9.26 ± 0.25 pg in E.sibirica to 15.93 ± 0.32 pg in E.stellata. Overall karyological affinity was highlighted between E.lobulata and E.stellata, on one side, and between E.byunsanensis and E.pinnatifida, on the other side. Interestingly, there was no significant correlation between total haploid (monoploid) chromosome length (THL) and 1Cx values in these species.


Dose response of intrathecal adenosine in experimental pain and allodynia.
Intrathecal adenosine reduces areas of mechanical hypersensitivity and provides analgesia in patients with neuropathic pain. Adenosine also causes side effects, yet its dose response for either efficacy or side effects has not been examined in double blind studies. We studied two doses of intrathecal adenosine in humans with experimental hypersensitivity and the ability of the adenosine receptor antagonist, aminophylline, to reverse adenosine's effects. Following Internal Review Board approval and written informed consent, 35 volunteers were studied. Five volunteers were studied to confirm the stability of a new method of inducing hypersensitivity with capsaicin. The remaining 30 volunteers received, in a randomized, double-blind manner, saline, or adenosine, 0.5 or 2.0 mg, by intrathecal injection 40 min after areas of allodynia and hyperalgesia were established from capsaicin. Two hr later, volunteers were randomized to receive intravenous saline or aminophylline, 5 mg/kg. Topical capsaicin with intermittent heating resulted in stable areas of allodynia and hyperalgesia. Intrathecal adenosine, but not saline, reduced areas of allodynia and hyperalgesia from capsaicin, with no differences between doses. Side effects occurred in 1, 2, and 6 volunteers receiving saline, 0.5 mg and 2.0 mg adenosine, respectively. Aminophylline failed to reverse adenosine's effects. There is no difference in efficacy to experimental hypersensitivity between the largest approved dose of intrathecal adenosine and a dose 25% this size, but side effects are more common with the larger dose. Failure of aminophylline to reverse adenosine's effects could reflect inadequate concentrations at receptors in the spinal cord after intravenous injection.


Modelling the effects of particle size pretreatment method on biogas yield of groundnut shells.
Optimising biogas yields from anaerobic digestion of organic wastes is significant to maximum energy recovery in the biodigestion process and has become an important topic of interest. Substrate particle size is an important process parameter in biogas production, and it precedes other pretreatments methods for the majority of the lignocellulose materials. Optimisation of biogas yield using Response Surface Methodology (RSM) was done, and temperature, hydraulic retention time and particle size were considered variables to develop the predictive models. Pretreatment of groundnut shells was investigated using particle size reduction of mechanical pretreatment methods. After pretreatment, 30 samples were digested in a batch digester at mesophilic temperature. The experimental results showed that the temperature, hydraulic retention time and particle size had significant effects of interaction (p < 0.05). The optimum experimental and predicted yields are: 44.70 and 42.92 (lNkgoDM) organic dry matter biogas yield, 20.80 and 19.09 (lN/kgFM) fresh mass biogas yield, 24.00 and 22.68 (lNCH4oDM) organic dry methane yield and 12.30 and 15.59 (lNCH4FM) fresh mass methane yield, respectively. The R2 recorded for the four yield components were 0.6268, 0.5875, 0.6109 and 0.5547. These values seem to be lower and a sign of the average fit of the model. Biogas production from groundnut shells was significantly improved with statistical optimisation and the pretreatment method.


DNA Topoisomerases Are Required for Preinitiation Complex Assembly during GAL Gene Activation.
To investigate the importance of topoisomerases for transcription of the galactose induced genes, we have studied the expression of GAL1, GAL2, GAL7 and GAL10 in Saccharomyces cerevisiae cells deficient for topoisomerases I and II. We find that topoisomerases are required for transcriptional activation of the GAL genes, but are dispensable for ongoing transcription, eliminating a role of the enzymes in transcriptional elongation. Furthermore, we demonstrate that promoter chromatin remodeling of the GAL genes is unaffected in the topoisomerase deficient strain. However, the cells fail to successfully recruit RNA polymerase II due to an inability of the TATA-binding protein (TBP) to bind to the TATA box in these promoters. We therefore argue that topoisomerases are required for accurate assembly of the preinitiation complex at the promoters of the GAL genes.


A new 5-alkylresorcinol glucoside derivative from Cybianthus magnus.
One new 5-alkylresorcinol glucoside (1) was isolated from leaves of Cybianthus magnus, along with 12 known compounds (2-13), isolated from four plants belonging to Myrsinaceae family. Their structures were determined on the basis of spectroscopic analysis and by comparison of their spectral data with those reported in the literature. Among the tested molecules, only compound 2 displayed a strong cytotoxic activity with IC50 values ranging between 22 and 100 μM for all cell lines tested. One new 5-alkylresorcinol glucoside (1) was isolated from leaves of Cybianthus magnus, along with 12 known compounds, isolated from four plants belonging to Myrsinaceae family (2, 3 isolated from C. magnus; 4-7, 10 and 11 isolated from Myrsine latifolia; 4, 8 and 9 isolated from Myrsine sessiflora; 6, 7, 10, 12 and 13 isolated from Myrsine congesta). Their structures were determined on the basis of spectroscopic analysis and by comparison of their spectral data with those reported in the literature. So far, only nine 5-alkylresorcinol glucosides were isolated from leaves of Grevillea robusta. Since resorcinols are known to exhibit strong cytotoxic activity, compounds 1 and 2 were tested against cell lines 3T3, H460, DU145 and MCF-7 for cytotoxicity in vitro and compounds 3-13 were tested for their antileishmanial activity. Compound 2 displayed a strong cytotoxic activity with IC50 values ranging between 22 and 100 μM for all tested cell lines. Compounds 3-13 were not active against Leishmania amazonensis amastigotes.


The social determinants of health: a contribution to the analysis of gender differences in health and illness.
While it is established that socioeconomic status and social integration influence the distribution of health and illness among men and women, little attention has been paid to the different ways in which women and men experience socioeconomic opportunities and social attachments to others. Drawing on evidence from the literature, the position developed in this article is that gender mediates the influence of both socioeconomic status and social integration on health, and for women, these are intricately linked. Women's relationship to the labour market establishes and perpetuates their socioeconomic inequality relative to men, and may produce contradictory influences on women's health. Furthermore, for women, the marital relationship is paradoxical: marriage may at once improve economic and social support opportunities, while diminishing control over paid and unpaid work--potentially increasing as well as compromising the health status of women. The article is intended to contribute to the growing body of literature on gender and the determinants of health.


It Was Me: The Use of Sense of Agency Cues Differs Between Cultures.
Sense of agency (SoA) is the sense of having control over one's own actions and through them events in the outside world. SoA may be estimated by integrating different agency cues. In the present study, we examined whether the use of different agency cues - action-effect congruency, temporal relation between action and effect, and affective valence of effects - differs between Eastern (Mongolian) and Western (Austrian) cultures. In a learning phase, participants learned to associate different actions (keypresses) with positive and negative action effects (smileys). In a test phase, participants performed the same keypresses. After different intervals positive and negative action effects, which were either congruent or incongruent with the previously acquired action-effect associations, were presented. In each trial participants were asked to rate how likely the action effect was caused by themselves or by the computer (authorship ratings). In both groups authorship ratings were higher for congruent compared to incongruent action effects and for positive compared to negative action effects. This indicates that action-effect congruency and affective valence of action effects modulate SoA. Further, in both groups the difference between positive and negative effects was higher with congruent effects than incongruent effects. This overadditive effect of action-effect congruency and affective valence might indicate that an integration of different agency cues takes place. Decreasing authorship ratings with increasing interval were observed in Austrians but not in Mongolians. For Mongolians, the temporal chronology of events might be less important when inferring causality. Therefore, information regarding the temporal occurrence of the effect might not be used as an agency cue in Mongolians. In conclusion, some agency cues might be similarly used in different cultures, but the use of others might be culture-dependent.


Surfactant-Stripped Semiconducting Polymer Micelles for Tumor Theranostics and Deep Tissue Imaging in the NIR-II Window.
Photoacoustic imaging (PA) in the second near infrared (NIR-II) window presents key advantages for deep tissue imaging owing to reduced light scattering and low background signal from biological structures. Here, a thiadiazoloquinoxaline-based semiconducting polymer (SP) with strong absorption in the NIR-II region is reported. After encapsulation of SP in Pluronic F127 (F127) followed by removal of excess surfactant, a dual functional polymer system named surfactant-stripped semiconductor polymeric micelles (SSS-micelles) are generated with water solubility, storage stability, and high photothermal conversion efficiency, permitting tumor theranostics in a mouse model. SSS-micelles have a wideband absorption in the NIR-II window, allowing for the PA imaging at both 1064 and 1300 nm wavelengths. The PA signal of the SSS-micelles can be detected through 6.5 cm of chicken breast tissue in vitro. In mice or rats, SSS-micelles can be visualized in bladder and intestine overlaid 5 cm (signal to noise ratio, SNR ≈ 17 dB) and 5.8 cm (SNR over 10 dB) chicken breast tissue, respectively. This work demonstrates the SSS-micelles as a nanoplatform for deep tissue theranostics.


Additional Value of 2-[18F]FDG PET/CT Comparing to MRI in Treatment Approach of Anal Cancer Patients.
Accurate staging and treatment planning are imperative for precise management in Anal Cancer (ACa) patients. We aimed to evaluate the additive and prognostic value of pre-treatment 2-[18F]fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (2-[18F]FDG PET/CT) in the staging and management of ACa compared to magnetic resonance imaging (MRI). This retrospective study was conducted on 54 patients. Pre-treatment 2-[18F]FDG PET/CT studies and MRI reports were compared considering the primary tumor, pelvic lymph nodes, and metastatic lesions. The impact of 2-[18F]FDG PET/CT in the management and its prognostic value, using maximum standardized uptake value (SUVmax), were assessed. Discordant findings were found in 46.3% of patients (5 in T; 1 in T and N; 18 in N; and 1 in M stage). 2-[18F]FDG PET/CT resulted in up-staging in 9.26% and down-staging in 3.7% of patients. Perirectal lymph nodes were metabolically inactive in 12.9% of patients. Moreover, 2-[18F]FDG PET/CT resulted in management change in 24.1% of patients. Finally, SUVmax provided no prognostic value. 2-[18F]FDG PET/CT altered staging and management in a sizable number of patients in this study, and supports a need for a change in guidelines for it to be used as a routine complementary test in the initial management of ACa.


Experimental verification of methane-carbon dioxide replacement in natural gas hydrates using a differential scanning calorimeter.
The methane (CH4) - carbon dioxide (CO2) swapping phenomenon in naturally occurring gas hydrates is regarded as an attractive method of CO2 sequestration and CH4 recovery. In this study, a high pressure microdifferential scanning calorimeter (HP μ-DSC) was used to monitor and quantify the CH4 - CO2 replacement in the gas hydrate structure. The HP μ-DSC provided reliable measurements of the hydrate dissociation equilibrium and hydrate heat of dissociation for the pure and mixed gas hydrates. The hydrate dissociation equilibrium data obtained from the endothermic thermograms of the replaced gas hydrates indicate that at least 60% of CH4 is recoverable after reaction with CO2, which is consistent with the result obtained via direct dissociation of the replaced gas hydrates. The heat of dissociation values of the CH4 + CO2 hydrates were between that of the pure CH4 hydrate and that of the pure CO2 hydrate, and the values increased as the CO2 compositions in the hydrate phase increased. By monitoring the heat flows from the HP μ-DSC, it was found that the noticeable dissociation or formation of a gas hydrate was not detected during the CH4 - CO2 replacement process, which indicates that a substantial portion of CH4 hydrate does not dissociate into liquid water or ice and then forms the CH4 + CO2 hydrate. This study provides the first experimental evidence using a DSC to reveal that the conversion of the CH4 hydrate to the CH4 + CO2 hydrate occurs without significant hydrate dissociation.


Successful conservative treatment for neglected rotatory atlantoaxial dislocation.
Rotatory atlantoaxial subluxation (RAS) is a rare condition that is often misdiagnosed and therefore incorrectly managed. We describe our experience and propose an algorithm for treating neglected RAS nonoperatively. All consecutive children with neglected (>6 wk) RAS were treated in our department between 2005 and 2010 by cervical traction using a Gleason traction device and nonsteroidal anti-inflammatory drugs and muscle relaxants. When reduction was not achieved, the Gleason device was replaced by a halo device without manipulative reduction, and weight was added as necessary until reduction was successful. Fixation of reduction was either by a sternooccipital mandibular immobilizer or a halo vest for 3 to 4 months. All 5 children (4 boys and 1 girl, aged 4 to 11 y) were successfully treated for neglected RAS. The mean duration from symptom onset (eg, limited neck range of motion, discomfort) to treatment initiation was 11.6 weeks (range, 6 to 16 wk). Closed reduction was achieved by a Gleason or a noninvasive halo device within 1 to 2 weeks in 4 cases. The fifth case was reduced after 5 weeks of traction using a halo with a 5 kg weight. All children had symmetrical full range of motion, normal neurological examination, and were fully engaged in educational and sports activities without recurrent dislocations at final follow-up (mean, 30 mo; range, 18 to 49 mo). Conservative treatment by gradual and prolonged traction without manipulative reduction in neglected RAS might be a successful method. Reduction can often be achieved within 2 weeks of treatment onset. Level IV (retrospective case series).


[A case report of Vp3 hepatocellular carcinoma responding to multidisciplinary treatment].
We report a 60-year-old man who had hepatocellular carcinoma with tumor thrombus in the main portal vein and left portal branch (VP3HCC). He was treated with transarterial chemo-embolization, surgical resection and intra-arterial infusion chemotherapy. He is now surviving without any sign of recurrence for 12 months after the initial therapy, even though the prognosis of VP3HCC is poor. This is a case in which the effect of multidisciplinary treatment was indicated.


Photochemical Synthesis and Spectroscopy of Covalent PAH Dimers.
Laser photochemistry of pressed-pellet samples of polycyclic aromatic hydrocarbons (PAHs) produces covalently bonded dimers and some higher polymers. This chemistry was discovered initially via laser desorption time-of-flight mass spectrometry experiments, which produced masses (m/z) of 2M-2 and 2M-4 (where M is the monomer parent mass). Dimers are believed to be formed from photochemical dehydrogenation and radical polymerization chemistry in the desorption plume. Replication of these ablation conditions at higher throughput allowed PAH dimers of pyrene, perylene, and coronene to be produced and collected in milligram quantities. Differential sublimation provided purification of the dimers and elimination of residual monomers. The purified dimers were investigated with UV-visible, IR, and Raman spectroscopy, complemented by computational studies using density functional theory at the CAM-B3LYP/def2-TZV level. Calculations and predicted spectra were calibrated by comparison with the corresponding monomers and used to determine the lowest energy dimer structures. Infrared and Raman spectroscopy provided few distinctive signatures, but UV-visible spectra detected new transitions for each dimer. The comparison of simulated and experimental spectra allows determination of the most prevalent structures for the PAH dimers. The work presented here provides interesting insights into the spectroscopy of extended aromatic systems and a new strategy for the photochemical synthesis of large PAH dimers.


The transverse dorsal approach to the Lisfranc joint.
While multiple longitudinal skin incisions can be utilized to visualize the joints of the midfoot, we feel that exposure can be difficult. Dorsal transverse and T incisions were undertaken to expose the tarsometatarsal joints (TMTJs) in 12 patients. Five of the 12 had some form of immunosuppression, including diabetes, methotrexate therapy and antirejection transplant therapy. One patient who had a lengthening of the midfoot with a structural autograft suffered a small area of skin necrosis that healed by secondary intention. The remainder of patient's wounds healed without complication. Three to six dorsal access intervals are created between the neurovascular and musculotendinous structures that overlie the TMTJs. The transverse incision can be extended into a medially based T incision to apply a medial plate as required. Transverse incisions are not recommended for patients who require lengthening of the midfoot.


Reliability of scapular positioning measurement procedure using the palpation meter (PALM).
Observation and measurement of the static position of the scapula is important for investigating both shoulder and neck pathology. Measurement of scapular position is complex and lacks a clinically useful instrument. The objective of this study was to investigate the reliability of the Palpation Meter (PALM) for measuring scapular position when the glenohumeral joint is held in various positions. Thirty normal subjects were recruited for a test-retest reliability study. Three raters conducted measurements on two different occasions to estimate intra- and inter-rater reliability. The scapular positions evaluated in this study were: (1) the horizontal distance between the scapula and the spine in the scapular resting position and during elevation of the arm in the scapular plane; and (2) the vertical distance between C(7) and the acromion (C(7)-A). Intraclass correlation coefficient (ICC), standard error of measurement (SEM) and Bland and Altman limits of agreement were calculated. Reliability values for measurements of the horizontal distance between the scapula and the spine were generally good for both intra-rater (ICC 0.81 to 0.89; SEM 0.56 to 1.17cm) and inter-rater (ICC 0.67 to 0.89; SEM 0.59 to 0.98cm) evaluation. Reliability values of measurement of depression of the acromion were also good for both intra-rater (ICC 0.72 to 0.78; SEM 0.66 to 0.79) and inter-rater (ICC 0.76; SEM 0.64) evaluation. No systematic bias was observed with Bland and Altman analysis. The PALM is a reliable tool for the measurement of scapular positioning in a healthy sample. Future studies should be conducted to further investigate the clinometric properties of the PALM in patient populations before its clinical usefulness for measuring scapular position can be established.


Characteristics of children undergoing dental extractions under general anaesthesia in Wolverhampton: 2007-2012.
Studying characteristics of children requiring extractions under dental general anaesthesia (DGA) can help identify trends, which can be used to facilitate future planning of healthcare services. To report on the profile of children who underwent extractions under DGA between 2007 and 2012 at the New Cross Hospital in Wolverhampton, England.Methods Retrospective analyses of hospital records. Of the 2692 patients seen between 2007 and 2012, 49.6% were boys and 50.4% were girls. The mean age was 7.1 and 7 to 12 years was the largest age group (43%). The majority of the sample was White British (67%). Of the 8,286 teeth extracted, 85% were primary teeth and 15% permanent. More teeth were extracted in boys than girls (P = 0.002) and 'Other' ethnicities had a higher mean number of extractions compared to White British (P <0.001) and South Asians (P = 0.046). The mean age of the patients has decreased over the years (P = 0.001) and the mean number of primary teeth extracted has increased (P = 0.001). A clear dental public health issue has been reinforced through the relatively high level of DGA activity reported. Though rigorous caries prevention remains the ultimate goal, a better assessment and discharge process may help reduce the need for first time DGAs as well as repeats.


Plasticity of the human auditory cortex induced by discrimination learning of non-native, mora-timed contrasts of the Japanese language.
In this magnetoencephalographic (MEG) study, we examined with high temporal resolution the traces of learning in the speech-dominant left-hemispheric auditory cortex as a function of newly trained mora-timing. In Japanese, the "mora" is a temporal unit that divides words into almost isochronous segments (e.g., na-ka-mu-ra and to-o-kyo-o each comprises four mora). Changes in the brain responses of a group of German and Japanese subjects to differences in the mora structure of Japanese words were compared. German subjects performed a discrimination training in 10 sessions of 1.5 h each day. They learned to discriminate Japanese pairs of words (in a consonant, anni-ani; and a vowel, kiyo-kyo, condition), where the second word was shortened by one mora in eight steps of 15 msec each. A significant increase in learning performance, as reflected by behavioral measures, was observed, accompanied by a significant increase of the amplitude of the Mismatch Negativity Field (MMF). The German subjects' hit rate for detecting durational deviants increased by up to 35%. Reaction times and MMF latencies decreased significantly across training sessions. Japanese subjects showed a more sensitive MMF to smaller differences. Thus, even in young adults, perceptual learning of non-native mora-timing occurs rapidly and deeply. The enhanced behavioral and neurophysiological sensitivity found after training indicates a strong relationship between learning and (plastic) changes in the cortical substrate.


High yield synthesis of bracelet-like hydrophilic Ni-Co magnetic alloy flux-closure nanorings.
A simple solvothermal method has been discovered to synthesize single-walled flux-closure Ni-Co magnetic alloy nanorings in high yield, which are directly fabricated in a reaction solution and able to chronically exist in solution.


Pattern of ziprasidone exposures reported to Texas poison centers, 2001-2005.
Information on potentially adverse exposures to the atypical antipsychotic drug ziprasidone is limited. This study described the pattern of exposures involving only ziprasidone (isolated exposures) reported to Texas poison control centers during 2001-2005. The mean dose was 666 mg. The patient age distribution was <or=5 years (11%), 6-19 years (30%), and >or=20 years (60%). The exposures were intentional in 53% of the cases. Seventy-five percent of the exposures were managed at health care facilities. The final medical outcome was classified as no effect for 39% of the cases and minor effects for 40% of the cases. Adverse clinical effects were listed for 53% of the patients; the most frequently reported being neurological (42%), cardiovascular (13%), and gastrointestinal (5%). The most frequently listed treatment was decontamination by charcoal (34%) or cathartic (28%). Potentially adverse ziprasidone exposures reported to poison control centers are likely to involve management at a health care facility and involve some sort of adverse clinical effect. With proper treatment, the outcomes of such exposures are generally favorable.


Camostate- and caerulein-induced delay of gastric emptying in the rat: effect of CCK receptor antagonists.
The effect of camostate, a potent releaser of endogenous cholecystokinin (CCK), and of caerulein, an amphibian peptide mimicking the biological actions of CCK, as well as of selective CCK receptor antagonists on gastric emptying of liquids was studied in the rat. Oral administration of camostate (200 mg/kg with the liquid test meal preceded by the same dose 10 min before the meal) significantly delayed gastric emptying of saline, an effect which was completely blocked by previous administration of the CCKA receptor antagonist, devazepide, at a dose (1 mg/kg i.v.) unable to modify the emptying rate when administered alone. Caerulein (0.03-30 nmol/kg i.v.) also delayed the emptying rate in a dose-dependent manner, with an ID50 of 3.94 nmol/kg. The effect of the peptide was also inhibited by devazepide. The CCKB receptor antagonist, L365,260 (3R-(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1, 4-benzodiazepine-3-yl)-N'-(3-methylphenyl)-urea; 3 mg/kg i.v.), was completely unable to modify the CCK (both endogenous and exogenous)-induced delay in gastric emptying. Repeated (7 days) camostate administration did not modify the gastric motor response to endogenous CCK, thus, suggesting that adaptation did not take place. These results demonstrate that endogenous and exogenous CCK delays gastric emptying of liquids through stimulation of CCKA receptors and suggest that adaptation of the gastric motor response to CCK does not occur.


Computed Tomography (CT) Simulated Fluoroscopy-Guided Transdiscal Approach in Transcrural Celiac Plexus Block.
Conventional transcrural CPB via the "walking off" the vertebra technique may injure vital organs while attempting to proximally spread injectate around the celiac plexus. Therefore, we attempted the CT-simulated fluoroscopy-guided transdiscal approach to carry out transcrural CPB in a safer manner, spreading the injectate more completely and closely within the celiac plexus area. A 54-year-old male patient with pancreatic cancer suffered from severe epigastric pain. The conventional transcrural approach was simulated, but the needle pathway was impeded by the kidney on the right side and by the aorta on the left side. After simulating the transdiscal pathway through the T11-12 intervertebral disc, we predetermined the optimal insertion point (3.6 cm from the midline), insertion angle (18 degrees), and advancement plane, as well as the proper depth. With the transdiscal approach, we successfully performed transcrural CPB within a narrow angle, and the bilateral approach was not necessary as we were able to achieve the bilateral spread of the injectate with the single approach.


The plant circadian clock influences rhizosphere community structure and function.
Plants alter chemical and physical properties of soil, and thereby influence rhizosphere microbial community structure. The structure of microbial communities may in turn affect plant performance. Yet, outside of simple systems with pairwise interacting partners, the plant genetic pathways that influence microbial community structure remain largely unknown, as are the performance feedbacks of microbial communities selected by the host plant genotype. We investigated the role of the plant circadian clock in shaping rhizosphere community structure and function. We performed 16S ribosomal RNA gene sequencing to characterize rhizosphere bacterial communities of Arabidopsis thaliana between day and night time points, and tested for differences in community structure between wild-type (Ws) vs clock mutant (toc1-21, ztl-30) genotypes. We then characterized microbial community function, by growing wild-type plants in soils with an overstory history of Ws, toc1-21 or ztl-30 and measuring plant performance. We observed that rhizosphere community structure varied between day and night time points, and clock misfunction significantly altered rhizosphere communities. Finally, wild-type plants germinated earlier and were larger when inoculated with soils having an overstory history of wild-type in comparison with clock mutant genotypes. Our findings suggest the circadian clock of the plant host influences rhizosphere community structure and function.


Induction of antroquinonol production by addition of hydrogen peroxide in the fermentation of Antrodia camphorata S-29.
Antroquinonol have significantly anti-tumour effects on various cancer cells. There is still lack of reports on regulation of environmental factors on antroquinonol production by Antrodia camphorata. An effective submerged fermentation method was employed to induce antroquinonol with adding H2 O2 . The production of antroquinonol was 57.81 mg L-1 after fermentation for 10 days when adding 25 mmol L-1 H2 O2 at day 4 of the fermentation process. Then, antroquinonol was further increased to 80.10 mg L-1 with cell productivity of 14.94 mg g-1 dry mycelium when the feeding rate of H2 O2 was adjusted to 0.2 mmol L-1 h-1 in the 7 L fermentation bioreactor. After inhibiting the generation of reactive oxygen species with the inhibitor diphenyleneiodoium, the synthesis of antroquinonol from A. camphorata was significantly reduced, and the yield was only 3.3 mg L-1 . The results demonstrated that addition of H2 O2 was a very effective strategy to induce and regulate the synthesis of antroquinonol in submerged fermentation. Reactive oxygen species generated by H2 O2 during fermentation caused oxidative stress, which induced the synthesis of antroquinonol and other chemical compounds. Moreover, it is very beneficial process to improve production and diversity of the active compounds during liquid fermentation of A. camphorata mycelium. © 2016 Society of Chemical Industry.


Birthweight, preterm births and neonatal mortality in Belgium and the United States.
Belgium is known to have a lesser low birthweight rate and a lower infant mortality rate than the United States. We used previously unpublished data to show that beneath this comparison lies a more complicated picture. Singleton live birth certificates for 1986-87 were analysed. Despite a lower mean birthweight in Belgium (3360 g) than in the United States (3420 g), Belgium had fewer (4.9%) low birthweight infants than the US (5.9%) because of fewer preterm births (4.4 vs. 9.3%). Consistent with the excess of preterm births in the US, the residual distribution of birthweight was smaller in Belgium (2.2% vs. 3.1%). Whereas neonatal mortality was 4.8/1000 in Belgium and 5.6/1000 in the US, birthweight-specific neonatal mortality was higher in Belgium. The challenge for Belgium is to improve the survival of newborns regardless of their birthweight. In the US, the task is to eliminate the excess of small preterm infants.


Does Religiosity/Spirituality Play a Role in Function, Pain-Related Beliefs, and Coping in Patients with Chronic Pain? A Systematic Review.
This systematic review examined the extent to which measures of religiosity/spirituality (R/S): (1) are associated with pain, function, pain-related beliefs (beliefs), coping responses, and catastrophizing in people with chronic pain; and (2) moderate the association between beliefs, coping and catastrophizing, and pain and function. Experimental and observational studies examining at least one of these research questions in adults with chronic pain were eligible. Two reviewers independently performed eligibility screening, data extraction, and quality assessment. Twenty studies were included. Most studies focused on the association between R/S and pain or function. When significant associations emerged, those between R/S and psychological function were weak to strong and positive; those between religious/spiritual well-being and pain and physical dysfunction were negative, but weak. Few studies examined the associations between R/S and beliefs/coping/catastrophizing; none examined the moderation role of R/S. The findings suggest that R/S is associated with pain and psychological function in people with chronic pain, and that viewing oneself as being "spiritual," regardless of religion, may contribute to positive psychological adjustment. More research is needed to determine the reliability of this finding. PROSPERO registry CRD42018088803.


[Perforation of hypopharynx -- a uncommon complication of transesophageal endosonography].
Today the endoscopical sonography of the oesophagus and heart is a useful diagnostic procedure. Perforations of the oesophagus or hypopharynx after this procedure are grave and life-threatening complications of this invasive diagnostic procedure. In the past 8 years we observed 3 cases of hypopharyngeal perforation as complication of endosonographic procedure. These cases were evaluated retrospectively. In all 3 cases an increased resistance against insertion of the probe had been observed. In two cases the perforation was found in the right sinus piriformis. The third patient had a perforation of the posterior hypopharyngeal wall adjacent to the upper oesophageal sphincter. The former patients underwent an open transcervical revision, in the latter patient the perforation was clipped endoluminally to his impaired general condition. Perforations of the hypopharynx represent a rare but potentially life threatening complication of transoesophageal sonography. The endoscopically working physician should know and recognize the clinical signs for surgical treatment before further complications (e. g. mediastinitis) may occur.


Additive effect of combined naproxen and paracetamol in rheumatoid arthritis.
The clinical effect and plasma naproxen levels were studied in 20 patients with RA receiving three doses of naproxen and two naproxen doses combined with paracetamol (acetaminophen) in a randomized, double-blind, comparison in five 2-wk treatment periods. A significant dose-concentration effect relationship was found for the three naproxen doses (500, 1000 and 1500 mg daily). The following variables were measured: global clinical effect, joint index, morning stiffness, activity of daily living (ADL), pain during movement and at rest. The naproxen dose-concentration effect relationship curve was moved to the left by the addition of 4 g paracetamol daily. No major side effects were observed, but complaints concerning the gastrointestinal tract were fewer on lower naproxen doses and these were not increased by concomitant paracetamol treatment. The results show that the clinical effect of naproxen in RA may be significantly increased by concomitant paracetamol administration.


The current TNM staging system of renal cell carcinoma: are further improvements needed?
Objective of the study is to review the current 7th edition of the TNM classification of renal tumors and to perform a critical analysis of the recent evidence in order to identify the limitations of this new staging system. A search of the english literature was performed through the Medline and Pubmed database using the following keywords: renal cell carcinoma, staging system and TNM. Overall, 2600 references were initially scrutinized. Forty papers were selected based on their pertinence with the topic of the review, level of evidence provided and overall contribution to the field. Few changes have been made in the current version of the TNM staging system of renal tumors. pT2 tumors have been divided in 2 subgroups based on tumor size with a cut-off at 10 cm; the invasion of the renal vein was classified as pT3a; finally, the invasion of the ispsilateral adrenal gland was classified as pT4. However, other changes were suggested by the analysis of the recent literature and have not been introduced in this new version. Further improvements of the TNM classification for renal tumors are needed especially with regard to locally advanced tumors and node-positive disease, in order to improve the accuracy of this important prognostic tool in renal oncology.


Mutational analysis of Bacillus megaterium QM B1551 cortex-lytic enzymes.
Molecular-genetic and muropeptide analysis techniques have been applied to examine the function in vivo of the Bacillus megaterium QM B1551 SleB and SleL proteins. In common with Bacillus subtilis and Bacillus anthracis, the presence of anhydromuropeptides in B. megaterium germination exudates, which is indicative of lytic transglycosylase activity, is associated with an intact sleB structural gene. B. megaterium sleB cwlJ double mutant strains complemented with engineered SleB variants in which the predicted N- or C-terminal domain has been deleted (SleB-ΔN or SleB-ΔC) efficiently initiate and hydrolyze the cortex, generating anhydromuropeptides in the process. Additionally, sleB cwlJ strains complemented with SleB-ΔN or SleB-ΔC, in which glutamate and aspartate residues have individually been changed to alanine, all retain the ability to hydrolyze the cortex to various degrees during germination, with concomitant release of anhydromuropeptides to the surrounding medium. These data indicate that while the presence of either the N- or C-terminal domain of B. megaterium SleB is sufficient for initiation of cortex hydrolysis and the generation of anhydromuropeptides, the perceived lytic transglycosylase activity may be derived from an enzyme(s), perhaps exclusively or in addition to SleB, which has yet to be identified. B. megaterium SleL appears to be associated with the epimerase-type activity observed previously in B. subtilis, differing from the glucosaminidase function that is apparent in B. cereus/B. anthracis.


Current status quo on COVID-19 including chest imaging.
With each day the number coronavirus disease 2019 (COVID-19) cases continue to rise rapidly and our imaging knowledge of this disease is expeditiously evolving. The role of chest computed tomography (CT) in the screening or diagnosis of COVID-19 remains the subject of much debate. Despite several months having passed since identifying the disease, and numerous studies related to it, controversy and concern still exists regarding the widespread use of chest CT in the evaluation and management of COVID-19 suspect patients. Several institutes and organizations around the world have released guidelines, recommendations and statements against the use of CT for diagnosing or screening COVID-19 infection and advocating its use only for those cases with a strong clinical suspicion of complication or an alternate diagnosis. However, these guidelines and recommendations are in disagreement with majority of the widely available literature, which strongly favour CT as a pivotal tool in the early diagnosis, management and even follow-up of COVID-19 infection. This article besides comprehensively reviewing the current status quo on COVID-19 disease in general, also writes upon the current consensus statements/recommendations on the use of diagnostic imaging in COVID-19 as well as highlighting the precautions and various disinfection procedures being employed world-wide at the workplace to prevent the spread of infection.


Neonatal brachial plexus palsy with neurotmesis of C5 and avulsion of C6: supraclavicular reconstruction strategies and outcome.
Nerve reconstruction strategies for restoration of elbow flexion and shoulder function in patients with neonatal brachial plexus palsy with neurotmesis of C5 and avulsion of C6 are not well defined and the outcomes are unclear. From 1990 to 2008, nerve surgery was performed in 421 patients with neonatal brachial plexus palsy. This study focused on thirty-four infants who had a neurotmetic lesion of C5 and avulsion or intraforaminal neurotmesis of C6, irrespective of C7. The C8 and T1 functions were intact. Intraplexal transfer of C6 to C5 with direct coaptation was preferred for restoration of elbow flexion. The suprascapular nerve was reconnected either by extra-intraplexal transfer of the accessory nerve or by grafting from C5 to restore shoulder function. Additional grafts were attached from C5 to the C5 contribution of the posterior division of the superior trunk when technically possible. Transfer of either the C6 anterior root filaments or the entire C6 nerve to C5 was performed in seventeen patients (group A) with direct coaptation in fifteen of them. Grafting from C5 to the anterior division of the superior trunk was performed in the remaining seventeen infants (group B). An accessory-to-suprascapular nerve transfer was applied in twenty-nine infants. The suprascapular nerve was reconnected in five patients by grafting from C5. It was possible to attach one, two, or three additional grafts from C5 to the posterior division of the superior trunk in twenty-one patients. All infants had biceps muscle recovery to a Medical Research Council (MRC) grade of ≥4, twenty-two (65%) of the thirty-four patients obtained Mallet grade-IV abduction, and eleven (32%) of the thirty-four obtained Mallet grade-IV external rotation. In patients with neonatal brachial plexus palsy who have neurotmesis of C5 and avulsion of C6, elbow flexion can be successfully restored with supraclavicular intraplexal reconstruction with use of C5 as the proximal outlet. However, shoulder function recovery following suprascapular nerve reinnervation and additional grafting from C5 to the posterior division of the superior trunk is less successful. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.


Evaluation and enhancement of physical stability of semi-solid dispersions containing piroxicam into hard gelatin capsules.
The aim of the study was to investigate the physical stability of the semi-solid dispersions into the hard gelatine capsules prepared with Gelucire 44/14, Labrasol and different additives such as microcrystalline cellulose (MCC), mannitol and lactose (alpha-monohydrate) used for enhancing the stability of the formulations. The master dispersion prepared with only Gelucire 44/14 (20% w/w) and Labrasol (80% w/w) was stored in a refrigerator (5 +/- 3 degrees C), while the modified dispersions with the additives (2% w/w) were kept in a climatic chamber (25 +/- 2 degrees C / 60 +/- 5% RH) for 12 months. Dissolution tests of the semi-solid dispersions were performed in media with different pH's immediatly after preparation and after 3, 6 and 12 months of storage. FTIR and DSC studies were also carried out at the same time points. The ideal storage condition for the master dispersion was found to be at 5 degrees C. The addition of MCC, mannitol and lactose (alpha-monohydrate) to the original dispersion afforded a solidification effect on the formulation at room temperature and showed the same dissolution behavior (not less than 85% of piroxicam within 30 min in pH 1.2, 4.5 and 6.8; and water) with the master. The dispersion including lactose was stable at 25 degrees C for 12 months. However, the ideal period of storage for the modified dispersions including MCC and mannitol was 6 months at 25 degrees C. FTIR and DSC results both confirmed the amorphous state of piroxicam in all semi-solid dispersions under storage conditions for 12 months.


Whole exome sequencing of well-differentiated liposarcoma and dedifferentiated liposarcoma in older woman: a case report.
Common kinds of soft tissue sarcomas (STS) include well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS). In this case, we present a comprehensive clinical profile of a patient who underwent multiple recurrences during the progression from WDLPS to DDLPS. A 62-year-old Asian female underwent retroperitoneal resection of a large tumor 11 years ago, the initial pathology revealed a fibrolipoma-like lesion. Over the next six years, the patient underwent three resections for recurrence of abdominal tumors. Postoperative histology shows mature adipose tissue with scattered "adipoblast"-like cells with moderate-to-severe heterogeneous spindle cells, pleomorphic cells, or tumor giant cells. Immunohistochemistry (IHC) demonstrated positive staining for MDM2 and CDK4, confirming that the abdominal tumor was WDLPS and gradually progressing to DDLPS. Post-operative targeted sequencing and IHC confirmed the POC1B::ROS1 fusion gene in DDLPS. Whole-exome sequencing (WES) revealed that WDLPS and DDLPS shared similar somatic mutations and copy number variations (CNVs), whereas DDLPS had more mutated genes and a higher and more concentrated amplification of the chromosome 12q region. Furthermore, somatic mutations in DDLPS were significantly reduced after treatment with CDK4 inhibitors, while CNVs remained elevated. Due to the high likelihood of recurrence of liposarcoma, various effective treatments should be taken into consideration even if surgery is the primary treatment for recurrent liposarcoma. To effectively control the course of the disease following surgery, combination targeted therapy may be a viable alternative to chemotherapy and radiotherapy in the treatment of liposarcoma.


Plasmonic green nanolaser based on a metal-oxide-semiconductor structure.
Realization of smaller and faster coherent light sources is critically important for the emerging applications in nanophotonics and information technology. Semiconductor lasers are arguably the most suitable candidate for such purposes. However, the minimum size of conventional semiconductor lasers utilizing dielectric optical cavities for sustaining laser oscillation is ultimately governed by the diffraction limit (∼(λ/2n)(3) for three-dimensional (3D) cavities, where λ is the free-space wavelength and n is the refractive index). Here, we demonstrate the 3D subdiffraction-limited laser operation in the green spectral region based on a metal-oxide-semiconductor (MOS) structure, comprising a bundle of green-emitting InGaN/GaN nanorods strongly coupled to a gold plate through a SiO(2) dielectric nanogap layer. In this plasmonic nanocavity structure, the analogue of MOS-type "nanocapacitor" in nanoelectronics leads to the confinement of the plasmonic field into a 3D mode volume of 8.0 × 10(-4) μm(3) (∼0.14(λ/2n)(3)).


Citrus Tissue Culture : AUXINS IN RELATION TO ABSCISSION IN EXCISED PISTILS.
An in vitro bioassay for chemicals that affect Citrus abscission was used to identify three inhibitors of stylar abscission in lemon pistil explants incubated on defined nutrient media. The three inhibitors (picloram, 4-chlorophenoxyacetic acid, and 3,5,6-trichloropyridine-2-oxyacetic acid) are all auxins, and the most potent of them (i.e. picloram) was found to be at least 10 times more active in the bioassay than 2,4-dichlorophenoxyacetic acid. Picloram (2 micromolar) also was shown to be effective in inhibiting stylar abscission in pistil explants from other Citrus cultivars such as mandarin, Valencia, and Washington navel oranges and grapefruit. To study the physiology of auxins active as abscission inhibitors versus inactive auxins in lemon pistils, the transport and metabolism of [1-(14)C]-2,4-dichlorophenoxyacetic acid was compared with that of [2-(14)C]indole-3-acetic acid, which is without effect in the bioassay over the range from 0.1-100 micromolar. Insignificant quantities of labeled indole-3-acetic acid and/or labeled derivatives were found to reach the presumptive zone of stylar abscission under the test conditions. Labeled 2,4-dichlorophenoxyacetic acid and/or labeled derivatives also were transported slowly through pistils, but some radioactivity could be detected in the stylar abscission zone as early as 24 hours after the start of incubation. Extensive conversion of [2-(14)C]indole-3-acetic acid to labeled compounds tentatively considered to be glycoside and cellulosic glucan derivatives was found with the use of solvent extraction methodology. A significantly smaller percentage of the radioactivity in pistils incubated on [1-(14)C]-2,4-dichlorophenoxyacetic acid was found in fractions corresponding to these derivatives. Both transport and metabolism appear to be important factors affecting the activity of auxins as abscission inhibitors in the bioassay.


Shunt surgery versus endoscopic sclerotherapy for variceal hemorrhage: late results of a randomized trial.
Between September 1982 and April 1988, 60 cirrhotic patients with prior variceal hemorrhage were randomized to undergo the placement of an elective shunt (distal splenorenal: 26; nonselective: 4) or long-term endoscopic sclerotherapy (n = 30). Eighty-six percent of patients had alcoholic cirrhosis, and 33% were classified as Child's class C. After a mean follow-up of 87 months, 60% of patients undergoing sclerotherapy and 17% of shunt patients experienced rebleeding (p < 0.001). Shunt patients have survived longer than those who had sclerotherapy (6-year survival rates of 53% and 26%, respectively; p < 0.05). In part because of the wide geographic distribution of patients, only 4 of 13 patients in whom sclerotherapy failed (31%) could undergo salvage by shunt surgery. Although hepatic portal perfusion was better maintained after sclerotherapy, there were no major differences between the groups in terms of post-therapy hepatic or psychoneurologic function. In a predominantly alcoholic cirrhotic patient population (half non-urban), the results of elective shunt surgery were superior to those of chronic endoscopic sclerotherapy with respect to the prevention of recurrent variceal hemorrhage and survival.


Nickel- and Palladium-Catalyzed Cross-Coupling Reactions of Organostibines with Organoboronic Acids.
A strategy for the formation of antimony-carbon bond was developed by nickel-catalyzed cross-coupling of halostibines. This method has been applied to the synthesis of various triaryl- and diarylalkylstibines from the corresponding cyclic and acyclic halostibines. This protocol showed a wide substrate scope (72 examples) and was compatible to a wide range of functional groups such as aldehyde, ketone, alkene, alkyne, haloarenes (F, Cl, Br, I), and heteroarenes. A successful synthesis of arylated stibine 3 a in a scale of 34.77 g demonstrates high synthetic potential of this transformation. The formed stibines (R3 Sb) were then used for the palladium-catalyzed carbon-carbon bond forming reaction with aryl boronic acids [R-B(OH)2 ], giving biaryls with high selectivity, even the structures of two organomoieties (R and R') are very similar. Plausible catalytic pathways were proposed based on control experiments.


Predictors of Helmet CPAP Failure in COVID-19 Pneumonia: A Prospective, Multicenter, and Observational Cohort Study.
Continuous positive airway pressure (CPAP) can be beneficial in acute respiratory failure (ARF) due to coronavirus (COVID-19) pneumonia, but delaying endotracheal intubation (ETI) in nonresponders may increase mortality. We aimed at investigating the performance of composite respiratory indexes as possible predictors of CPAP failure in ARF due to COVID-19. This was a multicenter, prospective, observational, and cohort study conducted in the respiratory units of three University hospitals in Milan and in a secondary care hospital in Codogno (Italy), on consecutive adult patients with ARF due to COVID-19 pneumonia that underwent CPAP between March 2020 and March 2021. ETI transfer to the intensive care unit or death is defined CPAP failure. Predictors of CPAP failure were assessed before T0 and 1 hour after T1 CPAP initiation and included mROX index (ratio of PaO2/FiO2 to respiratory rate), alveolar-to-arterial (A-a) O2 gradient, and the HACOR (heart rate, acidosis, consciousness, oxygenation, and respiratory rate) score. Three hundred and fifty four patients (mean age 64 years, 73% males) were included in the study; 136 (38.4%) satisfied criteria for CPAP failure. A-a O2 gradient, mROX, and HACOR scores were worse in patients who failed CPAP, both at T0 and T1 (p < 0.001 for all parameters). The HACOR score was associated with CPAP failure (odds ratio-OR-for every unit increase in HACOR = 1.361; 95%CI: 1.103-1.680; p=0.004; AUROC = 0.742; p < 0.001). CPAP failure was best predicted by a threshold of 4.50 (sensitivity = 53% and specificity = 87%). The HACOR score may be a reliable and early predictor of CPAP failure in patients treated for ARF in COVID-19 pneumonia.


A CT-Derived Measurement of Sarcopenia Fails to Predict Falls.
Sarcopenia and frailty have both emerged as risk factors for elderly falls. We investigated whether radiologic sarcopenia or frailty are associated with falls in a high-risk geriatric outpatient population. We reviewed 114 patients followed at the Center for Healthy Senior Living who had undergone a computerized tomography (CT) of the abdomen and pelvis for any reason from 2013 to 2019. Sarcopenia was determined by psoas muscle cross-sectional area at L3 on CT scan. Their individual frailty score was calculated. The primary outcome was admission to hospital for falls. There were no statistical differences in frailty score or sarcopenia between the 2 groups (left/right psoas muscle: no hospital admission = 6.8 ± 2.4/6.4 ± 2.5 vs falls requiring hospital admission 6.5 ± 2.3/6.5 ± 2.3 cm2). We concluded that neither frailty score nor sarcopenia predicted the occurrence of falls in our high-risk geriatric outpatient population.


Scavenging of peroxynitrite reduces renal ischemia/reperfusion injury.
Nitric oxide (NO) and peroxynitrite (OONO-) are implicated in the pathophysiology of renal ischemia/reperfusion (I/R). The aim of this study was to investigate and compare the efficiency of S-methylisothiourea (SMT), an iNOS inhibitor, and mercaptoethylguanidine (MEG), a scavenger of peroxynitrite, on renal dysfunction and injury induced by I/R of rat kidney. Thirty-two male Sprague-Dawley rats were divided into four groups: sham-operated, I/R, I/R+SMT, and I/R+MEG. Rats were given SMT (10 mg/kg i.p.) or MEG (10 mg/kg i.p.) 6 h prior to I/R and at the beginning of reperfusion. All rats except sham-operated underwent 60 min of bilateral renal ischemia followed by 6 h of reperfusion. After reperfusion, kidneys and blood were obtained for evaluation. Superoxide dismutase, glutathione peroxidase, malondialdehide, protein carbonyl content, and nitrite/nitrate level (NO(x)) were determined in the renal tissue. Serum creatinine (S(Cr)), blood urea nitrogen (BUN), and aspartate aminotransferase (AST) were determined in the blood. Additionally, renal sections were used for histological grade of renal injury. SMT and MEG significantly reduced the I/R-induced increases in S(Cr), BUN, and AST. Both SMT and MEG attenuated the tissue NO(x) levels, indicating reduced NO production. In addition, SMT and MEG markedly reduced elevated oxidative stress product, restored decreased antioxidant enzymes, and attenuated histological alterations. Interestingly, MEG exerted a greater renoprotective effect than SMT. These data support the finding that iNOS and peroxynitrite are involved in the renal I/R injury, and suggest that a scavenger of peroxynitrite might be more effective than iNOS inhibitors as a therapeutic intervention.


Readiness of the Kenyan public health sector to provide pre-referral care for severe paediatric malaria.
To assess readiness among primary public health facilities in Kenya to provide pre-referral antimalarials for severe malaria. Nine national surveys of randomly selected primary public health facilities undertaken bi-annually between 2017 and 2021 were analysed. The outcomes included the availability of pre-referral antimalarial drugs at the health facilities and health worker knowledge of recommended pre-referral treatment for severe malaria. A total of 1540 health workers from 1355 health facilities were interviewed. Injectable artesunate was available at 46%, injectable quinine at 7%, and artemether at 3% of the health facilities. None of the facilities had rectal artesunate suppositories in stock. A total of 960 (62%) health workers were trained on the use of injectable artesunate. 73% of the health workers who had ever referred a child with severe malaria were aware that artesunate was the recommended treatment, 49% said that intramuscular injection was the preferred route of administration, and 60% stated the correct dose. The overall knowledge level of the treatment policy was low at 21% and only slightly higher among trained than untrained health workers (24% vs 14%; p < 0.001) and those with access to guidelines versus those without access (29% vs 17%; p < 0.001). The readiness of primary health facilities and health workers to deliver appropriate pre-referral care to children with complicated malaria in Kenya is inadequate. Further investments are required to ensure (a) availability of nationally recommended pre-referral antimalarials; (b) appropriate training and supervision in their administration, and (c) monitoring of the entire referral process.


Treatment of toxoplasmic encephalitis in patients with AIDS. A randomized trial comparing pyrimethamine plus clindamycin to pyrimethamine plus sulfadiazine. The California Collaborative Treatment Group.
To compare pyrimethamine plus clindamycin (PC) to pyrimethamine plus sulfadiazine (PS) as a treatment for toxoplasmic encephalitis (TE) in patients with the acquired immunodeficiency syndrome (AIDS). Randomized, unblinded phase II, multicenter trial with provision for crossover for failure or intolerance of the assigned regimen. University hospitals. Eighty-four patients with presumptive TE were entered. Thirteen were excluded when they were found to have another diagnosis, and 12 were excluded because they did not meet entry criteria. The baseline characteristics in the remaining 26 patients randomized to PC and 33 randomized to PS were comparable. Patients were treated for 6 weeks with pyrimethamine and folinic acid plus either sulfadiazine or clindamycin. Clindamycin was given intravenously during the first 3 weeks. There was a trend toward greater survival in patients randomized to PS (hazard ratio, 3.25; 95% CI, 0.63 to 16.8; P = 0.13), but most study deaths were not directly related to TE. In contrast, patients randomized to PC appeared more likely to achieve complete clinical (odds ratio, 0.67; CI, 0.2 to 1.97; P greater than 0.2) and radiologic responses (odds ratio, 0.28; CI, 0.08 to 0.96; P = 0.02). Multivariate analysis revealed drug effects to be largely independent of other variables. Similar efficacy of the treatments was also suggested by a hazard analysis of resolution of abnormal mental status, fever, and headache. Skin rash was the most common adverse event in both treatment arms. Because of toxicity, six patients randomized to PC and 11 patients randomized to PS had to switch to the alternate treatment, but only three were unable to complete therapy after crossover. The results of several end points of efficacy, taken together, suggest that the relative efficacy of PC approximately equals that of PS. PC appears to be an acceptable alternative in patients unable to tolerate PS.


Alpha 4 integrins and vascular cell adhesion molecule-1 play a role in sympathetic innervation of the heart.
Sympathetic neurons innervate the heart early in postnatal development, an event that is crucial for proper modulation of blood pressure and cardiac function. However, the axon guidance cues that direct sympathetic neurons to the heart, and the neuronal receptors that recognize those cues, are poorly understood. Here we present evidence that interactions between the alpha4beta1 integrin on sympathetic neurons and vascular cell adhesion molecule-1 (VCAM-1) in the heart plays a role in cardiac innervation. The alpha4 subunit was detected on postnatal rat superior cervical ganglion (SCG) neurons in culture and in cryosections of SCG and heart. VCAM-1 immunoreactivity was detected on cardiac myocytes that associate with invading sympathetic neurons. Purified recombinant soluble VCAM-1 (rsVCAM-1) stimulated SCG neurite outgrowth at levels comparable with laminin 2/4 and fibronectin (Fn), and outgrowth on rs-VCAM-1 and Fn was blocked by antibodies specific for the alpha4 and beta1 integrin subunits. Intrathoracic injection of function-blocking antibodies to alpha4 and VCAM-1, as well as a small molecule inhibitor of alpha4 integrins, significantly reduced sympathetic innervation of the heart. These results indicate that the interaction between alpha4 integrin and VCAM-1 is important for sympathetic innervation of the heart.


Oligosaccharide structures present on asparagine-289 of recombinant human plasminogen expressed in a Chinese hamster ovary cell line.
The oligosaccharide structures linked to Asn289 of a recombinant (r) variant (R561S) human plasminogen (HPg) expressed in Chinese hamster ovary (CHO) cells, after transfection of these cells with a plasmid containing the cDNA coding for the variant HPg, have been determined. Employing high-performance anion-exchange liquid chromatography mapping of the oligosaccharide units cleaved from the protein by glycopeptidase F, compared with elution positions of standard oligosaccharides, coupled with monosaccharide compositional determinations and analyses of sequential exoglycosidase digestions and specific lectin binding, we find that considerable microheterogeneity in oligosaccharide structure exists at this sole potential N-linked glycosylation site on HPg. A variety of high-mannose structures, as well as bi-, tri-, and tetraantennary complex-type carbohydrate, has been found, in relative amounts of 1-25% of the total oligosaccharides. The complex-type structures contain variable amounts of sialic acid (Sia), ranging from 0 to 5 mol/mol of oligosaccharide in the different glycan structures. Neither hybrid-type molecules, N-acetylglucosamine bisecting oligosaccharides, nor N-acetyllactosaminyl-repeat structures were found to be present in the complex-type carbohydrate pool in observable amounts. Of interest, a significant portion of the Sia exists an outer arm structures in an (alpha 2,6) linkage to the penultimate galactose, a novel finding in CHO cell-directed glycosylation.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of topical application of platelet-rich plasma on chronic venous leg ulcerations.
Wound products that reliably support healing of chronic leg ulcers remain a huge unmet need in clinical practice. Due to the lack of standardized comparable protocols and different systems for platelet-rich plasma (PRP) preparation, there is limited data on healing rates in chronic venous ulcers. In our case series with a total of seven chronic leg ulcers in four patients, we investigated the healing rates based on standardized digital photographs of chronic venous ulcers after application of topical PRP using a digital imaging software. In 5 out of 7 ulcers, the PRP-treated wound half showed faster healing as compared the control half of the wound. In this case series, PRP-treated sides of chronic venous leg ulcers showed a tendency for accelerated healing as compared to nontreated collateral wound side. Our data support the evaluation of topical PRP treatment in the management of chronic venous leg ulcers.


Cheaters sometimes prosper: targeted worker reproduction in honeybee (Apis mellifera) colonies during swarming.
Kin selection theory predicts that honeybee (Apis mellifera) workers should largely refrain from producing their own offspring, as the workers collectively have higher inclusive fitness if they rear the sons of their mother, the queen. Studies that have quantified levels of ovary activation and reproduction among workers have largely supported this prediction. We sampled pre-emergent male pupae and adult workers from seven colonies at regular intervals throughout the reproductive part of the season. We show that the overall contribution of workers to male (drone) production is 4.2%, nearly 40 times higher than is generally reported, and is highest during reproductive swarming, when an average of 6.2% of the males genotyped are worker-produced. Similarly, workers in our samples were 100 times more likely to have active ovaries than previously assumed. Worker reproduction is seasonally influenced and peaks when colonies are rearing new queens. Not all worker subfamilies contribute equally to reproduction. Instead, certain subfamilies are massively over-represented in drone brood. By laying eggs within the period in which many colonies produce virgin queens, these rare worker subfamilies increase their direct fitness via their well-timed sons.


Two emerging perilymph fistula "syndromes" in children.
This paper proposes two relatively common "syndromes" seen in children with perilymph fistulas using illustrative case reports. One, a 2 1/2-year-old child with bilaterally symmetric progressive sensorineural hearing loss, was found to have bilateral oval and round window fistulas. The other was a child who presented originally with an unexplained unilateral sensorineural loss. It was only when hearing deteriorated in the opposite ear several years later that a perilymph fistula was suspected and confirmed by tympanotomy. The clinical presentations and other details of these cases diverge widely, but may represent two emerging syndromes of perilymph fistulas in children: 1. a congenital or hereditary predisposition, and the other, 2. sudden hearing loss in the "good" ear of children with an unexplained sensorineural hearing loss in the opposite ear.


NanoClick: A High Throughput, Target-Agnostic Peptide Cell Permeability Assay.
Macrocyclic peptides open new opportunities to target intracellular protein-protein interactions (PPIs) that are often considered nondruggable by traditional small molecules. However, engineering sufficient membrane permeability into these molecules is a central challenge for identifying clinical candidates. Currently, there is a lack of high-throughput assays to assess peptide permeability, which limits our capacity to engineer this property into macrocyclic peptides for advancement through drug discovery pipelines. Accordingly, we developed a high throughput and target-agnostic cell permeability assay that measures the relative cumulative cytosolic exposure of a peptide in a concentration-dependent manner. The assay was named NanoClick as it combines in-cell Click chemistry with an intracellular NanoBRET signal. We validated the approach using known cell penetrating peptides and further demonstrated a correlation to cellular activity using a p53/MDM2 model system. With minimal change to the peptide sequence, NanoClick enables the ability to measure uptake of molecules that enter the cell via different mechanisms such as endocytosis, membrane translocation, or passive permeability. Overall, the NanoClick assay can serve as a screening tool to uncover predictive design rules to guide structure-activity-permeability relationships in the optimization of functionally active molecules.


Multi-species host range of staphylococcal phages isolated from wastewater.
The host range of bacteriophages defines their impact on bacterial communities and genome diversity. Here, we characterize 94 novel staphylococcal phages from wastewater and establish their host range on a diversified panel of 117 staphylococci from 29 species. Using this high-resolution phage-bacteria interaction matrix, we unveil a multi-species host range as a dominant trait of the isolated staphylococcal phages. Phage genome sequencing shows this pattern to prevail irrespective of taxonomy. Network analysis between phage-infected bacteria reveals that hosts from multiple species, ecosystems, and drug-resistance phenotypes share numerous phages. Lastly, we show that phages throughout this network can package foreign genetic material enclosing an antibiotic resistance marker at various frequencies. Our findings indicate a weak host specialism of the tested phages, and therefore their potential to promote horizontal gene transfer in this environment.


Use of monoclonal antibodies to T-cell subsets for immunologic monitoring and treatment in recipients of renal allografts.
Using monoclonal antibodies and flow cytometry, wer serially monitored lymphocyte subpopulations in renal-allograft recipients treated with either conventional immunosuppression or a monoclonal antibody. In 29 patients given conventional suppression, highly significant correlations between changes in T-cell subsets and rejection were noted. Normal or elevated ratios of OKT4 (helper/inducer) to OKT8 (suppressor/cytotoxic) cells were associated with rejection unless the donor was HLA identical or the total number of T cells was extremely low. In patients with low ratios, rejection seldom occurred. Two patients treated with OKT3 monoclonal antibody for acute rejection had rapid disappearance of OKT3-reactive cells from the peripheral blood and prompt reversal of rejection. The use of monoclonal antibodies allows the precise determination of changes in T-cell subsets and promises the development of therapeutic protocols that can be designed to manipulate selected lymphocyte populations.


Preneoplastic transformation of human mammary epithelial cells.
Recent in-vitro models of mammary epithelial cell (MEC) immortalization have provided a practical approach to begin to dissect the molecular mechanisms of breast tumorigenesis. Introduction of a single oncogene, the human papilloma virus (HPV)-16 E6, induces efficient and reproducible preneoplastic transformation of normal MECs, by inducing degradation of the tumor suppressor protein p53. The role of p53 has also been demonstrated by analyses of a model of gamma-radiation-induced MEC transformation. Recently, efficient retroviral gene transfer has allowed identification of multiple mammary epithelial cell types that show distinct susceptibilities to HPV E6 and E7 oncogenes, indicating a cell-type-specific predominance of the tumor suppressor proteins p53 and Rb which are targeted by E6 and E7, respectively. Further analyses of these models are likely to elucidate the biochemical mechanisms of early mammary tumorigenesis.


Phosphorylation of yeast phosphatidylserine synthase in vivo and in vitro by cyclic AMP-dependent protein kinase.
Evidence is presented that demonstrates that phosphatidylserine synthase (CDPdiacylglycerol:L-serine O-phosphatidyltransferase, EC 220.127.116.11) from Saccharomyces cerevisiae is phosphorylated in vivo and in vitro by cAMP-dependent protein kinase. Phosphatidylserine synthase activity in cell extracts was reduced in the bcy1 mutant (which has high cAMP-dependent protein kinase activity) and elevated in the cyr1 mutant (which has low cAMP-dependent protein kinase activity) when compared with wild-type cells. The reduced phosphatidylserine synthase activity in the bcy1 mutant correlated with elevated levels of a phosphorylated form of the phosphatidylserine synthase Mr 23,000 subunit. The elevated phosphatidylserine synthase activity in the cyr1 mutant correlated with reduced levels of the phosphorylated form of the enzyme. There was negligible phosphorylation of the phosphatidylserine synthase Mr 23,000 subunit from stationary-phase cells. Pure phosphatidylserine synthase was phosphorylated by the cAMP-dependent protein kinase catalytic subunit, which resulted in a 60-70% reduction in phosphatidylserine synthase activity. The cAMP-dependent protein kinase catalytic subunit catalyzed the incorporation of 0.7 mol of phosphate per mol of phosphatidylserine synthase Mr 23,000 subunit. The specific cAMP-dependent protein kinase inhibitor prevented the phosphorylation of phosphatidylserine synthase and the inhibition of its activity by the catalytic subunit. Analysis of peptides derived from protease-treated labeled phosphatidylserine synthase showed only one labeled peptide. Phospho amino acid analysis of labeled phosphatidylserine synthase showed that the enzyme was phosphorylated at a serine residue.


Rethinking Alkylating(-Like) Agents for Solid Tumor Management.
Although old molecules, alkylating agents and platinum derivatives are still widely used in the treatment of various solid tumors. However, systemic toxicity and cellular resistance mechanisms impede their efficacy. Innovative strategies, including local administration, optimization of treatment schedule/dosage, synergistic combinations, and the encapsulation of bioactive molecules in smart, multifunctional drug delivery systems, have shown promising results in potentiating anticancer activity while circumventing such hurdles. Furthermore, questioning of the old paradigm according to which nuclear DNA is the critical target of their anticancer activity has shed light on subcellular alternative and neglected targets that obviously participate in the mediation of cytotoxicity or resistance. Thus, rethinking of the use of these pivotal antineoplastic agents appears critical to improve clinical outcomes in the management of solid tumors.


Structural, electronic, and chemical properties of multiply iodized aluminum clusters.
The electronic structure, stability, and reactivity of iodized aluminum clusters, which have been investigated via reactivity studies, are examined by first-principles gradient corrected density functional calculations. The observed behavior of Al13I(x)- and Al14I(x)- clusters is shown to indicate that for x < or = 8, they consist of compact Al13- and Al14++ cores, respectively, demonstrating that they behave as halogen- or alkaline earth-like superatoms. For x > 8, the Al cores assume a cagelike structure associated with the charging of the cores. The observed mass spectra of the reacted clusters reveal that Al13I(x)- species are more stable for even x while Al14I(x)- exhibit enhanced stability for odd x(x > or = 3). It is shown that these observations are linked to the formation and filling of "active sites," demonstrating a novel chemistry of superatoms.


Organ culture system as a means to detect celiac disease.
Anti-endomysial and anti-transglutaminase antibodies can be produced in vitro by the intestinal mucosa of celiac disease (CD) patients in clinical remission, when the culture is performed in the presence of gliadin peptides. Our aim was to use this organ culture system as a means to detect the pathognomonic antibodies of celiac disease (CD) in the culture supernatants. Organ culture was performed in the presence of three different activators to evaluate which one induced the strongest antibody response in intestinal mucosa from patients in clinical remission of CD. Our data confirm the high efficiency of synthetic peptide 31-43 as a specific immunological activator in CD and demonstrate its capability to stimulate production/secretion of CD-specific antibodies. We envision that this organ culture system may prove to be useful as a new technique for CD diagnosis.