Gamma frequencies as a predictor for the accomplishment of a motor task guided through the action observation network.
Action observation describes a concept where the subsequent motor behavior of an individual can be modulated though observing an action. This occurs through the activation of neurons in the action observation network, acting on a variety of motor learning processes. This network has been proven highly useful in the rehabilitation of patients with acquired brain injury, placing "action observation" as one of the most effective techniques for motor recovery in physical neurorehabilitation. The aim of this paper is to define an EEG marker for motor learning, guided through observation. Healthy subjects (n = 41) participated voluntarily for this research. They were asked to repeat an unknown motor behavior, immediately after observing a video. During the observation, EEG raw signals where collected with a portable EEG and the results were later compared with success and fail on repeating the motor procedure. The comparison was then analyzed with the Mann-Whitney U test for non-parametrical data, with a confidence interval of 95%. A significant relation between motor performance and neural activity was found for Alpha (p = 0,0149) and Gamma (0,0005) oscillatory patterns. Gamma oscillations with frequencies between 41 and 49,75 Hz, seem to be an adequate EEG marker for motor performance guided through the action observation network. The technology used for this paper is easy to use, low-cost and presents valid measurements for the recommended oscillatory frequencies, implying a possible use on rehabilitation, by collecting data in real-time during therapeutic interventions and assessments.


Both TNF receptors are required for TNF-mediated induction of apoptosis in PC60 cells.
A rat/mouse T cell hybridoma (PC60) was transfected either with human (h) TNF-R p55 (TNF-R55), p75 (TNF-R75) or both cDNAs. hTNF-R55 expression was below 50 molecules/cell, whereas the number of hTNF-R75 reached about 4000 molecules/cell. Only cells co-expressing the two types of receptor showed TNF-dependent apoptosis, in contrast to cells expressing similar levels of only one receptor type, indicating that both TNF-R55 and TNF-R75 are required. Stable co-transfection of the bcl-2 proto-oncogene largely prevented this TNF-mediated induction of apoptosis. We found that a high level of hTNF-R75 expression was essential for obtaining TNF-dependent apoptosis in PC60 cells in addition to a low number of hTNF-R55. Both receptors are signal transducing because simultaneous triggering of hTNF-R55 and hTNF-R75 by agonistic mAbs or by TNF-R-specific TNF muteins induced similar levels of apoptosis as wild-type hTNF. Apoptotic killing of only those lymphocytes expressing a high, induced level of TNF-R75, in addition to TNF-R55, may play a physiologically important role.


Doll play narratives about starting school in children of socially anxious mothers, and their relation to subsequent child school-based anxiety.
Child social anxiety is common, and predicts later emotional and academic impairment. Offspring of socially anxious mothers are at increased risk. It is important to establish whether individual vulnerability to disorder can be identified in young children. The responses of 4.5 year-old children of mothers with social phobia (N = 62) and non-anxious mothers (N = 60) were compared, two months before school entry, using a Doll Play (DP) procedure focused on the social challenge of starting school. DP responses were examined in relation to teacher reports of anxious-depressed symptoms and social worries at the end of the child's first school term. The role of earlier child behavioral inhibition and attachment, assessed at 14 months, was also considered. Compared to children of non-anxious mothers, children of mothers with social phobia were significantly more likely to give anxiously negative responses in their school DP (OR = 2.57). In turn, negative DP predicted teacher reported anxious-depressed and social worry problems. There were no effects of infant behavioral inhibition or attachment. Vulnerability in young children at risk of anxiety can be identified using Doll Play narratives.


Defective activation of T suppressor cell function in nonobese diabetic mice. Potential relation to cytokine deficiencies.
Nonobese diabetic (NOD) is an inbred mouse strain susceptible to development of T cell-mediated autoimmune diabetes. The strain is characterized by high percentages of T lymphocytes in lymphoid organs. The syngeneic mixed lymphocyte reaction (SMLR), a T cell response to self MHC class II Ag, is reportedly involved in the generation of a number of immunoregulatory cells, including suppressor inducers. A severely depressed SMLR characteristic of certain other autoimmune strains was found in NOD but not in nonautoimmune SWR/Bm mice. Moreover, IL-2 produced by NOD T cells at day 6 in an SMLR was at least one hundredfold reduced compared with SWR, and NOD T cells harvested from an SMLR at day 6 were functionally defective when tested for ability to induce suppression of an allogeneic MLR. However, functionally competent suppressor T cells were generated in NOD splenic leukocyte cultures in response to Con A, and IL-2 release from these was equivalent to that released by Con A-stimulated SWR splenocytes. A deficiency in cytokine release was not limited to IL-2, because peritoneal exudate cells from NOD exhibited a greatly diminished sensitivity to LPS-stimulated IL-1 release in comparison to SWR mice. IL-2 supplementation both in vitro and in vivo restored the ability of NOD T cells to respond in a SMLR, with production of cells capable of inducing suppression. Like SMLR-activated T cells from untreated SWR controls, SMLR blasts from IL-2-treated NOD mice were enriched for the L3T4 phenotype. IL-1 supplementation in vitro resulted in partial restoration of T suppressor activation in a SMLR. The depressed SMLR exhibited by NOD mice was apparently a stimulator cell dysfunction, because NOD stimulator cells failed to activate T cells from (SWR x NOD)F1 mice, whereas stimulators from SWR or F1 mice were capable of doing so. Collectively, these results suggest a defect in suppressor cell activation rather than an absence of this immunoregulatory cell population.


Structural insight into pH-induced conformational changes within the native human transthyretin tetramer.
Acidification of the transthyretin (TTR) tetramer facilitates dissociation and conformational changes in the protein, allowing alternatively folded monomers to self-assemble into insoluble amyloid fibers by a downhill polymerization mechanism in vitro. To investigate the influence of acidification on the quaternary and tertiary structures of TTR, crystal structures of wild-type human TTR at pH 4.0 and pH 3.5 have been determined to 1.7 A resolution. The acidic pH crystals are isomorphous to most of the previously reported TTR structures, containing two subunits in the asymmetric unit (the so-called A and B subunits) but forming a tetramer through crystallographic symmetry. The pH 4.0 crystal structure reveals that the native fold of the tetramer remains mostly undisturbed. In particular, subunit A of the TTR pH 4.0 structure is very similar to the wild-type TTR pH 7.4 structure with an r.m.s.d. of 0.38 A. In contrast, subunit B of the TTR pH 4.0 structure exhibits several significant changes. The EF-helix (residues 75-81) and the adjacent EF-loop (residues 82-90) show an r.m.s.d. greater than 2.0 A. The acidic residues within this region (Glu72, Asp74, Glu89, and Glu92) undergo significant conformational changes that instigate movement of the EF helix-loop region and make residues Lys70, Lys76, His88, and His90 orient their side chains toward these acidic residues. In particular, Glu89 undergoes a maximum deviation of 5.6 A, occupying Phe87's initial position in the wild-type TTR pH 7.4 structure, and points its side chain into a hydrophobic pocket of the neighboring subunit. In the pH 3.5 structure, the EF helix-loop region is completely disordered. These results demonstrate that acidic conditions increase the susceptibility of the EF helix-loop region of the TTR B subunit to undergo conformational changes and unfold, likely destabilizing the tetramer and identifying at least the initial conformational changes likely occurring within the tetramer that leads to the amyloidogenic monomer.


A Narrative Review of Evidence-Based Preventive Options for Chronic Migraine.
Chronic migraine is a debilitating disorder that affects 2 % of the global population and imparts a significant societal and economic impact. The cornerstones of chronic migraine management include making an accurate diagnosis, patient education, treatment of comorbid conditions, and selection of an appropriate, evidence-based acute and preventive treatment regimen. Although it is common to treat chronic migraine with preventive medications effective for episodic migraine, a number of treatment options exist with specific evidence for effectiveness in chronic migraine. Currently, onabotulinumtoxinA injections are the only FDA-approved preventive treatment for chronic migraine. A number of non-medication treatment options including occipital nerve and supraorbital nerve stimulation have shown promise as effective prevention for patients either unable to tolerate or unable to obtain relief from oral medications, but more research is necessary.


Brain Targeting of a Water Insoluble Antipsychotic Drug Haloperidol via the Intranasal Route Using PAMAM Dendrimer.
Delivery of therapeutics to the brain is challenging because many organic molecules have inadequate aqueous solubility and limited bioavailability. We investigated the efficiency of a dendrimer-based formulation of a poorly aqueous soluble drug, haloperidol, in targeting the brain via intranasal and intraperitoneal administration. Aqueous solubility of haloperidol was increased by more than 100-fold in the developed formulation. Formulation was assessed via different routes of administration for behavioral (cataleptic and locomotor) responses, and for haloperidol distribution in plasma and brain tissues. Dendrimer-based formulation showed significantly higher distribution of haloperidol in the brain and plasma compared to a control formulation of haloperidol administered via intraperitoneal injection. Additionally, 6.7 times lower doses of the dendrimer-haloperidol formulation administered via the intranasal route produced behavioral responses that were comparable to those induced by haloperidol formulations administered via intraperitoneal injection. This study demonstrates the potential of dendrimer in improving the delivery of water insoluble drugs to brain.


Hereditary angioedema and lupus: A French retrospective study and literature review.
Hereditary angioedema (HAE) is a rare genetic disorder that is primarily caused by a defect in the C1 inhibitor (C1-INH). The recurrent symptoms are subcutaneous edema and abdominal pain. Laryngeal edema, which can also occur, is life threatening if it goes untreated. HAE can be associated with some inflammatory and autoimmune disorders, particularly lupus. The aim of this study was to describe cases of lupus among HAE patients in France and to perform a literature review of lupus and HAE studies. Case detection and data collection (a standardized form) were performed, thanks to the French Reference Center for Kinin-related angioedema. Data were collected from 6 patients with type 1 HAE and lupus in France; no cases of systemic lupus erythematosus were reported. In the literature review, 32 cases of lupus combined with HAE were identified, including 26 female patients. The median patient age at the time of first reported HAE symptoms and at diagnosis were 17.5 years (range, 9-41 years) and 19 years (range, 9-64 years), respectively for our 6 patients and 14 years (range, 3-30 years) and 17 years (range, 7-48 years), respectively, for the literature review. The clinical manifestations of HAE were mainly abdominal pain (83% in our patients vs 47% in the literature) and edema of the limbs (83% vs 38%). The C4 levels were low (for 100% of our cases vs 93% in the literature). Eighteen patients in the literature demonstrated HAE symptoms prior to the lupus onset vs 5 for our patients. The mean patient age at lupus onset was 20 years (range, 13-76 years) for our patients and 19.5 years (range, 1-78 years) in the literature, respectively. In the literature, 81% of the patients had skin manifestations, 25% had renal involvement and 28% received systemic steroids to treat lupus. Treatment with danazol did not modify the clinical expression of lupus. The association between lupus and HAE is a rare but not unanticipated event. Patients are often symptomatic for HAE before developing lupus. Lupus cases associated with HAE share some characteristics of lupus cases related to other complement deficiencies, such as the absence of severity and the predominance of cutaneous symptoms.


Modeling human disease in humans: the ciliopathies.
Soon, the genetic basis of most human Mendelian diseases will be solved. The next challenge will be to leverage this information to uncover basic mechanisms of disease and develop new therapies. To understand how this transformation is already beginning to unfold, we focus on the ciliopathies, a class of multi-organ diseases caused by disruption of the primary cilium. Through a convergence of data involving mutant gene discovery, proteomics, and cell biology, more than a dozen phenotypically distinguishable conditions are now united as ciliopathies. Sitting at the interface between simple and complex genetic conditions, these diseases provide clues to the future direction of human genetics.


A population genetic assessment of coral recovery on highly disturbed reefs of the Keppel Island archipelago in the southern Great Barrier Reef.
Coral reefs surrounding the islands lying close to the coast are unique to the Great Barrier Reef (GBR) in that they are frequently exposed to disturbance events including floods caused by cyclonic rainfall, strong winds and occasional periods of prolonged above-average temperatures during summer. In one such group of islands in the southern GBR, the Keppel Island archipelago, climate-driven disturbances frequently result in major coral mortality. Whilst these island reefs have clearly survived such dramatic disturbances in the past, the consequences of extreme mortality events may include the loss of genetic diversity, and hence adaptive potential, and a reduction in fitness due to inbreeding, especially if new recruitment from external sources is limited. Here we examined the level of isolation of the Keppel Island group as well as patterns of gene flow within the Keppel Islands using 10 microsatellite markers in nine populations of the coral, Acropora millepora. Bayesian cluster analysis and assignment tests indicated gene flow is restricted, but not absent, between the outer and inner Keppel Island groups, and that extensive gene flow exists within each of these island groups. Comparison of the Keppel Island data with results from a previous GBR-wide study that included a single Keppel Island population, confirmed that A. millepora in the Keppel Islands is genetically distinct from populations elsewhere on the GBR, with exception of the nearby inshore High Peak Reef just north of the Keppel Islands. We compared patterns of genetic diversity in the Keppel Island populations with those from other GBR populations and found them to be slightly, but significantly lower, consistent with the archipelago being geographically isolated, but there was no evidence for recent bottlenecks or deviation from mutation-drift equilibrium. A high incidence of private alleles in the Keppel Islands, particularly in the outer islands, supports their relative isolation and contributes to the conservation value of the archipelago. The lack of evidence for genetic erosion, in combination with our observation that the North Keppel Island population samples collected in 2002 and 2008, respectively, exhibited a pairwise genetic distance of zero, supports previous published work indicating that, following bleaching, Acropora corals in the Keppel Islands predominantly recover from regrowth of small amounts of remaining live tissue in apparently dead coral colonies. This is likely supplemented by recruitment of larvae from genetically similar, less disturbed populations at nearby reefs, particularly following extreme flood events.


Vaginal misoprostol for cervical ripening and induction of labour.
Misoprostol (Cytotec, Searle) is a prostaglandin E1 analogue marketed for use in the prevention and treatment of peptic ulcer disease. It is inexpensive, easily stored at room temperature and has few systemic side effects. It is rapidly absorbed orally and vaginally. Although not registered for such use, misoprostol has been widely used for obstetric and gynaecological indications, such as induction of abortion and of labour. This is one of a series of reviews of methods of cervical ripening and labour induction using standardised methodology. To determine the effects of vaginal misoprostol for third trimester cervical ripening or induction of labour. The Cochrane Pregnancy and Childbirth Group trials register, the Cochrane Controlled Trials Register and bibliographies of relevant papers. Date of last search: April 2001. The criteria for inclusion included the following: (1) clinical trials comparing vaginal misoprostol used for third trimester cervical ripening or labour induction with placebo/no treatment or other methods listed above it on a predefined list of labour induction methods; (2) random allocation to the treatment or control group; (3) adequate allocation concealment; (4) violations of allocated management not sufficient to materially affect conclusions; (5) clinically meaningful outcome measures reported; (6) data available for analysis according to the random allocation; (7) missing data insufficient to materially affect the conclusions. A strategy has been developed to deal with the large volume and complexity of trial data relating to labour induction. This involved a two-stage method of data extraction. The initial data extraction was done centrally, and incorporated into a series of primary reviews arranged by methods of induction of labour, following a standardised methodology. The data will then be extracted from the primary reviews into a series of secondary reviews, arranged by category of woman. To avoid duplication of data in the primary reviews, the labour induction methods have been listed in a specific order, from one to 25. Each primary review includes comparisons between one of the methods (from two to 25) with only those methods above it on the list. Forty-five trials have been included. Compared to placebo, misoprostol was associated with increased cervical ripening (relative risk of unfavourable or unchanged cervix after 12 to 24 hours with misoprostol 0.09, 95% confidence interval 0.03 to 0.24). It was also associated with a reduced need for oxytocin (relative risk 0.52, 95% confidence interval 0.41 to 0.68) and reduced failure to achieve vaginal delivery within 24 hours (relative risk 0.36, 95% confidence interval 0.19 to 0.68). Uterine hyperstimulation, without fetal heart rate changes, was increased (relative risk 10.11, 95% confidence interval 1.91 to 53.6). Compared with vaginal prostaglandin E2, intracervical prostaglandin E2 and oxytocin, vaginal misoprostol labour induction resulted in fewer failures to achieve vaginal delivery within 24 hours and more uterine hyperstimulation without fetal heart rate changes. Compared with vaginal or intracervical prostaglandin E2, unchanged or unfavourable cervix after 12 to 24 hours, and oxytocin augmentation were less common with misoprostol. Compared with intracervical prostaglandin E2, uterine hyperstimulation with fetal heart rate changes and meconium stained liquor were increased and epidural analgesia was reduced. Compared with oxytocin, caesarean sections and epidural analgesia were reduced with misoprostol. Lower doses of misoprostol compared to higher doses did not show significant differences except for more need for oxytocin augmentation and less uterine hyperstimulation, with and without fetal heart rate changes. Information on women's views is conspicuously lacking. Although vaginal misoprostol appears to be more effective than conventional methods of cervical ripening and labour induction, the apparent increase in uterine hyperstimulation is of concern. The studies were not large enough to exclude the possibility of rare but serious adverse effects, particularly uterine rupture, which has been reported anecdotally following misoprostol use in women with and without previous caesarean section. The authors request information on cases of uterine rupture known to readers. Further research is needed to establish safety.


Calcium phosphate cement augmentation of cancellous bone screws can compensate for the absence of cortical fixation.
An obvious means to improve the fixation of a cancellous bone screw is to augment the surrounding bone with cement. Previous studies have shown that bone augmentation with Calcium Phosphate (CaP) cement significantly improves screw fixation. Nevertheless, quantitative data about the optimal distribution of CaP cement is not available. The present study aims to show the effect of cement distribution on the screw fixation strength for various cortical thicknesses and to determine the conditions at which cement augmentation can compensate for the absence of cortical fixation in osteoporotic bone. In this study, artificial bone materials were used to mimic osteoporotic cancellous bone and cortical bone of varying thickness. These bone constructs were used to test the fixation strength of cancellous bone screws in different cortical thicknesses and different cement augmentation depths. The cement distribution was measured with microCT. The maximum pullout force was measured experimentally. The microCT analysis revealed a pseudo-conic shape distribution of the cement around the screws. While the maximum pullout strength of the screws in the artificial bone only was 30±7N, it could increase up to approximately 1000N under optimal conditions. Cement augmentation significantly increased pullout force in all cases. The effect of cortical thickness on pullout force was reduced with increased cement augmentation depth. Indeed, cement augmentation without cortical fixation increased pullout forces over that of screws without cement augmentation but with cortical fixation. Since cement augmentation significantly increased pullout force in all cases, we conclude that the loss of cortical fixation can be compensated by cement augmentation.


In vitro versus in vivo compositional landscapes of histone sequence preferences in eucaryotic genomes.
Although the nucleosome occupancy along a genome can be in part predicted by in vitro experiments, it has been recently observed that the chromatin organization presents important differences in vitro with respect to in vivo. Such differences mainly regard the hierarchical and regular structures of the nucleosome fiber, whose existence has long been assumed, and in part also observed in vitro, but that does not apparently occur in vivo. It is also well known that the DNA sequence has a role in determining the nucleosome occupancy. Therefore, an important issue is to understand if, and to what extent, the structural differences in the chromatin organization between in vitro and in vivo have a counterpart in terms of the underlying genomic sequences. We present the first quantitative comparison between the in vitro and in vivo nucleosome maps of two model organisms (S. cerevisiae and C. elegans). The comparison is based on the construction of weighted k-mer dictionaries. Our findings show that there is a good level of sequence conservation between in vitro and in vivo in both the two organisms, in contrast to the abovementioned important differences in chromatin structural organization. Moreover, our results provide evidence that the two organisms predispose themselves differently, in terms of sequence composition and both in vitro and in vivo, for the nucleosome occupancy. This leads to the conclusion that, although the notion of a genome encoding for its own nucleosome occupancy is general, the intrinsic histone k-mer sequence preferences tend to be species-specific. The files containing the dictionaries and the main results of the analysis are available at http://math.unipa.it/rombo/material. Supplementary data are available at Bioinformatics online.


Human RECQL5beta stimulates flap endonuclease 1.
Human RECQL5 is a member of the RecQ helicase family which is implicated in genome maintenance. Five human members of the family have been identified; three of them, BLM, WRN and RECQL4 are associated with elevated cancer risk. RECQL1 and RECQL5 have not been linked to any human disorder yet; cells devoid of RECQL1 and RECQL5 display increased chromosomal instability. Here, we report the physical and functional interaction of the large isomer of RECQL5, RECQL5beta, with the human flap endonuclease 1, FEN1, which plays a critical role in DNA replication, recombination and repair. RECQL5beta dramatically stimulates the rate of FEN1 cleavage of flap DNA substrates. Moreover, we show that RECQL5beta and FEN1 interact physically and co-localize in the nucleus in response to DNA damage. Our findings, together with the previous literature on WRN, BLM and RECQL4's stimulation of FEN1, suggests that the ability of RecQ helicases to stimulate FEN1 may be a general feature of this class of enzymes. This could indicate a common role for the RecQ helicases in the processing of oxidative DNA damage.


Sex determination and the evolution of dioecy from monoecy in Sagittaria latifolia (Alismataceae).
The role of mutations of small versus large effect in adaptive evolution is of considerable interest to evolutionary biologists. The major evolutionary pathways for the origin of dioecy in plants (the gynodioecy and monoecy-paradioecy pathways) are often distinguished by the number of mutations involved and the magnitude of their effects. Here, we investigate the genetic and environmental determinants of sex in Sagittaria latifolia, a species with both monoecious and dioecious populations, and evaluate evidence for the evolution of dioecy via gynodioecy or monoecy-paradioecy. We crossed plants of the two sexual systems to generate F1, F2 and backcross progeny, and grew clones from dioecious populations in low-and high-fertilizer conditions to examine sex inconstancy in females and males. Several lines of evidence implicate two-locus control of the sex phenotypes. In dioecious populations sex is determined by Mendelian segregation of alleles, with males heterozygous at both the male- and female-sterility loci. In monoecious populations, plants are homozygous for alleles dominant to male sterility in females and recessive to female sterility in males. Experimental manipulation of resources revealed sex inconstancy in males but not females. These results are consistent with predictions for the evolution of dioecy via gynodioecy, rather than the expected monoecy-paradioecy pathway, given the ancestral monoecious condition.


Estimating the atmospheric correlation length with stochastic parallel gradient descent algorithm.
The atmospheric turbulence measurement has received much attention in various fields due to its effects on wave propagation. One of the interesting parameters for characterization of the atmospheric turbulence is the Fried parameter or the atmospheric correlation length. We numerically investigate the feasibility of estimating the Fried parameter using a simple and low-cost system based on the stochastic parallel gradient descent (SPGD) algorithm without the need for wavefront sensing. We simulate the atmospheric turbulence using Zernike polynomials and employ a wavefront sensor-less adaptive optics system based on the SPGD algorithm and report the estimated Fried parameter after compensating for atmospheric-turbulence-induced phase distortions. Several simulations for different atmospheric turbulence strengths are presented to validate the proposed method.


Health-related quality-of-life status in Veterans with spinal disorders.
To measure the impact of spinal disorders on health-related quality of life (HRQOL) among Veterans, to describe demographic patterns of Veterans with spinal disorders, and to quantify HRQOL scores as they relate to demographics, medical comorbidities, pain severity, and depressive symptoms. From 2009 to 2010, 112 lumbar and 56 cervical spinal disorder patients completed SF-12, Oswestry Disability Index, visual analog pain scale, and Beck Depression Inventory surveys. Multivariate analysis identified predictors of HRQOL, disability, and depressive symptoms. A total of 168 patients completed surveys for this study. The median age of all patients was 60. Nearly 30% of lumbar and 16% of cervical patients were aged 65 or older. Approximately 96% of patients were men. Sixty percent of patients were currently receiving or had pending disability compensation. Nearly 60% of patients were current smokers, approximately 26% reported alcoholism or intravenous drug use, and 26% self-reported post-traumatic stress disorder. The most common lumbar spine diagnoses were disk herniation (36.6%) and stenosis (34.8%), and most common cervical spine diagnoses were stenosis (50.0%) and disk herniation (23.2%). Back pain was reported by 93.8% of lumbar patients and leg pain by 83.0%. Neck pain was reported by 96.4% of cervical patients and arm pain by 69.6%. Median SF-12 physical component scores were more than two standard deviations below the US average. Ninety percent of patients had at least moderate physical disability. Sixty-four percent met criteria for depressive symptoms. Visual analog pain score was the strongest predictor of SF-12 physical (β = -1.32, P < 0.001) and mental (β = -1.63, P < 0.001) HRQOL and was the prime determinant of depressive symptoms (β = 1.52, P < 0.001) and disability index score (β = 4.39, P < 0.0001). Charlson Comorbidity Score and smoking status had no significant impact on HRQOL or disability scores. Age was negatively correlated with depressive symptoms and positively correlated with SF-12 mental component scores. Spinal disorders have a severe impact on both physical and emotional HRQOL of Veterans and are associated with severe disability and an unusually high prevalence of depressive symptoms. Therapeutic interventions should be targeted to reduce pain, which is a prime determinant of HRQOL, disability, and depressive symptoms. Given high prevalence of multiple risk factors for poor outcomes, studies of spine surgery outcomes in Veterans are needed.


Decreased sensitivity of 5-HT(1D) receptors in melancholic depression.
Brain serotonin (5-HT) function is abnormal in major depression, but the involvement of different 5-HT receptor subtypes has been little studied. The availability of selective ligands now makes it possible to test the sensitivity of 5-HT(1D) receptors in patients with depression. The aim of the study was to use the 5-HT(1D) receptor agonist, zolmitriptan, to test the sensitivity of 5-HT(1D) receptors in patients with depression before and after treatment with selective serotonin reuptake inhibitors (SSRIs). We measured the growth hormone response to zolmitriptan (5 mg orally) in patients with major depression before and after SSRI treatment. A matched sample of healthy subjects acted as a control group. The growth hormone response to zolmitriptan was blunted in patients with a melancholic depressive syndrome. SSRI treatment produced a marked reduction in zolmitriptan-induced growth hormone release. Patients with melancholic depression have impaired sensitivity of the post-synaptic 5-HT(1D) receptors that mediate growth hormone release. The reduction in 5-HT(1D) receptor sensitivity following SSRI treatment is probably an adaptive response to increased levels of synaptic 5-HT.


The unusual S locus of Leavenworthia is composed of two sets of paralogous loci.
The Leavenworthia self-incompatibility locus (S locus) consists of paralogs (Lal2, SCRL) of the canonical Brassicaceae S locus genes (SRK, SCR), and is situated in a genomic position that differs from the ancestral one in the Brassicaceae. Unexpectedly, in a small number of Leavenworthia alabamica plants examined, sequences closely resembling exon 1 of SRK have been found, but the function of these has remained unclear. BAC cloning and expression analyses were employed to characterize these SRK-like sequences. An SRK-positive Bacterial Artificial Chromosome clone was found to contain complete SRK and SCR sequences located close by one another in the derived genomic position of the Leavenworthia S locus, and in place of the more typical Lal2 and SCRL sequences. These sequences are expressed in stigmas and anthers, respectively, and crossing data show that the SRK/SCR haplotype is functional in self-incompatibility. Population surveys indicate that < 5% of Leavenworthia S loci possess such alleles. An ancestral translocation or recombination event involving SRK/SCR and Lal2/SCRL likely occurred, together with neofunctionalization of Lal2/SCRL, and both haplotype groups now function as Leavenworthia S locus alleles. These findings suggest that S locus alleles can have distinctly different evolutionary origins.


Ube3a, the E3 ubiquitin ligase causing Angelman syndrome and linked to autism, regulates protein homeostasis through the proteasomal shuttle Rpn10.
Ubiquitination, the covalent attachment of ubiquitin to a target protein, regulates most cellular processes and is involved in several neurological disorders. In particular, Angelman syndrome and one of the most common genomic forms of autism, dup15q, are caused respectively by lack of or excess of UBE3A, a ubiquitin E3 ligase. Its Drosophila orthologue, Ube3a, is also active during brain development. We have now devised a protocol to screen for substrates of this particular ubiquitin ligase. In a neuronal cell system, we find direct ubiquitination by Ube3a of three proteasome-related proteins Rpn10, Uch-L5, and CG8209, as well as of the ribosomal protein Rps10b. Only one of these, Rpn10, is targeted for degradation upon ubiquitination by Ube3a, indicating that degradation might not be the only effect of Ube3a on its substrates. Furthermore, we report the genetic interaction in vivo between Ube3a and the C-terminal part of Rpn10. Overexpression of these proteins leads to an enhanced accumulation of ubiquitinated proteins, further supporting the biochemical evidence of interaction obtained in neuronal cells.


Fertility and Life Satisfaction in Rural Ethiopia.
Despite recent strong interest in the link between fertility and subjective well-being, the focus has centered on developed countries. For poorer countries, in contrast, the relationship remains rather elusive. Using a well-established panel survey-the Ethiopian Rural Household Survey (ERHS)-we investigate the empirical relationship between fertility and life satisfaction in rural Ethiopia, the largest landlocked country in Africa. Consistent with the fertility theories for developing countries and with the sociodemographic characteristics of rural Ethiopia, we hypothesize that this relationship varies by gender and across life stages, being more positive for men and for parents in old age. Indeed, our results suggest that older men benefit the most in terms of life satisfaction from having a large number of children, while the recent birth of a child is detrimental for the subjective well-being of women at reproductive ages. We address endogeneity issues by using lagged life satisfaction in ordinary least squares regressions, through fixed-effects estimation and the use of instrumental variables.


Patients at risk of complications of Staphylococcus aureus bloodstream infection.
Staphylococcus aureus is one of the most common causative pathogens of bloodstream infections (BSIs). In approximately one-half of patients with S. aureus BSI, no portal of entry can be documented. This group of patients has a high risk of developing septic metastases. Similarly, patient populations at high risk of S. aureus BSI and BSI-associated complications include patients receiving hemodialysis, injection drug users, patients with diabetes, and patients with preexisting cardiac conditions or other comorbidities. One of the most severe complications of S. aureus BSI is infective endocarditis, and S. aureus is now the most common cause of infective endocarditis in the developed world. Patients with methicillin-resistant S. aureus BSI or infective endocarditis have higher rates of mortality, compared with patients with methicillin-susceptible S. aureus infection. Nasal carriage is the most important source of S. aureus BSI. Better eradication and control strategies, including nasal decolonization and more-active antibiotics, are needed to combat S. aureus BSIs.


Project on the Good Physician: Further Evidence for the Validity of a Moral Intuitionist Model of Virtuous Caring.
In the Project on the Good Physician, the authors propose a moral intuitionist model of virtuous caring that places the virtues of Mindfulness, Empathic Compassion, and Generosity at the heart of medical character education. Hypothesis 1a: The virtues of Mindfulness, Empathic Compassion, and Generosity will be positively associated with one another (convergent validity). Hypothesis 1b: The virtues of Mindfulness and Empathic Compassion will explain variance in the action-related virtue of Generosity beyond that predicted by Big Five personality traits alone (discriminant validity). Hypothesis 1c: Virtuous students will experience greater well-being ("flourishing"), as measured by four indices of well-being: life meaning, life satisfaction, vocational identity, and vocational calling (predictive validity). Hypothesis 1d: Students who self-report higher levels of the virtues will be nominated by their peers for the Gold Humanism Award (predictive validity). Hypothesis 2a-2c: Neuroticism and Burnout will be positively associated with each other and inversely associated with measures of virtue and well-being. The authors used data from a 2011 nationally representative sample of U.S. medical students (n = 499) in which medical virtues (Mindfulness, Empathic Compassion, and Generosity) were measured using scales adapted from existing instruments with validity evidence. Supporting the predictive validity of the model, virtuous students were recognized by their peers to be exemplary doctors, and they were more likely to have higher ratings on measures of student well-being. Supporting the discriminant validity of the model, virtues predicted prosocial behavior (Generosity) more than personality traits alone, and students higher in the virtue of Mindfulness were less likely to be high in Neuroticism and Burnout. Data from this descriptive-correlational study offered additional support for the validity of the moral intuitionist model of virtuous caring. Applied to medical character education, medical school programs should consider designing educational experiences that intentionally emphasize the cultivation of virtue.


Lactation is associated with greater maternal bone size and bone strength later in life.
The association between lactation and bone size and strength was studied in 145 women 16 to 20 years after their last parturition. Longer cumulative duration of lactation was associated with larger bone size and strength later in life. Pregnancy and lactation have no permanent negative effect on maternal bone mineral density but may positively affect bone structure in the long term. We hypothesized that long lactation promotes periosteal bone apposition and hence increasing maternal bone strength. Body composition, bone area, bone mineral content, and areal bone mineral density of whole body and left proximal femur were assessed using DXA, and cross-sectional area and volumetric bone mineral density of the left tibia shaft were measured by pQCT in 145 women (mean age 48 years, range 36-60 years) 16 to 20 years after their last parturition. Hip (HSI) and tibia strength indexes (TBSI) were calculated. Medical history and lifestyle factors including breastfeeding patterns and durations were collected via a self-administered questionnaire. Weight change during each pregnancy was collected from personal maternity tracking records. Sixteen to 20 years after the last parturition, women who had breastfed in total more than 33 months in their life, regardless of the number of children, had greater bone strength estimates of the hip (HSI = 1.92 vs. 1.61) and the tibia (TBSI = 5,507 vs. 4,705) owing to their greater bone size than mothers who had breastfed less than 12 months (p < 0.05 for all). The differences in bone strength estimates were independent of body height and weight, menopause status, use of hormone replacement therapy, and present leisure time physical activity level. Breastfeeding is beneficial to maternal bone strength in the long run.


Comparative study of air-core and coaxial Bragg fibers: single-mode transmission and dispersion characteristics.
Using an asymptotic formalism we developed in an earlier paper, we compare the dispersion properties of the air-core Bragg fiber with those of the coaxial Bragg fiber. In particular we are interested in the way the inner core of the coaxial fiber influence the dispersion relation. It is shown that, given appropriate structural parameters, large single-mode frequency windows with a zero-dispersion point can be achieved for the TM mode in coaxial fibers. We provide an intuitive interpretation based on perturbation analysis and the results of our asymptotic calculations are confirmed by Finite Difference Time Domain (FDTD) simulations.


Menopause, only for women? The social construction of menopause as an exclusively female condition.
Over the last three decades the menopause has continued to interest the medical profession, the pharmaceutical industry and the mass media. Although there exist many different views on the menopause, there is one common denominator. Menopause is depicted as an exclusively female condition. The medical discourse on menopause seems to exclude men. However, a closer look at the history of the medical sciences reveals that there have been and still are, attempts to classify symptoms of ageing men as male menopause or climacterium. Despite these attempts to put men on the menopausal agenda, most attention is focused on women. How can we understand this almost exclusive focus on female bodies? Why does there exist such an emphasis on the medicalization of the third age of women rather than of men? Maybe we might be inclined to think of a male conspiracy, as has been suggested by feminists: women take the pills, while men cash the bills. We might consider the enormous profits of the pharmaceutical industry. This paper is concerned with finding an alternative explanation for the almost exclusive attention for the female menopause. Based on historical data and more recent discussions in medical journals, the paper shows that the medicalization of the female menopause and the relative silence around the male climacterium can be understood in terms of the social and cultural processes that underly the classification of health problems as specific diseases. The imbalance in medical treatment of climacteric health problems in women and men is not simply rooted in biological sex differences, but can be ascribed to men's attitudes towards health problems and organizational infrastructures of the medical institutions.


Clinical and analytical experience of the National Poison Control Centre with synthetic cannabinoids.
A rising number of patients are being treated for overdosing with new psychoactive substances (NPS) available at the illegal drug market in Serbia. The aim of this study was to report clinical and analytical experience of the National Poison Control Centre of Serbia (NPCC) with synthetic cannabinoids (SCs) and point to the NPS available at the illegal drug market in our country. From January 2013 to December 2016, 58 patients (aged between 14 and 25) were treated for the effects of synthetic cannabinoids at the NPCC. Tachycardia was established in 53, mydriasis in 31, somnolence, nausea, vomiting, and agitation in 16, dizziness in 10, disorientation in 9, dyspnoea and chest pain in 4, and loss of consciousness, pallor, paraesthesia, muscle twitches, and short-term memory impairment in 2 patients. After receiving symptomatic and supportive treatment in the emergency ward, all patients had fully recovered within 8 h and were discharged shortly afterwards. Another part of the study was focused on the analysis of the products known under their local street names as "Biljni tamjan" (herbal incense), "Beli slez", and "Rainbow Special" and the analysis of urine sampled from the patients with gas chromatography - mass spectrometry and high performance liquid chromatography. The detected synthetic cannabinoids were AB-PINACA, JWH-018, JWH-122, JWH-210, 5F-AKB48, and MDMB-CHMICA in herbal products and AB-FUBINACA, AB-CHMINACA, and MDMB-CHMICA in the urine samples. Our findings have shown the great capacity of NPCC to I) monitor NPS abuse in Serbia, II) reliably detect SCs in illicit products and biological samples, and III) clinically manage the adverse effects in their users. Future commitments of the NPCC will include systematic collection of relevant data on SCs and their adverse effects, detection of changes in purity and composition of the controlled NPS-based products, and raising the public awareness of NPS to improve the effectiveness of the national Early Warning System.


Diabetic nephropathy: a disease causing and complicated by hypertension.
In examining the pathophysiology underlying the development of hypertension in diabetes mellitus, it is important to draw clear distinctions between Type I and Type II diabetes. In patients with Type I diabetes, with a peak onset of disease early in the second decade of life, hypertension clearly represents the sequelae to the development of substantial renal lesions, especially in the glomerulus. Thus the prevalence of hypertension in those patients without substantial glomerular lesions approximates the incidence of hypertension in the general population (approximately 4%). In patients with Type II diabetes mellitus and onset generally later in adult life, an increase in blood pressure can often be demonstrated early after or even before diagnosis of the disease (most readily demonstrated in the Pima Indians). Furthermore, clear familial tendencies towards the development of nephropathic complications of diabetes can be shown. In patients with Type I disease, the fall in glomerular filtration rate parallels the fall in glomerular capillary surface available for filtration. This reduction in the peripheral glomerular capillary surface correlates well with the expansion of the mesangium, strongly implicating the mesangial expansion in the demise in renal function. For both Type I and Type II diabetes mellitus, the increase in albuminuria may reflect an opening of large pores in the glomerular basement membrane, thereby allowing serum proteins to cross into the filtration space.


The delivery of Primary Health Care in remote communities: A Grounded Theory study of the perspective of nurses.
Australia has vast areas of desert, wilderness and offshore islands where nurses provide the majority of health care services. The residents of Australia's remote communities generally have poorer health status than their metropolitan counterparts. Despite recognition of Primary Health Care as a comprehensive model of acute and preventative care well suited to areas of high health and social need, there is little known about how nurses employ the Primary Health Care model in practice. This study described and explained from the perspective of nurses, the actions and interactions involved in the delivery of Primary Health Care in remote communities. This study was conducted from a Constructivist Grounded Theory perspective. The setting was community health centres or Aboriginal Medical Services located in 'remote' or 'very remote' areas. Communities with inpatient health services were excluded. Twenty four Nurse Practitioners, Registered Nurses and nursing academics participated. Participants had worked or were working, in a variety of remote communities across Australia. Length of service ranged from three months to over 15 years nursing in remote areas. Data were collected through 23 telephone interviews and an expert reference group. Theoretical sampling and constant comparative analysis were used to reach theoretical saturation. The core issue participants faced was the inability to provide Primary Health Care. Four conditions impacted on the core issue: understanding the social world of the remote community, availability of resources, clinical knowledge and skill and, shared understanding and support. The process of doing the best you can with what you have, emerged as the way participants dealt with the inability to provide Primary Health Care. The process involved four primary activities: facilitating access to health care, continually learning, seeking understanding, and home-making in a work environment. The outcome of this process was considered to be making compromises to provide Primary Health Care. This study describes the substantive theory: making compromises to provide Primary Health care services in the remote Australian setting. Understanding the process of making compromises could direct employers and educators in their efforts to improve the provision of Primary Health Care in a variety of settings. Increased attention to the education, resources and support of nurses is likely to increase access to safe, quality care for remote communities.


Mast cell subsets and neuropeptides in leprosy reactions.
The immunohistochemical identification of neuropeptides (calcitonin gene-related peptide, vasoactive intestinal polypeptide, substance P, alpha-melanocyte stimulating hormone and gamma-melanocyte stimulating hormone) quantification of mast cells and their subsets (tryptase/chymase-immunoreactive mast cells = TCMC and tryptase-immunoreactive mast cells = TMC) were determined in biopsies of six patients with leprosy reactions (three patients with type I reaction and three with type II). Biopsies were compared with those taken from the same body site in the remission stage of the same patient. We found a relative increase of TMC in the inflammatory infiltrate of the reactional biopsies compared to the post-reactional biopsy. Also, the total number of mast cells and the TMC/TCMC ratio in the inflammatory infiltrate was significantly higher than in the intervening dermis of the biopsies of both periods. No significant difference was found regarding neuroptide expression in the reactional and post-reactional biopsies. The relative increase of TMC in the reactional infiltrates could implicate this mast cell subset in the reported increase of the immune response in leprosy reactions.


Adrenocortical carcinoma: a comprehensive immunohistochemical study of 40 cases.
Adrenocortical carcinomas (ACC) are uncommon tumors of the adrenal cortex that are known to follow an aggressive clinical course. The distinction of these tumors from other neoplasms may sometimes prove difficult due to overlapping clinical, morphologic, and even immunophenotypical features. To this end, we performed a comprehensive immunohistochemical analysis using traditional and novel markers in 40 cases of ACC. An immunohistochemical panel consisting of 10 traditional and novel antibodies was applied to whole tissue sections of ACC including high-molecular weight cytokeratin (HMWCK), low-molecular weight cytokeratin (CAM5.2), inhibin-α, melan A, chromogranin A, synaptophysin, calretinin, steroid receptor coactivator-1 (SRC-1), Pax8, and Ki67. The percentage of positive tumor cells as well as the intensity of staining were evaluated and scored; for Ki67 the percentage of positive tumor cells was recorded. Positive staining was observed for SRC-1 (39/40; 97.5%), inhibin-α (37/40; 92.5%), calretinin (32/40; 80%), synaptophysin (29/40; 72.5%), melan A (26/40; 65%), and CAM5.2 (9/40; 22.5%). Rare cases showed positivity for chromogranin A (2/40; 5%) and Pax8 (1/40; 2.5%). None of the cases showed any reactivity with HMWCK. The Ki67 index ranged from <5% to 20%. We conclude that there is no single specific marker to reliably distinguish ACC from other primary or metastatic neoplasms. However, a combination of immunohistochemical stains in a panel consisting of SRC-1, inhibin-α, calretinin, and HMWCK may be of aid in the differential diagnosis of these tumors. In addition, Pax8 is only rarely positive in ACC, which is a useful tool in their separation from renal neoplasms.


IL1B and DEFB1 Polymorphisms Increase Susceptibility to Invasive Mold Infection After Solid-Organ Transplantation.
Single-nucleotide polymorphisms (SNPs) in immune genes have been associated with susceptibility to invasive mold infection (IMI) among hematopoietic stem cell but not solid-organ transplant (SOT) recipients. Twenty-four SNPs from systematically selected genes were genotyped among 1101 SOT recipients (715 kidney transplant recipients, 190 liver transplant recipients, 102 lung transplant recipients, 79 heart transplant recipients, and 15 recipients of other transplants) from the Swiss Transplant Cohort Study. Association between SNPs and the end point were assessed by log-rank test and Cox regression models. Cytokine production upon Aspergillus stimulation was measured by enzyme-linked immunosorbent assay in peripheral blood mononuclear cells (PBMCs) from healthy volunteers and correlated with relevant genotypes. Mold colonization (n = 45) and proven/probable IMI (n = 26) were associated with polymorphisms in the genes encoding interleukin 1β (IL1B; rs16944; recessive mode, P = .001 for colonization and P = .00005 for IMI, by the log-rank test), interleukin 1 receptor antagonist (IL1RN; rs419598; P = .01 and P = .02, respectively), and β-defensin 1 (DEFB1; rs1800972; P = .001 and P = .0002, respectively). The associations with IL1B and DEFB1 remained significant in a multivariate regression model (P = .002 for IL1B rs16944; P = .01 for DEFB1 rs1800972). The presence of 2 copies of the rare allele of rs16944 or rs419598 was associated with reduced Aspergillus-induced interleukin 1β and tumor necrosis factor α secretion by PBMCs. Functional polymorphisms in IL1B and DEFB1 influence susceptibility to mold infection in SOT recipients. This observation may contribute to individual risk stratification.


Measurement of environmental pollutants using passive sampling devices--an updated commentary on the current state of the art.
The following provides a short overview of the important topics arising from the 6(th) International Passive Sampling Workshop and Symposium (IPSW 2013) held in Bordeaux, France between 26 and 29(th) June, 2013. Most of the discussions focussed on monitoring non-polar and polar organic pollutants in water with less coverage on air (probably already seen as a mature technology for this medium) and sediments. The use of passive sampling devices within regulatory water monitoring programmes was also a major theme of the Workshop.


Good death? An exploration of newly qualified nurses' understanding of good death.
The dominant professional understanding of good death is death where symptoms are controlled, the inevitability of death has been accepted and preparations have been made leading to peace for all involved. It seems surprising, in a pluralistic society, that there might be such a clear common understanding of good death. This study looks at the understandings of good death voiced by 28 staff nurses who were interviewed about their experiences of caring for dying people in hospital. The findings suggest that a nurse's understanding of good death had elements that were shared with her colleagues, but also that there was a personal understanding of a good death. The concept of good death is perhaps a reduction of the acceptable way to care for a dying person. The concept of 'personally ideal death' is proposed as a refinement of good death that recognizes that the beliefs and values of each individual influences what they understand to be acceptable death.


Implications of the 21st Century Cures Act for the Behavioral and Social Sciences at the National Institutes of Health.
The 21st Century Cures Act provides funding for key initiatives relevant to the behavioral and social sciences and includes administrative provisions that facilitate health research and increase the privacy protections of research participants. At about the same time as the passage of the Act, the National Institutes of Health Office of Behavioral and Social Sciences Research released its Strategic Plan 2017-2021, which addresses three scientific priorities: (a) improve the synergy of basic and applied behavioral and social sciences research; (b) enhance and promote the research infrastructure, methods, and measures needed to support a more cumulative and integrated approach to behavioral and social sciences; and (c) facilitate the adoption of behavioral and social sciences research findings in health research and in practice. This commentary describes the implications of the Cures Act on these scientific priorities and on the behavioral and social sciences more broadly.


[A neurofunctional model of consciousness: its neurophysiological and cognitive bases].
Interest in the causal relation between consciousness and the underlying neuronal activity has grown in recent decades. Numerous experimental studies have been carried out on the brain structures and networks underlying consciousness in animal models, in patients with brain damage and with very precise functional neuroimaging. In spite of the great multitude of findings, there is no theoretical proposal that integrates this knowledge under a coherent theoretical framework based on the evidence obtained. Existing theories offer a dismembered view of consciousness, since they pose causal explanations that do not include a global functional perspective of the interaction of the different brain networks involved in consciousness. This work offers a theoretical framework that integrates the empirical knowledge, generated in recent decades, into a neurofunctional model of consciousness. This model represents consciousness as an epiphenomenon resulting from the sequential activation of different neural loops that are formed by specific brain structures and networks which receive feedback from their own operations in order to reconfigure their own functional states and the entire system. The ascending reticular activating system, the thalamocortical networks and the cortico-cortical networks sustain cognitive processes that are differentiated, although highly dependent and fundamental for the final experience of consciousness. All these systems form a single physiological space where the individual can deploy different cognitive skills that allow the emergence of complex behaviours such as language, thought and social cognition.


Efficacy and Safety of Ticagrelor Monotherapy by Clinical Presentation: Pre-Specified Analysis of the GLOBAL LEADERS Trial.
Background The optimal duration of dual antiplatelet therapy after coronary drug-eluting stent placement in adults with stable coronary artery disease (SCAD) versus acute coronary syndromes (ACS) remains uncertain. Methods and Results This was a prespecified subgroup analysis of the GLOBAL LEADERS trial. Participants were randomly assigned 1:1 to the experimental or reference strategy, stratified by ACS (experimental, n=3750; reference, n=3737) versus SCAD (experimental, n=4230; reference, n=4251). The experimental strategy was 75 to 100 mg aspirin daily plus 90 mg ticagrelor twice daily for 1 month, followed by 23 months of ticagrelor monotherapy. The reference strategy was 75 to 100 mg aspirin daily plus either 75 mg clopidogrel daily (for SCAD) or 90 mg ticagrelor twice daily (for ACS) for 12 months, followed by aspirin monotherapy for 12 months. The primary end point at 2 years was a composite of all-cause mortality or non-fatal centrally adjudicated new Q-wave myocardial infarction. The key secondary safety end point was site-reported Bleeding Academic Research Consortium grade 3 or 5 bleeding. The primary end point occurred in 147 (3.92%) versus 169 (4.52%) patients with ACS (rate ratio [RR], 0.86; 95% CI, 0.69-1.08; P=0.189), and in 157 (3.71%) versus 180 (4.23%) patients with SCAD (RR, 0.87; 95% CI, 0.71-1.08; P=0.221) with experimental and reference strategy, respectively (P-interaction=0.926). Bleeding Academic Research Consortium grade 3 or 5 bleeding occurred in 73 (1.95%) versus 100 (2.68%) patients with ACS (RR, 0.73; 95% CI, 0.54-0.98; P=0.037), and in 90 (2.13%) versus 69 (1.62%) patients with SCAD (RR, 1.32; 95% CI, 0.97-1.81; P=0.081; P-interaction=0.007). Conclusions While there was no evidence for differences in efficacy between treatment strategies by subgroup, the experimental strategy appeared to reduce bleeding risk in patients with ACS but not in patients with SCAD. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01813435.


The First-in-class Anti-EGFR Antibody Mixture Sym004 Overcomes Cetuximab Resistance Mediated by EGFR Extracellular Domain Mutations in Colorectal Cancer.
Approved anti-EGFR antibodies cetuximab and panitumumab provide significant clinical benefit in patients with metastatic colorectal cancer (MCRC). However, patients ultimately develop disease progression, often driven by acquisition of mutations in the extracellular domain (ECD) of EGFR. Sym004 is a novel 1:1 mixture of two nonoverlapping anti-EGFR mAbs that recently showed promising clinical activity in a phase I trial in MCRC. Our aim was to determine the efficacy of Sym004 to circumvent cetuximab resistance driven by EGFR ECD mutations. Functional studies were performed to assess drug-receptor binding as well as ligand-dependent activation of individual EGFR mutants in the presence of cetuximab, panitumumab, and Sym004. Cell viability and molecular effects of the drugs were assayed in cetuximab-resistant cell lines and in tumor xenograft models. Efficacy of Sym004 was evaluated in patients progressing to cetuximab that harbored EGFR mutation in the post-cetuximab tumor sample. Contrary to cetuximab and panitumumab, Sym004 effectively bound and abrogated ligand-induced phosphorylation of all individual EGFR mutants. Cells resistant to cetuximab harboring mutations in EGFR maintained sensitivity to Sym004, which was consistent with an effective suppression of EGFR downstream signaling, translating into profound and sustained tumor regression in the xenograft model. As proof-of-principle, a patient with a tumor harboring an EGFR mutation (G465R) following cetuximab therapy benefited from Sym004 therapy. Sym004 is an active drug in MCRC resistant to cetuximab/panitumumab mediated by EGFR mutations. EGFR mutations are potential biomarkers of response to Sym004 to be evaluated in ongoing large clinical trials. Clin Cancer Res; 22(13); 3260-7. ©2016 AACR.


Early rehabilitation to prevent postintensive care syndrome in patients with critical illness: a systematic review and meta-analysis.
We examined the effectiveness of early rehabilitation for the prevention of postintensive care syndrome (PICS), characterised by an impaired physical, cognitive or mental health status, among survivors of critical illness. We performed a systematic literature search of several databases (Medline, Embase and Cochrane Central Register of Controlled Trials) and a manual search to identify randomised controlled trials (RCTs) comparing the effectiveness of early rehabilitation versus no early rehabilitation or standard care for the prevention of PICS. The primary outcomes were short-term physical-related, cognitive-related and mental health-related outcomes assessed during hospitalisation. The secondary outcomes were the standardised, long-term health-related quality of life scores (EuroQol 5 Dimension (EQ5D) and the Medical Outcomes Study 36-Item Short Form Health Survey Physical Function Scale (SF-36 PF)). We used the Grading of Recommendations Assessment, Development and Evaluation approach to rate the quality of evidence (QoE). Six RCTs selected from 5105 screened abstracts were included. Early rehabilitation significantly improved short-term physical-related outcomes, as indicated by an increased Medical Research Council scale score (standardised mean difference (SMD): 0.38, 95% CI 0.10 to 0.66, p=0.009) (QoE: low) and a decreased incidence of intensive care unit-acquired weakness (OR 0.42, 95% CI 0.22 to 0.82, p=0.01, QoE: low), compared with standard care or no early rehabilitation. However, the two groups did not differ in terms of cognitive-related delirium-free days (SMD: -0.02, 95% CI -0.23 to 0.20, QoE: low) and the mental health-related Hospital Anxiety and Depression Scale score (OR: 0.79, 95% CI 0.29 to 2.12, QoE: low). Early rehabilitation did not improve the long-term outcomes of PICS as characterised by EQ5D and SF-36 PF. Early rehabilitation improved only short-term physical-related outcomes in patients with critical illness. Additional large RCTs are needed.


Limited PSA testing in indigent men in South Texas: an appropriate care or missing a prevention opportunity?
No previous study has examined racial ethnic differences in prostate-specific antigen (PSA) testing and followup in primary care practices serving an indigent population. From electronic medical records of primary care practices affiliated with one health care system in San Antonio, we identified 9,267 men aged 50 to 74 with 2+ clinic visits from 2008 through 2010 and no prior prostate cancer diagnosis. Logistic regression was used to examine the association of race ethnicity with the use of PSA testing and, if tested, with an abnormal result (≥4 ng/mL) adjusted for demographics, health care, and clinical factors. Time to a follow-up activity after an abnormal PSA was assessed using Cox proportional models. The race ethnicity of this cohort was 63% Hispanic, 27% non-Hispanic white, 7% African-American, and 3% other. In a 3-year period, 26.8% of men had at least one PSA test. Compared with African-Americans, non-Hispanic whites were less likely to be tested [OR, 0.68; 95% confidence interval (CI), 0.55-0.83] but Hispanics did not differ (OR = 0.95; 95% CI 0.79-1.15). African-Americans were more likely to have an abnormal PSA than others (12.4% vs. 5.2%, P < 0.001) and the shortest adjusted time to follow-up (P = 0.004). In this 3-year indigent cohort, about one quarter had a PSA test, approximately half of the national testing rate. African-Americans were more likely to be tested than non-Hispanic whites but had more abnormal results, raising concerns about missed prevention opportunities. African-Americans with high PSA results had the shortest time until follow-up, reflecting awareness of the threat of prostate cancer for African-Americans by physicians.


Adventitious arsenate reductase activity of the catalytic domain of the human Cdc25B and Cdc25C phosphatases.
A number of eukaryotic enzymes that function as arsenate reductases are homologues of the catalytic domain of the human Cdc25 phosphatase. For example, the Leishmania major enzyme LmACR2 is both a phosphatase and an arsenate reductase, and its structure bears similarity to the structure of the catalytic domain of human Cdc25 phosphatase. These reductases contain an active site C-X(5)-R signature motif, where C is the catalytic cysteine, the five X residues form a phosphate binding loop, and R is a highly conserved arginine, which is also present in human Cdc25 phosphatases. We therefore investigated the possibility that the three human Cdc25 isoforms might have adventitious arsenate reductase activity. The sequences for the catalytic domains of Cdc25A, -B, and -C were cloned individually into a prokaryotic expression vector, and their gene products were purified from a bacterial host using nickel affinity chromatography. While each of the three Cdc25 catalytic domains exhibited phosphatase activity, arsenate reductase activity was observed only with Cdc25B and -C. These two enzymes reduced inorganic arsenate but not methylated pentavalent arsenicals. Alteration of either the cysteine and arginine residues of the Cys-X(5)-Arg motif led to the loss of both reductase and phosphatase activities. Our observations suggest that Cdc25B and -C may adventitiously reduce arsenate to the more toxic arsenite and may also provide a framework for identifying other human protein tyrosine phosphatases containing the active site Cys-X(5)-Arg loop that might moonlight as arsenate reductases.


Comparing Outcomes of Competitive Athletes Versus Nonathletes Undergoing Hip Arthroscopy for Treatment of Femoroacetabular Impingement Syndrome.
A growing number of studies have examined return to sport in competitive athletes after undergoing hip arthroscopy for femoroacetabular impingement syndrome (FAIS); however, few have evaluated the rate of achieving meaningful clinical outcomes in this group. To determine if competitive athletes (professional, semiprofessional, or collegiate) have better 2-year patient-reported outcomes and achieve the minimal clinically important difference (MCID) and substantial clinical benefit at higher rates when compared with nonathletes undergoing hip arthroscopy for the treatment of FAIS. Cohort study; Level of evidence, 3. The study was a retrospective analysis of all consecutive patients who identified as either a competitive athlete or a nonathlete and had undergone hip arthroscopy for FAIS by a single fellowship-trained surgeon between January 2012 and April 2017. Patients in the 2 groups were matched 1:2 by age, sex, and body mass index. Baseline and clinical outcomes, including the Hip Outcome Score-Activities of Daily Living, Hip Outcome Score-Sports Subscale (HOS-SS), modified Harris Hip Score, and international Hip Outcome Tool-12, were collected preoperatively and at 2 years postoperatively and compared between the groups. The MCID and substantial clinical benefit were calculated for each group separately and compared using chi-square analysis. A total of 59 competitive athletes and 118 nonathletes were included in the final analysis. Most of the competitive athletes were soccer players (23.7%), followed by softball players (10.2%) and runners (10.2%). Postoperative score comparison between competitive athletes and nonathletes demonstrated a statistically significant difference in the HOS-SS (mean ± SD, 84.5 ± 19.0 vs 76.1 ± 23.8; P = .02). Meaningful outcome analysis demonstrated that competitive athletes had a higher rate of achieving the HOS-SS threshold for the MCID (97.4% vs 82.5%; P = .021). There was no other difference in frequency of achieving the threshold for any other meaningful clinical outcome between the groups. Hip arthroscopy for the treatment of FAIS in competitive athletes and nonathletes produced clinically meaningful outcomes in both patient groups. However, competitive athletes achieved the MCID on the HOS-SS at higher rates than nonathletes and had significantly higher scores at 2 years postoperatively on the HOS-SS.


Characterization of quinoxaline derivatives for protection against iatrogenically induced hearing loss.
Hair cell loss is the leading cause of hearing and balance disorders in humans. It can be caused by many factors, including noise, aging, and therapeutic agents. Previous studies have shown the therapeutic potential of quinoxaline against drug-induced ototoxicity. Here, we screened a library of 68 quinoxaline derivatives for protection against aminoglycoside-induced damage of hair cells from the zebrafish lateral line. We identified quinoxaline-5-carboxylic acid (Qx28) as the best quinoxaline derivative that provides robust protection against both aminoglycosides and cisplatin in zebrafish and mouse cochlear explants. FM1-43 and aminoglycoside uptake, as well as antibiotic efficacy studies, revealed that Qx28 is neither blocking the mechanotransduction channels nor interfering with aminoglycoside antibacterial activity, suggesting that it may be protecting the hair cells by directly counteracting the ototoxin's mechanism of action. Only when animals were incubated with higher doses of Qx28 did we observe a partial blockage of the mechanotransduction channels. Finally, we assessed the regulation of the NF-κB pathway in vitro in mouse embryonic fibroblasts and in vivo in zebrafish larvae. Those studies showed that Qx28 protects hair cells by blocking NF-κB canonical pathway activation. Thus, Qx28 is a promising and versatile otoprotectant that can act across different species and toxins.


IBIS (Inferred Biomolecular Interaction Server) reports, predicts and integrates multiple types of conserved interactions for proteins.
We have recently developed the Inferred Biomolecular Interaction Server (IBIS) and database, which reports, predicts and integrates different types of interaction partners and locations of binding sites in proteins based on the analysis of homologous structural complexes. Here, we highlight several new IBIS features and options. The server's webpage is now redesigned to allow users easier access to data for different interaction types. An entry page is added to give a quick summary of available results and to now accept protein sequence accessions. To elucidate the formation of protein complexes, not just binary interactions, IBIS currently presents an expandable interaction network. Previously, IBIS provided annotations for four different types of binding partners: proteins, small molecules, nucleic acids and peptides; in the current version a new protein-ion interaction type has been added. Several options provide easy downloads of IBIS data for all Protein Data Bank (PDB) protein chains and the results for each query. In this study, we show that about one-third of all RefSeq sequences can be annotated with IBIS interaction partners and binding sites. The IBIS server is available at http://www.ncbi.nlm.nih.gov/Structure/ibis/ibis.cgi and updated biweekly.


Applications of the layer-KKR method to photonic crystals.
A brief introduction of the layer-Korringa-Kohn-Rostoker method for calculations of the frequency band structure of photonic crystals and of the transmission and reflection coefficients of light incident on slabs of such crystals is followed by two applications of the method. The first relates to the frequency band structure of metallodielectric composites and demonstrates the essential difference between cermet and network topology of such composites at low frequencies. The second application is an analysis of recent measurements of the reflection of light from a slab of a colloidal system consisting of latex spheres in air.


Hepatotoxicity of herbal and dietary supplements: an update.
Herbal and dietary supplements (HDS) have been used for health-related purposes since more than 5000 years, and their application is firmly anchored in all societies worldwide. Over last decades, a remarkable renaissance in the use of HDS can be noticed in affluent societies for manifold reasons. HDS are forms of complementary and alternative medicines commonly used to prevent or treat diseases, or simply as a health tonic. Another growing indication for HDS is their alleged benefit for weight loss or to increase physical fitness. Access is easy via internet and mail-order pharmacies, and their turnover reaches billions of dollars in the USA and Europe alone. However, HDS are generally not categorized as drugs and thus less strictly regulated in most countries. As a result, scientific evidence proving their beneficial effects is mostly lacking, although some HDS may have purported benefits. However, the majority lacks such proof of value, and their use is predominantly based on belief and hope. In addition to missing scientific evidence supporting their use, HDS are typically prone to batch-to-batch variability in composition and concentration, contamination, and purposeful adulteration. Moreover, numerous examples of preparations emerged which have been linked to significant liver injury. These include single ingredients, such as kava, germander, and several Chinese herbals. Other HDS products associated with liver toxicity consist of multiple, often ill-defined ingredients, such as Hydroxycut and Herbalife. Affirmative diagnostic tests are not available, and the assessment of liver injury ascribed to HDS depends on a thorough and proactive medical history, careful exclusion of other causes, and a search for available reports on similar events linked to the intake of the suspected preparation or ingredients contained therein.


Animal studies implicating fat and fecal steroids in intestinal cancer.
There is epidemiological and experimental evidenced that the ingestion of excessive amounts of fat enhances intestinal cancer formation. This may be due to the interaction of luminal steroids with the bacterial flora in the colon, forming carcinogens or promoting agents. Increased fecal steroids induced by drugs, diet, or by mechanical means enhance intestinal tumor formation in rats given injections of azoxymethane. The effect appears to be promotional rather than initiative. Dietary fiber inhibits carcinogenesis only when the fat content of the diet is not excessive. Apparently, a quantitative relationship exists between these two dietary elements that further studies may define for prevention of cancer in humans.


Understanding Leisure-related Program Effects by Using Process Data in the HealthWise South Africa Project.
As the push for evidence-based programming gathers momentum, many human services programs and interventions are under increased scrutiny to justify their effectiveness across different conditions and populations. Government agencies and the public want to be assured that their resources are being put to good use on programs that are effective and efficient (Guskey, 2000). Thus, programs are increasingly based on theory and evaluated through randomized control trials using longitudinal data. Despite this progress, hypothesized outcomes are often not detected and/or their effect sizes are small (Gingiss, Roberts-Gray, Boerm, 2006). Moreover, findings may go against intuition or "gut feelings" on the part of project staff. Given the need to understand how program implementation issues relate to outcomes, this study focuses on whether process measures that focus on program implementation and fidelity can shed light on associated outcomes. In particular, we linked the process evaluation of the HealthWise motivation lesson with outcomes across four waves of data collection. We hypothesized that HealthWise would increase learners' intrinsic and identified forms of motivation, and decrease amotivation and extrinsic motivation. We did not hypothesize a direction of effects on introjected motivation due to its conceptual ambiguity. Data came from youth in four intervention schools (n = 902, 41.1%) and five control schools (n = 1291, 58.9%) who were participating in a multi-cohort, longitudinal study. The schools were in a township near Cape Town, South Africa. For each cohort, baseline data are collected on learners as they begin Grade 8. We currently have four waves of data collected on the first cohort, which is the focus of this paper. The mean age of the sample at Wave 3 was 15.0 years (SD = .86) and 51% of students were female. Results suggested that there was evidence of an overall program effect of the curriculum on amotivation regardless of fidelity of implementation. Compared to the control schools, all treatment school learners reported lower levels of amotivation in Wave 4 compared to Wave 3, as hypothesized. Using process evaluation data to monitor implementation fidelity, however, we also conclude that the school with better trained teachers who also reported higher levels of program fidelity had better outcomes than the other schools. We discuss the implications of linking process data with outcome data and associated methodological challenges in linking these data.


Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer.
Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10(-5)). For three cis-eQTL associations (P<1.4 × 10(-3), FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10(-10) for risk variants (P<10(-4)) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.


Association of clinical and magnetic resonance imaging findings with outcome in dogs with presumptive acute noncompressive nucleus pulposus extrusion: 42 cases (2000-2007).
To assess associations of severity of neurologic signs (neurologic score), involvement of an intumescence, and findings of magnetic resonance imaging (MRI) with interval to recovery and outcome in dogs with presumptive acute noncompressive nucleus pulposus extrusions. Retrospective case series. 42 dogs with presumptive acute noncompressive nucleus pulposus extrusions. Medical records and magnetic resonance (MR) images of dogs evaluated from 2000 through 2007 were reviewed. Inclusion criteria were acute onset of nonprogressive myelopathy following trauma or strenuous exercise, MRI of the spine performed within 7 days after onset, MRI findings consistent with acute noncompressive nucleus pulposus extrusions, and complete medical records and follow-up. Clinical neuroanatomic localization of lesions was to the C1-C5 (n = 6), C6-T2 (6), T3-L3 (28), and L4-S3 (2) spinal cord segments. Median neurologic score was 3.5. Median duration of follow-up was 804 days (range, 3 to 2,134 days) after onset of neurologic signs. Outcome was successful in 28 (67%) dogs and unsuccessful in 14 (33%) dogs. Severity of neurologic signs, extent of the intramedullary hyperintensity on sagittal and transverse T2-weighted MR images, and detection of intramedullary hypointensity on GRE images were all associated with outcome on univariate analysis. Results of multivariate analysis suggested that maximal cross-sectional area of the intramedullary hyperintensity on transverse T2-weighted MR images was the best predictor of outcome. Clinical and MRI findings can help predict outcome in dogs with acute noncompressive nucleus pulposus extrusions.


Growth response of drought-stressed Pinus sylvestris seedlings to single- and multi-species inoculation with ectomycorrhizal fungi.
Many trees species form symbiotic associations with ectomycorrhizal (ECM) fungi, which improve nutrient and water acquisition of their host. Until now it is unclear whether the species richness of ECM fungi is beneficial for tree seedling performance, be it during moist conditions or drought. We performed a pot experiment using Pinus sylvestris seedlings inoculated with four selected ECM fungi (Cenococcum geophilum, Paxillus involutus, Rhizopogon roseolus and Suillus granulatus) to investigate (i) whether these four ECM fungi, in monoculture or in species mixtures, affect growth of P. sylvestris seedlings, and (ii) whether this effect can be attributed to species number per se or to species identity. Two different watering regimes (moist vs. dry) were applied to examine the context-dependency of the results. Additionally, we assessed the activity of eight extracellular enzymes in the root tips. Shoot growth was enhanced in the presence of S. granulatus, but not by any other ECM fungal species. The positive effect of S. granulatus on shoot growth was more pronounced under moist (threefold increase) than under dry conditions (twofold increase), indicating that the investigated ECM fungi did not provide additional support during drought stress. The activity of secreted extracellular enzymes was higher in S. granulatus than in any other species. In conclusion, our findings suggest that ECM fungal species composition may affect seedling performance in terms of aboveground biomass.


Connexin 43 acts as a cytoprotective mediator of signal transduction by stimulating mitochondrial KATP channels in mouse cardiomyocytes.
Potassium (K+) channels in the inner mitochondrial membrane influence cell function and survival. Increasing evidence indicates that multiple signaling pathways and pharmacological actions converge on mitochondrial ATP-sensitive K+ (mitoKATP) channels and PKC to confer cytoprotection against necrotic and apoptotic cell injury. However, the molecular structure of mitoKATP channels remains unresolved, and the mitochondrial phosphoprotein(s) that mediate cytoprotection by PKC remain to be determined. As mice deficient in the main sarcolemmal gap junction protein connexin 43 (Cx43) lack this cytoprotection, we set out to investigate a possible link among mitochondrial Cx43, mitoKATP channel function, and PKC activation. By patch-clamping the inner membrane of subsarcolemmal murine cardiac mitochondria, we found that genetic Cx43 deficiency, pharmacological connexin inhibition by carbenoxolone, and Cx43 blockade by the mimetic peptide 43GAP27 each substantially reduced diazoxide-mediated stimulation of mitoKATP channels. Suppression of mitochondrial Cx43 inhibited mitoKATP channel activation by PKC. MitoKATP channels of interfibrillar mitochondria, which do not contain any detectable Cx43, were insensitive to both PKC activation and diazoxide, further demonstrating the role of Cx43 in mitoKATP channel stimulation and the compartmentation of mitochondria in cell signaling. Our results define a role for mitochondrial Cx43 in protecting cardiac cells from death and provide a link between cytoprotective stimuli and mitoKATP channel opening, making Cx43 an attractive therapeutic target for protection against cell injury.


Surfactant-free CO2-based microemulsion-like systems.
The presence of water-rich and water-lean nanodomains in a transparent, pressurized "water-acetone-CO2" mixture was revealed by Raman spectroscopy. This nano-structured liquid can be classified as a surfactant-free microemulsion-like system and has the capacity to dissolve hydrophobic compounds, such as ibuprofen, in the presence of large amounts of water. This finding opens new opportunities in the fields of confined reactions and material templating.


Travellers' diarrhoea: causes, prevention and treatment.
This article describes the prevention and treatment of travellers' diarrhoea, the leading cause of illness in people travelling abroad. The most common cause of travellers' diarrhoea worldwide is bacterial pathogens, which account for up to 80% of cases. Exercising caution over dietary selection and personal hygiene is the most common method used for reducing the risk of acquiring travellers' diarrhoea. Antibiotics, probiotics, prebiotics and bismuth subsalicylate have all been indicated for the prevention of this distressing condition. Treatments include antimotility agents, oral rehydration salts and antibiotics.


Pattern of drug utilization in acute tonsillitis in a teaching hospital in Nepal.
A prospective study was undertaken to find out the baseline data on prescribing patten of drugs in acute tonsillitis. Prescriptions far acute tonsillitis were collected outside the ENT-OPD over a period of 6 months and were analyzed. The average number of drugs per prescription was 3.24. Ninety five percent of the prescriptions contained antimicrobial agents (AMA with an average of 1.03 AMAs per prescription. AMA was the most commonly prescribed (31.81%) group of drugs followed by analgesics and antipyretics (20.70%). Amoxicillin (38.80%) and azithromycin (20.63%) were the most commonly prescribed AMAs. Erythromyein was prescribed in 11(6.73) patients while penicillin was not at all prescribed. Culture and sensitivity test was advised only in 14.75% of cases. Cough expectorants were the most commonly used fixed dose combination. Of the total drugs used, 96.9% were prescribed by brand names. The duration of therapy was not mentioned for 35.60% of the drugs prescribed. the iatyprtyriate and over use off antimicrobil agents make treatment east effective.


Metabolic and Microbial Modulation of the Large Intestine Ecosystem by Non-Absorbed Diet Phenolic Compounds: A Review.
Phenolic compounds represent a diverse group of phytochemicals whose intake is associated with a wide spectrum of health benefits. As consequence of their low bioavailability, most of them reach the large intestine where, mediated by the action of local microbiota, a series of related microbial metabolites are accumulated. In the present review, gut microbial transformations of non-absorbed phenolic compounds are summarized. Several studies have reached a general consensus that unbalanced diets are associated with undesirable changes in gut metabolism that could be detrimental to intestinal health. In terms of explaining the possible effects of non-absorbed phenolic compounds, we have also gathered information regarded their influence on the local metabolism. For this purpose, a number of issues are discussed. Firstly, we consider the possible implications of phenolic compounds in the metabolism of colonic products, such as short chain fatty acids (SCFA), sterols (cholesterol and bile acids), and microbial products of non-absorbed proteins. Due to their being recognized as affective antioxidant and anti-inflammatory agents, the ability of phenolic compounds to counteract or suppress pro-oxidant and/or pro-inflammatory responses, triggered by bowel diseases, is also presented. The modulation of gut microbiota through dietetic maneuvers including phenolic compounds is also commented on. Although the available data seems to assume positive effects in terms of gut health protection, it is still insufficient for solid conclusions to be extracted, basically due to the lack of human trials to confirm the results obtained by the in vitro and animal studies. We consider that more emphasis should be focused on the study of phenolic compounds, particularly in their microbial metabolites, and their power to influence different aspects of gut health.


Biocompatible CdSe-ZnS core-shell quantum dots coated with hydrophilic polythiols.
We designed four polymeric ligands for semiconductor quantum dots and synthesized these macromolecular constructs in four steps, starting from commercial precursors. These ligands have a poly(methacrylate) backbone with pendant thiol groups and poly(ethylene glycol) chains. The thiol groups anchor these ligands on the surface of preformed CdSe-ZnS core-shell quantum dots, and the poly(ethylene glycol) chains impose hydrophilic character on the resulting assemblies. Indeed, three of the four sets of quantum dots are soluble in aqueous environments and are stable under these conditions for days over a wide pH range (5.0-9.0). Furthermore, the polymeric coatings wrapped around the inorganic nanoparticles preserve the photophysical properties of the CdSe core and ensure relatively compact dimensions. Specifically, the luminescence quantum yield is ca. 0.4 and the hydrodynamic diameter ranges from 15 to 29 nm with the nature of the polymeric ligand. Model studies with human umbilical vein endothelial cells demonstrated that these hydrophilic quantum dots cross the cell membrane and localize either in the cytosol or in the nucleus. The length of the poly(ethylene glycol) chains appears to guide the intracellular localization of these luminescent probes. In addition, these studies indicated that these particular nanoparticles are not cytotoxic. In fact, their cellular internalization has essentially no influence on cell growth. In summary, we developed novel polymeric ligands able to impose hydrophilic character and biocompatibility on CdSe-ZnS core-shell nanoparticles. Thus, our results can lead to a new family of valuable luminescent probes for cellular imaging, based on the unique photophysical properties of semiconductor quantum dots.


Comparing 3 dietary pattern methods--cluster analysis, factor analysis, and index analysis--With colorectal cancer risk: The NIH-AARP Diet and Health Study.
The authors compared dietary pattern methods-cluster analysis, factor analysis, and index analysis-with colorectal cancer risk in the National Institutes of Health (NIH)-AARP Diet and Health Study (n = 492,306). Data from a 124-item food frequency questionnaire (1995-1996) were used to identify 4 clusters for men (3 clusters for women), 3 factors, and 4 indexes. Comparisons were made with adjusted relative risks and 95% confidence intervals, distributions of individuals in clusters by quintile of factor and index scores, and health behavior characteristics. During 5 years of follow-up through 2000, 3,110 colorectal cancer cases were ascertained. In men, the vegetables and fruits cluster, the fruits and vegetables factor, the fat-reduced/diet foods factor, and all indexes were associated with reduced risk; the meat and potatoes factor was associated with increased risk. In women, reduced risk was found with the Healthy Eating Index-2005 and increased risk with the meat and potatoes factor. For men, beneficial health characteristics were seen with all fruit/vegetable patterns, diet foods patterns, and indexes, while poorer health characteristics were found with meat patterns. For women, findings were similar except that poorer health characteristics were seen with diet foods patterns. Similarities were found across methods, suggesting basic qualities of healthy diets. Nonetheless, findings vary because each method answers a different question.


Oligomeric and phosphorylated alpha-synuclein as potential CSF biomarkers for Parkinson's disease.
Despite decades of intensive research, to date, there is no accepted diagnosis for Parkinson's disease (PD) based on biochemical analysis of blood or CSF. However, neurodegeneration in the brains of PD patients begins several years before the manifestation of the clinical symptoms, pointing to serious flaw/limitations in this approach. To explore the potential use of alpha-synuclein (α-syn) species as candidate biomarkers for PD, we generated specific antibodies directed against wide array of α-syn species, namely total-, oligomeric- and phosphorylated-Ser129-α-syn (t-, o- and p-S129-α-syn). Next we sought to employ our antibodies to develop highly specific ELISA assays to quantify α-syn species in biological samples. Finally we verified the usefulness of our assays in CSF samples from 46 PD patients and 48 age-matched healthy controls. We also assessed the discriminating power of combining multiple CSF α-syn species with classical Alzheimer's disease biomarkers. The combination of CSF o-/t-α-syn, p-S129-α-syn and p-tau provided the best fitting predictive model for discriminating PD patients from controls. Moreover, CSF o-α-syn levels correlated significantly with the severity of PD motor symptoms (r = -0.37). Our new ELISA assays can serve as research tools to address the unmet need for reliable CSF biomarkers for PD and related disorders.


Ratiometric Semiconducting Polymer Nanoparticle for Reliable Photoacoustic Imaging of Pneumonia-Induced Vulnerable Atherosclerotic Plaque in Vivo.
Acute pneumonia can greatly increase the vulnerable risk of atherosclerotic plaque and contribute to the mortality of cardiovascular disease. To accurately assess the rupture risk caused by acute pneumonia, we developed a novel kind of ratiometric semiconducting polymer nanoparticle (RSPN) for photoacoustic imaging of vulnerable plaque in apolipoprotein E-deficient mice complicated with pneumonia. Specifically, RSPN can react with O2•- and exhibit the enhanced photoacoustic signals at about 690 nm, while 800 nm is regarded as an internal photoacoustic reference. As a result, RSPN can provide reliable determination of O2•- within aortic atherosclerosis by analyzing the ratios of photoacoustic signals, which can successfully reflect the oxidative stress level in vulnerable plaque. Therefore, RSPN enable to specifically distinguish plaque-bearing mice and plaque-bearing mice complicated with pneumonia from healthy mice, which provides a promising tool to predict the vulnerability of plaque for reducing the mortality of atherosclerotic-induced cardiovascular disease.