How do we strengthen the health workforce in a rapidly developing high-income country? A case study of Abu Dhabi's health system in the United Arab Emirates.
The United Arab Emirates (UAE) is a rapidly developing high-income country that was formed from the union of seven emirates in 1971. The UAE has experienced unprecedented population growth coupled with increased rates of chronic diseases over the past few decades. Healthcare workers are the core foundation of the health system, especially for chronic care conditions, and the UAE health workforce needs to be fully prepared for the increased rates of chronic diseases in the adult population. Abu Dhabi is the largest emirate in terms of land mass and population size, and the purpose of this paper was to assess how the health system has been using the Chronic Care Model to improve its capacity to reach out to all patients in the population. The Abu Dhabi health workforce has twice the number of doctors (52.4 vs. 23.2 per 10 000 population) and nurses (134.7 vs. 50.4 per 10 000 population) compared to the entire UAE health workforce. In addition to an overreliance on expatriate workers, there is an excess of some specializations such as general medicine and gynecology and a severe undersupply of other specialties including trauma and injury, and medical oncology. The digital infrastructure and skills of the health workforce need to be improved to minimize the proportion of the appointment time required to complete administrative tasks for a health insurance system and maximize the doctor-patient face-to-face interaction time for consultation and lifestyle counseling. A greater emphasis needs to be placed on developing self-management support strategies using a combination of nurse health educators and community-based patient-led health programs. The UAE Vision 2021 includes developing a world-class healthcare system, and full implementation of the Chronic Care Model seems to facilitate the detailed planning and preparation of healthcare services and workers required to achieve this goal.


Selective engineering of oxygen-containing functional groups using the alkyl ligand oleylamine for revealing the luminescence mechanism of graphene oxide quantum dots.
Oxygen-containing functional groups such as epoxy, hydroxyl, carboxylic, and carboxyl groups have a great influence on the luminescence properties of graphene oxide quantum dots (GOQDs). Understanding their roles is essential for the design and optimization of GOQD performance. Herein, we investigate the effect of epoxide functional groups in GOQDs on the luminescence mechanism through passivation of the epoxide functional groups using the alkyl ligand oleylamine. Luminescence in the as-synthesized GOQDs has two separate origins: intrinsic states derived from localized sp2 carbon subdomains and extrinsic states formed by oxygen-functional groups. When the oleylamine ligand is conjugated on the GOQDs, intrinsic PL emission from the localized sp2 carbon subdomains decreases. This is discussed in detail, based on optical characterization and first-principles density functional theory calculations, which reveal that the role of the epoxide functional groups is to form localized sp2 carbon subdomains emitting intrinsic PL. To the best of our knowledge, this is the first investigation of the role of epoxide functional groups on the luminescence mechanism in GOQDs.


Macrophages facilitate the excystation and differentiation of Toxoplasma gondii sporozoites into tachyzoites following oocyst internalisation.
Toxoplasma gondii is a common parasite of humans and animals, which is transmitted via oocysts in cat faeces or tissue cysts in contaminated meat. The robust oocyst and sporocyst walls protect the infective sporozoites from deleterious external attacks including disinfectants. Upon oocyst acquisition, these walls lose their integrity to let the sporozoites excyst and invade host cells following a process that remains poorly understood. Given the resistance of the oocyst wall to digestive enzymes and the ability of oocysts to cause parenteral infections, the present study investigated the possible contribution of macrophages in supporting sporozoite excystation following oocyst internalisation. By using single cell micromanipulations, real-time and time-point imaging techniques, we demonstrated that RAW macrophages could interact rapidly with oocysts and engulfed them by remodelling of their actin cytoskeleton. Internalised oocysts were associated to macrophage acidic compartments and showed evidences of wall disruption. Sporozoites were observed in macrophages containing oocyst remnants or in new macrophages, giving rise to dividing tachyzoites. All together, these results highlight an unexpected role of phagocytic cells in processing T. gondii oocysts, in line with non-classical routes of infection, and open new perspectives to identify chemical factors that lead to oocyst wall disruption under physiological conditions.


Heart failure treated with low-dose milrinone in a full-term newborn.
A term newborn with a hypocontractile myocardium complicating persistent pulmonary hypertension of the newborn was successfully treated with a low-dose phosphodiesterase III inhibitor milrinone. Echocardiography diagnosed heart failure with a left ventricular ejection fraction of 35% and a left ventricular shortening fraction of 18% and severe persistent pulmonary hypertension of the newborn with oxygenation index of 28. Milrinone was started at an initial dose of 50 mcg/kg, followed by continuous infusion of 0.20 mcg/kg/min. With lowdose milrinone oxygenation index decreased to 3 within 6 hours, left ventricular ejection fraction and left ventricular shortening fraction increased to 57%, and 30%, respectively. Low doses of milrinone might be promising in the treatment of heart failure and persistent pulmonary hypertension of the newborn in term newborns.


Characterization of 2'-fluoro-RNA aptamers that bind preferentially to disease-associated conformations of prion protein and inhibit conversion.
We have isolated artificial ligands or aptamers for infectious prions in order to investigate conformational aspects of prion pathogenesis. The aptamers are 2'-fluoro-modified RNA produced by in vitro selection from a large, randomized library. One of these ligands (aptamer SAF-93) had more than 10-fold higher affinity for PrPSc than for recombinant PrPC and inhibited the accumulation of PrPres in near physiological cell-free conversion assay. To understand the molecular basis of these properties and to distinguish specific from non-specific aptamer-PrP interactions, we studied deletion mutants of bovine PrP in denatured, alpha-helix-rich and beta-sheet-rich forms. We provide evidence that, like scrapie-associated fibrils (SAF), the beta-oligomer of PrP bound to SAF-93 with at least 10-fold higher affinity than did the alpha-form. This differential affinity could be explained by the existence of two binding sites within the PrP molecule. Site 1 lies within residues 23-110 in the unstructured N terminus and is a nonspecific RNA binding site found in all forms of PrP. The region between residue 90 and 110 forms a hinge region that is occluded in the alpha-rich form of PrP but becomes exposed in the denatured form of PrP. Site 2 lies in the region C-terminal of residue 110. This site is beta-sheet conformation-specific and is not recognized by control RNAs. Taken together, these data provide for the first time a specific ligand for a disease conformation-associated site in a region of PrP critical for conformational conversion. This aptamer could provide tools for the further analysis of the processes of PrP misfolding during prion disease and leads for the development of diagnostic and therapeutic approaches to TSEs.


Optimal Length of Conformational Transition Region in Protein Search for Targets on DNA.
The starting point of many fundamental biological processes is associated with protein molecules finding and recognizing specific sites on DNA. However, despite a large number of experimental and theoretical studies on protein search for targets on DNA, many molecular aspects of underlying mechanisms are still not well understood. Experiments show that proteins bound to DNA can switch between slow recognition and fast search conformations. However, from a theoretical point of view, such conformational transitions should slow down the protein search for specific sites on DNA, in contrast to available experimental observations. In addition, experiments indicate that the nucleotide composition near the target site is more symmetrically homogeneous, leading to stronger effective interactions between proteins and DNA at these locations. However, as has been shown theoretically, this should also make the search less efficient, which is not observed. We propose a possible resolution of these problems by suggesting that conformational transitions occur only within a segment around the target where stronger interactions between proteins and DNA are observed. Two theoretical methods, based on continuum and discrete-state stochastic calculations, are developed, allowing us to obtain a comprehensive dynamic description for the protein search process in this system. The existence of an optimal length of the conformational transition zone with the shortest mean search time is predicted.


Human Cytomegalovirus Modifies Placental Small Extracellular Vesicle Composition to Enhance Infection of Fetal Neural Cells In Vitro.
Although placental small extracellular vesicles (sEVs) are extensively studied in the context of pregnancy, little is known about their role during viral congenital infection, especially at the beginning of pregnancy. In this study, we examined the consequences of human cytomegalovirus (hCMV) infection on sEVs production, composition, and function using an immortalized human cytotrophoblast cell line derived from first trimester placenta. By combining complementary approaches of biochemistry, electron microscopy, and quantitative proteomic analysis, we showed that hCMV infection increases the yield of sEVs produced by cytotrophoblasts and modifies their protein content towards a potential proviral phenotype. We further demonstrate that sEVs secreted by hCMV-infected cytotrophoblasts potentiate infection in naive recipient cells of fetal origin, including human neural stem cells. Importantly, these functional consequences are also observed with sEVs prepared from an ex vivo model of infected histocultures from early placenta. Based on these findings, we propose that placental sEVs could be important actors favoring viral dissemination to the fetal brain during hCMV congenital infection.


Cerebrospinal fluid tau and Abeta42 concentrations in healthy subjects: delineation of reference intervals and their limitations.
Many limitations and conflicting results have cast serious doubts on the validity of cerebrospinal fluid tau and Abeta42 levels for the biological diagnosis of Alzheimer's disease, particularly extreme variations of the reference limits found by unrelated groups as a consequence of different reference populations used. In this study, we addressed the issue of defining reference limits for cerebrospinal fluid tau and Abeta42 in healthy adult individuals. One hundred and five neurologically intact subjects were enrolled according to strict inclusion criteria, 10 of them with autopsy confirmation of brain integrity. All cerebrospinal fluid samples were similarly and optimally processed as were the dosage methods used and the statistical analyses performed. A robust correlation with age was demonstrated for Abeta42 but not for tau. For tau, we found that an upper cut-off value of 443 ng/l allowed 95% of the subjects to be correctly classified as normal. For Abeta42, a lower cut-off value of 90 ng/l allowed a correct classification of 90% of the subjects. However, a large variance of the reference values, partly explained by the potential contamination of the reference population with presymptomatic dementia patients, may limit the use of reference limits based on living subjects. We propose that the issue of defining reference limits for both cerebrospinal fluid tau and Abeta42 may ultimately be settled by studying large numbers of autopsy-proven neurologically intact individuals only.


Food plant diversity as broad-scale determinant of avian frugivore richness.
The causes of variation in animal species richness at large spatial scales are intensively debated. Here, we examine whether the diversity of food plants, contemporary climate and energy, or habitat heterogeneity determine species richness patterns of avian frugivores across sub-Saharan Africa. Path models indicate that species richness of Ficus (their fruits being one of the major food resources for frugivores in the tropics) has the strongest direct effect on richness of avian frugivores, whereas the influences of variables related to water-energy and habitat heterogeneity are mainly indirect. The importance of Ficus richness for richness of avian frugivores diminishes with decreasing specialization of birds on fruit eating, but is retained when accounting for spatial autocorrelation. We suggest that a positive relationship between food plant and frugivore species richness could result from niche assembly mechanisms (e.g. coevolutionary adaptations to fruit size, fruit colour or vertical stratification of fruit presentation) or, alternatively, from stochastic speciation-extinction processes. In any case, the close relationship between species richness of Ficus and avian frugivores suggests that figs are keystone resources for animal consumers, even at continental scales.


Characterization of macaque pulmonary fluid proteome during monkeypox infection: dynamics of host response.
Understanding viral pathogenesis is challenging because of confounding factors, including nonabrasive access to infected tissues and high abundance of inflammatory mediators that may mask mechanistic details. In diseases such as influenza and smallpox where the primary cause of mortality results from complications in the lung, the characterization of lung fluid offers a unique opportunity to study host-pathogen interactions with minimal effect on infected animals. This investigation characterizes the global proteome response in the pulmonary fluid, bronchoalveolar lavage fluid, of macaques during upper respiratory infection by monkeypox virus (MPXV), a close relative of the causative agent of smallpox, variola virus. These results are compared and contrasted against infections by vaccinia virus (VV), a low pathogenic relative of MPXV, and with extracellular fluid from MPXV-infected HeLa cells. To identify changes in the pulmonary protein compartment, macaque lung fluid was sampled twice prior to infection, serving as base line, and up to six times following intrabronchial infection with either MPXV or VV. Increased expression of inflammatory proteins was observed in response to both viruses. Although the increased expression resolved for a subset of proteins, such as C-reactive protein, S100A8, and S100A9, high expression levels persisted for other proteins, including vitamin D-binding protein and fibrinogen γ. Structural and metabolic proteins were substantially decreased in lung fluid exclusively during MPXV and not VV infection. Decreases in structural and metabolic proteins were similarly observed in the extracellular fluid of MPXV-infected HeLa cells. Results from this study suggest that the host inflammatory response may not be the only facilitator of viral pathogenesis, but rather maintaining pulmonary structural integrity could be a key factor influencing disease progression and mortality.


Effects of the 5-HT2A agonist psilocybin on mismatch negativity generation and AX-continuous performance task: implications for the neuropharmacology of cognitive deficits in schizophrenia.
Previously the NMDA (N-methyl-D-aspartate) receptor (NMDAR) antagonist ketamine was shown to disrupt generation of the auditory event-related potential (ERP) mismatch negativity (MMN) and the performance of an 'AX'-type continuous performance test (AX-CPT)--measures of auditory and visual context-dependent information processing--in a similar manner as observed in schizophrenia. This placebo-controlled study investigated effects of the 5-HT(2A) receptor agonist psilocybin on the same measures in 18 healthy volunteers. Psilocybin administration induced significant performance deficits in the AX-CPT, but failed to reduce MMN generation significantly. These results indirectly support evidence that deficient MMN generation in schizophrenia may be a relatively distinct manifestation of deficient NMDAR functioning. In contrast, secondary pharmacological effects shared by NMDAR antagonists and the 5-HT(2A) agonist (ie disruption of glutamatergic neurotransmission) may be the mechanism underlying impairments in AX-CPT performance observed during both psilocybin and ketamine administration. Comparable deficits in schizophrenia may result from independent dysfunctions of 5-HT(2A) and NMDAR-related neurotransmission.


Human dorsal striatal activity during choice discriminates reinforcement learning behavior from the gambler's fallacy.
Reinforcement learning theory has generated substantial interest in neurobiology, particularly because of the resemblance between phasic dopamine and reward prediction errors. Actor-critic theories have been adapted to account for the functions of the striatum, with parts of the dorsal striatum equated to the actor. Here, we specifically test whether the human dorsal striatum--as predicted by an actor-critic instantiation--is used on a trial-to-trial basis at the time of choice to choose in accordance with reinforcement learning theory, as opposed to a competing strategy: the gambler's fallacy. Using a partial-brain functional magnetic resonance imaging scanning protocol focused on the striatum and other ventral brain areas, we found that the dorsal striatum is more active when choosing consistent with reinforcement learning compared with the competing strategy. Moreover, an overlapping area of dorsal striatum along with the ventral striatum was found to be correlated with reward prediction errors at the time of outcome, as predicted by the actor-critic framework. These findings suggest that the same region of dorsal striatum involved in learning stimulus-response associations may contribute to the control of behavior during choice, thereby using those learned associations. Intriguingly, neither reinforcement learning nor the gambler's fallacy conformed to the optimal choice strategy on the specific decision-making task we used. Thus, the dorsal striatum may contribute to the control of behavior according to reinforcement learning even when the prescriptions of such an algorithm are suboptimal in terms of maximizing future rewards.


Safety, Feasibility, and Efficiency of a New Cooling Device Using Intravenous Cold Infusions for Fever Control.
Fever control plays a key role in therapy of patients with acute brain injury. The infusion of cold saline could serve as an alternative or additional method for targeted temperature management. However, it is difficult to estimate the amount of fluid required to achieve normothermia merely on the basis of body weight. There is no standardized load management regarding the administration of cold saline, and no closed-loop systems based on continuous temperature-controlled feedback are available. The primary purpose of the present study was to evaluate the feasibility, efficacy, and safety of a new automated fluid infusion system. Twelve patients with acute brain injury and febrile episodes were treated with the automated infusion device tempedy (seiratherm GmbH, Herzogenaurach, Germany). Patients were included if bladder temperature still was ≥ 37.9 °C after administration of antipyretic medication, cold washing solutions, and ice packs more than 2 h earlier. The efficacy was examined by measuring the time and amount of fluid needed to reach and maintain target temperature. Feasibility and safety were assessed based on recording any technical difficulties with the new device and the occurrence of clinical signs of fluid overload such as acute pulmonary edema, electrolyte disturbances, or acid-base dysfunction. The mean time was 73 min (range from 15 to 330 min) and 1650 ml the mean amount of fluid (21.2 ml/kg; SD 28.5 ml/kg) to reach the target temperature. The mean total fluid balance to reach and maintain the target temperature in the first 12 h was 1350 ml (SD 1550 ml). In the first 12 h 89.4% of the time temperature values were in the target range (median 95.3%, range 83.8-10%). No clinical signs of fluid overload such as an acute pulmonary edema or device-related adverse events occurred. Target temperature management with the new automated infusion device is feasible. Although we provided first data regarding safety, further controlled randomized studies are needed to evaluate the long-time safety, as well as the best indications and timing for this cooling device.


Resistance Pattern and Molecular Characterization of Enterotoxigenic Escherichia coli (ETEC) Strains Isolated in Bangladesh.
Enterotoxigenic Escherichia coli (ETEC) is a common cause of bacterial infection leading to acute watery diarrhea in infants and young children as well as in travellers to ETEC endemic countries. Ciprofloxacin is a broad-spectrum antimicrobial agent nowadays used for the treatment of diarrhea. This study aimed to characterize ciprofloxacin resistant ETEC strains isolated from diarrheal patients in Bangladesh. A total of 8580 stool specimens from diarrheal patients attending the icddr,b Dhaka hospital was screened for ETEC between 2005 and 2009. PCR and Ganglioside GM1- Enzyme Linked Immuno sorbent Assay (ELISA) was used for detection of Heat labile (LT) and Heat stable (ST) toxins of ETEC. Antimicrobial susceptibilities for commonly used antibiotics and the minimum inhibitory concentration (MIC) of nalidixic acid, ciprofloxacin and azithromycin were examined. DNA sequencing of representative ciprofloxacin resistant strains was performed to analyze mutations of the quinolone resistance-determining region of gyrA, gyrB, parC and parE. PCR was used for the detection of qnr, a plasmid mediated ciprofloxacin resistance gene. Clonal variations among ciprofloxacin resistant (CipR) and ciprofloxacin susceptible (CipS) strains were determined by Pulsed-field gel electrophoresis (PFGE). Among 1067 (12%) ETEC isolates identified, 42% produced LT/ST, 28% ST and 30% LT alone. Forty nine percent (n = 523) of the ETEC strains expressed one or more of the 13 tested colonization factors (CFs) as determined by dot blot immunoassay. Antibiotic resistance of the ETEC strains was observed as follows: ampicillin 66%, azithromycin 27%, ciprofloxacin 27%, ceftriazone 13%, cotrimaxazole 46%, doxycycline 44%, erythromycin 96%, nalidixic acid 83%, norfloxacin 27%, streptomycin 48% and tetracycline 42%. Resistance to ciprofloxacin increased from 13% in 2005 to 34% in 2009. None of the strains was resistant to mecillinam. The MIC of the nalidixic acid and ciprofloxacin of representative CipR strains were 256 μg/ml and 32μg/ml respectively. A single mutation (Ser83-Leu) in gyrA was observed in the nalidixic acid resistant ETEC strains. In contrast, double mutation in gyrA (Ser83-Leu, Asp87-Asn) and a single mutation in parC (Glu84-Ly) were found in ciprofloxacin resistant strains. Mutation of gyrB was not found in either the nalidixic acid or ciprofloxacin resistant strains. None of the ciprofloxacin resistant strains was found to be positive for the qnr gene. Diverse clones were identified from all ciprofloxacin resistant strains by PFGE analysis in both CF positive and CF negative ETEC strains. Emergence of ciprofloxacin resistant ETEC strains results in a major challenge in current treatment strategies of ETEC diarrhea.


Characterization of DNA binding, transcriptional activation, and regulated nuclear association of recombinant human NFATp.
NFATp is one member of a family of transcriptional activators whose nuclear accumulation and hence transcriptional activity is regulated in mammalian cells. Human NFATp exists as a phosphoprotein in the cytoplasm of naive T cells. Upon antigen stimulation, NFATp is dephosphorylated, accumulates in nuclei, and functions to regulate transcription of genes including those encoding cytokines. While the properties of the DNA binding domain of NFATp have been investigated in detail, biochemical studies of the transcriptional activation and regulated association with nuclei have remained unexplored because of a lack of full length, purified recombinant NFATp. We developed methods for expressing and purifying full length recombinant human NFATp that has all of the properties known to be associated with native NFATp. The recombinant NFATp binds DNA on its own and cooperatively with AP-1 proteins, activates transcription in vitro, is phosphorylated, can be dephosphorylated by calcineurin, and exhibits regulated association with nuclei in vitro. Importantly, activation by recombinant NFATp in a reconstituted transcription system required regions of the protein outside of the central DNA binding domain. We conclude that NFATp is a bona fide transcriptional activator. Moreover, the reagents and methods that we developed will facilitate future studies on the mechanisms of transcriptional activation and nuclear accumulation by NFATp, a member of an important family of transcriptional regulatory proteins.


Consequences of intangibility in the management of new mental health services.
To analyze work organization in psychosocial healthcare services from the logic of the service management field. Organizational analysis was performed, using a case study in a psychosocial healthcare service located in the city of São Paulo, Southeastern Brazil, between 2006 and 2007. A total of five sources of information were analyzed: Ministério da Saúde (Brazilian Ministry of Health) documents, research reports made in the service studied, service records, interviews with healthcare workers and managers and simple observation. Interviews dealt with objectives, results and assessment of work process. Each source was treated differently, according to its purpose. A subsequent dialogue about the results obtained aimed to make a set of observations on which the case study was founded. The service proposes to deliver a very intangible result, which views the user in their social context. The intended change in the user's conditions was described as 'the person living better'. Such condition is difficult to be defined and understood in terms of the details and limits of this change, thus hindering measurement of results. In addition, the work process involves activities which are not routinary, not predictable and sometimes simultaneous, so that the team finds it difficult to recognize and legitimize efforts made to perform work, a fact described as 'work invisibility' by workers. The assessment process was found to be a complex aspect of this intangibility, associated with inadequacy and insufficiency of the municipal health system's management structure to include a service of this nature. Results enabled better understanding of a field of work where workers' and users' subjectivity is inherent in the service management process.


Therapeutic Small Molecules Target Inhibitor of Apoptosis Proteins in Cancers with Deregulation of Extrinsic and Intrinsic Cell Death Pathways.
The Cancer Genome Atlas (TCGA) has unveiled genomic deregulation of various components of the extrinsic and intrinsic apoptotic pathways in different types of cancers. Such alterations are particularly common in head and neck squamous cell carcinomas (HNSCC), which frequently display amplification and overexpression of the Fas-associated via death domain (FADD) and inhibitor of apoptosis proteins (IAP) that complex with members of the TNF receptor family. Second mitochondria-derived activator of caspases (SMAC) mimetics, modeled after the endogenous IAP antagonist SMAC, and IAP inhibitors represent important classes of novel small molecules currently in phase I/II clinical trials. Here we review the physiologic roles of IAPs, FADD, and other components involved in cell death, cell survival, and NF-κB signaling pathways in cancers, including HNSCC. We summarize the results of targeting IAPs in preclinical models of HNSCC using SMAC mimetics. Synergistic activity of SMAC mimetics together with death agonists TNFα or TRAIL occurred in vitro, whereas their antitumor effects were augmented when combined with radiation and chemotherapeutic agents that induce TNFα in vivo In addition, clinical trials testing SMAC mimetics as single agents or together with chemo- or radiation therapies in patients with HNSCC and solid tumors are summarized. As we achieve a deeper understanding of the genomic alterations and molecular mechanisms underlying deregulated death and survival pathways in different cancers, the role of SMAC mimetics and IAP inhibitors in cancer treatment will be elucidated. Such developments could enhance precision therapeutics and improve outcomes for cancer patients. Clin Cancer Res; 23(6); 1379-87. ©2016 AACR.


Filamin B deficiency in mice results in skeletal malformations and impaired microvascular development.
Mutations in filamin B (FLNB), a gene encoding a cytoplasmic actin-binding protein, have been found in human skeletal disorders, including boomerang dysplasia, spondylocarpotarsal syndrome, Larsen syndrome, and atelosteogenesis phenotypes I and III. To examine the role of FLNB in vivo, we generated mice with a targeted disruption of Flnb. Fewer than 3% of homozygous embryos reached term, indicating that Flnb is important in embryonic development. Heterozygous mutant mice were indistinguishable from their wild-type siblings. Flnb was ubiquitously expressed; strong expression was found in endothelial cells and chondrocytes. Flnb-deficient fibroblasts exhibited more disorganized formation of actin filaments and reduced ability to migrate compared with wild-type controls. Flnb-deficient embryos exhibited impaired development of the microvasculature and skeletal system. The few Flnb-deficient mice that were born were very small and had severe skeletal malformations, including scoliotic and kyphotic spines, lack of intervertebral discs, fusion of vertebral bodies, and reduced hyaline matrix in extremities, thorax, and vertebrae. These mice died or had to be euthanized before 4 weeks of age. Thus, the phenotypes of Flnb-deficient mice closely resemble those of human skeletal disorders with mutations in FLNB.


A follow-up study: acute behavioural effects of Delta(9)-THC in female heterozygous neuregulin 1 transmembrane domain mutant mice.
Heavy cannabis use is linked with an increased risk for schizophrenia. We showed previously that male heterozygous neuregulin 1 transmembrane domain (Nrg1 HET) mice are more sensitive to some effects of the psychotropic cannabis constituent Delta(9)-tetrahydrocannabinol (THC). We report data from a follow-up study in female Nrg1 HET mice, investigating THC effects on behaviours with some relevance to schizophrenia. Mice were injected with THC (0, 5 or 10 mg/kg i.p.) 30 min before a test battery: open field, elevated plus maze, novel object recognition (set 1) or light-dark, social interaction (SI) and prepulse inhibition (PPI 1: variable interstimulus interval (ISI); set 2). Another set (set 3) was injected with the same doses of THC before a fixed interstimulus interval PPI test (PPI 2). Female Nrg1 HETs displayed the hallmark increased locomotor activity at 5 months and anxiolytic-like behaviour in the open field at 3 and 5 months. THC decreased locomotor activity in both genotypes. THC selectively reduced some SI behaviours in WT mice. Baseline PPI was enhanced in mutants under a variable ISI, while THC had no effect on PPI using either protocol. This study reports novel findings on the baseline PPI profile and resistance to THC-induced social withdrawal in female Nrg1 HET mice. This is the first description of THC effects in females of this mouse model and suggests that the transmembrane domain Nrg1 mutation does not appear to have a severe impact on the behavioural sensitivity to THC in female mice.


Development of a synthetic phantom for the selection of optimal scanning parameters in CAD-CT colonography.
The aim of this paper is to present the development of a synthetic phantom that can be used for the selection of optimal scanning parameters in computed tomography (CT) colonography. In this paper we attempt to evaluate the influence of the main scanning parameters including slice thickness, reconstruction interval, field of view, table speed and radiation dose on the overall performance of a computer aided detection (CAD)-CTC system. From these parameters the radiation dose received a special attention, as the major problem associated with CTC is the patient exposure to significant levels of ionising radiation. To examine the influence of the scanning parameters we performed 51 CT scans where the spread of scanning parameters was divided into seven different protocols. A large number of experimental tests were performed and the results analysed. The results show that automatic polyp detection is feasible even in cases when the CAD-CTC system was applied to low dose CT data acquired with the following protocol: 13 mAs/rotation with collimation of 1.5 mm x 16 mm, slice thickness of 3.0mm, reconstruction interval of 1.5 mm, table speed of 30 mm per rotation. The CT phantom data acquired using this protocol was analysed by an automated CAD-CTC system and the experimental results indicate that our system identified all clinically significant polyps (i.e. larger than 5 mm).


Linkage disequilibrium based association mapping of fiber quality traits in G. hirsutum L. variety germplasm.
Cotton is the world's leading cash crop, but it lags behind other major crops for marker-assisted breeding due to limited polymorphisms and a genetic bottleneck through historic domestication. This underlies a need for characterization, tagging, and utilization of existing natural polymorphisms in cotton germplasm collections. Here we report genetic diversity, population characteristics, the extent of linkage disequilibrium (LD), and association mapping of fiber quality traits using 202 microsatellite marker primer pairs in 335 G. hirsutum germplasm grown in two diverse environments, Uzbekistan and Mexico. At the significance threshold (r (2) >or= 0.1), a genome-wide average of LD extended up to genetic distance of 25 cM in assayed cotton variety accessions. Genome wide LD at r (2) >or= 0.2 was reduced to approximately 5-6 cM, providing evidence of the potential for association mapping of agronomically important traits in cotton. Results suggest linkage, selection, inbreeding, population stratification, and genetic drift as the potential LD-generating factors in cotton. In two environments, an average of ~20 SSR markers was associated with each main fiber quality traits using a unified mixed liner model (MLM) incorporating population structure and kinship. These MLM-derived significant associations were confirmed in general linear model and structured association test, accounting for population structure and permutation-based multiple testing. Several common markers, showing the significant associations in both Uzbekistan and Mexican environments, were determined. Between 7 and 43% of the MLM-derived significant associations were supported by a minimum Bayes factor at 'moderate to strong' and 'strong to very strong' evidence levels, suggesting their usefulness for marker-assisted breeding programs and overall effectiveness of association mapping using cotton germplasm resources.


Prospective neurocognitive function over 5 years after allogeneic hematopoietic cell transplantation for cancer survivors compared with matched controls at 5 years.
Research has documented cognitive deficits both before and after high-dose treatment followed by allogeneic hematopoietic cell transplantation (HCT), with partial recovery by 1 year. This study prospectively examined the trajectory and extent of long-term cognitive dysfunction, with a focus on 1 to 5 years after treatment. Allogeneic HCT recipients completed standardized neuropsychological tests including information processing speed (Trail Making A and Digit Symbol Substitution Test), verbal memory (Hopkins Verbal Learning Test-Revised), executive function (Controlled Oral Word Association Test and Trail Making B), and motor dexterity and speed (Grooved Pegboard). Survivors (n = 92) were retested after 80 days and 1 and 5 years after transplantation. Case-matched controls (n = 66) received testing at the 5-year time point. A Global Deficit Score (GDS) summarized overall impairment. Response profiles were analyzed using linear mixed effects models. Survivors recovered significant cognitive function from post-transplantation (80 days) to 5 years in all tests (P < .0001) except verbal recall (P > .06). Between 1 and 5 years, verbal fluency improved (P = .0002), as did executive function (P < .01), but motor dexterity did not (P > .15), remaining below controls (P < .0001) and more than 0.5 standard deviation below population norms. In GDS, 41.5% of survivors and 19.7% of controls had mild or greater deficits (NcNemar test = 7.04, P = .007). Although neurocognitive function improved from 1 to 5 years after HCT, deficits remained for more than 40% of survivors. Risk factors, mechanisms and rehabilitation strategies need to be identified for these residual deficits.


Role of Matrix Metalloproteinases-1 and -2 in Interleukin-13-Suppressed Elastin in Airway Fibroblasts in Asthma.
Elastin synthesis and degradation in the airway and lung parenchyma contribute to airway mechanics, including airway patency and elastic recoil. IL-13 mediates many features of asthma pathobiology, including airway remodeling, but the effects of IL-13 on elastin architecture in the airway wall are not known. We hypothesized that IL-13 modulates elastin expression in airway fibroblasts from subjects with allergic asthma. Twenty-five subjects with mild asthma (FEV1, 89 ± 3% predicted) and 30 normal control subjects (FEV1, 102 ± 2% predicted) underwent bronchoscopy with endobronchial biopsy. Elastic fibers were visualized in airway biopsy specimens using Weigert's resorcin-fuchsin elastic stain. Airway fibroblasts were exposed to IL-13; a pan-matrix metalloproteinase (MMP) inhibitor (GM6001); specific inhibitors to MMP-1, -2, -3, and -8; and combinations of IL-13 with MMP inhibitors in separate conditions in serum-free media for 48 hours. Elastin (ELN) expression as well as MMP secretion and activity were quantified. Results of this study show that elastic fiber staining of airway biopsy tissue was significantly associated with methacholine PC20 (i.e., the provocative concentration of methacholine resulting in a 20% fall in FEV1 levels) in patients with asthma. IL-13 significantly suppressed ELN expression in asthmatic airway fibroblasts as compared with normal control fibroblasts. The effect of IL-13 on ELN expression was significantly correlated with postbronchodilator FEV1/FVC in patients with asthma. MMP inhibition significantly stimulated ELN expression in patients with asthma as compared with normal control subjects. Specific inhibition of MMP-1 and MMP-2, but not MMP-3 or MMP-8, reversed the IL-13-induced suppression of ELN expression. In asthma, MMP-1 and MMP-2 mediate IL-13-induced suppression of ELN expression in airway fibroblasts.


Resistance of MHC class I-deficient mice to experimental systemic lupus erythematosus.
Experimental systemic lupus erythematosus (SLE) can be induced in mice by immunization with a human monoclonal antibody to DNA that bears a common idiotype (16/6Id). These mice generate antibodies to 16/6Id, antibodies to DNA, and antibodies directed against nuclear antigens. Subsequently, manifestations of SLE develop, including leukopenia, proteinuria, and immune complex deposits in the kidney. In contrast, after immunization with 16/6Id, mice lacking major histocompatibility complex (MHC) class I molecules generated antibodies to 16/6Id but did not generate antibodies to DNA or to nuclear antigen. Furthermore, they did not develop any of the above clinical manifestations. These results reveal an unexpected function of MHC class I in the induction of autoimmune SLE.


How to diagnose amyloidosis.
Amyloidosis is a rare but devastating condition caused by deposition of misfolded proteins as aggregates in the extracellular tissues of the body, leading to impairment of organ function. High clinical suspicion is required to facilitate early diagnosis. Correct identification of the causal amyloid protein is absolutely crucial for clinical management in order to avoid misdiagnosis and inappropriate, potentially harmful treatment, to assess prognosis, and to offer genetic counselling if relevant. This review summarises the current evidence on which the diagnosis and subtyping of amyloidosis is based, outlines the limitations of various diagnostic techniques, particularly in an Australian and New Zealand context, and discusses optimal strategies for the diagnostic approach to these patients. Recommendations are provided for when particularly to suspect amyloidosis, what investigations are required, as well as an approach to accurate subtyping of amyloidosis.


Examining the Impact of Separate Components of a Multicomponent Intervention Designed to Reduce At-Risk Drinking Among Older Adults: The Project SHARE Study.
Health promotion interventions often include multiple components and several patient contacts. The objective of this study was to examine how participation within a multicomponent intervention (Project SHARE) is associated with changes in at-risk drinking among older adults. We analyzed observational data from a cluster-randomized trial of 31 primary care physicians and their patients aged ≥60 years, at a community-based practice with 7 clinics. Recruitment occurred between 2005 and 2007. At-risk drinkers in a particular physician's practice were randomly assigned as a group to usual care (n = 640 patients) versus intervention (n = 546 patients). The intervention included personalized reports, educational materials, drinking diaries, in-person physician advice, and telephone counseling by health educators (HEs). The primary outcome was at-risk drinking at follow-up, defined by scores on the Comorbidity Alcohol Risk Evaluation Tool (CARET). Predictors included whether a physician-patient alcohol risk discussion occurred, HE call occurred, drinking agreement with the HE was made, and patients self-reported keeping a drinking diary as suggested by the HE. At 6 months, there was no association of at-risk drinking with having had a physician-patient discussion. Compared to having had no HE call, the odds of at-risk drinking at 6 months were lower if an agreement was made or patients reported keeping a diary (odds ratio [OR] 0.58, 95% confidence interval [CI] 0.37 to 0.90), or if an agreement was made and patients reported keeping a diary (OR 0.52, CI 0.28 to 0.97). At 12 months, a physician-patient discussion (OR 0.61, CI 0.38 to 0.98) or an agreement and reported use of a diary (OR 0.45, CI 0.25) were associated with lower odds of at-risk drinking. Within the Project SHARE intervention, discussing alcohol risk with a physician, making a drinking agreement, and/or self-reporting the use of a drinking diary were associated with lower odds of at-risk drinking at follow-up. Future studies targeting at-risk drinking among older adults should consider incorporating both intervention components.


MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program.
Diffuse large B-cell lymphoma (DLBCL) is stratified into prognostically favorable germinal center B-cell (GCB)-like and unfavorable activated B-cell (ABC)-like subtypes based on gene expression signatures. In this study, we analyzed 893 de novo DLBCL patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). We show that MYC/BCL2 protein coexpression occurred significantly more commonly in the ABC subtype. Patients with the ABC or GCB subtype of DLBCL had similar prognoses with MYC/BCL2 coexpression and without MYC/BCL2 coexpression. Consistent with the notion that the prognostic difference between the 2 subtypes is attributable to MYC/BCL2 coexpression, there is no difference in gene expression signatures between the 2 subtypes in the absence of MYC/BCL2 coexpression. DLBCL with MYC/BCL2 coexpression demonstrated a signature of marked downregulation of genes encoding extracellular matrix proteins, those involving matrix deposition/remodeling and cell adhesion, and upregulation of proliferation-associated genes. We conclude that MYC/BCL2 coexpression in DLBCL is associated with an aggressive clinical course, is more common in the ABC subtype, and contributes to the overall inferior prognosis of patients with ABC-DLBCL. In conclusion, the data suggest that MYC/BCL2 coexpression, rather than cell-of-origin classification, is a better predictor of prognosis in patients with DLBCL treated with R-CHOP.


Current concepts in glucocorticoid resistance.
Glucocorticoids (GCs) are the most potent anti-inflammatory agents known. A major factor limiting their clinical use is the wide variation in responsiveness to therapy. The high doses of GC required for less responsive patients means a high risk of developing very serious side effects. Variation in sensitivity between individuals can be due to a number of factors. Congenital, generalized GC resistance is very rare, and is due to mutations in the glucocorticoid receptor (GR) gene, the receptor that mediates the cellular effects of GC. A more common problem is acquired GC resistance. This localized, disease-associated GC resistance is a serious therapeutic concern and limits therapeutic response in patients with chronic inflammatory disease. It is now believed that localized resistance can be attributed to changes in the cellular microenvironment, as a consequence of chronic inflammation. Multiple factors have been identified, including alterations in both GR-dependent and -independent signaling downstream of cytokine action, oxidative stress, hypoxia and serum derived factors. The underlying mechanisms are now being elucidated, and are discussed here. Attempts to augment tissue GC sensitivity are predicted to permit safe and effective use of low-dose GC therapy in inflammatory disease.


The effect of non-steroidal anti-inflammatory agents on behavioural changes and cytokine production following systemic inflammation: Implications for a role of COX-1.
Systemic inflammation gives rise to metabolic and behavioural changes, largely mediated by pro-inflammatory cytokines and prostaglandin production (PGE(2)) at the blood-brain barrier. Despite numerous studies, the exact biological pathways that give rise to these changes remains elusive. This study investigated the mechanisms underlying immune-to-brain communication following systemic inflammation using various anti-inflammatory agents. Mice were pre-treated with selective cyclo-oxygenase (COX) inhibitors, thromboxane synthase inhibitors or dexamethasone, followed by intra-peritoneal injection of lipopolysaccharide (LPS). Changes in body temperature, open-field activity, and burrowing were assessed and mRNA and/or protein levels of inflammatory mediators measured in serum and brain. LPS-induced systemic inflammation resulted in behavioural changes and increased production of IL-6, IL-1beta and TNF-alpha, as well as PGE(2) in serum and brain. Indomethacin and ibuprofen reversed the effect of LPS on behaviour without changing peripheral or central IL-6, IL-1beta and TNF-alpha mRNA levels. In contrast, dexamethasone did not alter LPS-induced behavioural changes, despite complete inhibition of cytokine production. A selective COX-1 inhibitor, piroxicam, but not the selective COX-2 inhibitor, nimesulide, reversed the LPS-induced behavioural changes without affecting IL-6, IL-1beta and TNF-alpha protein expression levels in the periphery or mRNA levels in the hippocampus. Our results suggest that the acute LPS-induced changes in burrowing and open-field activity depend on COX-1. We further show that COX-1 is not responsible for the induction of brain IL-6, IL-1beta and TNF-alpha synthesis or LPS-induced hypothermia. Our results may have implications for novel therapeutic strategies to treat or prevent neurological diseases with an inflammatory component.


Long term running biphasically improves methylglyoxal-related metabolism, redox homeostasis and neurotrophic support within adult mouse brain cortex.
Oxidative stress and neurotrophic support decline seem to be crucially involved in brain aging. Emerging evidences indicate the pro-oxidant methylglyoxal (MG) as a key player in the age-related dicarbonyl stress and molecular damage within the central nervous system. Although exercise promotes the overproduction of reactive oxygen species, habitual exercise may retard cellular aging and reduce the age-dependent cognitive decline through hormetic adaptations, yet molecular mechanisms underlying beneficial effects of exercise are still largely unclear. In particular, whereas adaptive responses induced by exercise initiated in youth have been broadly investigated, the effects of chronic and moderate exercise begun in adult age on biochemical hallmarks of very early senescence in mammal brains have not been extensively studied. This research investigated whether a long-term, forced and moderate running initiated in adult age may affect the interplay between the redox-related profile and the oxidative-/MG-dependent molecular damage patterns in CD1 female mice cortices; as well, we investigated possible exercise-induced effects on the activity of the brain derived neurotrophic factor (BDNF)-dependent pathway. Our findings suggested that after a transient imbalance in almost all parameters investigated, the lately-initiated exercise regimen strongly reduced molecular damage profiles in brains of adult mice, by enhancing activities of the main ROS- and MG-targeting scavenging systems, as well as by preserving the BDNF-dependent signaling through the transition from adult to middle age.


Exposure of dogs to spotted fever group rickettsiae in urban sites associated with human rickettsioses in Costa Rica.
The zoonotic transmission cycles of Rickettsia rickettsii and other spotted fever group (SFG) rickettsiae in Latin America have usually been associated with rural or sylvatic environments, although domestic dogs can be implicated in more populated settings. In this study, exposure of dogs to SFG rickettsiae in the Greater Metropolitan Area of Costa Rica was investigated. Dogs from sites associated with human cases and from dog shelters were evaluated by indirect immunofluorescence assay (IFA) using antigen of SFG rickettsiae. Rickettsia spp. were detected in ectoparasites by polymerase chain reaction (PCR). A total 18.5% (31/168) of dogs associated with human cases and 6.8% (11/161) of dogs in shelters had IgG end titers≥64 to Rickettsia spp. The odds of being seropositive were greater in dogs from areas associated with human cases when compared to shelters (OR: 3.2; 95% C.I: 1.5-5.6). Rhipicephalus sanguineus sensu lato (s. l.) was present in all sites associated with human cases. Rickettsia felis URRWXCal2 and R. felis-like RF2125 were detected in Ctenocephalides felis, and Rickettsia sp. IbR/CRC in Ixodes boliviensis. Results demonstrate that dogs from the main urban center of Costa Rica have been exposed to SFG rickettsiae, especially in areas with known human infection. Both human and animal health sectors must be aware of possible rickettsial diseases in urban areas, where dogs may also serve as sentinels for human infection.


Status of and prospects for cancer vaccines against hepatocellular carcinoma in clinical trials.
Current therapies to treat advanced hepatocellular carcinoma (HCC) are not satisfactory because of the high rate of recurrence after treatment and because of severe complications after surgery. Cancer vaccines have been studied for decades to achieve effective, micro-invasive, long-lasting anti-tumor action. Cancer vaccines are designed to promote tumor-specific immune responses and increase specific cytotoxic CD8-positive T cells. This review summarizes 16 phase I clinical trials of cancer vaccines against HCC that have been conducted over the past 10 years. According to those trials, the Alpha fetoprotein (AFP), Glypican-3 (GPC3), and Multidrug resistance-associated protein 3 (MRP3) vaccines were well tolerated and safe. Some early clinical trials have shown that vaccination resulted in a large number of T cells activated by a specific tumor-associated antigen in the circulation, but clinical outcomes were not satisfactory. This may be because targets for immunosuppressive agents have yet to be clearly determined in HCC. Therapeutic regimens that combine activative agents and suppressive agents may profoundly improve clinical outcomes for patients with HCC in the future.


The Impact of Federal and State Conservation Programs on Farmer Nitrogen Management.
The U.S. federal government, as well as many state and local governments, operate a number of conservation programs aimed at ameliorating the environmental problems associated with agriculture. While motives and barriers to conservation program participation and adoption of conservation practices have been extensively studied, the direct impacts of programs on ongoing farm operations remains underexplored. To examine the effects of conservation programs on nitrogen management, an aspect of crop production with significant environmental impacts we conducted interviews with 154 corn producers in three Midwestern U.S. states with a range of program experiences. We found that programs shifted farmer N management behavior through three social processes: (1) engaging farmers in the conservation system by introducing them to the state and federal conservation agencies, (2) incentivizing trialing of specific N management practices, and (3) increasing practice adoption through continued program engagement. Working-lands programs were far more effective at shifting on-farm nutrient management practices than land retirement, certification, or outreach-based programs, though all programs had the indirect benefit of increasing farmer familiarity with conservation agencies and programs. Working-lands programs directly motivated practice adoption; including soil testing regimes, implementing nutrient management plans, and splitting nitrogen applications to improving availability; by reducing producer risk and providing technical assistance, especially whole-farm planning. The additional benefits of all programs were moderated by participant selection bias, in particular that program participants were more predisposed to conservation efforts by existing stewardship and innovation attitudes.


Changing climate both increases and decreases European river floods.
Climate change has led to concerns about increasing river floods resulting from the greater water-holding capacity of a warmer atmosphere1. These concerns are reinforced by evidence of increasing economic losses associated with flooding in many parts of the world, including Europe2. Any changes in river floods would have lasting implications for the design of flood protection measures and flood risk zoning. However, existing studies have been unable to identify a consistent continental-scale climatic-change signal in flood discharge observations in Europe3, because of the limited spatial coverage and number of hydrometric stations. Here we demonstrate clear regional patterns of both increases and decreases in observed river flood discharges in the past five decades in Europe, which are manifestations of a changing climate. Our results-arising from the most complete database of European flooding so far-suggest that: increasing autumn and winter rainfall has resulted in increasing floods in northwestern Europe; decreasing precipitation and increasing evaporation have led to decreasing floods in medium and large catchments in southern Europe; and decreasing snow cover and snowmelt, resulting from warmer temperatures, have led to decreasing floods in eastern Europe. Regional flood discharge trends in Europe range from an increase of about 11 per cent per decade to a decrease of 23 per cent. Notwithstanding the spatial and temporal heterogeneity of the observational record, the flood changes identified here are broadly consistent with climate model projections for the next century4,5, suggesting that climate-driven changes are already happening and supporting calls for the consideration of climate change in flood risk management.


An adaptive system identification approach to optical trap calibration.
A method of adaptive system identification for the modeling of an optical trap's system dynamics is presented. The system dynamics can be used to locate the corner frequency for trapping stiffness calibration using the power spectral method. The method is based on an adaptive least-mean-square (LMS) algorithm, which adjusts weights of a tapped delay line filter using a gradient descent method. The identified model is the inverse of the high order finite impulse response (FIR) filter. The model order is reduced using balanced model reduction, giving the corner frequency which can be used to calibrate the trapping stiffness. This method has an advantage over other techniques in that it is quick, does not explicitly require operator interaction, and can be acquired in real time. It is also a necessary step for an adaptive controller that can automatically update the controller for changes in the trap (e.g., power fluctuations) and for particles of different sizes and refractive indices.


Influence of crystal tilt on solar irradiance of cirrus clouds.
The single and multiple scattering and absorption properties of hexagonal ice columns with different degrees of particle orientation are modeled in the solar spectral range by means of a ray-tracing single-scattering code and a Monte Carlo radiative-transfer code. The scattering properties are most sensitive to particle orientation for the solar zenith angles of 50 degrees (asymmetry parameter) and 90 degrees (single-scattering albedo). Provided that the ice columns are horizontally oriented, the usual assumption of random orientation leads to an overestimation (underestimation) of the reflected (transmitted) solar broadband radiation at high Sun elevation and to an underestimation (overestimation) at medium solar zenith angles. The orientation effect is more (less) pronounced in scattering and transmission (absorption) for smaller ice crystals.


Ellipticine and benzo(a)pyrene increase their own metabolic activation via modulation of expression and enzymatic activity of cytochromes P450 1A1 and 1A2.
Two compounds known to covalently bind to DNA after their activation with cytochromes P450 (CYPs), carcinogenic benzo(a)pyrene (BaP) and an antineoplastic agent ellipticine, were investigated for their potential to induce CYP and NADPH:CYP reductase (POR) enzymes in rodent livers, the main target organ for DNA adduct formation. Two animal models were used in the study: (i) rats as animals mimicking the fate of ellipticine in humans and (ii) mice, especially wild-type (WT) and hepatic POR null (HRN™) mouse lines. Ellipticine and BaP induce expression of CYP1A enzymes in livers of experimental models, which leads to increase in their enzymatic activity. In addition, both compounds are capable of generating DNA adducts, predominantly in livers of studied organisms. As determined by (32)P postlabelling analysis, levels of ellipticine-derived DNA adducts formed in vivo in the livers of HRN™ mice were reduced (by up to 65%) relative to levels in WT mice, indicating that POR mediated CYP enzyme activity is important for the activation of ellipticine. In contrast to these results, 6.4 fold higher DNA binding of BaP was observed in the livers of HRN™ mice than in WT mice. This finding suggests a detoxication role of CYP1A in BaP metabolism in vivo. In in vitro experiments, DNA adduct formation in calf thymus DNA was up to 25 fold higher in incubations of ellipticine or BaP with microsomes from pretreated animals than with controls. This stimulation effect was attributed to induction of CYP1A1/2 enzymes, which are responsible for oxidative activation of both compounds to the metabolites generating major DNA adducts in vitro. Taken together, these results demonstrate that by inducing CYP1A1/2, ellipticine and BaP modulate their own enzymatic metabolic activation and detoxication, thereby modulating their either pharmacological (ellipticine) and/or genotoxic potential (both compounds).


Regulation of Cortical Dynamic Range by Background Synaptic Noise and Feedforward Inhibition.
The cortex encodes a broad range of inputs. This breadth of operation requires sensitivity to weak inputs yet non-saturating responses to strong inputs. If individual pyramidal neurons were to have a narrow dynamic range, as previously claimed, then staggered all-or-none recruitment of those neurons would be necessary for the population to achieve a broad dynamic range. Contrary to this explanation, we show here through dynamic clamp experiments in vitro and computer simulations that pyramidal neurons have a broad dynamic range under the noisy conditions that exist in the intact brain due to background synaptic input. Feedforward inhibition capitalizes on those noise effects to control neuronal gain and thereby regulates the population dynamic range. Importantly, noise allows neurons to be recruited gradually and occludes the staggered recruitment previously attributed to heterogeneous excitation. Feedforward inhibition protects spike timing against the disruptive effects of noise, meaning noise can enable the gain control required for rate coding without compromising the precise spike timing required for temporal coding.


Vitamin D receptor gene polymorphisms are not related to bone turnover, rate of bone loss, and bone mass in postmenopausal women: the OFELY Study.
Vitamin D receptor (VDR) gene polymorphisms have been reported to account for most of the well established genetic influence on bone mineral density (BMD). However, discordant studies have been published and it is still not clear whether VDR genotypes influence bone mass accretion and/or postmenopausal bone loss. In this study, we analyzed VDR gene polymorphisms, i.e., that of BsmI, ApaI, and TaqI restriction enzymes in 268 untreated postmenopausal women 1-26 years postmenopausal. There were 37 BBAA homozygote (absence of BsmI and ApaI restriction sites on both alleles), 55 bbaa homozygote (presence of restriction sites on both alleles), and 176 heterozygotes. At baseline, women between the three genotypes did not differ significantly in age, years since menopause, body mass index (BMI), nor dietary calcium intake. We found no relationship between VDR genotypes and bone turnover assessed by three serum markers of bone formation and three urinary bone resorption markers, nor with BMD measured at the spine, hip, forearm, and whole body by dual-energy X-ray absorptiometry (DXA). Rates of bone loss assessed by repeated DXA measurements over 2 years were highly significant (p = 0.02-0.0001) at all skeletal sites except for the lumbar spine but did not differ between genotypes at any sites either before or after adjustment for potential confounding factors such as years since menopause, BMI, calcium intake, serum 25 hydroxyvitamin D levels, and baseline BMD. When we restricted the analysis to early postmenopausal women, within 10 years of menopause (n = 128), lumbar spine bone loss became significant, but no significant difference between VDR genotypes in the rate of bone loss measured at any site was found. We conclude that VDR genotypes are not predictive of bone turnover, rate of postmenopausal bone loss, and bone mass in either early or late postmenopausal women. In a subgroup of women with a low calcium intake (below 600 mg/day), we also found no significant differences between genotypes in BMD and the rate of bone loss measured at any site, although the sample size (n = 64) may be too small to detect small differences. In conclusion, these data, along with the absence of relationships between VDR gene polymorphisms and peak bone mass that we recently reported, suggest that the determination of VDR genotypes is probably not a useful clinical test for the risk assessment of osteoporosis.


Familiar units prevail over statistical cues in word segmentation.
In language acquisition research, the prevailing position is that listeners exploit statistical cues, in particular transitional probabilities between syllables, to discover words of a language. However, other cues are also involved in word discovery. Assessing the weight learners give to these different cues leads to a better understanding of the processes underlying speech segmentation. The present study evaluated whether adult learners preferentially used known units or statistical cues for segmenting continuous speech. Before the exposure phase, participants were familiarized with part-words of a three-word artificial language. This design allowed the dissociation of the influence of statistical cues and familiar units, with statistical cues favoring word segmentation and familiar units favoring (nonoptimal) part-word segmentation. In Experiment 1, performance in a two-alternative forced choice (2AFC) task between words and part-words revealed part-word segmentation (even though part-words were less cohesive in terms of transitional probabilities and less frequent than words). By contrast, an unfamiliarized group exhibited word segmentation, as usually observed in standard conditions. Experiment 2 used a syllable-detection task to remove the likely contamination of performance by memory and strategy effects in the 2AFC task. Overall, the results suggest that familiar units overrode statistical cues, ultimately questioning the need for computation mechanisms of transitional probabilities (TPs) in natural language speech segmentation.


Diagnosing invasive fungal disease in critically ill patients.
Fungal infections are increasing, with a changing landscape of pathogens and emergence of new groups at risk for invasive disease. We review current diagnostic techniques, focusing on studies in critically ill patients. Microbiological cultures, the current "gold standard", demonstrate poor sensitivity, thus diagnosis of invasive disease in the critically ill is difficult. This diagnostic dilemma results in under- or over-treatment of patients, potentially contributing to poor outcomes and antifungal resistance. While other current diagnostic tests perform moderately well, many lack timeliness, efficacy, and are negatively affected by treatments common to critically ill patients. New nucleic acid-based research is promising.


Bird Satellite Tracking Revealed Critical Protection Gaps in East Asian⁻Australasian Flyway.
Most migratory birds depend on stopover sites, which are essential for refueling during migration and affect their population dynamics. In the East Asian⁻Australasian Flyway (EAAF), however, the stopover ecology of migratory waterfowl is severely under-studied. The knowledge gaps regarding the timing, intensity and duration of stopover site usages prevent the development of effective and full annual cycle conservation strategies for migratory waterfowl in EAAF. In this study, we obtained a total of 33,493 relocations and visualized 33 completed spring migratory paths of five geese species using satellite tracking devices. We delineated 2,192,823 ha as the key stopover sites along the migration routes and found that croplands were the largest land use type within the stopover sites, followed by wetlands and natural grasslands (62.94%, 17.86% and 15.48% respectively). We further identified the conservation gaps by overlapping the stopover sites with the World Database on Protected Areas (PA). The results showed that only 15.63% (or 342,757 ha) of the stopover sites are covered by the current PA network. Our findings fulfil some key knowledge gaps for the conservation of the migratory waterbirds along the EAAF, thus enabling an integrative conservation strategy for migratory water birds in the flyway.


A cross-sectional and 6-year follow-up study of associations between leisure time physical activity and vertebral fracture in adults.
Vertebral fractures are common osteoporotic fractures, affecting 2-46% of the population, causing morbidity and increased risk of mortality. Physical activity has beneficial effects for bone health, including increased bone mineral density and reduced hip fractures. However, evidence concerning prevention of vertebral fractures is scarce. Therefore, the aim of this study was to investigate the association between leisure time physical activity and vertebral fracture risk. The data were retrieved from the 2001 and 2007-2008 surveys of the Tromsø Study, a longitudinal population study in Norway. A total of 1904 participants (1030 women and 874 men, age 38-87 yr and 40-87 yr respectively) were included in the cross-sectional analysis (2007-2008). Prospective follow-up data (2001 to 2007) on physical activity were available for 1131 participants (636 women and 495 men, age 32-69 yr and 33-69 yr respectively). Physical activity was assessed by a questionnaire and vertebral fracture by lateral vertebral fracture assessment from dual-energy x-ray absorptiometry scans. Logistic regression was used to examine associations between physical activity and vertebral fracture. After controlling for confounders (age, height, weight, smoking, osteoporosis, osteoporosis medication, left hip total bone mineral density, and use of hormones in women only), no cross-sectional associations between physical activity levels and vertebral fracture were observed, OR 1.13 (95% CI: 0.59-2.13), for moderately active women and 1.44 (0.61-3.42) for highly active women, compared with sedentary women. In men, the respective ORs were 1.74 (95% CI: 0.91-3.35) and 1.64 (0.78-3.41). In the prospective analyses, OR for vertebral fracture in women with reduced physical activity was 0.81 (95% CI: 0.18-3.62), 1.24 (95% CI: 0.29-5.26) for increased physical activity and 1.54 (95% CI: 0.43-5.50) for active unchanged physical activity pattern, compared with sedentary unchanged physical activity. In men, the respective ORs were 2.05 (95% CI: 0.57-7.42), 2.23 (95% CI: 0.63-7.87), and 1.81 (95% CI: 0.54-6.02). Subanalyses of women and men ≥50 yr showed similar results. Our findings suggest that physical activity does not play a major role in preventing vertebral fractures in Norwegian adults. Future studies may benefit from data on incident vertebral fracture, and objectively measured physical activity.


Person-Based Brain Morphometric Similarity is Heritable and Correlates With Biological Features.
The characterization of the functional significance of interindividual variation in brain morphometry is a core aim of cognitive neuroscience. Prior research has focused on interindividual variation at the level of regional brain measures thus overlooking the fact that each individual brain is a person-specific ensemble of interdependent regions. To expand this line of inquiry we introduce the person-based similarity index (PBSI) for brain morphometry. The conceptual unit of the PBSI is the individual person's brain structural profile which considers all relevant morphometric measures as features of a single vector. In 2 independent cohorts (total of 1756 healthy participants), we demonstrate the foundational validity of this approach by affirming that the PBSI scores for subcortical volume and cortical thickness in healthy individuals differ between men and women, are heritable, and robust to variation in neuroimaging parameters, sample composition, and regional brain morphometry. Moreover, the PBSI scores correlate with age, body mass index, and fluid intelligence. Collectively, these results suggest that the person-based measures of brain morphometry are biologically and functionally meaningful and have the potential to advance the study of human variation in multivariate brain imaging phenotypes in healthy and clinical populations.


Image formation in image scanning microscopy, including the case of two-photon excitation.
The effect of combining the image scanning microscopy (ISM) technique with two-photon fluorescence microscopy is analyzed. The effective spatial frequency cutoff can be doubled, as compared with conventional two-photon fluorescence microscopy, and the magnitude of the optical transfer function near the cutoff of conventional two-photon microscopy is increased by orders of magnitude. For the two-photon case, it is found that the optimum pixel reassignment factor in ISM is not equal to one half, as is often assumed in single-photon fluoresence image scanning microscopy, because the excitation and detection point spread functions are different. The optimum reassignment factor depends on the noise level, and in general the useful cutoff spatial frequency is about 1.8 times that for conventional two-photon microscopy. The effect of altering the reassignment factor in single-photon fluorescence ISM with a Stokes shift is also investigated. Illumination using pupil filters, such as by a Bessel beam, is considered. Using a ring detector array is found to result in good imaging behavior, exhibiting a sharpening of the point spread function by a factor of 1.7 compared with conventional fluorescence. Image formation in ISM can be considered in a four-dimensional spatial frequency space, giving new insight into the imaging properties. This approach is related to phase space representations such as the Wigner distribution function and the ambiguity function. A noniterative algorithm for image restoration is proposed.


Melatonin suppression by static and extremely low frequency electromagnetic fields: relationship to the reported increased incidence of cancer.
An increased cancer incidence has been reported in individuals living and/or working in an environment in which they are exposed to higher than normal artificial electromagnetic fields. One of the most uniform changes associated with the exposure of animals to either pulsed static geomagnetic fields or to sinusoidal extremely low frequency magnetic fields has been a reduction in high night-time levels of melatonin. Melatonin is a hormone produced especially at night in the pineal gland, a pea-sized organ near the center of the human brain. The high nocturnal production of melatonin leads to elevated blood melatonin levels at night as well. The exposure of humans or animals to light (visible electromagnetic radiation) at night rapidly depresses pineal melatonin production and blood melatonin levels. Likewise, the exposure of animals to various pulsed static and extremely low frequency magnetic fields also reduces melatonin levels. Melatonin is a potent oncostatic agent and it prevents both the initiation and promotion of cancer. Reduction of melatonin, at night, by any means, increases cells' vulnerability to alteration by carcinogenic agents. Thus, if in fact artificial electromagnetic field exposure increases the incidence of cancer in humans, a plausible mechanism could involve a reduction in melatonin which is the consequence of such exposures.


Neuromyelitis optica and the evolving spectrum of autoimmune aquaporin-4 channelopathies: a decade later.
The discovery of AQP4-IgG (a pathogenic antibody that targets the astrocytic water channel aquaporin-4), as the first sensitive and specific biomarker for any inflammatory central nervous system demyelinating disease (IDD), has shifted emphasis from the oligodendrocyte and myelin to the astrocyte as a central immunopathogenic player. Neuromyelitis optica (NMO) spectrum disorders (SDs) represent an evolving spectrum of IDDs extending beyond the optic nerves and spinal cord to include the brain (especially in children) and, rarely, muscle. NMOSD typical brain lesions are located in areas that highly express the target antigen, AQP4, including the circumventricular organs (accounting for intractable nausea and vomiting) and the diencephalon (accounting for sleep disorders, endocrinopathies, and syndrome of inappropriate antidiuresis). Magnetic resonance imaging brain abnormalities fulfill Barkoff criteria for multiple sclerosis in up to 10% of patients. As the spectrum broadens, the importance of highly specific assays that detect pathogenic AQP4-IgG targeting extracellular epitopes of AQP4 cannot be overemphasized. The rapid evolution of our understanding of the immunobiology of AQP4 autoimmunity necessitates continuing revision of NMOSD diagnostic criteria. Here, we describe scientific advances that have occurred since the discovery of NMO-IgG in 2004 and review novel targeted immunotherapies. We also suggest that NMOSDs should now be considered under the umbrella term autoimmune aquaporin-4 channelopathy.


Crystallization and preliminary structural analysis of dibenzothiophene monooxygenase (DszC) from Rhodococcus erythropolis.
Dibenzothiophene (DBT) and its derivatives are typical sulfur compounds found in fossil fuels. These compounds show resistance to the hydrodesulfurization treatment that is commonly used in industry. Dibenzothiophene monooxygenase (DszC) is responsible for the oxidation of DBT, which is the first and the rate-limiting step in the DBT enzymatic desulfurization 4S pathway. In this study, the crystal structure of DszC from Rhodococcus erythropolis DS-3 is reported. The crystal of native DszC belonged to space group P1, with unit-cell parameters a = 96.16, b = 96.27, c = 98.56 Å, α = 81.03, β = 67.57, γ = 85.84°. To determine the phase, SAD X-ray diffraction data were collected from a SeMet-derivative DszC crystal, which also belonged to space group P1, with unit-cell parameters a = 95.379, b = 95.167, c = 94.891 Å, α = 87.046, β = 70.536, γ = 79.738°. Further structural analysis of DszC is in progress.


Depression in patients with cancer. Diagnosis, biology, and treatment.
This article reviews the challenge of diagnosing depression in patients with cancer. Major depression and depressive symptoms, although commonly encountered in medical populations, are frequently underdiagnosed and undertreated. This is especially true for patients with cancer in whom the diagnosis of major depression is clouded by neurovegetative symptoms that may be secondary to either cancer or depression. Well-established biological markers for major depression are proposed as diagnostic adjuncts in patients with cancer. Studies using biological markers in depressed patients with and without cancer are reviewed, and the implications of diminished immune function in depressed patients with cancer are discussed. The limited database on treatment of depression in patients with cancer also is reviewed. Treatment of depression in these patients improves their dysphoria and other signs and symptoms of depression, improves quality of life, and may improve immune function and survival time. Guidelines for future research are proposed.


The GreenCut2 resource, a phylogenomically derived inventory of proteins specific to the plant lineage.
The plastid is a defining structure of photosynthetic eukaryotes and houses many plant-specific processes, including the light reactions, carbon fixation, pigment synthesis, and other primary metabolic processes. Identifying proteins associated with catalytic, structural, and regulatory functions that are unique to plastid-containing organisms is necessary to fully define the scope of plant biochemistry. Here, we performed phylogenomics on 20 genomes to compile a new inventory of 597 nucleus-encoded proteins conserved in plants and green algae but not in non-photosynthetic organisms. 286 of these proteins are of known function, whereas 311 are not characterized. This inventory was validated as applicable and relevant to diverse photosynthetic eukaryotes using an additional eight genomes from distantly related plants (including Micromonas, Selaginella, and soybean). Manual curation of the known proteins in the inventory established its importance to plastid biochemistry. To predict functions for the 52% of proteins of unknown function, we used sequence motifs, subcellular localization, co-expression analysis, and RNA abundance data. We demonstrate that 18% of the proteins in the inventory have functions outside the plastid and/or beyond green tissues. Although 32% of proteins in the inventory have homologs in all cyanobacteria, unexpectedly, 30% are eukaryote-specific. Finally, 8% of the proteins of unknown function share no similarity to any characterized protein and are plant lineage-specific. We present this annotated inventory of 597 proteins as a resource for functional analyses of plant-specific biochemistry.


Inorganic mixed phase templated by a fatty acid monolayer at the air-water interface: the Mn and Mg case.
We studied by means of Grazing Incidence X-ray Diffraction (GIXD) coupled with X-ray fluorescence spectroscopy the structure of a behenic acid monolayer spread at the surface of Mg2+/Mn2+ mixed aqueous solutions. For the pure Mg2+ and Mn2+ aqueous solutions, the cations induce at the surface different 2D lattice superstructures of the organic monolayer. These superstructures correspond to an inorganic organized monolayer anchored to the hydrophilic group of the ordered behenic acid monolayer. Among the various diffraction peaks, we focused on those characteristics of the behenic acid oblique cell. As the Mg2+ mole fraction x increases in the Mg2+/Mn2+ mixed subphase, a continuous evolution of the oblique cell parameters is observed indicating the insertion of Mg2+ cations in the Mn2+ ordered monolayer. Then, a further increase leads to the appearance of a coexistence between two oblique surface phases. The cell parameters of both phases evolve continuously along the x range of the transition until a single Mg-rich ordered phase is detected. However, although the intensities of the peaks in the coexistence region are in agreement with a first-order phase transition, the cell parameters evolve simultaneously. Considering a thermodynamics analysis, this evidences that, apart from the concentration, another unidentified intensive parameter is varying. We suggest that it is the ionic strength, which appears to be strongly related to the concentrations.


Metabolite profiles during oral glucose challenge.
To identify distinct biological pathways of glucose metabolism, we conducted a systematic evaluation of biochemical changes after an oral glucose tolerance test (OGTT) in a community-based population. Metabolic profiling was performed on 377 nondiabetic Framingham Offspring cohort participants (mean age 57 years, 42% women, BMI 30 kg/m(2)) before and after OGTT. Changes in metabolite levels were evaluated with paired Student t tests, cluster-based analyses, and multivariable linear regression to examine differences associated with insulin resistance. Of 110 metabolites tested, 91 significantly changed with OGTT (P ≤ 0.0005 for all). Amino acids, β-hydroxybutyrate, and tricarboxylic acid cycle intermediates decreased after OGTT, and glycolysis products increased, consistent with physiological insulin actions. Other pathways affected by OGTT included decreases in serotonin derivatives, urea cycle metabolites, and B vitamins. We also observed an increase in conjugated, and a decrease in unconjugated, bile acids. Changes in β-hydroxybutyrate, isoleucine, lactate, and pyridoxate were blunted in those with insulin resistance. Our findings demonstrate changes in 91 metabolites representing distinct biological pathways that are perturbed in response to an OGTT. We also identify metabolite responses that distinguish individuals with and without insulin resistance. These findings suggest that unique metabolic phenotypes can be unmasked by OGTT in the prediabetic state.


Myofibre damage in human skeletal muscle: effects of electrical stimulation versus voluntary contraction.
Disruption to proteins within the myofibre after a single bout of unaccustomed eccentric exercise is hypothesized to induce delayed onset of muscle soreness and to be associated with an activation of satellite cells. This has been shown in animal models using electrical stimulation but not in humans using voluntary exercise. Untrained males (n=8, range 22-27 years) performed 210 maximal eccentric contractions with each leg on an isokinetic dynamometer, voluntarily (VOL) with one leg and electrically induced (ES) with the other leg. Assessments from the skeletal muscle were obtained prior to exercise and at 5, 24, 96 and 192 h postexercise. Muscle tenderness rose in VOL and ES after 24 h, and did not differ between groups. Maximal isometric contraction strength, rate of force development and impulse declined in the VOL leg from 4 h after exercise, but not in ES (except at 24 h). In contrast, a significant disruption of cytoskeletal proteins (desmin) and a rise of myogenic growth factors (myogenin) occurred only in ES. Intracellular disruption and destroyed Z-lines were markedly more pronounced in ES (40%) compared with VOL (10%). Likewise, the increase in satellite cell markers [neural cell adhesion molecule (N-CAM) and paired-box transcription factor (Pax-7)] was more pronounced in ES versus VOL. Finally, staining of the intramuscular connective tissue (tenascin C) was increased equally in ES and VOL after exercise. The present study demonstrates that in human muscle, the delayed onset of muscle soreness was not significantly different between the two treatments despite marked differences in intramuscular histological markers, in particular myofibre proteins and satellite cell markers. An increase in tenascin C expression in the midbelly of the skeletal muscle in both legs provides further evidence of a potential role for the extracellular matrix in the phenomenon of delayed onset of muscle soreness.


Refinement of pairwise potentials via logistic regression to score protein-protein interactions.
Protein-protein interactions (PPIs) are ubiquitous and functionally of great importance in biological systems. Hence, the accurate prediction of PPIs by protein-protein docking and scoring tools is highly desirable in order to characterize their structure and biological function. Ab initio docking protocols are divided into the sampling of docking poses to produce at least one near-native structure, and then to evaluate the vast candidate structures by scoring. Concurrent development in both sampling and scoring is crucial for the deployment of protein-protein docking software. In the present work, we apply a machine learning model on pairwise potentials to refine the task of protein quaternary structure native structure detection among decoys. A decoy set was featurized using the Knowledge and Empirical Combined Scoring Algorithm 2 (KECSA2) pairwise potential. The highly unbalanced decoy set was then balanced using a comparison concept between native and decoy structures. The resultant comparison descriptors were used to train a logistic regression (LR) classifier. The LR model yielded the optimal performance for native detection among decoys compared with conventional scoring functions, while exhibiting lesser performance for the detection of low root mean square deviation decoy structures. Its deployment on an independent benchmark set confirms that the scoring function performs competitively relative to other scoring functions. The scripts used are available at https://github.com/TanemuraKiyoto/PPI-native-detection-via-LR.


Supervised, Vigorous Intensity Exercise Intervention for Depressed Female Smokers: A Pilot Study.
Few studies have evaluated exercise interventions for smokers with depression or other psychiatric comorbidities. This pilot study evaluated the potential role of supervised vigorous exercise as a smoking cessation intervention for depressed females. Thirty adult women with moderate-severe depressive symptoms were enrolled and randomly assigned to 12 weeks of thrice weekly, in person sessions of vigorous intensity supervised exercise at a YMCA setting (EX; n = 15) or health education (HE; n = 15). All participants received behavioral smoking cessation counseling and nicotine patch therapy. Assessments were done in person at baseline, at the end of 12 weeks of treatment, and at 6 months post-target quit date. Primary end points were exercise adherence (proportion of 36 sessions attended) and biochemically confirmed 7-day point prevalence abstinence at Week 12. Biomarkers of inflammation were explored for differences between treatment groups and between women who smoked and those abstinent at Week 12. Treatment adherence was high for both groups (72% for EX and 66% for HE; p = .55). The Week 12 smoking abstinence rate was higher for EX than HE (11/15 [73%] vs. 5/15 [33%]; p = .028), but no significant differences emerged at 6-month follow-up. Interleukin-6 levels increased more for those smoking than women abstinent at Week 12 (p = .040). Vigorous intensity supervised exercise is feasible and enhances short-term smoking cessation among depressed female smokers. Innovative and cost-effective strategies to bolster long-term exercise adherence and smoking cessation need evaluation in this population. Inflammatory biomarkers could be examined in future research as mediators of treatment efficacy. This preliminary study found that vigorous intensity supervised exercise is feasible and enhances short-term smoking cessation among depressed female smokers. This research addressed an important gap in the field. Despite decades of research examining exercise interventions for smoking cessation, few studies were done among depressed smokers or those with comorbid psychiatric disorders. A novel finding was increases in levels of a pro-inflammatory biomarker observed among women who smoked at the end of the intervention compared to those who did not.


Polyphenolic Characterization and Antioxidant Activity of Malus domestica and Prunus domestica Cultivars from Costa Rica.
The phenolic composition of skin and flesh from Malus domestica apples (Anna cultivar) and Prunus domestica plums (satsuma cultivar) commercial cultivars in Costa Rica, was studied using Ultra Performance Liquid Chromatography coupled with High Resolution Mass Spectrometry (UPLC-DAD-ESI-MS) on enriched-phenolic extracts, with particular emphasis in proanthocyanidin and flavonoids characterization. A total of 52 compounds were identified, including 21 proanthocyanidins ([(+)-catechin and (-)-epicatechin]) flavan-3-ols monomers, five procyanidin B-type dimers and two procyanidin A-type dimers, five procyanidin B-type trimers and two procyanidin A-type trimers, as well as one procyanidin B-type tetramer, two procyanidin B-type pentamers, and two flavan-3-ol gallates); 15 flavonoids (kaempferol, quercetin and naringenin derivatives); nine phenolic acids (protochatechuic, caffeoylquinic, and hydroxycinnamic acid derivatives); five hydroxychalcones (phloretin and 3-hydroxyphloretin derivatives); and two isoprenoid glycosides (vomifoliol derivatives). These findings constitute the first report of such a high number and diversity of compounds in skins of one single plum cultivar and of the presence of proanthocyanidin pentamers in apple skins. Also, it is the first time that such a large number of glycosylated flavonoids and proanthocyanidins are reported in skins and flesh of a single plum cultivar. In addition, total phenolic content (TPC) was measured with high values observed for all samples, especially for fruits skins with a TPC of 619.6 and 640.3 mg gallic acid equivalents/g extract respectively for apple and plum. Antioxidant potential using 2,2-diphenyl-1-picrylhidrazyl (DPPH) and oxygen radical absorbance capacity (ORAC) methods were evaluated, with results showing also high values for all samples, especially again for fruit skins with IC50 of 4.54 and 5.19 µg/mL (DPPH) and 16.8 and 14.6 mmol TE/g (ORAC) respectively for apple and plum, indicating the potential value of these extracts. Significant negative correlation was found for both apple and plum samples between TPC and DPPH antioxidant values, especially for plum fruits (R = -0.981, p < 0.05) as well as significant positive correlation between TPC and ORAC, also especially for plum fruits (R = 0.993, p < 0.05) and between both, DPPH and ORAC antioxidant methods (R = 0.994, p < 0.05).


Losing Years Doing Time: Incarceration Exposure and Accelerated Biological Aging among African American Adults.
Research suggests that incarceration exposure increases the prevalence of morbidity and premature mortality. This work is only beginning to examine whether the stressors of the incarceration experience become biologically embedded in ways that affect physiological deterioration. Using data from a longitudinal sample of 410 African American adults in the Family and Community Health Study and an epigenetic index of aging, this study tests the extent to which incarceration accelerates epigenetic aging and whether experiences with violence moderate this association. Results from models that adjust for selection effects suggest that incarceration exposure predicted accelerated aging, leaving formerly incarcerated African American individuals biologically older than their calendar age. Direct experiences with violence also exacerbated the effects of incarceration. These findings suggest that incarceration possibly triggers a stress response that affects a biological signature of physiological deterioration.


Employer-Supported Volunteerism in Rural Worksites.
Employer-supported volunteerism has the potential to benefit employees and ultimately have a positive business impact. Volunteerism has been linked to improved quality of life, reduced morbidity, and higher self-rated health. This study was designed to understand what small, rural worksites are doing with regard to volunteerism, and what their barriers are to such activities. An online survey was distributed to worksites using the social network of a Resource, Conservation, and Development Council, a rural nonprofit entity. Analyses included descriptive statistics, and for qualitative data, review and summary of common themes. Thirty-eight worksites responded, representing a wide range of worksite types. Volunteer activities requiring less time and resources to organize were more commonly employed versus group-based activities. Identified barriers included time, costs, small staffing numbers, perceived employee lack of interest, worksite policies, distance to volunteer sites, language barriers, and lack of awareness of opportunities. Despite a variety of challenges, some forms of employer-supported volunteerism seem feasible even in very small rural worksites. Worksite type, culture, and leadership are likely to be determinants of the extent and nature of employer-supported volunteerism. Strategies to encourage greater volunteerism need to be tailored to the interests and resources of each site. Occupational health nurses should consider incorporating some form of employee volunteerism activities within their health promotion programming, as it is consistent with an overall strategy of enhancing employee well-being. This could lead to positive business impacts such as increased employee engagement, improved recruitment and retention, and improved productivity.


Association between inflammatory potential of diet and risk of depression in middle-aged women: the Australian Longitudinal Study on Women's Health.
Dietary factors and inflammation markers have been shown to play a role in the development of depression. However, there are very few studies that have explored the association between inflammatory potential of diet and risk of depression. In this study, we examined the association between the dietary inflammatory index (DII), which was developed specifically to measure the inflammatory potential of diet, and risk of depression in the middle-aged cohort of the Australian Longitudinal Study on Women's Health. A total of 6438 women with a mean age of 52·0 (sd 1·4) years at baseline were followed-up at five surveys over 12 years (2001-2013). Depression was defined as a score of ≥10 on the Center for Epidemiologic Studies Depression-10 scale. The DII score, a literature-derived, population-based dietary index that has been validated against several inflammatory markers, was computed on the basis of dietary intake assessed using a validated FFQ. Generalised estimating equations were used to estimate relative risk (RR) of depression according to DII score. Models were adjusted for energy intake, highest education completed, marital status, menopause status and symptoms, personal illness or injury, smoking status, physical activity, BMI and depression diagnosis or treatment. In total, 1156 women (18 %) had scores≥10 on the CESD scale over the course of 9 years. Women with the most anti-inflammatory diet had an approximately 20 % lower risk of developing depression compared with women with the most pro-inflammatory diet (RRDII quartile 1 v. 4: 0·81; 95 % CI 0·69, 0·96; P trend=0·03). These results suggest that an anti-inflammatory diet is associated with lower risk of depression in middle-aged Australian women.